bluuebunny/crossref_metadata_2025 huggingface dataset:
Ratio of 5,6,7,8-tetrahydrobiopterin to 7,8-dihydrobiopterin in endothelial cells determines glucose-elicited changes in NO vs. superoxide production by eNOS
Authors: Crabtree Mark J. , Smith Caroline L. , Lam George , Goligorsky Michael S. , Gross Steven S.
Published: January 2008

5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOSs). Oxidation of BH4, in the setting of diabetes and other chronic vasoinflammatory conditions, can cause cofactor insufficiency and uncoupling of endothelial NOS (eNOS), manifest by a switch from nitric oxide (NO) to superoxide production. Here we tested the hypothesis that eNOS uncoupling is not simply a consequence of BH4insufficiency, but rather results from a diminished ratio of BH4vs. its catalytically incompetent oxidation product, 7,8-dihydrobiopterin (BH2). In support of this hypothesis, [3H]BH4binding studies revealed that BH4and BH2bind eNOS with equal affinity ( Kd≈ 80 nM) and BH2can rapidly and efficiently replace BH4in preformed eNOS-BH4complexes. Whereas the total biopterin pool of murine endothelial cells (ECs) was unaffected by 48-h exposure to diabetic glucose levels (30 mM), BH2levels increased from undetectable to 40% of total biopterin. This BH2accumulation was associated with diminished calcium ionophore-evoked NO activity and accelerated superoxide production. Since superoxide production was suppressed by NOS inhibitor treatment, eNOS was implicated as a principal superoxide source. Importantly, BH4supplementation of ECs (in low and high glucose-containing media) revealed that calcium ionophore-evoked NO bioactivity correlates with intracellular BH4:BH2and not absolute intracellular levels of BH4. Reciprocally, superoxide production was found to negatively correlate with intracellular BH4:BH2. Hyperglycemia-associated BH4oxidation and NO insufficiency was recapitulated in vivo, in the Zucker diabetic fatty rat model of type 2 diabetes. Together, these findings implicate diminished intracellular BH4:BH2, rather than BH4depletion per se, as the molecular trigger for NO insufficiency in diabetes.
Evolving changes in lung interstitial fluid content after acute myocardial infarction: mechanisms and pathophysiological correlates
Authors: Guazzi Marco , Arena Ross , Guazzi Maurizio D.
Published: January 2008

In acute myocardial infarction (AMI), alveolar interstitium edema is generally attributed to a hydrostatic imbalance. However, inflammatory burden and/or neural/hormonal/hemodynamic stimulation might injure the microvascular endothelium, eliciting interstitial overflow and altering alveolar-capillary gas diffusion. In 118 patients with AMI (ejection fraction ≥50% and wedge pulmonary pressure <16 mmHg), admission alveolar-capillary gas diffusing membrane conductance (DM) averaged 35.1 ml·min−1·mmHg−1 and was 27% lower than in 25 controls ( P < 0.01). Infusion of saline in the pulmonary circulation (to test sodium exchange across the pulmonary capillary wall) lowered DM by 7.1% ( P < 0.01) and was neutral in controls. At 1 wk, 83 patients that showed DM improvement >5% were assigned to group 1, and 28 patients with DM worsening >5% were assigned to group 2. Saline retained efficacy in group 2 and had no DM effect in group 1 (supporting a link between changes in baseline DM and those in microvascular salt exchange). Ventricular function was unchanged in group 1, whereas group 2 had developed diastolic dysfunction. At 1 yr, 3% of cases in group 1 and 37% of cases in group 2 had alveolar edema. Thus, AMI is frequently associated with abnormal pulmonary microvascular sodium transport/water conductance that, in the case of ventricular dysfunction supervenience, may persist and worsen the outcome. In 37 AMI similar patients and 11 control subjects, nitric oxide overexpression with l-arginine improved baseline DM and in AMI patients prevented DM reduction by saline, suggesting a mechanistic role of an impaired nitric oxide pathway in the microvascular barrier dysfunction.
Calcineurin-induced energy wasting in a transgenic mouse model of heart failure
Authors: Pinz Ilka , Ostroy Sanford E. , Hoyer Kirsten , Osinska Hanna , Robbins Jeffrey , Molkentin Jeffery D. , Ingwall Joanne S.
Published: January 2008

Overexpression of calcineurin (CLN) in the mouse heart induces severe hypertrophy that progresses to heart failure, providing an opportunity to define the relationship between energetics and contractile performance in the severely failing mouse heart. Contractile performance was studied in isolated hearts at different pacing frequencies and during dobutamine challenge. Energetics were assessed by 31P-NMR spectroscopy as ATP and phosphocreatine concentrations ([ATP] and [PCr]) and free energy of ATP hydrolysis (|Δ G∼ATP|). Mitochondrial and glycolytic enzyme activities, myocardial O2 consumption, and myocyte ultrastructure were determined. In transgenic (TG) hearts at all levels of work, indexes of systolic performance were reduced and [ATP] and capacity for ATP synthesis were lower than in non-TG hearts. This is the first report showing that myocardial [ATP] is lower in a TG mouse model of heart failure. [PCr] was also lower, despite an unexpected increase in the total creatine pool. Because Pi concentration remained low, despite lower [ATP] and [PCr], |Δ G∼ATP| was normal; however, chemical energy did not translate to systolic performance. This was most apparent with β-adrenergic stimulation of TG hearts, during which, for similar changes in |Δ G∼ATP|, systolic pressure decreased, rather than increased. Structural abnormalities observed for sarcomeres and mitochondria likely contribute to decreased contractile performance. On the basis of the increases in enzyme activities of proteins important for ATP supply observed after treatment with the CLN inhibitor cyclosporin A, we also conclude that CLN directed inhibition of ATP-producing pathways in non-TG and TG hearts.
Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium
Authors: Juhasz Bela , Thirunavukkarasu Mahesh , Pant Rima , Zhan Lijun , Penumathsa Suresh Varma , Secor Eric R. , Srivastava Sapna , Raychaudhuri Utpal , Menon Venugopal P. , Otani Hajime , Thrall Roger S. , Maulik Nilanjana
Published: January 2008

Bromelain (Br), a proteolytic enzyme extracted from the stem of the pineapple, is known to possess anti-inflammatory activity and has been shown to reduce blood viscosity, prevent the aggregation of blood platelets, and improve ischemia-reperfusion (I/R) injury in a skeletal muscle model. We investigated the capacity of Br to limit myocardial injury in a global I/R model. Adult male Sprague-Dawley rats were divided into two groups: control (PBS) and Br at 10 mg/kg in PBS administered via intraperitoneal injection (twice/day) for 15 consecutive days. On day 16, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Br treatment showed higher left ventricular functional recovery throughout reperfusion compared with the controls [maximum rate of rise in intraventricular pressure (dP/d tmax), 2,225 vs. 1,578 mmHg/s at 2 h reperfusion]. Aortic flow was also found to be increased in Br treatment when compared with that in untreated rats (11 vs. 1 ml). Furthermore, Br treatment reduced both the infarct size (34% vs. 43%) and the degree of apoptosis (28% vs. 37%) compared with the control animals. Western blot analysis showed an increased phosphorylation of both Akt and FOXO3A in the treatment group compared with the control. These results demonstrated for the first time that Br triggers an Akt-dependent survival pathway in the heart, revealing a novel mechanism of cardioprotective action and a potential therapeutic target against I/R injury.
Identification of 15-hydroxy-11,12-epoxyeicosatrienoic acid as a vasoactive 15-lipoxygenase metabolite in rabbit aorta
Authors: Chawengsub Yuttana , Aggarwal Nitin T. , Nithipatikom Kasem , Gauthier Kathryn M. , Anjaiah Siddam , Hammock Bruce D. , Falck John R. , Campbell William B.
Published: January 2008

Arachidonic acid (AA) causes endothelium-dependent smooth muscle hyperpolarizations and relaxations that are mediated by a 15-lipoxygenase-I (15-LO-I) metabolite, 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA). We propose that AA is metabolized sequentially by 15-LO-I and hydroperoxide isomerase to an unidentified hydroxyepoxyeicosatrienoic acid (HEETA), which is hydrolyzed by a soluble epoxide hydrolase (sEH) to 11,12,15-THETA. After incubation of aorta with 14C-labeled AA, metabolites were extracted and the HEETAs were resolved by performing HPLC. Mass spectrometric analyses identified 15-Hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA). Incubation of aortic incubates with methanol and acetic acid trapped the acid-sensitive 15-H-11,12-EETA as methoxydihydroxyeicosatrienoic acids (MDHEs) (367 m/ z, M-H). Pretreatment of the aortic tissue with the sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA; 10−6 M) increased the formation of 15-H-11,12-EETA, measured as MDHEs. Thus 15-H-11,12-EETA is an acid- and sEH-sensitive precursor of 11,12,15-THETA. Aortic homogenates and endothelial cells contain a 57-kDa protein corresponding to the rabbit sEH. In preconstricted aortic rings, AA (10−7–10−4 M) and acetylcholine (10−9–10−6 M) caused concentration-related relaxations that were enhanced by pretreatment with AUDA. These enhanced relaxations were inhibited by increasing extracellular [K+] from 4.8 to 20 mM. AA (3 × 10−6 M) induced cell membrane hyperpolarization (from −31.0 ± 1 to −46.8 ± 2 mV) in aortic strips with an intact endothelium, which was enhanced by AUDA. These results indicate that 15-H-11,12-EETA is produced by the aorta, hydrolyzed by sEH to 11,12,15-THETA, and mediates relaxations by membrane hyperpolarization. 15-H-11,12-EETA represents an endothelium-derived hyperpolarizing factor.
Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the α-myosin heavy chain expression
Authors: Pillai Jyothish B. , Chen Martin , Rajamohan Senthilkumar B. , Samant Sadhana , Pillai Vinodkumar B. , Gupta Madhu , Gupta Mahesh P.
Published: January 2008

Fructose feeding has been shown to induce the cardiac α-myosin heavy chain (MHC) expression and protect the heart from ischemia- and reperfusion-mediated cell injury. This study was designed to investigate the mechanism involved in the effect of this sugar on MHC gene expression and cardiac protection. Adult mice were fed with a 6-propyl-2-thiouracil (PTU) diet or PTU combined with a fructose-rich diet. PTU treatment made animals hypothyroid and that resulted in total replacement of cardiac α-MHC with the β-MHC isoform. Addition of fructose in the PTU diet led to reexpression of the α-MHC isoform to a significant level. Similar induction of α-MHC expression was also seen when PTU diet was combined with resveratrol, an agonist of sirtuin (SIRT) 1 deacetylase. Analysis of heart lysate of these animals indicated that fructose feeding augmented the NAD-to-NADH ratio and the cardiac SIRT1 levels, thus suggesting a role of SIRT1 in fructose-mediated activation of α-MHC isoform. To analyze a direct effect of SIRT1 on MHC isoform expression, we generated transgenic mice expressing SIRT1 in the heart. Treatment of these transgenic mice with PTU diet did not lead to disappearance of α-MHC, as it did in the nontransgenic animals. SIRT1 overexpression also activated the α-MHC gene promoter in transient transfection assays, thus confirming a role of SIRT1 in the induction of α-MHC expression. Fructose feeding also attenuated the MHC isoform shift and blocked the cardiac hypertrophy response associated with pressure overload, which was again associated with the induction of cardiac SIRT1 levels. These results demonstrate that fructose feeding protects the heart by induction of the SIRT1 deacetylase and highlight its role in the induction of α-MHC gene expression.
Ontological Assumptions of Psychiatric Taxonomy: Main Rival Positions and Their Critical Assessment
Authors: Oulis Panagiotis
Published: January 2008

The scientific classification of human psychopathology raises a host of important philosophical issues ranging over all major areas of philosophical inquiry; logic, semantics, ontology, epistemology and ethics. The paper focuses on the major views of the ontological status of our psychodiagnostic constructs; idealism, nominalism and finally, neoaristotelian realism. Idealism holds that our psychodiagnostic constructs represent ideal essences, instantiated imperfectly by individual mental patients of the same psychodiagnostic class. These ideal essences are construed either as abstract forms dwelling in an autonomous realm of eternal abstract objects – platonistic idealism – or as ideal objects emerging in and grasped directly by a pure or absolute consciousness – husserlian idealism. By contrast, nominalism claims that our psychodiagnostic constructs are nothing but conventional common names of sets of individual mental patients, invented and adopted on purely pragmatic grounds such as their practical utility, especially in predicting their clinical course and outcome under various types of treatment. Finally, neoaristotelian realism holds that, though our psychodiagnostic constructs are concepts, and thus of our own making, they are not arbitrary ones but grounded in objective features shared by individual mental patients of a given psychodiagnostic class. It is argued that both idealism and nominalism are flawed and thus untenable – though for different reasons – and a refined version of neoaristotelian realism defended.
Anti-Inflammatory Effect of Sulodexide during Acute Peritonitis in Rats
Authors: Karoń Jacek , Połubinska Alicja , Antoniewicz Artur A. , Sumińska-Jasińska Katarzyna , Bręborowicz Andrzej
Published: January 2008

Background/Aims: Peritonitis is one of the complications of peritoneal dialysis. We demonstrate the systemic and intraperitoneal anti-inflammatory action of sulodexide given systemically. Methods: Dialysis was performed in male Wistar rats with acute peritonitis induced by addition of endotoxin to the fluid. Sulodexide (10 mg/kg b.w.) was used acutely as supplement to the dialysis fluid or chronically, during 7 days preceding the study by intramuscular (IM) injection. Results: In rats given IM sulodexide the dialysate cell count was lower by 45% (p < 0.001) versus untreated rats with peritonitis. Dialysate elastase activity in IM sulodexide-treated rats was lower by 22% (p < 0.05) compared to peritonitis. In rats treated with IM sulodexide the increase of plasma tumor necrosis factor-α was reduced by 53% (p < 0.002). Pretreatment with IM sulodexide reduced transperitoneal loss of total protein and albumin during peritonitis by 26% (p < 0.002) and by 16% (p < 0.05), respectively. Conclusion: Sulodexide given systemically reduces the intraperitoneal and vascular inflammatory response during acute peritonitis in rats.
Lack of Evidence for Arterial Ischemia in Transient Global Amnesia
Authors: Toledo Manuel , Pujadas Francesc , Grivé Elisenda , Álvarez-Sabin José , Quintana Manuel , Rovira Alex
Published: January 2008

Background and Purpose—

Lesions in diffusion-weighted imaging (DWI-L) have been commonly described in transient global amnesia (TGA). We investigated a possible relationship between brain ischemia and TGA.

Methods—

Twenty-eight patients underwent transcranial and carotid Doppler ultrasonography (including microembolus detection) and MRI within 24 hours of TGA onset (including DWI, perfusion-weighted imaging and angio-MRI). MRI was repeated at 48 to 96 hours (21 patients) and 30 days (18 patients).

Results—

Punctate DWI-L were observed in 16 patients (57%) and were not attributable to perfusion abnormalities, arterial stenoses or underlying cardioembolic disease. MRIs performed between 12 and 72 hours showed the highest frequency of DWI-L (88%;
P
<0.001). No pathological findings were observed at 30 days.

Conclusions—

These results suggest that TGA is not related to cerebral arterial ischemia.
Iranian Glass Perfume Vessel from the Pichvnari Greek Cemetery of the Fifth Century BC
Authors: Kakhidze Amiran
Published: January 2008

Publication of an Iranian Kohl-Tube found during the excavations of the 5th century BC Pichvnari necropolis. It was probably imported into Colchis by land through eastern Georgia.
Spatial Interconnect Analysis for Predictable Nanotechnologies
Authors: Yanushkevich S. N. , Shmerko V. P. , Steinbach B.
Published: January 2008

This paper addresses the interconnect problem for the representation of logic networks in spatial dimensions. Interest in spatial interconnects is motivated by the advent of nanotechnologies and by consequent attempts to evaluate and explore the appropriate nanoscale architectures.
It have been shown in our previous study that a 3D logic network with target topology can be designed by replacing each elementary logic block in a network by its 3D model. In this paper, we study the problem of the partitioning of these 3D blocks with respect to the constraints of logic function
interconnects and hypercube-like topology. We found that decomposition techniques provide flexibility in choosing switching functions for assembling the decomposed sub-networks.
Use of Intranasal Corticosteroids in the Management of Congestion and Sleep Disturbance in Pediatric Patients With Allergic Rhinitis
Authors: Lanier Bob Q.
Published: January 2008

Allergic rhinitis affects a large number of children and exerts a considerable socioeconomic impact. It is underdiagnosed and inadequately treated, which predisposes children to potentially serious comorbidities. Allergic rhinitis symptoms may create nighttime breathing problems and sleep disturbances and have a negative effect on a child's ability to learn in the classroom. Although antihistamines have shown efficacy in relieving many symptoms, they have little effect on nasal congestion. This article summarizes the advantages of intranasal corticosteroids, including their effectiveness against congestion and excellent safety profile. Intranasal corticosteroids with minimal systemic bioavailability provide topical drug delivery that minimizes the potential for systemic side-effects.
10-Year Case Review of Nutritional Rickets in Children's Hospital of Michigan
Authors: Lazol Judith P. , Çakan Nedim , Kamat Deepak
Published: January 2008

Nutritional rickets has been on the rise in the United States. A chart review of patients with nutritional rickets from April 1995 to May 2005 was performed. Fifty-eight subjects were studied (62% males, 38% females, with an age range between 2 and 132 months). Of the subjects, 81% were African Americans and 14% were Arabic; 33% were Christians and 19% were Muslims. An increasing number of cases of nutritional rickets have been noted since 2000. Seventy-nine percent of patients with nutritional rickets presented at the emergency department, and in 69% of the cases, rickets was an incidental finding; 96% of patients were exclusively breast-fed, and none received multivitamin supplements. 25-OH vitamin D levels were below 5 ng/mL in 42% of the patients, all of whom were African Americans. We could document complete resolution of nutritional rickets in only 8 patients, and 3 of these patients showed sequelae of rickets.
Periodic Use of Inhaled Steroids in Children With Mild Persistent Asthma: What Are Pediatricians Recommending?
Authors: Sawicki Gregory S. , Smith Lauren , Bokhour Barbara , Gay Charlene , Hohman Katherine H. , Galbraith Alison A. , Lieu Tracy A.
Published: January 2008

Although asthma treatment guidelines recommend daily inhaled corticosteroid (ICS) use for all persistent asthma, pediatricians may recommend alternative treatment plans for children with mild persistent disease. The authors administered a survey of pediatricians to describe prescribing patterns for mild persistent asthma. More than 99% of providers agreed that periodic ICS could be effective for some asthma patients. Overall, 129/251 providers (51%) reported prescribing daily ICS to most patients with mild persistent asthma, whereas 78 (31%) reported recommending periodic ICS for most such patients. Providers with patient populations ≥ 25% black were significantly less likely to report prescribing daily ICS (odds ratio, 0.3; 95% confidence interval, 0.2-0.6) for mild persistent asthma. Further research is needed on the effectiveness of periodic ICS use for children with mild persistent asthma and on underlying reasons for differing provider practice patterns.
Economic Reforms and Democracy
Authors: Gans-Morse Jordan , Nichter Simeon
Published: January 2008

This article explores the relationship between economic reforms and democracy in Latin America between 1970 and 1995. Existing theories suggest divergent effects across time horizons. The implementation of reforms— economic liberalization—may initially destabilize democracy due to popular backlash or overzealous reformers' usurpation of democratic institutions. However, the potential outcome of reforms—greater economic liberalism— may later foster or reinforce democracy by dispersing economic assets, making rulers more susceptible to international constraints, or demobilizing social groups that may otherwise make politically destabilizing redistributive demands. Time-series cross-section analyses using an error correction model provide evidence of this J-curve relationship. Although countries engaging in economic reforms may experience a temporary deterioration of democracy, they tend to become more democratic in the long run. Findings are robust to numerous control variables, country and time fixed effects, and specifications using either Polity IV or Freedom House democracy indicators.
The Use of Levetiracetam in a Child with Nonconvulsive Status Epilepticus
Authors: Alehan Füsun , Ozcay Figen , Haberal Mehmet
Published: January 2008

Levetiracetam is an antiepileptic drug that was shown to be effective in various seizure types. Experience with this agent for treating status epilepticus is just emerging. To the best of our knowledge, there is no report in the literature regarding its use in children with nonconvulsive status epilepticus. We here report a liver-transplanted child with nonconvulsive status epilepticus who responded well to oral levetiracetam treatment.
Neonatal Seizures: Relation of Ictal Video-Electroencephalography (EEG) Findings With Neurodevelopmental Outcome
Authors: Pisani Francesco , Copioli Cristiana , Di Gioia Caterina , Turco Emanuela , Sisti Lisa
Published: January 2008

Neonatal electroencephalographic background activity has been found to be a predictive factor of the neurodevelopmental outcome. The aim of our study was to identify if the electrical ictal findings present on the first electroencephalography (EEG) recording are related to the outcome of newborns with neonatal seizures. The study is based on the prospective evaluation of newborns consecutively admitted to the Neonatal Intensive Care Unit at the University of Parma between September 2001 and September 2004. Thirty-eight subjects were enrolled in the study on the basis of the following inclusion criteria: presence on the first EEG of at least 1 seizure, neurodevelopmental follow-up until 18 months of corrected age, and performance of several ultrasound brain scans during the neonatal period and of at least 1 cerebral MRI within the first year of life. For each seizure, the following were considered: onset topography, morphology of the epileptiform discharges, spread of the discharge, number of electrographic regions of seizure onset, number of seizures per hour, duration of the seizures, and the Ictal Fraction (= total duration of the seizures/duration of the EEG recording × hour). At the last follow-up, the unfavorable neurodevelopmental outcome seems significantly related to the moderate/severe background activity abnormalities ( p = .006), to the spread of ictal discharge to the contralateral hemisphere ( p = .02), and to the Ictal Fraction, when it exceeds 10 minutes ( p = .036). In conclusion, the analysis of the propagation of the ictal discharge and of the Ictal Fraction might suggest significant prognostic information since the first hours of life.
Primary Cerebral Intraventricular Hydatid Cyst: A Case Report and Review of the Literature
Authors: Guzel Aslan , Tatli Mehmet , Maciaczyk Jaroslaw , Altinors Nur
Published: January 2008

Intracranial hydatid cysts, which are common in certain areas worldwide, almost always develop at an intraparenchymal site. However, the literature on intraventricular hydatid cysts consists of only 6 independent case reports and about 30 cases that are described in large series. We report on a 10-year-old girl who was admitted with an intracranial cyst. She complained of headache of 10 months' duration that had intensified significantly over the 3 weeks immediately before her admission. The results of a neurologic examination showed bilateral papilledema and slight left hemiparesis. Magnetic resonance imaging revealed a right temporo-parieto-occipital cystic lesion that was causing the shifting of the midline structures to the contralateral side. The giant cyst was successfully removed without rupture. The possibility of infection with Echinococcus granulosus should be included in the differential diagnosis of unspecific neurologic symptoms such as a progressively worsening headache, especially in pediatric patients from the geographic areas in which that parasite is endemic.
Epidemiology of Attention Problems Among Turkish Children and Adolescents
Authors: Erol Nese , Simsek Zeynep , Öner Özgür , Munir Kerim
Published: January 2008

Objective: To evaluate the epidemiology of attention problems using parent, teacher, and youth informants among a nationally representative Turkish sample. Method: The children and adolescents, 4 to 18 years old, were selected from a random household survey. Attention problems derived from the Child Behavior Checklist (CBCL) ( N = 4,488), Teacher Report Form (TRF) ( N = 2,360), and the Youth Self Report (YSR) ( N = 2,206) were examined. Results: The CBCL and TRF attention problems scores were higher among young male children, whereas the YSR reported scores were higher among older adolescents without a gender effect. The CBCL and YSR scores were also higher by urban residence. Conclusion: Compared with other European samples, our national sample had higher mean attention problems scores than the Scandinavian but lower mean scores than the former Soviet Union samples. In addition to elucidating the profile of attention problems in Turkey, our results also contribute to understanding the comparative global epidemiology of attention problems. (J. of Att. Dis. 2008; 11(5) 538-545)
Agreement Rates Between Parent and Self-Report on Past ADHD Symptoms in an Adult Clinical Sample
Authors: Dias Gabriela , Mattos Paulo , Coutinho Gabriel , Segenreich Daniel , Saboya Eloisa , Ayrão Vanessa
Published: January 2008

Objective: To investigate agreement rates between parent and self-report on childhood symptoms of ADHD. Method: Sixty-eight self-referred treatment-naïve adults (33 men, 35 women) were interviewed with a modified version of the Kiddie Schedule for Affective Disorders and Schizophrenia—Epidemiological Version (K-SADS-E) and asked about past ADHD symptoms, using modified Diagnostic and Statistical Manual of Mental Disorders (4th edition; DSM-IV) criteria (at least six symptoms in either domain for present and past symptoms). Parents were given a questionnaire with DSM-IV symptoms list. Results: Forty-six patients (67.6%) agreed on the presence of past ADHD diagnosis with their parents; there was agreement on subtype in more than half of cases (58.7%). Fifty patients (73.5%) reported positive past inattention symptomatology, and 31 of them (62.0%) agreed with their parents on their presence in childhood. Thirty-six patients (52.9%) reported positive hyperactivity—impulsivity symptomatology, and 20 of them (55.6%) agreed with their parents' reports. Conclusions: Results suggest retrospective information provided by adults with ADHD has moderate agreement rates with parents' reports for both domains. (J. of Att. Dis. 2008; 12(1) 70-75)
Divided Government, Political Turnover, and State Bond Ratings
Authors: Krueger Skip , Walker Robert W.
Published: January 2008

Credit markets face an inherent risk that derives from future policy changes when considering the purchase of debt issued by state governments. An enacting government coalition issuing long-term debt cannot make a credible commitment to maintain the existing debt repayment policy into the future. In the face of this commitment problem, investors (and the rating agencies that serve those investors) look to recent political turnover and the existence of divided government to estimate the possibility that some future government coalition will remain substantially similar to the enacting coalition. Political turnover and divided government suggest to the credit markets that future coalitions may act opportunistically regarding debt repayment. This risk of opportunistic behavior, we argue, manifests in lower ratings of state debt. We empirically examine this claim in a model of state bond ratings from 1995 through 2000.
AML1 mutations induced MDS and MDS/AML in a mouse BMT model
Authors: Watanabe-Okochi Naoko , Kitaura Jiro , Ono Ryoichi , Harada Hironori , Harada Yuka , Komeno Yukiko , Nakajima Hideaki , Nosaka Tetsuya , Inaba Toshiya , Kitamura Toshio
Published: January 2008

Myelodysplastic syndrome (MDS) is a hematopoietic stem-cell disorder characterized by trilineage dysplasia and susceptibility to acute myelogenous leukemia (AML). Analysis of molecular basis of MDS has been hampered by the heterogeneity of the disease. Recently, mutations of the transcription factor AML1/RUNX1 have been identified in 15% to 40% of MDS–refractory anemia with excess of blasts (RAEB) and MDS/AML. We performed mouse bone marrow transplantation (BMT) using bone marrow cells transduced with the AML1 mutants. Most mice developed MDS and MDS/AML-like symptoms within 4 to 13 months after BMT. Interestingly, among integration sites identified, Evi1 seemed to collaborate with an AML1 mutant harboring a point mutation in the Runt homology domain (D171N) to induce MDS/AML with an identical phenotype characterized by marked hepatosplenomegaly, myeloid dysplasia, leukocytosis, and biphenotypic surface markers. Collaboration between AML1-D171N and Evi1 was confirmed by a BMT model where coexpression of AML1-D171N and Evi1 induced acute leukemia of the same phenotype with much shorter latencies. On the other hand, a C-terminal truncated AML1 mutant (S291fsX300) induced pancytopenia with erythroid dysplasia in transplanted mice, followed by progression to MDS-RAEB or MDS/AML. Thus, we have developed a useful mouse model of MDS/AML that should help in the understanding of the molecular basis of MDS and the progression of MDS to overt leukemia.
Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease
Authors: Ashley-Koch Allison E. , Elliott Laine , Kail Melanie E. , De Castro Laura M. , Jonassaint Jude , Jackson Terry L. , Price Jennifer , Ataga Kenneth I. , Levesque Marc C. , Weinberg J. Brice , Orringer Eugene P. , Collins Ann , Vance Jeffery M. , Telen Marilyn J.
Published: January 2008

Up to 30% of adult patients with sickle cell disease (SCD) will develop pulmonary hypertension (pHTN), a complication associated with significant morbidity and mortality. To identify genetic factors that contribute to risk for pHTN in SCD, we performed association analysis with 297 single nucleotide polymorphisms (SNPs) in 49 candidate genes in patients with sickle cell anemia (Hb SS) who had been screened for pHTN by echocardiography (n = 111). Evidence of association was primarily identified for genes in the TGFβ superfamily, including activin A receptor, type II–like 1 (ACVRL1), bone morphogenetic protein receptor 2 (BMPR2), and bone morphogenetic protein 6 (BMP6). The association of pHTN with ACVRL1 and BMPR2 corroborates the previous association of these genes with primary pHTN. Moreover, genes in the TGFβ pathway have been independently implicated in risk for several sickle cell complications, suggesting that this gene pathway is important in overall sickle cell pathophysiology. Genetic variation in the β-1 adrenergic receptor (ADRB1) was also associated with pHTN in our dataset. A multiple regression model, which included age and baseline hemoglobin as covariates, retained SNPs in ACVRL1, BMP6, and ADRB1 as independently contributing to pHTN risk. These findings may offer new promise for identifying patients at risk for pHTN, developing new therapeutic targets, and reducing the occurrence of this life-threatening SCD complication.
Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML
Authors: Sallmyr Annahita , Fan Jinshui , Datta Kamal , Kim Kyu-Tae , Grosu Dan , Shapiro Paul , Small Donald , Rassool Feyruz
Published: January 2008

Activating mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor occur in approximately 30% of acute myeloid leukemia (AML) patients and, at least for internal tandem duplication (ITD) mutations, are associated with poor prognosis. FLT3 mutations trigger downstream signaling pathways including RAS-MAP/AKT kinases and signal transducer and activator of transcription-5 (STAT5). We find that FLT3/ITD mutations start a cycle of genomic instability whereby increased reactive oxygen species (ROS) production leads to increased DNA double-strand breaks (DSBs) and repair errors that may explain aggressive AML in FLT3/ITD patients. Cell lines transfected with FLT3/ITD and FLT3/ITD-positive AML cell lines and primary cells demonstrate increased ROS. Increased ROS levels appear to be produced via STAT5 signaling and activation of RAC1, an essential component of ROS-producing NADPH oxidases. A direct association of RAC1-GTP binding to phosphorylated STAT5 (pSTAT5) provides a possible mechanism for ROS generation. A FLT3 inhibitor blocked increased ROS in FLT3/ITD cells resulting in decreased DSB and increased repair efficiency and fidelity. Our study suggests that the aggressiveness of the disease and poor prognosis of AML patients with FLT3/ITD mutations could be the result of increased genomic instability that is driven by higher endogenous ROS, increased DNA damage, and decreased end-joining fidelity.
Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia
Authors: Ataga Kenneth I. , Smith Wally R. , De Castro Laura M. , Swerdlow Paul , Saunthararajah Yogen , Castro Oswaldo , Vichinsky Elliot , Kutlar Abdullah , Orringer Eugene P. , Rigdon Greg C. , Stocker Jonathan W.
Published: January 2008

Senicapoc, a novel Gardos channel inhibitor, limits solute and water loss, thereby preserving sickle red blood cell (RBC) hydration. Because hemoglobin S polymerization is profoundly influenced by intracellular hemoglobin concentration, senicapoc could improve sickle RBC survival. In a 12-week, multicenter, phase 2, randomized, double-blind, dose-finding study, we evaluated senicapoc's safety and its effect on hemoglobin level and markers of RBC hemolysis in sickle cell anemia patients. The patients were randomized into 3 treatment arms: placebo; low-dose (6 mg/day) senicapoc; and high-dose (10 mg/day) senicapoc. For the primary efficacy end point (change in hemoglobin level from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (6.8 g/L [0.68 g/dL] vs 0.1 g/L [0.01 g/dL], P < .001). Treatment with high-dose senicapoc also produced significant decreases in such secondary end points as percentage of dense RBCs (−2.41 vs −0.08, P < .001); reticulocytes (−4.12 vs −0.46, P < .001); lactate dehydrogenase (−121 U/L vs −15 U/L, P = .002); and indirect bilirubin (−1.18 mg/dL vs 0.12 mg/dL, P < .001). Finally, senicapoc was safe and well tolerated. The increased hemoglobin concentration and concomitant decrease in the total number of reticulocytes and various markers of RBC destruction following senicapoc administration suggests a possible increase in the survival of sickle RBCs. This study is registered at http://clinicaltrials.gov as NCT00040677.
Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components
Authors: Alici Evren , Sutlu Tolga , Björkstrand Bo , Gilljam Mari , Stellan Birgitta , Nahi Hareth , Quezada Hernan Concha , Gahrton Gösta , Ljunggren Hans-Gustaf , Dilber M. Sirac
Published: January 2008

Multiple myeloma (MM) is an incurable plasma cell malignancy with poor outcome. The most promising therapeutic options currently available are combinations of transplantation, targeted pharmacotherapy, and immunotherapy. Cell-based immunotherapy after hematopoietic stem-cell transplantation has been attempted, but with limited efficacy. Natural killer (NK) cells are interesting candidates for new means of immunotherapy; however, their potential clinical use in MM has not been extensively studied. Here, we explored the possibility of expanding NK cells from the peripheral blood of 7 newly diagnosed, untreated MM patients, using good manufacturing practice (GMP)–compliant components. After 20 days of culture, the number of NK cells from these patients had expanded on average 1600-fold. Moreover, expanded NK cells showed significant cytotoxicity against primary autologous MM cells, yet retained their tolerance against nonmalignant cells. Based on these findings, we propose that autologous NK cells expanded ex vivo deserve further attention as a possible new treatment modality for MM.
Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders
Authors: Kunishima Shinji , Hamaguchi Motohiro , Saito Hidehiko
Published: January 2008

MYH9 disorders such as May-Hegglin anomaly are characterized by macrothrombocytopenia and cytoplasmic granulocyte inclusion bodies that result from mutations in MYH9, the gene for nonmuscle myosin heavy chain-IIA (NMMHC-IIA). We examined the expression of mutant NMMHC-IIA polypeptide in peripheral blood cells from patients with MYH9 5770delG and 5818delG mutations. A specific antibody to mutant NMMHC-IIA (NT629) was raised against the abnormal carboxyl-terminal residues generated by 5818delG. NT629 reacted to recombinant 5818delG NMMHC-IIA but not to wild-type NMMHC-IIA, and did not recognize any cellular components of normal peripheral blood cells. Immunofluorescence and immunoblotting revealed that mutant NMMHC-IIA was present and sequestrated only in inclusion bodies within neutrophils, diffusely distributed throughout lymphocyte cytoplasm, sparsely localized on a diffuse cytoplasmic background in monocytes, and uniformly distributed at diminished levels only in large platelets. Mutant NMMHC-IIA did not translocate to lamellipodia in surface activated platelets. Wild-type NMMHC-IIA was homogeneously distributed among megakaryocytes derived from the peripheral blood CD34+ cells of patients, but coarse mutant NMMHC-IIA was heterogeneously scattered without abnormal aggregates in the cytoplasm. We show the differential expression of mutant NMMHC-IIA and postulate that cell-specific regulation mechanisms function in MYH9 disorders.
Multiple ITAM-coupled NK-cell receptors engage the Bcl10/Malt1 complex via Carma1 for NF-κB and MAPK activation to selectively control cytokine production
Authors: Gross Olaf , Grupp Christina , Steinberg Christian , Zimmermann Stephanie , Strasser Dominikus , Hannesschläger Nicole , Reindl Wolfgang , Jonsson Helena , Huo Hairong , Littman Dan R. , Peschel Christian , Yokoyama Wayne M. , Krug Anne , Ruland Jürgen
Published: January 2008

Natural killer (NK) cells are innate immune cells that mediate resistance against viruses and tumors. They express multiple activating receptors that couple to immunoreceptor tyrosine-based activation motif (ITAM)–containing signaling chains for downstream cell activation. Ligation of activating NK-cell receptors induces NK-cell cytotoxicity and cytokine release. How these distinct events are selectively controlled is not well defined. Here we report the identification of a specific signaling pathway that operates downstream of the ITAM-coupled NK-cell receptors NK1.1, Ly49D, Ly49H, and NKG2D. Using primary NK cells from Bcl10−/−, Malt1−/−, Carma1−/−, and Card9−/− mice, we demonstrate a key role for Bcl10 signalosomes in the activation of canonical NF-κB signaling as well as JNK and p38 MAPK upon NK-cell triggering. Bcl10 directly cooperates with Malt1 and depends on Carma1 (Card11) but not on Card9 for NK-cell activation. These Bcl10-dependent cascades selectively control cytokine and chemokine production but do not affect NK-cell differentiation or killing. Thus, we identify a molecular basis for the segregation of NK-cell receptor–induced signals for cytokine release and target cell killing and extend the previously recognized roles for CARD-protein/Bcl10/Malt1 complexes in ITAM receptor signaling in innate and adaptive immune cells.
Ly49 C/I-dependent NKT cell-derived IL-10 is required for corneal graft survival and peripheral tolerance
Authors: Watte C M , Nakamura T , Lau C H , Ortaldo J R , Stein-Streilein J
Published: January 2008

Similar to their activity on NK cells, Ly49 molecules play a pivotal role in influencing how NKT cells respond. It is known that Ly49 C/I is an inhibitory receptor capable of down-modulating proliferation, IFN-γ response, and cytotoxic activity in cells that express it. In a model of peripheral tolerance induced via the eye, we observed that Ly49 C/I-positive, invariant NKT cells were required. To test if the NK inhibitory receptor functionally contributed to tolerance development, we used blocking antibody, in vivo and in vitro, to interfere with the development of antigen-specific suppression. A result of blocking ligation of Ly49 C/I inhibitory receptor prevented NKT cell production of IL-10 and the subsequent development of tolerance. Ly49 C/I-blocking antibodies also prevented corneal graft survival, a phenomenon dependent on eye-induced tolerance. Furthermore, in the presence of TCR stimulation, cross-linking of Ly49 C/I on CD4+ NKT cells stimulated an increase in IL-10 mRNA and a decrease in IFN-γ. The concept of Ly49 inhibitory receptors regulating immune reactivity to self by regulating immune activity of individual cells is thus expanded to include a role for the inhibitory receptors in the more global process of peripheral tolerance to foreign antigens.
Time-domain modeling of electromagnetic diffusion with a frequency-domain code
Authors: Mulder Wim A. , Wirianto Marwan , Slob Evert C.
Published: January 2008

We modeled time-domain EM measurements of induction currents for marine and land applications with a frequency-domain code. An analysis of the computational complexity of a number of numerical methods shows that frequency-domain modeling followed by a Fourier transform is an attractive choice if a sufficiently powerful solver is available. A recently developed, robust multigrid solver meets this requirement. An interpolation criterion determined the automatic selection of frequencies. The skin depth controlled the construction of the computational grid at each frequency. Tests of the method against exact solutions for some simple problems and a realistic marine example demonstrate that a limited number of frequencies suffice to provide time-domain solutions after piecewise-cubic Hermite interpolation and a fast Fourier transform.
Seismic inversion combining rock physics and multiple-point geostatistics
Authors: González Ezequiel F. , Mukerji Tapan , Mavko Gary
Published: January 2008

A novel inversion technique combines rock physics and multiple-point geostatistics. The technique is based on the formulation of the inverse problem as an inference problem and incorporates multiple-point geostatistics and conditional rock physics to characterize previously known geologic information. The proposed implementation combines elements of sampling from conditional probabilities and elements of optimization. The technique provides multiple solutions, all consistent with the expected geology, well-log data, seismic data, and the local rock-physics transformations. A pattern-based algorithm was selected as the multiple-point geostatistics component. Rock-physics principles are incorporated at the beginning of the process, defining the links between reservoir properties (e.g., lithology, saturation) and physical quantities (e.g., compressibility, density), making it possible to predict situations not sampled by log data. Results for seismic lithofacies inversion on a synthetic test and a real data application demonstrate the validity and applicability of the proposed inversion technique.
The Effect of Neonatal Leptin Treatment on Postnatal Weight Gain in Male Rats Is Dependent on Maternal Nutritional Status during Pregnancy
Authors: Vickers Mark H. , Gluckman Peter D. , Coveny Alice H. , Hofman Paul L. , Cutfield Wayne S. , Gertler Arieh , Breier Bernhard H. , Harris Mark
Published: January 2008

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity, hyperleptinemia, insulin resistance, and type 2 diabetes. Although the mechanisms are unclear, this “programming” has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition (UN) during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Using this model of maternal UN, we have recently shown that neonatal leptin treatment in females reverses the postnatal sequelae induced by developmental programming. To examine possible gender-related effects of neonatal leptin treatment, the present study investigated the effect of neonatal leptin treatment on the metabolic phenotype of adult male offspring. Leptin treatment (recombinant rat leptin, 2.5 μg/g·d, sc) from postnatal d 3–13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring. Neonatal leptin treatment of male offspring from normally nourished mothers caused an increase in diet-induced weight gain and related metabolic sequelae, including hyperinsulinemia and increased total body adiposity compared with saline-treated controls. This occurred without an increase in caloric intake. These effects were specific to offspring of normal pregnancies and were not observed in offspring of mothers after UN during pregnancy. In the latter, neonatal leptin treatment conferred protection against the development of the programmed phenotype, particularly in those fed the chow diet postnatally. These data further reinforce the importance of leptin in determining long-term energy homeostasis, and suggest that leptin’s effects are modulated by gender and both prenatal and postnatal nutritional status.