bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reliability and equivalence of alternate forms for the Symbol Digit Modalities Test: implications for multiple sclerosis clinical trials
Authors: Benedict Ralph HB , Smerbeck Audrey , Parikh Rajavi , Rodgers Jonathan , Cadavid Diego , Erlanger David 
Published: January 2012

Background: Cognitive impairment is common in multiple sclerosis (MS), but is seldom assessed in clinical trials investigating the effects of disease-modifying therapies. The Symbol Digit Modalities Test (SDMT) is a particularly promising tool due to its sensitivity and robust correlation with brain magnetic resonance imaging (MRI) and vocational disability. Unfortunately, there are no validated alternate SDMT forms, which are needed to mitigate practice effects. Objective: The aim of the study was to assess the reliability and equivalence of SDMT alternate forms. Methods: Twenty-five healthy participants completed each of five alternate versions of the SDMT – the standard form, two versions from the Rao Brief Repeatable Battery, and two forms specifically designed for this study. Order effects were controlled using a Latin-square research design. Results: All five versions of the SDMT produced mean values within 3 raw score points of one another. Three forms were very consistent, and not different by conservative statistical tests. The SDMT test–retest reliability using these forms was good to excellent, with all r values exceeding 0.80. Conclusions: For the first time, we find good evidence that at least three alternate versions of the SDMT are of equivalent difficulty in healthy adults. The forms are reliable, and can be implemented in clinical trials emphasizing cognitive outcomes.
Renal effects of long-term darbepoetin alpha treatment in hypertensive TGR(mRen2)27 rats
Authors: Frenay Anne-Roos S , Ruifrok Willem-Peter T , Bulthuis Marian , Huitema Sippie , de Boer Rudolf A , van Goor Harry 
Published: January 2012

Introduction: Erytropoietin (EPO) has cytoprotective and angiogenic properties and has a beneficial effect in ischaemic conditions. Since the development of renal interstitial abnormalities are often associated with ischaemia, we studied the effects of the long-acting EPO analogue darbepoetin alpha (DA) on kidney damage in TGR(mRen2)27 (Ren2) rats. Materials and methods: Ren2 rats were randomised to DA or vehicle (VEH) or to DA + angiotensin converting enzyme inhibitor (ACEi) or VEH + ACEi. Sprague Dawley (SD) rats served as controls. Blood pressure was measured weekly and 24-h urine was collected to measure proteinuria. Blood samples were collected for creatinine and haematocrit. Kidneys were studied for inflammation and pre-fibrosis. Renal mRNA expression was studied for EPO, EPO-receptor, collagen-3α1 and kidney injury molecule-1 (KIM-1). Results: DA had no effect on SBP, serum creatinine and proteinuria. Interstitial and glomerular α-SMA expression was significantly increased in Ren2. ACEi but not DA improved the increased renal inflammatory and pro-fibrotic profile in Ren2 rats. DA on top of ACEi further reduced glomerular α-SMA and KIM-1 expression. Conclusion: Long-term DA treatment has no beneficial effects on renal structural and functional changes in TGR(mRen2)27 rats in the time frame studied and the dose provided.
Associations between the angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to vasculitis: a meta-analysis
Authors: Lee Young Ho , Choi Sung Jae , Ji Jong Dae , Song Gwan Gyu 
Published: January 2012

Introduction: To explore whether the insertion (I) and deletion (D) polymorphism of angiotensin-converting enzyme ( ACE) confers susceptibility to vasculitis. Materials and methods: A meta-analysis was conducted on the associations between the ACE I/D polymorphism and vasculitis. Results: Twelve studies, including four on Behçet’s disease (BD), four on Henoch–Schenlein purpura (HSP), three on Kawasaki disease (KD), and one on Wegener’s granulomatosis, were available for the meta-analysis. Meta-analysis showed that the DD + ID genotype was associated with susceptibility to vasculitis (odds ratio [OR] 1.468, 95% confidence interval [CI] 1.214–1.468, p = 7.4 × 10−5). The overall OR for the D allele was significantly increased in BD (OR 1.313, 95% CI 1.017–1.695). Meta-analysis of the DD+ID genotype, the DD genotype and the DD vs. II genotype showed marginal associations with BD, but meta-analysis of the D allele, and the DD+ID genotype showed significant associations with HSP (OR 1.446, 95% CI 1.021–2.049, p = 0.038; OR 1.881, 95% CI 1.385–2.595, p = 6.6 × 10−5). On the other hand, meta-analysis showed no association between KD and the ACE I/D polymorphism. Conclusions: This meta-analysis shows that the ACE I/D polymorphism is associated with vasculitis susceptibility, especially in BD and HSP.
Meta-analysis of the association between the insertion/deletion polymorphism in ACE gene and coronary heart disease among the Chinese population
Authors: Zhou Liang , Xi Bo , Wei Yuan , Shen Weihua , Li Yixiang 
Published: January 2012

Objective: Many studies have suggested that the angiotensin-converting enzyme ( ACE) gene might be involved in the development of coronary heart disease (CHD). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to assess the association between ACE I/D polymorphism and CHD susceptibility among the Chinese population. Methods: Published literature from PubMed, EMBASE, CNKI and Wan Fang Data was searched. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed or random-effects model. Results: Forty-six studies (5215 cases and 4782 controls) were identified. The results from the meta-analysis indicated statistically significant association between ACE I/D polymorphism and CHD risk under all three genetic models (co-dominant model DD vs. II: OR=2.40, 95% CI 2.02–2.84, DI vs. II: OR=1.19, 95% CI 1.05–1.34; dominant model: OR=1.51, 95% CI 1.33–1.70; recessive model: OR=2.14, 95% CI 1.86–2.45; multiplicative model: OR=1.57, 95% CI 1.43–1.72 ). Further sensitivity analysis confirmed the significant association. Conclusions: The meta-analysis indicated a significant association between ACE I/D polymorphism and CHD susceptibility among the Chinese population. However, further studies with the consideration of gene–gene and gene–environment interactions should be conducted to investigate the association.
Mortality prediction in the elderly by an easily measured metabolic index
Authors: Venskutonyte Laura , Rydén Lars , Nilsson Göran , Öhrvik John 
Published: January 2012

Objective: Hyperglycaemia enhances the risk of cardiovascular events and death, while high-density lipoprotein cholesterol (HDLc) is protective. Information on these associations among the elderly population is scanty. We applied a cardiometabolic risk index (CMRI) based on HDLc and fasting plasma glucose (FPG) in an elderly Swedish population. Methods: In total, 432 75-year-olds were followed for 10-year mortality. The impact of risk factors on survival was analysed using Cox regression. Results: HDLc (mmol/l; median and interquartile range) was 1.6 (1.3–2.0) in women and 1.4 (1.2–1.5) in men, while FPG was 5.9 (5.5–6.6) and 5.9 (5.5–6.5). Some 89 persons were at high risk according to CMRI, and 163 persons died. FPG was related to mortality in women (HR; 95% CI: 1.23; 1.10–1.37) and there was a similar trend in men (1.08; 1.00–1.17; p = 0.061). Increasing HDLc was protective in men (0.38; 0.19–0.77) but not in women (0.77; 0.45–1.29). CMRI was related to mortality in both genders even after adjustment for established risk factors (1.79; 1.14–2.79; p = 0.011). Conclusions: The CMRI helps identify elderly subjects at risk and may serve as a cost-effective risk prediction tool.
Mesenteric endothelial dysfunction in a cardiopulmonary bypass rat model: The effect of diabetes
Authors: Le Guillou Vincent , Tamion Fabienne , Jouet Isabelle , Richard Vincent , Mulder Paul , Bessou Jean Paul , Doguet Fabien 
Published: January 2012

Background: Diabetes is a risk factor for perioperative complications after cardiac surgery. We studied its effects on mesenteric endothelial function in a cardiopulmonary bypass (CPB) model. Methods: Forty Wistar rats were divided into four groups: sham (D-CPB-), cardiopulmonary bypass (D-CPB+), diabetic (D+CPB-) and diabetic that have undergone CPB (D+CPB+). Two samples of mesenteric artery were used for nitric oxide synthase (NOS) Western blot analysis, and two others for assessing contractile response and endothelium relaxations. Nitrite products and tumour necrosis factor-alpha (TNF-α) were assessed as markers of inflammatory response. Results: We observed an enhanced contractile response to the α-adrenergic agonist associated with impairment of mesenteric vasorelaxation in D+CPB+ rats. Western immunoblot analysis of D+CPB+ highlighted an additive effect of hyper-expression of inducible NOS. A significantly increased inflammatory response was observed after CPB in diabetic animals. Conclusions: This work confirms the potential deleterious impact of diabetes on the mesenteric endothelium during CPB in cardiac surgery.
S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release
Authors: Golan Karin , Vagima Yaron , Ludin Aya , Itkin Tomer , Cohen-Gur Shiri , Kalinkovich Alexander , Kollet Orit , Kim Chihwa , Schajnovitz Amir , Ovadya Yossi , Lapid Kfir , Shivtiel Shoham , Morris Andrew J. , Ratajczak Mariusz Z. , Lapidot Tsvee 
Published: January 2012

Abstract
The mechanisms of hematopoietic progenitor cell egress and clinical mobilization are not fully understood. Herein, we report that in vivo desensitization of Sphingosine-1-phosphate (S1P) receptors by FTY720 as well as disruption of S1P gradient toward the blood, reduced steady state egress of immature progenitors and primitive Sca-1+/c-Kit+/Lin− (SKL) cells via inhibition of SDF-1 release. Administration of AMD3100 or G-CSF to mice with deficiencies in either S1P production or its receptor S1P1, or pretreated with FTY720, also resulted in reduced stem and progenitor cell mobilization. Mice injected with AMD3100 or G-CSF demonstrated transient increased S1P levels in the blood mediated via mTOR signaling, as well as an elevated rate of immature c-Kit+/Lin− cells expressing surface S1P1 in the bone marrow (BM). Importantly, we found that S1P induced SDF-1 secretion from BM stromal cells including Nestin+ mesenchymal stem cells via reactive oxygen species (ROS) signaling. Moreover, elevated ROS production by hematopoietic progenitor cells is also regulated by S1P. Our findings reveal that the S1P/S1P1 axis regulates progenitor cell egress and mobilization via activation of ROS signaling on both hematopoietic progenitors and BM stromal cells, and SDF-1 release. The dynamic cross-talk between S1P and SDF-1 integrates BM stromal cells and hematopoeitic progenitor cell motility.
JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths
Authors: Tefferi Ayalew 
Published: January 2012

Abstract
On November 16, 2011, the Food and Drug Administration approved ruxolitinib (a JAK1 and JAK2 inhibitor) for use in the treatment of high and intermediate risk myelofibrosis. This is welcome news for those patients in whom such therapy is indicated and treatment benefit outweighs attendant risk. The question is who are these patients, what should they expect in terms of both short-term effects and long-term impact, and why would they choose ruxolitinib over other JAK inhibitors that are freely available for use in a research setting. Ruxolitinib and most other JAK inhibitors exert a salutary effect on constitutional symptoms and splenomegaly but have yet to produce histopathologic or cytogenetic remissions, reverse bone marrow fibrosis, or improve survival over best supportive care. Furthermore, the palliative value of JAK inhibitors is diminished by notable side effects, including anemia, thrombocytopenia, gastrointestinal disturbances, metabolic abnormalities, peripheral neuropathy, and hyperacute relapse of symptoms during treatment discontinuation. Therefore, risk-benefit balance favors use of currently available JAK inhibitors in only a select group of patients with myelofibrosis, and their potential value in polycythemia vera, outside of special circumstances (eg, intractable pruritus), is undermined by the absence of evidence for a disease-modifying effect and presence of arguably superior alternatives.
Hyaluronan synthase mediates dye translocation across liposomal membranes
Authors: Medina Andria P , Lin Jialing , Weigel Paul H 
Published: January 2012

Abstract

Background
Hyaluronan (HA) is made at the plasma membrane and secreted into the extracellular medium or matrix by phospolipid-dependent hyaluronan synthase (HAS), which is active as a monomer. Since the mechanism by which HA is translocated across membranes is still unresolved, we assessed the presence of an intraprotein pore within HAS by adding purified Streptococcus equisimilis HAS (SeHAS) to liposomes preloaded with the fluorophore Cascade Blue (CB).

Results
CB translocation (efflux) was not observed with mock-purified material from empty vector control E. coli membranes, but was induced by SeHAS, purified from membranes, in a time- and dose-dependent manner. CB efflux was eliminated or greatly reduced when purified SeHAS was first treated under conditions that inhibit enzyme activity: heating, oxidization or cysteine modification with N-ethylmaleimide. Reduced CB efflux also occurred with SeHAS K48E or K48F mutants, in which alteration of K48 within membrane domain 2 causes decreased activity and HA product size. The above results used liposomes containing bovine cardiolipin (BCL). An earlier study testing many synthetic lipids found that the best activating lipid for SeHAS is tetraoleoyl cardiolipin (TO-CL) and that, in contrast, tetramyristoyl cardiolipin (TM-CL) is an inactivating lipid (Weigel et al, J. Biol. Chem. 281, 36542, 2006). Consistent with the effects of these CL species on SeHAS activity, CB efflux was more than 2-fold greater in liposomes made with TO-CL compared to TM-CL.

Conclusions
The results indicate the presence of an intraprotein pore in HAS and support a model in which HA is translocated to the exterior by HAS itself.
Electroacupuncture pretreatment attenuates cerebral ischemic injury through α7 nicotinic acetylcholine receptor-mediated inhibition of high-mobility group box 1 release in rats
Authors: Wang Qiang , Wang Feng , Li Xin , Yang Qianzi , Li Xuying , Xu Ning , Huang Yi , Zhang Qiaomei , Gou Xingchun , Chen Shaoyang , Xiong Lize 
Published: January 2012

Abstract

Background
We have previously reported that electroacupuncture (EA) pretreatment induced tolerance against cerebral ischemic injury, but the mechanisms underlying this effect of EA are unknown. In this study, we assessed the effect of EA pretreatment on the expression of α7 nicotinic acetylcholine receptors (α7nAChR), using the ischemia-reperfusion model of focal cerebral ischemia in rats. Further, we investigated the role of high mobility group box 1 (HMGB1) in neuroprotection mediated by the α7nAChR and EA.

Methods
Rats were treated with EA at the acupoint "Baihui (GV 20)" 24 h before focal cerebral ischemia which was induced for 120 min by middle cerebral artery occlusion. Neurobehavioral scores, infarction volumes, neuronal apoptosis, and HMGB1 levels were evaluated after reperfusion. The α7nAChR agonist PHA-543613 and the antagonist α-bungarotoxin (α-BGT) were used to investigate the role of the α7nAChR in mediating neuroprotective effects. The roles of the α7nAChR and HMGB1 release in neuroprotection were further tested in neuronal cultures exposed to oxygen and glucose deprivation (OGD).

Results
Our results showed that the expression of α7nAChR was significantly decreased after reperfusion. EA pretreatment prevented the reduction in neuronal expression of α7nAChR after reperfusion in the ischemic penumbra. Pretreatment with PHA-543613 afforded neuroprotective effects against ischemic damage. Moreover, EA pretreatment reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis and HMGB1 release following reperfusion, and the beneficial effects were attenuated by α-BGT. The HMGB1 levels in plasma and the penumbral brain tissue were correlated with the number of apoptotic neurons in the ischemic penumbra. Furthermore, OGD in cultured neurons triggered HMGB1 release into the culture medium, and this effect was efficiently suppressed by PHA-543,613. Pretreatment with α-BGT reversed the inhibitory effect of PHA-543,613 on HMGB1 release.

Conclusion
These data demonstrate that EA pretreatment strongly protects the brain against transient cerebral ischemic injury, and inhibits HMGB1 release through α7nAChR activation in rats. These findings suggest the novel potential for stroke interventions harnessing the anti-inflammatory effects of α7nAChR activation, through acupuncture or pharmacological strategies.
Characterizing operant hyperactivity in the Spontaneously Hypertensive Rat
Authors: Hill Jade C , Herbst Katrina , Sanabria Federico 
Published: January 2012

Abstract

Background
Operant hyperactivity, the emission of reinforced responses at an inordinately high rate, has been reported in children with ADHD and in the Spontaneously Hypertensive Rat (SHR), the most widely studied animal model of ADHD. The SHR emits behavior at hyperactive levels, relative to a normoactive strain, only when such behavior is seldom reinforced. Because of its dependence on rate of reinforcement, operant hyperactivity appears to be driven primarily by incentive motivation, not motoric capacity. This claim was evaluated in the present study using a novel strategy, based on the organization of behavior in bouts of reinforced responses separated by pauses.

Method
Male SHR, Wistar-Kyoto (WKY) and Wistar rats (WIS) were exposed each to a multiple variable-interval schedule of sucrose reinforcement (12, 24, 48, 96, and 192 s) between post-natal days (PND) 48 and 93. Responding in each schedule was examined in two epochs, PND 58-62 and 89-93. Parameters of response-reinforcement functions (Herrnstein's hyperbola) and bout-organized behavior were estimated in each epoch.

Results
SHR emitted higher response rates than WKY and WIS, but only when rate of reinforcement was low (fewer than 2 reinforcers per minute), and particularly in the second epoch. Estimates of Herrnstein's hyperbola parameters suggested the primacy of motivational over motoric factors driving the response-rate differential. Across epochs and schedules, a more detailed analysis of response bouts by SHR revealed that these were shorter than those by WKY, but more frequent than those by WKY and WIS. Differences in bout length subsided between epochs, but differences in bout-initiation rate were exacerbated. These results were interpreted in light of robust evidence linking changes in bout-organization parameters and experimental manipulations of motivation and response-reinforcement contingency.

Conclusions
Operant hyperactivity in SHR was confirmed. Although incentive motivation appears to play an important role in operant hyperactivity and motoric capacity cannot be ruled out as a factor, response-bout patterns suggest that operant hyperactivity is primarily driven by steeper delay-of-reinforcement gradients. Convergence of this conclusion with theoretical accounts of ADHD and with free-operant performance in children with ADHD supports the use of SHR as an animal model of ADHD.
Clinical and neurocognitive outcome in symptomatic isovaleric acidemia
Authors: Grünert Sarah C , Wendel Udo , Lindner Martin , Leichsenring Michael , Schwab K Otfried , Vockley Jerry , Lehnert Willy , Ensenauer Regina 
Published: January 2012

Abstract

Background
Despite its first description over 40 years ago, knowledge of the clinical course of isovaleric acidemia (IVA), a disorder predisposing to severe acidotic episodes during catabolic stress, is still anecdotal. We aimed to investigate the phenotypic presentation and factors determining the neurological and neurocognitive outcomes of patients diagnosed with IVA following clinical manifestation.

Methods
Retrospective data on 21 children and adults with symptomatic IVA diagnosed from 1976 to 1999 were analyzed for outcome determinants including age at diagnosis and number of catabolic episodes. Sixteen of 21 patients were evaluated cross-sectionally focusing on the neurological and neurocognitive status. Additionally, 155 cases of patients with IVA published in the international literature were reviewed and analyzed for outcome parameters including mortality.

Results
57% of study patients (12/21) were diagnosed within the first weeks of life and 43% (9/21) in childhood. An acute metabolic attack was the main cause of diagnostic work-up. 44% of investigated study patients (7/16) showed mild motor dysfunction and only 19% (3/16) had cognitive deficits. No other organ complications were found. The patients' intelligence quotient was not related to the number of catabolic episodes but was inversely related to age at diagnosis. In published cases, mortality was high (33%) if associated with neonatal diagnosis, following manifestation at an average age of 7 days.

Conclusions
Within the group of "classical" organic acidurias, IVA appears to be exceptional considering its milder neuropathologic implications. The potential to avoid neonatal mortality and to improve neurologic and cognitive outcome under early treatment reinforces IVA to be qualified for newborn screening.
Serum TSH and Risk of Papillary Thyroid Cancer in Nodular Thyroid Disease
Authors: Fiore Emilio , Vitti Paolo 
Published: January 2012

Context:
TSH is the main factor involved in the control of proliferation of thyrocytes. Recently, a strong relationship between serum TSH and risk of thyroid malignancy has been reported.

Objectives:
The aim was to review published papers about the relationship between serum TSH and frequency of differentiated thyroid cancer.

Evidence Acquisition:
PubMed was used to identify studies focused on the relationship between TSH and differentiated thyroid cancer.

Evidence Synthesis:
In patients with nodular thyroid disease, the risk of thyroid malignancy increases with serum TSH, and even within normal ranges, higher TSH values are associated with a higher frequency and more advanced stage of thyroid cancer. The likelihood of papillary thyroid carcinoma is reduced when TSH is lower, as in thyroid autonomy, and increased when TSH is higher, as in thyroid autoimmunity. Treatment with l-thyroxine (LT4), which reduces serum TSH, is associated with significantly lower risk of developing clinically detectable thyroid cancer.

Conclusions:
TSH plays a key role in the development of clinically detectable thyroid cancer, and LT4 treatment reduces the risk of thyroid malignancy in patients with nodular thyroid disease. According to the guidelines of the main scientific societies, LT4 therapy is not currently recommended for the treatment of patients with nodular goiter. Even if the available data are not sufficient to advise LT4 treatment in all patients with nodular goiter with the aim of reducing the risk of papillary thyroid carcinoma, we propose that this indication should be reconsidered, taking into account recent evidence reported in the literature.