bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PL04-04: Altered gene expression patterns in phenotypically normal cells from individuals heterozygous for mutations in tumor suppressor genes: Identification of candidate biomarkers of cancer risk
Authors: Bellacosa Alfonso
Published: January 2011

In an effort to identify the earliest molecular changes in tumorigenesis, we analyzed the gene and protein expression profile of morphologically normal epithelial cells bearing a single-hit in a tumor suppressor gene. This approach is based on the hypothesis that, while biallelic inactivation of the gatekeeper tumor suppressor gene is necessary to initiate tumorigenesis of a given target epithelium, heterozygous mutations of this gene might be associated with initial molecular alterations (preinitiation) present in the morphologically “normal” mucosa. In turn, the altered mRNA and protein expression repertoire of single-hit cells may identify targets for measures that could delay or even prevent progression to carcinoma.

We studied four different sites: breast, ovary (predisposing genotypes: BRCA1 and BRCA2), kidney (predisposing genotypes: VHL and TSC1/2), and colon (predisposing genotype: APC).

Our comparisons of epithelial cells from tumor suppressor gene mutation-carriers and controls identified multiple changes in gene expression, that were independently validated by real-time RT-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers, including mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings demonstrate that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner; these detectable effects of “one-hit” represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention.

Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL04-04.
Hydrogen Sulfide, a Toxic Gas with Cardiovascular Properties in Uremia: How Harmful Is It?
Authors: Perna Alessandra F. , Lanza Diana , Sepe Immacolata , Raiola Ilaria , Capasso Rosanna , De Santo Natale G. , Ingrosso Diego
Published: January 2011

Hydrogen sulfide (H2S) is a poisonous gas which can be lethal. However, it is also produced endogenously, thus belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. H2S is in fact involved in mediating several signaling and cytoprotective functions, for example in the nervous, cardiovascular, and gastrointestinal systems, such as neuronal transmission, blood pressure regulation and insulin release, among others. When increased, it can mediate inflammation and apoptosis, with a role in shock. When decreased, it can be involved in atherosclerosis, hypertension, myocardial infarction, diabetes, sexual dysfunction, and gastric ulcer; it notably interacts with the other gaseous mediators. Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are the principal enzymes involved in H2S production. We have recently studied H2S metabolism in the plasma of chronic hemodialysis patients and reported that its levels are significantly decreased. The plausible mechanism lies in the transcription inhibition of the cystathionine γ-lyase gene. The finding could be of importance considering that hypertension and high cardiovascular mortality are characteristic in these patients.
Cardiovascular Imaging in Patients with Chronic Kidney Disease
Authors: Karohl Cristina , Raggi Paolo
Published: January 2011

Cardiovascular disease is highly prevalent in chronic kidney disease and has been associated with increased morbidity and mortality. Several morphological and functional tests are available to assess the cardiovascular system. Since structural and functional cardiovascular abnormalities have prognostic implications, their identification may become crucial for the implementation of effective preventive and therapeutic strategies. We review the most frequently used imaging methods to investigate structural and functional cardiovascular changes in patients with chronic kidney disease.
Intestinal-Renal Syndrome: Mirage or Reality?
Authors: Ritz Eberhard
Published: January 2011

The recent interest in the role of the intestine in the cardiovascular stability of uremic patients, specifically on dialysis, but potentially also in chronic kidney disease, must be seen against the background of the recent great interest in the role of the gut in chronic heart failure [Curr Opin Clin Nutr Metab Care 2008;11:632–639]. There has been a long-standing interest in the role of the intestine in renal failure, mainly concerning the role of metabolites of bacterial metabolism in the gut as potential uremic toxins. This area has recently been given a new twist by the finding that increased endotoxin concentrations in the blood of dialyzed patients are associated with hypotensive episodes and myocardial ‘stunning’. Recent studies suggest that intradialytic underperfusion of myocardial areas, the so-called stunning, may be related to the entry of bacterial endotoxin and/or cytokines across the mucosal barrier into the circulation, where they have a negative impact on myocardial function (and presumably beyond the negative cardiac side effect also contribute to catabolism and malnutrition). Entry of bacterial endotoxin during dialysis sessions is presumably the result of intermittent underperfusion of the intestine if the effective blood volume is rapidly reduced causing breakdown of the mucosal barrier. Apart from the impact on myocardial perfusion, the entry of bacterial endotoxin and/or cytokines across the mucosal barrier may also contribute to malnutrition, wasting and reduced life expectancy in hemodialyzed patients. Such a causal relationship is absolutely plausible in view of an extensive literature on congestive heart failure where clinical and experimental evidence indicates that bacterial endotoxin and/or cytokines may escape from a hypoperfused edematous gut, entering the circulation, triggering an inflammatory response, upregulating circulating cytokines and interfering with the function of the heart through several pathogenic mechanisms.
Chronic Kidney Disease Stages Are Appropriate at All Ages
Authors: Goilav Beatrice , Kaskel Frederick J.
Published: January 2011

Chronic kidney disease (CKD) is associated with multiple detrimental consequences to the cardiovascular and musculoskeletal systems. The effects of CKD are even more significant when they begin in childhood as they affect growth and (neuro-) development as well. The division into stages of CKD serves as a guideline for the physician to better anticipate and treat early and later manifestations of CKD. For that matter, in adults, the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative has published clinical practice guidelines, which are based on estimated glomerular filtration rate (eGFR). There are no such explicit guidelines published for the pediatric CKD population, mostly (and thankfully) due to its small number. However, given the excellent guidelines published in the adult literature and ongoing clinical work done by dedicated pediatric nephrologists, similar guidelines for children could be extrapolated and determined. As a matter of fact, the pediatric nephrology community is anxiously anticipating the results of the ongoing Chronic Kidney Disease in Children study, which is the first multicenter, prospective, observational pediatric study of such kind. This article summarizes the adequacy of CKD stages at all ages based not only on opinions of experienced clinicians, but also on evidence provided by cross-sectional data analyses of the Chronic Kidney Disease in Children study.
Sodium Gradient: A Tool to Individualize Dialysate Sodium Prescription in Chronic Hemodialysis Patients?
Authors: Penne E. Lars , Sergeyeva Olga
Published: January 2011

Low dialysate sodium concentrations have been associated with intradialytic symptoms such as muscle cramps and hypotensive episodes. High dialysate sodium concentrations lead to sodium loading, thirst and subsequent increase in interdialytic weight gain and hypertension. The optimal dialysate sodium concentration for an individual depends on the serum sodium concentration. The difference between the dialysate sodium concentration and the predialysis serum sodium concentration has been defined as the sodium gradient. In this article, the role of the sodium gradient in fluid overload, hypertension, intradialytic symptoms and clinical outcome is discussed. Absolute serum sodium levels should always be taken into account when interpreting the relation between sodium gradient and clinical outcomes. Alignment of the dialysate sodium with the serum sodium concentration may be beneficial in many patients.
Chronic Kidney Disease Anemia Management: What Should Be Done?
Authors: Szczech Lynda Anne
Published: January 2011

A transition in the approach to anemia management in nephrology occurred when randomized trials demonstrated that higher hemoglobin targets do not result in better outcomes and may arguably cause harm. Contradicting the speculative conclusions drawn based on earlier observational data, this has resulted in hypotheses regarding the cause of these seemingly disparate but substantively similar messages. The renal community now must struggle with how to incentivize quality care and maximize patient quality of life while minimizing the real safety signal of which we are now aware.
Adolescents and Emerging Adults with Chronic Kidney Disease: Their Unique Morbidities and Adherence Issues
Authors: Diaz-Gonzalez de Ferris Maria E.
Published: January 2011

Medical advances have increased the survival rates of adolescents and emerging adults with chronic kidney disease and end-stage kidney disease. Patients in these two age groups share many characteristics: their brain will fully develop in their late 20s; they have cognitive impairment related to disease severity and duration, are at greater risk of nonadherence, and need to learn to manage their complex medical condition and comorbidities while trying to achieve independence from their parents. The medical and psychosocial characteristics of these patients are discussed, and possible strategies for their care suggested.
A Case of Agonadism, Skeletal Malformations, Bicuspid Aortic Valve, and Delayed Development with a 16p13.3 Duplication Including GNG13 and SOX8 Upstream Enhancers: Are Either, Both or Neither Involved in the Phenotype?
Authors: Erickson R.P. , Yatsenko S.A. , Larson K. , Cheung S.W.
Published: January 2011

We report a female patient with delayed growth and development, skeletal and cardiac defects, and a male XY sex chromosome complement with early failure of gonad development. SRY sequencing was normal. Array comparative genome hybridization (CGH) analysis revealed a gain in copy number in the subtelomeric region of the short arm of chromosome 16, encompassing a region of approximately 560 kb in size including GNG13 which may be involved in ovarian development. The proximal breakpoint of the duplication maps about 18 kb upstream of SOX8 and involves evolutionary conserved regulatory elements. SOX8, like SOX9, is a transcription factor expressed in many tissues, including neural crest, nervous system, muscle, cartilage, adrenal gland, kidney, and testis. There was no increase in GNG13 or SOX8 expression in the patient’s lymphoblastoid line. It is possible that an alteration of SOX8 or/and GNG13 expression is responsible for the multiple congenital anomalies and sex reversal in our patient.
Olfactory Receptor-Related Duplicons Mediate a Microdeletion at 11q13.2q13.4 Associated with a Syndromic Phenotype
Authors: Wischmeijer A. , Magini P. , Giorda R. , Gnoli M. , Ciccone R. , Cecconi I. , Franzoni E. , Mazzanti L. , Romeo G. , Zuffardi O. , Seri M.
Published: January 2011

By array-CGH, we identified a cryptic deletion of about 3.4 Mb involving the chromosomal region 11q13.2q13.4 in a child with speech and developmental delay. Highly homologous segmental duplications related to the well-known olfactory receptor (OR)-containing clusters at 8p and 4p are located at the breakpoints of the imbalance and may be involved in its occurrence. Although these structural features are known to promote recurrent chromosomal rearrangements and previous studies had included the 11q13.2q13.4 deletion region among those considered potentially more unstable, neither deletions nor duplications of this region had been reported until now. Among the deleted genes, SHANK2 might play a role in the phenotype of the patient since it encodes a postsynaptic scaffolding protein similar to SHANK3, whose haploinsufficiency is a well-known cause of severe speech delay and autistic-like behavior, and recently deletions and mutations of SHANK2 have been described in patients with an autistic spectrum disorder or mental retardation.
Vocal Acoustic Characteristics of Patients with Parkinson’s Disease
Authors: Tanaka Yasuhiro , Nishio Masaki , Niimi Seiji
Published: January 2011

Speech samples obtained from 39 idiopathic Parkinson’s disease (PD) patients with vocal pathologies were compared with those from 62 age-matched vocally normal non-PD controls. Voice samples collected from sustained vowel phonation and passage reading were acoustically analyzed using Computer Speech Lab and Multi-Dimensional Voice Program software. Noise-to-harmonic ratio, voice turbulence index (VTI) and soft phonation index (SPI) were incorporated as noise-related measurements, fundamental frequency-tremor intensity index (FTRI), amplitude tremor intensity, fundamental frequency-tremor frequency (Fftr), and amplitude-tremor frequency as tremor-related measurements. Compared with controls, the following results were noted: (1) male and female PD patients exhibited significant differences in acoustic parameters of all frequency and amplitude perturbation measurements and noise-related measurements (except VTI in males); (2) speaking fundamental frequency was significantly higher only in male PD patients; (3) FTRI and Fftr in male (only FTRI in female) PD patients were significantly higher, and (4) disease severity and MDVP analysis showed significant correlations between SPI and the Unified Parkinson’s Disease Rating Scale Part I (mentation, behavior, mood) and Part II (activities of daily living) in male PD patients; however, this was not the case in female PD patients.
Central Artery Pulse Pressure in End-Stage Renal Disease: The Roles of Aortic Diameter, Aortic Stiffness and Wave Reflection
Authors: Pannier B. , Guérin A.P. , Marchais S.J. , Safar M.E. , London G.M.
Published: January 2011

In elderly subjects and patients with end-stage renal disease (ESRD), carotid pulse pressure (PP) is an independent and significant predictor of cardiovascular (CV) risk. Whereas in the elderly carotid diameter, but not carotid stiffness, is an associated CV risk factor, an opposite CV risk pattern was observed in ESRD patients that was associated with stiffness. Whether in ESRD patients arterial diameter, stiffness or both are involved in the mechanism(s) of increased carotid PP has never been investigated. Nondiabetic ESRD patients (n = 144) were compared with 57 control subjects matched for age, sex and mean blood pressure, but with higher brachial and carotid PP. Noninvasive echo-Doppler techniques and pulse wave velocity (PWV) and pulse wave analysis were used to evaluate cardiac and carotid arterial structures and functions using multiple stepwise regressions. In controls, carotid PP was associated only with stroke volume, arterial wave reflections and aortic PWV, but not aortic diameter. In ESRD patients, it was associated with wave reflections, aortic PWV, stroke volume and higher aortic diameter. In ESRD patients and controls, elevated carotid PP mainly reflected increased aortic PWV and earlier wave reflections. Aortic diameter had an impact only on ESRD patients, where it compensated for enhanced aortic stiffness and the more pronounced effect of reflected waves. This hemodynamic profile differs consistently from that in elderly subjects of the general population and selectively influences CV risk and drug treatment.
Unexplained Hyponatremia: Seek and You Will Find
Authors: Hoorn Ewout J. , Hotho Daphne , Hassing Robert Jan , Zietse Robert
Published: January 2011

Background: Hyponatremia is a common diagnostic challenge. Methods: An index case is presented to discuss the diagnostic approach to chronic and unexplained hyponatremia. Results: The index case concerns a 60-year-old man with chronic hepatitis C and previous alcohol use who was referred because of weight loss, poor dietary intake, dizzy spells, and unexplained hyponatremia (serum sodium 124–129 mmol/l). A low urine sodium concentration (20 mmol/l) and a lowfractional sodium excretion (0.07%) were observed repeatedly, while urine osmolality washigh (>400 mosm/kg). The central questions in this case are: what is the differential diagnosis, which tests are needed to confirm or exclude a diagnosis, and how would you proceed if no obvious cause is found? Conclusions: The diagnosis of this case of unexplained hyponatremia was unexpected, but important because it was treatable. The challenges and caveats of the diagnostic approach to hyponatremia are discussed. A diagnostic algorithm to guide clinicians who are confronted with similar cases is presented.
Influence of the Task on Hand Preference: Individual Differences among Gorillas (Gorilla gorilla gorilla)
Authors: Pouydebat E. , Reghem E. , Gorce P. , Bels V.
Published: January 2011

The degree of task complexity and bimanual complementarity have been proposed as factors affecting lateralization strength in humans. However, a large number of studies have demonstrated group-level lateral hand bias for different manual activities in numerous non-human primate species. However, no study has tested the effects that a variety of tasks may have in inducing differences in hand preference. Here, we aim to test if 3 adult gorillas exhibited a greater hand preference bias performing 4 tasks of varying complexity: grasping small versus large foods, proto-tool use task and tool use task involving greater visuospatial requirements. We found that (1) the complexity of the task does not necessarily induce a right-handed bias and (2) a subject can be right-handed for a complex task and left-handed for another one. These results, complemented by many publications on hand preference in non-human primates, reveal a great variability in hand preference, which makes it very difficult to deduce any details of hominin handedness with artefacts.
Cryorecanalization of an Obstructed Bronchial Stent in a 12-Year-Old Boy
Authors: Hetzel J. , Kumpf M. , Hetzel M. , Hofbeck M. , Baden W.
Published: January 2011

We report a 12-year-old boy who underwent stent implantation into the left main bronchus at the age of 9.5 years for palliation of severe bronchial stenosis. He had developed complete obstruction of the stent by granulation tissue resulting in respiratory deterioration and the requirement of mechanical ventilation. The stent obstruction was treated at the age of 11.5 years by cryorecanalization. In this technique, cooling of the tip of the cryoprobe is used to induce adherence of the obstructing tissue allowing the subsequent removal of tissue particles by retraction of the probe. Under general anesthesia, a miniaturized cryoprobe was advanced via the working channel of a flexible bronchoscope. Repeat maneuvers of freezing and retraction resulted in complete recanalization of the stent. Repeat bronchoscopies 4 and 12 weeks later revealed recurrent formation of some granulation tissue which was removed by repeat cryorecanalization. Seven months after the initial procedure there was a complete patency of the stent. According to our experience, cryorecanalization is a safe and effective alternative for the treatment of stent obstruction by granulation tissue. Due to the introduction of a miniaturized probe, this method is well applicable in children since it can be performed via the working channel of a flexible pediatric bronchoscope.
Thymulin Gene Therapy Prevents the Histomorphometric Changes Induced by Thymulin Deficiency in the Thyrotrope Population of Mice
Authors: Martines Eliana V. , Reggiani Paula C. , Schwerdt José I. , Goya Rodolfo G. , Cónsole Gloria M.
Published: January 2011

There is evidence of the existence of a bidirectional relationship between the thymus gland and the thyroid axis. Since the thymic peptide thymulin possesses hypophysiotropic activity, we undertook the task of assessing the histomorphometric changes induced by thymulin deficiency on the thyrotrope population of normal mice and the action of neonatal thymulin gene therapy on the thyrotropin (TSH)-cells of nude mice. C57BL/6 mice were subjected to immunoneutralization of circulating thymulin from postnatal day 1 to the end of the study (postnatal day 32) by intraperitoneal injections of rabbit anti-factor thymulin serum (α-FTS) and normal rabbit serum in controls. Also, neonatal thymulin gene therapy was implemented in athymic nude mice using an adenoviral vector expressing a gene for thymulin (RAd-FTS). On postnatal day 1, heterozygous (nu/+) and homozygous (nu/nu) pups received a single bilateral intramuscular (i.m.) injection of either RAd-FTS or RAd-GFP (the latter being the control vector). The pituitaries were immunostained for TSH. Thymulin immunoneutralization severely reduced serum thymulin (p < 0.01). We detected a significant (p < 0.05) decrease in cell size (CS) and volume density (VD) with a nonsignificant decrease in cell density (CD) in C57BL/6 in both males and females. A single neonatal i.m. injection of RAd-FTS markedly increased the circulating levels of serum thymulin in the athymic mice and increased the CD (p < 0.05), CS (p < 0.01) and VD (p < 0.01) of the thyrotrope population in nu/nu mice. Thyroid histology was not affected. Our results suggest a possible modulating effect of thymulin on the thyrotrope population.
Challenges to the Management of High-Risk Stroke Patients with Multiple-Site Occlusive Vascular Disease
Authors: Sander Dirk , Carolei Antonio , Diehm Curt , Hennerici Michael G. , Rothwell Peter M.
Published: January 2011

Stroke patients are at high risk of secondary vascular events. Although in the short term the risk of experiencing a second stroke is high, in the long term patients are more likely to have myocardial infarction. Many stroke patients have also developed polyvascular disease in the form of coronary artery disease and peripheral arterial disease, which is a marker of increased morbidity and mortality in patients with non-cardioembolic ischemic stroke. Despite the high risk of events in these patients, current evidence-based guidelines make very few recommendations that address the need to detect and manage polyvascular disease following a stroke. Optimised Stroke Care for Re-Admission Reduction in Europe (OSCARE) is an initiative that has been set up to address some of these shortcomings.
A Predictive Clinical Grading System for Immunoglobulin A Nephropathy by Combining Proteinuria and Estimated Glomerular Filtration Rate
Authors: Okonogi Hideo , Utsunomiya Yasunori , Miyazaki Yoichi , Koike Kentarou , Hirano Keita , Tsuboi Nobuo , Suzuki Takahide , Hara Yoriko , Ogura Makoto , Hosoya Tatsuo , Kawamura Tetsuya
Published: January 2011

Background: There is no clinical classification of immunoglobulin A nephropathy (IgAN) in clinical practice. In this study, we used receiver-operating characteristic (ROC) analysis to create accurate clinical grades based on clinical parameters associated with the development of end-stage renal disease (ESRD) in IgAN patients. Methods: We performed a retrospective analysis of 116 patients with IgAN. The association between clinical variables and progression to ESRD was examined. Results: Logistic regression analysis indicated that 24-hour urinary protein excretion (UPE) and the estimated glomerular filtration rate (eGFR) at the time of renal biopsy (RBx) were independently associated with the development of ESRD. When combining UPE and eGFR, the areas under the curve were superior to those for UPE or eGFR alone. Moreover, two-graph ROC analysis indicated that the threshold values for UPE and eGFR in predicting future ESRD were 1.0 g/day and 64.0 ml/min/1.73 m2, respectively. Of note, the patients were classified into 4 grades by levels of UPE and/or eGFR, and the OR for risk of ESRD rose significantly from grade I to grade IV. Conclusion: The combination of UPE and eGFR at the time of RBx can improve the predictive accuracy of risk for subsequent ESRD in IgAN patients.
Contact with Human Facilities Appears to Enhance Technical Skills in Wild Vervet Monkeys (Chlorocebus aethiops)
Authors: Waal Erica van de , Bshary Redouan
Published: January 2011

Technical abilities of primates are typically tested in the laboratory. It has been argued that close contact between animals and humans may lead to an increase in skills due to an ‘enculturation’ of subjects. Here, we provide evidence that exposure to human facilities may improve wild vervet monkeys’ technical skills in a social learning task using the ‘artificial fruit’ approach. Two of our 6 study groups had access to human facilities within their territories. Only members of these 2 groups were likely to open successfully ‘artificial fruit’ during their first attempt. Success appeared to be independent of individual sex or the type of task. Our results highlight the possibility that human enculturation may allow captive monkeys to acquire more technical skills than their wild counterparts, and we suggest that this possibility should be tested in further field experiments.
Nocturnal Home Pulse Oximetry: Variability and Clinical Implications in Home Mechanical Ventilation
Authors: Fernández Ramón , Rubinos Gemma , Cabrera Cristina , Galindo Rosa , Fumero Sergio , Sosa Alejandro , González Isidro , Casan Pere
Published: January 2011

Background: Nocturnal home pulse oximetry (NHPO) provides information by measuring a series of variables: time spent with SaO2 <90% expressed as percentage (T90) or in minutes (Tm90), mean SaO2 (MnS), and lowest SaO2 (LwS.) The presence of significant nocturnal desaturation has been proposed as a parameter in decision making with regard to initiating home mechanical ventilation (HMV) or monitoring HMV effectiveness. However, there is limited information on the possible variability of the test, and this could influence the interpretation of results. Objectives: To explore the variability between 2 consecutive measurements of NHPO and to determine clinical applications in HMV. Methods: The patients presented diseases susceptible to HMV treatment and were enrolled in stable condition without respiratory failure. NHPO was conducted on 2 consecutive nights. The variables analyzed were: T90, Tm90, Mns, and LwS. The coefficient of variation (CV), a concordance coefficient (CC), and the Bland-Altman method were used in order to explore the variability. Results: We studied 40 cases. Two were excluded, and the remaining 38 were aged 58 ± 16 years (19 males). Eighteen were receiving HMV. CV values exceeded 100% for T90 and Tm90 and were below 5% for MnS and LwS. The CC for T90, Tm90, and LwS showed confidence intervals with lower limits below 0.5, while for MnS the value was 0.88 (0.79–0.93). Conclusions: There is a wide variability in NHPO recordings for T90, Tm90, and LwS, so a single determination to detect nocturnal desaturation may not be valid for decision making; the parameter with the least interindividual variability and intraindividual variability was MnS.
Matrix Metalloproteinases in Myasthenia Gravis
Authors: Helgeland Geir , Petzold Axel , Luckman Steven Paul , Gilhus Nils Erik , Plant Gordon T. , Romi Fredrik Robert
Published: January 2011

Introduction: Myasthenia gravis (MG) is an autoimmune disease with weakness in striated musculature due to anti-acetylcholine receptor (AChR) antibodies or muscle specific kinase at the neuromuscular junction. A subgroup of patients has periocular symptoms only; ocular MG (OMG). Matrix metalloproteinases (MMP) are increased in several autoimmune diseases, including generalized MG (GMG), and have been suggested to play a role in immune cell infiltration, basement membrane breakdown and autoimmune pathogenesis. Methods: Total levels of MMP2, MMP3 and MMP9 were measured in serum by ELISA. Results: The MG patients had increased serum levels of MMP2 (median values 200.7 vs. 159.7 ng/ml, p < 0.001) and MMP9 (median values 629.6 vs. 386.4 ng/ml, p < 0.001) compared to controls. A subgroup of patients had increased MMP3 concentration (p = 0.001). The differences were not dependent on presence of AChR antibodies. No difference was observed between GMG and OMG patients with regard to MMP2 (p = 0.598), MMP3 (p = 0.450) and MMP9 (p = 0.271). Discussion: The increased MMP levels in our MG patients group and the lack of dependence on anti-AChR antibodies suggest that MMP2, MMP3 and MMP9 play a role in the development of MG. The similarities between GMG and OMG support OMG as a systemic disease.
Pomegranate Juice Protects Macrophages from Triglyceride Accumulation: Inhibitory Effect on DGAT1 Activity and on Triglyceride Biosynthesis
Authors: Rosenblat Mira , Aviram Michael
Published: January 2011

Background/Aims: To analyze the effects of pomegranate juice (PJ) and punicalagin on macrophage triglyceride metabolism. Methods: Triglyceride metabolism was analyzed in PJ- or punicalagin-treated J774A.1 macrophages or in mouse peritoneal macrophages (MPM) harvested from C57BL/6 mice or from paraoxonase 2 (PON2)-deficient mice. Results: PJ (0–50 µM) significantly and dose-dependently decreased the triglyceride content and triglyceride biosynthesis rate in J774A.1 macrophages or in C57BL/6 MPM by about 30%. Similarly, punicalagin, the major PJ polyphenol, inhibited the MPM triglyceride biosynthesis rate by 40%. The triglyceride hydrolytic rate, however, was not significantly affected by PJ or punicalagin. The activity of diacylglycerol acyltransferase 1 (DGAT1; the rate-limiting enzyme in triglyceride biosynthesis) was significantly inhibited, by 54%, in C57BL/6 MPM that were treated with 50 µM PJ or punicalagin, with no significant effect on DGAT1 mRNA or protein expression. Both PJ and punicalagin increased (1.7-fold) MPM PON2 mRNA expression, and PON2 was previously shown to inhibit DGAT1 activity. However, the addition of PJ or punicalagin (50 µM) to microsomes from PON2-deficient MPM still resulted in a significant reduction (50–58%) in DGAT1 activity. Conclusions: We conclude that the inhibitory effect of PJ on triglyceride biosynthesis could be attributed to a direct effect of PJ on DGAT1 activity.
Abciximab Does Not Prevent Ischemic Lesions Related to Cerebral Angiography: A Randomized Placebo-Controlled Trial
Authors: Brockmann Carolin , Hoefer Thomas , Diepers Michael , Neumaier-Probst Eva , Noelte Ingo , Brockmann Marc-Alexander , Weiss Christel , Groden Christoph , Scharf Johann
Published: January 2011

Background: To assess the efficiency of IIb/IIIa platelet receptor inhibition by abciximab in the prevention of silent embolism during digital subtraction angiography. Methods: In this randomized, double-blind, prospective study, pre- and postangiographic diffusion-weighted magnetic resonance imaging (DWI) of 184 participants was evaluated for the occurrence of silent embolism. Results: No significant relationship was found between the patients receiving abciximab before digital subtraction angiography (15 of 90; 16.7%) and patients in the placebo group (16 of 94; 17.0%) regarding postangiographic appearance of silent emboli (p = 0.9). Conclusions: IIb/IIIa receptor inhibition by abciximab does not diminish the occurrence of silent embolism during digital subtraction angiography. Our findings indicate that solid blood clots are not the origin of hyperintense lesions observed on DWI and enhance the role of alternative mechanisms.
Simulating Sequences of the Human Genome with Rare Variants
Authors: Peng Bo , Liu Xiaoming
Published: January 2011

Objective: Simulated samples have been widely used in the development of efficient statistical methods identifying genetic variants that predispose to human genetic diseases. Although it is well known that natural selection has a strong influence on the number and diversity of rare genetic variations in human populations, existing simulation methods are limited in their ability to simulate multi-locus selection models with realistic distributions of the random fitness effects of newly arising mutants. Methods: We developed a computer program to simulate large populations of gene sequences using a forward-time simulation approach. This program is capable of simulating several multi-locus fitness schemes with arbitrary diploid single-locus selection models with random or locus-specific fitness effects. Arbitrary quantitative trait or disease models can be applied to the simulated populations from which individual- or family-based samples can be drawn and analyzed. Results: Using realistic demographic and natural selection models estimated from empirical sequence data, datasets simulated using our method differ significantly in the number and diversity of rare variants from datasets simulated using existing methods that ignore natural selection. Our program thus provides a useful tool to simulate datasets with realistic distributions of rare genetic variants for the study of genetic diseases caused by such variants.
Racial Liberalism, the Moynihan Report & the Dædalus Project on “The Negro American”
Authors: Geary Daniel
Published: January 2011

In 1965, Daniel Patrick Moynihan, then an official in the Johnson administration, published The Negro Family: The Case for National Action, better known as the Moynihan Report. He was influenced by his participation in two conferences organized by the American Academy of Arts and Sciences in the mid-1960s, as well as two issues of its journal Dceda-lus, on the topic of “The Negro American.” Arguing that the “damaged” family structure of African Americans would impede efforts to achieve full racial equality in the United States, the Moynihan Report launched an explosive debate that helped fracture a fragile liberal consensus on civil rights. Geary examines the report alongside the Dcedalus project, establishing its roots in the racial liberalism of the mid-1960s and connecting it to efforts by liberals to address the socioeconomic dimensions of racial inequality. He considers the close relationship between scholarship and public policy that existed at the time and reflects on the ways liberal ideas about race have changed in the decades since.
Race & Inheritance in Barack Obama's Dreams from My Father
Authors: Carpio Glenda R.
Published: January 2011

When and how did Barack Obama's now well-known “hope” mantra take shape? Carpio's essay explores this question through close readings of key passages from Obama's autobiography. It is nearly three hundred pages into the autobiography before the phrase “the audacity of hope” appears, at the end of the “Chicago” section. Obama has just been accepted to Harvard Law School and has yet to take his first trip to Africa to find his paternal family when he hears the phrase from his infamous ex-pastor, Jeremiah Wright. The essay places this moment from the “Chicago” section in the context of the entire autobiography to illuminate why, for Obama, it takes audacity to hope that we can transcend America's history of racial conflict. In the process, the essay reveals Obama's dark view of race relations in America before he became the symbol of a supposedly post-racial America that he is now.
A Numerical Study of Clear-Air Turbulence (CAT) Encounters over South Korea on 2 April 2007
Authors: Kim Jung-Hoon , Chun Hye-Yeong
Published: January 2011

On 2 April 2007, nine cases of moderate-or-greater-level clear-air turbulence (CAT) were observed from pilot reports over South Korea during the 6.5 h from 0200 to 0830 UTC. Those CAT events occurred in three different regions of South Korea: the west coast, Jeju Island, and the eastern mountain areas. The characteristics and possible mechanisms of the CAT events in the different regions are investigated using the Weather Research and Forecasting model. The simulation consists of six nested domains focused on the Korean Peninsula, with the finest horizontal grid spacing of 0.37 km. The simulated wind and temperature fields in a 30-km coarse domain are in good agreement with those of the Regional Data Assimilation and Prediction System (RDAPS) analysis data of the Korean Meteorological Administration and observed soundings of operational radiosondes over South Korea. In synoptic features, an upper-level front associated with strong meridional temperature gradients is intensified, and the jet stream passing through the central part of the Korean Peninsula exceeds 70 m s−1. Location and timing of the observed CAT events are reproduced in the finest domains of the simulated results in three different regions. Generation mechanisms of the CAT events revealed in the model results are somewhat different in the three regions. In the west coast area, the tropopause is deeply folded down to about z = 4 km because of the strengthening of an upper-level front, and the maximized vertical wind shear below the jet core produces localized turbulence. In the Jeju Island area, localized mixing and turbulence are generated on the anticyclonic shear side of the enhanced jet, where inertial instability and ageostrophic flow are intensified in the lee side of the convective system. In the eastern mountain area, large-amplitude gravity waves induced by complex terrain propagate vertically and subsequently break down over the lee side of topography, causing localized turbulence. For most of the CAT processes considered, except for the mountain-wave breaking, standard NWP resolutions of tens of kilometers are adequate to capture the CAT events.
Linear Stability Analysis of Runge–Kutta-Based Partial Time-Splitting Schemes for the Euler Equations
Authors: Baldauf Michael
Published: January 2011

For atmospheric simulation models with resolutions from about 10 km to the subkilometer cloud-resolving scale, the complete nonhydrostatic compressible Euler equations are often used. An important integration technique for them is the time-splitting (or split explicit) method. This article presents a comprehensive numerical stability analysis of Runge–Kutta (RK)-based partial time-splitting schemes. To this purpose a linearized two-dimensional (2D) compressible Euler system containing advection (as the slow process), sound, and gravity wave terms (as fast processes) is considered. These processes are the most important ones in limiting stability. First, the detailed stability properties are discussed with regard to several off-centering weights for each fast process described by horizontally explicit, vertically implicit schemes. Then the stability properties of the temporally and spatially discretized three-stage RK scheme for the complete 2D Euler equations and their stabilization (e.g., by divergence damping) are discussed. The main goal is to find optimal values for all of the occurring numerical parameters to guarantee stability in operational model applications. Furthermore, formal orders of temporal truncation errors for the time-splitting schemes are calculated. With the same methodology, two alternatives to the three-stage RK method, a so-called RK3-TVD method, and a new four-stage, second-order RK method are inspected.
The Spatial and Temporal Distribution of Organized Convective Structures over the Northeast and Their Ambient Conditions
Authors: Lombardo Kelly A. , Colle Brian A.
Published: January 2011

Organized convective structures over the northeastern United States were classified for two warm seasons (May–August) using 2-km composite radar [i.e., the National Operational Weather Radar (NOWrad)] data. Nine structures were identified: three types of cellular convection (clusters of cells, isolated cells, and broken lines), five types of linear convection (lines with no stratiform precipitation, lines with trailing stratiform precipitation, lines with parallel stratiform precipitation, lines with leading stratiform precipitation, and bow echoes), and one nonlinear system. The occurrence of all structures decreases from the western Appalachian slopes eastward to the Atlantic coast. Isolated cellular convection forms primarily during the morning to late afternoon (1200–2100 UTC) mainly over the high terrain. Clusters of cells form primarily over the Appalachians and the Atlantic coastal plain during the daytime (1200–0000 UTC). Linear convection is favored from midafternoon to early evening (1800–0000 UTC) over land areas. Nonlinear systems develop mainly from midafternoon to late evening (1800–0600 UTC) over the inland areas and over the coastal zone during the early morning (∼1200 UTC).

Composites using the North American Regional Reanalysis (NARR) highlight the ambient conditions for three main convective structures: cellular, linear, and nonlinear. Cellular convection initiates with limited quasigeostrophic forcing and moderate instability [i.e., average most unstable CAPE (MUCAPE) ∼973 J kg−1]. A majority of cells develop in orographically favored upslope areas. Linear convection organizes along surface troughs, supported by 900-hPa frontogenesis and an average ambient MUCAPE of ∼1011 J kg−1. Nonlinear convection organizes along warm fronts associated with larger-scale baroclinic systems, and the MUCAPE is relatively small (∼207 J kg−1).
Monotonic Limiters for a Second-Order Finite-Volume Advection Scheme Using Icosahedral-Hexagonal Meshes
Authors: Mittal Rashmi , Skamarock William C.
Published: January 2011

An assessment of a recently developed (by Miura) second-order numerical advection scheme for icosahedral-hexagonal grids on the sphere is presented, and the effects of monotonic limiters that can be used with the scheme are examined. The cases address both deformational and nondeformational flow and continuous and discontinuous advected quantities; they include solid-body rotation of a cosine bell and slotted cylinder, and moving dynamic vortices. The limiters of Zalesak, Dukowicz and Kodis, and Thuburn are tested within this numerical scheme. The Zalesak and Thuburn limiters produce solutions with similar accuracy, and the Thuburn limiter, while computationally less expensive per time step, results in more stringent stability conditions for the overall scheme. The Dukowicz limiter is slightly more diffusive than the other two, but it costs the least.
Seeking Consensus: A New Approach
Authors: Roebber Paul J.
Published: January 2011

Simulated evolution is used to generate consensus forecasts of next-day minimum temperature for a site in Ohio. The evolved forecast algorithm logic is interpretable in terms of physics that might be accounted for by experienced forecasters, but the logic of the individual algorithms that form the consensus is unique. As a result, evolved program consensus forecasts produce substantial increases in forecast accuracy relative to forecast benchmarks such as model output statistics (MOS) and those from the National Weather Service (NWS). The best consensus produces a mean absolute error (MAE) of 2.98°F on an independent test dataset, representing a 27% improvement relative to MOS. These results translate to potential annual cost savings for electricity production in the state of Ohio of the order of $2 million relative to the NWS forecasts. Perfect forecasts provide nearly $6 million in additional annual electricity production cost savings relative to the evolved program consensus.

The frequency of outlier events (forecast busts) falls from 24% using NWS to 16% using the evolved program consensus. Information on when busts are most likely can be provided through a logistic regression equation with two variables: forecast wind speed and the deviation of the NWS minimum temperature forecast from persistence. A forecast of a bust is 4 times more likely to be correct than wrong, suggesting some utility in anticipating the most egregious forecast errors. Discussion concerning the probabilistic applications of evolved programs, the application of this technique to other forecast problems, and the relevance of these findings to the future role of human forecasting is provided.
High Risk of Peripheral Arterial Disease in the United Kingdom: 2-Year Results of a Prospective Registry
Authors: Stansby Gerard , Mister Rebecca , Fowkes Gerry , Roughton Michael , Nugara Fiona , Brittenden Julie , Bradbury Andrew , Ashley Simon , Shearman Cliff , Hannon Ray , Flather Marcus ,   PREPARED (Prospective Registry and Evaluation of Peripheral Arterial Risks, Events and Distribution) Investigators
Published: January 2011

We report a prospective 2-year, multicenter study of patients presenting with intermittent claudication (IC; ankle brachial blood pressure index, ABPI ≤ 0.9). Mean age of the 473 patients enrolled was 68 years, 20% were diabetics, 30% had prior symptomatic coronary heart disease (CHD), 7% had prior stroke, and 39% were current smokers. At baseline, 26.2% of patients had BP ≤ 140/85 mm Hg or lower and at 2 years this figure was 32.5% (P = .01). Current smokers had fallen to 27% (from 39%) at 2 years (P < .001). Use of antiplatelet agents, statins, and angiotensin converting enzyme inhibitors increased significantly during the course of the study as did claudication distance. Death and the composite of death, stroke or myocardial infarction (MI), occurred in 8.4% and 11.6% of patients, respectively. Prognosis was worse in patients with prior history of CHD, older age, those with diabetes and a lower ABPI.
Trends and Directions in Contemporary Theology: Anglican Theology
Authors: Markham Ian
Published: January 2011

This article provides a map of trends and directions in contemporary Anglican Theology. It divides the main protagonists into five camps: the liberals, the conservatives, those advocating ‘mystical theology’ and ‘radical orthodoxy’, those stressing ecclesiology and culture, and finally, in a camp all of his own the Archbishop of Canterbury, Rowan Williams. The article argues that one of the enduring legacies of Rowan Williams may be the way in which he is influenced by all the other camps and is thereby influencing Anglican theology in a highly distinctive way.
A Blessed Rage for the Common Good
Authors: Riordan Patrick
Published: January 2011

Recent crises provoke appeals to the common good. Can the structures and procedures of liberal democracies belong among Gaudium et Spes’s conditions for human fulfilment? And are they to be respected even when they lead to undesirable outcomes? How can we integrate the notion of conflict as central to democratic politics, that is, a conflict which is not simply due to moral fault, or the inordinate pursuit of particular interests? The common good is not available as an already known quantity to determine correct solutions in conflict situations. Its core idea is heuristic, naming that which is being sought, but which is not yet known, although enough about it is known to be able to specify the programme for its discovery. Its two operative criteria are succinctly expressed in the themes of Populorum Progressio and Caritas in Veritate, concern for the development of every person and of the whole person.
Grounding Speech and Silence: Cataphaticism and Apophaticism in Denys and Aquinas
Authors: McDonough Conor
Published: January 2011

This article investigates the interplay of cataphatic and apophatic theology in the works of Denys (Pseudo-Dionysius) and Aquinas. In each case, the reasons given for the possibility of speech about God, and the denial of this possibility, are investigated. This classical theological understanding of ‘speech’ and ‘silence’ is set against two contemporary presentations of apophaticism as found in the writings of Jacques Derrida and Anthony Kenny.