bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of Life, Wishes, and Needs in Women with Gestational Diabetes: Italian DAWN Pregnancy Study
Authors: Lapolla A. , Di Cianni G. , Di Benedetto A. , Franzetti I. , Napoli A. , Sciacca L. , Torlone E. , Tonutti L. , Vitacolonna E. , Mannino D.
Published: April 2012

The DAWN (Diabetes Attitudes, Wishes and Needs) study is a survey promoted by the International Diabetes Federation to recognize the perceptions and attitudes of people suffering from diabetes mellitus. In this context, we evaluated the quality of life of Italian and immigrant women with gestational diabetes mellitus (GDM). Information was gathered using a structured questionnaire for patients’ self-compilation. In a 3-month period, a 51-item questionnaire was submitted to 198 Italians and 88 immigrants (from 27 different foreign nationalities). Italian women were older and had higher education than the immigrants. 60% of the Italians and 38% of the immigrants had a family history of diabetes mellitus. In both groups, the diagnosis of GDM caused anxiety; one-third of women feared their child could contract diabetes at delivery and/or have congenital malformations. Some women had trouble in following treatment regimens: the major concern being dietary advice and blood glucose testing. Most women were satisfied (34%) or highly satisfied (60%) with the quality of care, although the degree of cooperation between diabetes specialists and gynaecologists was considered sometimes unsatisfactory. In order to optimize maternal and foetal outcomes, educational projects and improved communication between patients and the healthcare provider team are recommended.
Randomized Controlled Trial of the Effectiveness of Genetic Counseling and a Distance, Computer-Based, Lifestyle Intervention Program for Adult Offspring of Patients with Type 2 Diabetes: Background, Study Protocol, and Baseline Patient Characteristics
Authors: Nishigaki M. , Tokunaga-Nakawatase Y. , Nishida J. , Taru C. , Miyawaki I. , Sanada H. , Kazuma K.
Published: April 2012

Relatives of type 2 diabetic patients are at a high risk of developing type 2 diabetes and should be regarded as target of intervention for diabetes prevention. However, it is usually hard to motivate them to implement preventive lifestyle changes, because of lack of opportunity to take advises from medical professionals, inadequate risk perception, and low priority for preventive behavior. Prevention strategy for them therefore should be highly acceptable and suited for them. The parallel, three-group trial is now being conducted to investigate the effects of genetic counseling and/or a computerized behavioral program on the prevention of type 2 diabetes in that population. The preventive strategies used in this study could provide a novel solution to the numbers of genetically high-risk individuals, if found to be effective. The objective of this paper is to describe the background, protocol, and baseline patient characteristics of the trial.
A Small-Molecule Inhibitor Targeting the Mitotic Spindle Checkpoint Impairs the Growth of Uterine Leiomyosarcoma
Authors: Shan Weiwei , Akinfenwa Patricia Y. , Savannah Kari B. , Kolomeyevskaya Nonna , Laucirica Rudolfo , Thomas Dafydd G. , Odunsi Kunle , Creighton Chad J. , Lev Dina C. , Anderson Matthew L.
Published: April 2012

Purpose: Uterine leiomyosarcoma (ULMS) is a poorly understood cancer with few effective treatments. This study explores the molecular events involved in ULMS with the goal of developing novel therapeutic strategies.

Experimental Design: Genome-wide transcriptional profiling, Western blotting, and real-time PCR were used to compare specimens of myometrium, leiomyoma, and leiomyosarcoma. Aurora A kinase was targeted in cell lines derived from metastatic ULMS using siRNA or MK-5108, a highly specific small-molecule inhibitor. An orthotopic model was used to evaluate the ability of MK-5108 to inhibit ULMS growth in vivo.

Results: We found that 26 of 50 gene products most overexpressed in ULMS regulate mitotic centrosome and spindle functions. These include UBE2C, Aurora A and B kinase, TPX2, and Polo-like kinase 1 (PLK1). Targeting Aurora A inhibited proliferation and induced apoptosis in LEIO285, LEIO505, and SK-LMS1, regardless of whether siRNA or MK-5108 was used. In vitro, MK-5108 did not consistently synergize with gemcitabine or docetaxel. Gavage of an orthotopic ULMS model with MK-5108 at 30 or 60 mg/kg decreased the number and size of tumor implants compared with sham-fed controls. Oral MK-5108 also decreased the rate of proliferation, increased intratumoral apoptosis, and increased expression of phospho-histone H3 in ULMS xenografts.

Conclusions: Our results show that dysregulated centrosome function and spindle assembly are a robust feature of ULMS that can be targeted to slow its growth both in vitro and in vivo. These observations identify novel directions that can be potentially used to improve clinical outcomes for this disease. Clin Cancer Res; 18(12); 3352–65. ©2012 AACR.
Romidepsin for Cutaneous T-cell Lymphoma
Authors: Prince H. Miles , Dickinson Michael
Published: April 2012

Cutaneous T-cell lymphomas (CTCL) are relatively rare lymphomas with an annual incidence of approximately 0.2 to 0.8/100,000 and comprise a variety of clinical entities; mycosis fungoides or its leukemic variant Sezary syndrome account for the majority of cases. Advanced-stage disease is typically treated with bexarotene (a retinoid), interferon, or conventional chemotherapeutic agents, but relapses are inevitable. Histone deacetylase inhibitors, which modify the epigenome, are an attractive addition to the armamentarium. On the basis of 2 large phase II studies, the U.S. Food and Drug Administration approved intravenous romidepsin for patients with relapsed and/or refractory CTCL. Romidepsin provides a subset of patients with an opportunity for prolonged clinical responses with a tolerable side effect profile. Clin Cancer Res; 18(13); 3509–15. ©2012 AACR.
Distinguishing Clinicopathologic Features of Patients with V600E and V600K BRAF-Mutant Metastatic Melanoma
Authors: Menzies Alexander M. , Haydu Lauren E. , Visintin Lydia , Carlino Matteo S. , Howle Julie R. , Thompson John F. , Kefford Richard F. , Scolyer Richard A. , Long Georgina V.
Published: April 2012

Purpose: Certain clinicopathologic features correlate with BRAF mutation status in melanoma including younger age and primary subtype. This study sought to determine the BRAF mutation status by age-decade and whether BRAF-mutant genotypes correlated with clinicopathologic features and outcome in patients with metastatic melanoma.

Methods: A prospectively assembled cohort of Australian patients were followed from diagnosis of metastatic melanoma (N = 308). Clinicopathologic variables were correlated with BRAF mutational status, genotype, and survival.

Results: Forty-six percent of patients had a BRAF mutation; 73% V600E, 19% V600K, and 8% other genotypes. An inverse relationship existed between BRAF mutation prevalence and age-decade (P < 0.001). All patients <30 years and only 25% ≥70 years had BRAF-mutant melanoma. Amongst BRAF-mutant melanoma, the frequency of non-V600E genotypes (including V600K) increased with increasing age. Non-V600E genotypes comprised <20% in patients <50 years and >40% in those ≥70 years. A higher degree of cumulative sun-induced damage correlated with V600K but not V600E melanoma (P = 0.002). The disease-free interval from diagnosis of primary melanoma to first distant metastasis was shorter for patients with V600K compared with V600E melanoma (17.4 vs. 39.2 months, P = 0.048), with no difference in survival thereafter. In patients BRAF tested at diagnosis of metastatic melanoma, one year survival from diagnosis of metastasis was significantly longer for patients with BRAF-mutant melanoma treated with an inhibitor (83%), than those not treated with an inhibitor (29%, P < 0.001), or patients with BRAF wild-type melanoma (37%, P < 0.001).

Conclusion: Different genotypes exist within BRAF-mutant metastatic melanoma, representing biologically and clinically discrete subtypes, suggesting distinct etiology and behavior. Clin Cancer Res; 18(12); 3242–9. ©2012 AACR.
Differentiated Epidermal Cells Regain the Ability to Regenerate a Skin Equivalent by Increasing the Level of β-Catenin in the Cells
Authors: Zhao Zhili , Zhang Cuiping , Fu Xiaobing , Yang Rongya , Peng Chen , Gu Tingmin , Sui Zhifu , Wang Congmin , Liu Chang
Published: April 2012

Epidermal stem cells are of major importance for skin regeneration and tissue engineering, but differentiated epidermal cells lost their proliferative capacity and are no longer able to regenerate a skin equivalent. Here, we investigated the role of β-catenin in regulating regenerative functions of differentiated epidermal cells. Lithium chloride and a highly specific glycogen synthase kinase (GSK)-3β inhibitor were applied to induce the expression of β-catenin in differentiated epidermal cells. After a 6-day induction, the large flat-shaped cells with a small nuclear-cytoplasmic ratio had changed into small round-shaped cells with a large nuclear-cytoplasmic ratio. Phenotypic assays showed a remarkably higher expression of CK19, β1-integrin, Oct4 and Nanog in induced cells than in the control group (p < 0.01). In addition, the results of growth and functional investigations demonstrated that the induced epidermal cells exhibited a high colony-forming ability, a long-term proliferative potential and the ability to regenerate a skin equivalent, which were regarded as the most important features of epidermal stem cells. These results suggest that the activation of β-catenin favors the reversion or dedifferentiation of differentiated epidermal cells to an immature or a less differentiated state. This study may also offer a new approach to yield enough epidermal stem cells for skin regeneration and tissue engineering.
Early Neurodevelopmental Outcome of Infants with High-Risk Fetal Lung Lesions
Authors: Danzer Enrico , Siegle Jennifer , D’Agostino Jo Ann , Gerdes Marsha , Hoffman Casey , Bernbaum Judy , Rintoul Natalie E. , Flake Alan W. , Adzick N. Scott , Hedrick Holly L.
Published: April 2012

Objective: To evaluate the neurodevelopmental outcome of infants with high-risk fetal lung lesions defined as (1) requiring fetal intervention and/or ex utero intrapartum therapy (EXIT), or (2) acute respiratory decompensation postnatally necessitating emergent resection within 48 h of life. Methods: We reviewed the medical records of 13 consecutive patients with high-risk fetal lung lesions who were enrolled in our prospective interdisciplinary follow-up program. Neurodevelopmental status was evaluated using the Bayley Scales of Infant Development-III (children ≤3 years, n = 12), or the Wechsler Preschool and Primary Scale of Intelligence-III (children ≥4 years, n = 1). Results: Eight children (62%) underwent prenatal intervention (EXIT, n = 6; fetal resection, n = 1; intrauterine shunt placement, n = 1), and 5 (38%) required emergent resection postnatally. Median age at evaluation was 25 months (range: 5–80). Average scores for cognitive development were found in all children assessed under 3 years of age. The one child who was tested for cognitive ability at 6 years of age scored in the borderline range of intellectual functioning. For language outcome, 15% scored above average, 54% scored within the average range, and 31% had mild deficits. Overall, 77% scored within the average range for neuromotor outcome, while 23% scored within the mildly delayed range. None of the children had severe delays. Cognitive, language, and psychomotor scores were similar between both groups. Hypotonicity was found in 23%. Autism was suspected in one child who underwent an EXIT procedure and was postnatally diagnosed with mosaic trisomy 18. Conclusion: The majority of children with high-risk fetal lung lesions have age-appropriate neurodevelopmental scores.
ABCD2 as a Screening Tool for Cerebral Infarction on Stroke MRI?
Authors: Hotter Benjamin A. , Lechner Jan M. , Nolte Christian H. , Audebert Heinrich J. , Malzahn Uwe , Heuschmann Peter U. , Fiebach Jochen B. , Jungehulsing Gerhard J.
Published: April 2012

Background: The newly proposed transient ischemic attack (TIA) definition demands for MRI exclusion of infarction. Due to limited resources other tools than MRI predicting tissue infarction would be valuable. We hypothesized that ABCD2 risk score is a valid screening tool for diffusion-weighted imaging (DWI) lesions. Methods: TIA patients were prospectively enrolled in an observational MRI study to receive acute and follow-up stroke MRI. ABCD2 scores were calculated, and sociodemographics and risk factors were recorded. Results: One hundred and thirty-two TIA patients were enrolled over nine months. Five patients were excluded due to different diagnosis. Forty-five of the 127 remaining patients showed acute ischemic lesions on DWI. Median ABCD2 scores for DWI-negative and -positive patients were 4 and 5, respectively. Ordinal, trichotomized and dichotomized ABCD2 were significantly associated to DWI. Univariate analysis of single score items and other risk factors demonstrated unilateral weakness, duration of symptoms and smoking as predictive for DWI restrictions. In multivariate analysis unilateral weakness remained significant. Conclusions: High-risk ABCD2 score due to the impact of hemiparesis is associated with the occurrence of DWI lesions but is still not accurate enough for a reliable differentiation of cerebrovascular events with and without MRI lesions.
Elevated Immunoreactivity against Class I Histone Deacetylases in Adenomyosis
Authors: Liu Xishi , Nie Jichan , Guo Sun-Wei
Published: April 2012

Background/Aims: Adenomyosis is a common condition with a poorly understood pathogenesis. Recent data suggest that it may be an epigenetic disease. This study investigated the expression and localization of class I histone deacetylases (HDACs) in women with and without adenomyosis. Methods: The ectopic and homologous eutopic endometrium of 50 women with adenomyosis and the endometrium of 18 age- and menstrual phase-matched women without adenomyosis were used for immunohistochemical analysis. Tissue sections were immunostained with HDAC1, -2, and -3. Microscopic evaluation to assess the presence and localization of HDAC1–3 throughout the menstrual cycle in both eutopic endometrial and endometriotic tissues of women with adenomyosis was performed and compared with the normal endometrium. Results: We found that, compared with the normal endometrium, immunoreactivity against HDAC1 and HDAC3 was higher in both the eutopic and the ectopic endometrium. Increased HDAC2 in the eutopic endometrium was found to be associated with the severity of dysmenorrhea. Conclusion: Given the potential wide-ranging effect of histone deacetylation on gene expression, these findings suggest that HDACs may be involved in adenomyosis. They also suggest the possibility that HDAC2 may be involved in dysmenorrhea and its severity and that HDACs may be potential therapeutic targets in adenomyosis.
Sexual Response in Patients Treated with Sacral Neuromodulation for Lower Urinary Tract Symptoms or Fecal Incontinence
Authors: van Voskuilen A.C. , Oerlemans D.J. , Gielen N. , Lansen-Koch S.M.P. , Weil E.H.J. , van Lankveld J.J.D.M. , van den Hombergh U. , Baeten C.G.M.I. , van Kerrenbroeck P.E.V.
Published: April 2012

Objectives: To determine whether sacral neuromodulation (SNM) for urinary symptoms or fecal incontinence gives improvement of female sexual function and whether improvement is due to physiological or psychological factors. Methods: Between 2002 and 2008, 8 patients had an array of questionnaires before and after SNM implantation. The questionnaires were: the Questionnaire for Screening for Sexual Dysfunctions, the Golombok Rust Inventory of Sexual Satisfaction, the Symptom Checklist-90, the Maudsley Marital Questionnaire and the McGill-Mah Orgasm Questionnaire. Three of these 8 patients underwent vaginal plethysmography before and after implantation. Results: No statistically significant changes were found, although there seems to be a trend toward improvement in orgasm scores. In plethysmography all 3 patients showed increased vaginal pulse amplitude with the stimulator turned on with both erotic and non-erotic stimuli. Conclusions: This study does not show a clear effect of SNM on sexual function, although there seems to be an improvement in orgasm scores. The lack of response on psychological questionnaires and the increase in vaginal pulse amplitude after SNM implantation indicate that there might be a physiological response.
Is Dialysis a Viable Option for the Older Patient? Outcomes for Patients Starting Dialysis Aged 80 Years or Older
Authors: Isaacs Anthony , Burns Aine , Davenport Andrew
Published: April 2012

Background: Maximum conservative management (MCM) has been proposed as an alternative care pathway for the increasing number of elderly patients with progressive chronic kidney disease. Methods: Retrospective analysis of patients aged ≥80 years of age, starting dialysis between 2000 and 2009 in a centre with an established MCM programme. Demographic data, baseline biochemical markers and survival were collected. Results: 93 consecutive patients were studied; median age 83 years (IQR 81–86). 67 male, 32% diabetic. Median survival 46.5 months (range 0–107), with 1- and 5-year survival 78.5 and 38.3%, respectively. Factors predicting poorer survival were Caucasoid ethnicity (p = 0.04) and serum albumin ≤30 g/l (p = 0.01) at dialysis initiation. Duration of nephrology care prior to dialysis initiation did not effect survival. Conclusion: The very elderly electing dialysis were found to have good survival. Further patient characterisation is required to improve decision-making between dialysis and MCM for elderly patients with progressive chronic kidney disease.
Characteristics and Outcome in Acute Coronary Syndrome Patients with and without Established Modifiable Cardiovascular Risk Factors: Insights from the Nationwide AMIS Plus Registry 1997–2010
Authors: Erne Paul , Gutzwiller Felix , Urban Philip , Maggiorini Marco , Keller Pierre-Frédéric , Radovanovic Dragana ,   for the AMIS Plus Investigators
Published: April 2012

Objectives: Little is known about patients without known modifiable risk factors presenting initially with acute coronary syndrome (ACS). This study assessed baseline characteristics and outcomes of ACS patients with and without the known modifiable risk factors arterial hypertension, dyslipidemia, obesity, smoking or diabetes. Methods: All ACS patients enrolled in the AMIS Plus Registry between 1997 and 2010 were analyzed until hospital discharge; a subgroup was re-assessed at the 1-year follow-up. Outcome measures were in-hospital mortality and major adverse cardiac or cerebrovascular events (MACCE) defined as a composite outcome of mortality, re-infarction and cerebrovascular events. Results: Of 33,306 patients, 2,125 (6.4%) had none of these modifiable risk factors. They were older (males), had less moderate or severe comorbidities and were more frequently in Killip class I on admission. Treatment of ACS patients with or without modifiable risk factors was similar with regard to interventional therapies and use of antiplatelet agents. In-hospital mortality was lower in patients without modifiable risk factors but in-hospital MACCE and 1-year survival was similar. Conclusion: Lack of modifiable risk factors was an independent predictor of lower in-hospital mortality but not of MACCE in patients who presented with ACS.
Microarray Screening for Novel Preeclampsia Biomarker Candidates
Authors: Lapaire Olav , Grill Simon , Lalevee Sebastien , Kolla Varaprasad , Hösli Irene , Hahn Sinuhe
Published: April 2012

Introduction: Our aim was to identify novel biomarker candidates for the near-term prediction of preeclampsia in a homogenous collective. In this study, we screened at the genome-wide level for gene expression in placental villous tissue from patients with severe preeclampsia in comparison to normal healthy pregnancies. Material and Methods: Total RNA was extracted from placental villous tissue from 9 preeclamptic patients and 7 normotensive controls after scheduled cesarean sections. After sample pooling, gene expression analysis was performed using six Affymetrix Human Gene 1.0 ST arrays, followed by quantitative RT-PCR and validation of selected markers in the serum of patients at the protein level. Results: In total, 896 significantly differentially expressed genes were identified (p ≤ 0.05). After restricting these to molecules present in the circulation, 9 upregulated and 5 downregulated genes were selected. Four of them (β-hCG, HTRA4, LHB1, all upregulated; and NOX4, downregulated) were validated by quantitative real-time RT-PCR. Finally, the maternal plasma protein levels of 2 of these genes (LHB and β-hCG) were confirmed to be significantly different between preeclampsia cases and controls. Discussion: We identified 14 potential new biomarker candidates for preeclampsia and validated 4 of them by quantitative RT-PCR and 2 of them with subsequent serum protein analyses. Further studies will assess the optimal marker combination for the imminent prediction of impending preeclampsia.
Glycated Albumin in Patients with Neonatal Diabetes Mellitus Is Apparently Low in Relation to Glycemia Compared with That in Patients with Type 1 Diabetes Mellitus
Authors: Suzuki Shigeru , Koga Masafumi , Takahashi Hironori , Matsuo Kumihiro , Tanahashi Yusuke , Azuma Hiroshi
Published: April 2012

Background: Although glycated albumin (GA) is a useful glycemic control marker in neonatal diabetes mellitus (NDM), there has been no report comparing GA levels between NDM patients and non-diabetic infants. Moreover, GA in NDM patients may be apparently low in relation to glycemia due to the assumed elevation of albumin metabolism in neonates. Methods: We compared GA levels between 6 patients with NDM and 18 non-diabetic infants or 14 patients with type 1 diabetes mellitus (T1DM). Mean blood glucose (MBG) was calculated on the basis of self-monitoring of blood glucose for 1 month before GA measurement. Results: GA in NDM patients was significantly higher than that in non-diabetic infants (22.0 ± 5.8 vs. 10.2 ± 1.4%; p < 0.0001), and GA levels significantly correlated with MBG in both NDM and T1DM patients. However, GA in NDM patients was significantly lower than in T1DM patients (25.8 ± 5.3%; p = 0.0046), whereas MBG in NDM patients was significantly higher than in T1DM patients (233 ± 79 vs. 183 ± 41 mg/dl; p = 0.0006). Conclusion: GA levels in NDM patients were apparently low in relation to glycemia. Therefore, reference values for infants should be used for assessing the GA level in NDM.
Angiotensin II Differentially Regulates Morg1 Expression in Kidney Cells
Authors: Bondeva Tzvetanka , Heinzig Juliane , Franke Sybille , Wolf Gunter
Published: April 2012

Background: The mitogen-activated protein kinase organizer 1 (Morg1) belongs to the WD-40 repeat protein family and is a scaffold molecule for the extracellular regulated kinase signaling pathway. Morg1 also binds to prolyl-hydroxylase 3 (PHD3) and regulates the hypoxia-inducible factor-1α (HIF-1α) expression via PHD3 stabilization. Morg1 has been detected in the kidney as well as in other cell tissues but its expression in renal cells has not been well investigated. It has been widely shown that angiotensin II (ANG II) mediates renal damage. We have previously shown that ANG II downregulates the expression of PHD3 in PC12 cells. The aim of this study was to analyze whether ANG II regulates Morg1 expression in mouse mesangial cells (MMC), mouse proximal tubular cells (MTC) and in differentiated podocytes. The correlation between the expression of Morg1 and PHD3 activity was also addressed. Methods: Effect of ANG II on the Morg1 mRNA expression level was assessed by real-time PCR. Morg1 and HIF-1α cellular localization was analyzed by immunohistochemistry. HIF-1α promoter activity was investigated using a reporter gene system. PHD3 hydroxylase activity test was measured with a hydroxylation-coupled decarboxylation assay. Results: ANG II differentially regulates Morg1 expression in MMC, MTC and differentiated podocytes. We detected a biphasic effect of ANG II on Morg1 mRNA expression which was time dependent. While 9-hour ANG II treatment downregulated Morg1 expression in MMC, it induced Morg1 expression in MTC. Conversely, 24-hour ANG II stimulation upregulated the expression of Morg1 mRNA in MMC, but showed an opposite effect in MTC and differentiated podocytes. In addition, we found that ANG II signals mostly through the AT1 receptor subtype in MMC and via the AT2 subtype in MTC. PHD3 activity correlated to Morg1 expression patterns. Our data also demonstrate that HIF-1α transcriptional activity in MTC contrasted to PHD3 activity at 9 and 24 h, whereas in the MMC and in podocytes we did not find any correlation between PHD3 HIF-1α hydroxylation ability and HIF-1α transcriptional activation, suggesting a different mechanism of regulation in these cell types. Interestingly, the reduced expression of Morg1 in mesangial cells isolated from Morg1 (+/–) heterozygous mice correlated with a reduced PHD3 enzymatic activity and an increased HIF-1α transcriptional activity compared with mesangial cells originated from wild-type (Morg1 +/+) mice. Conclusions: We show for the first time in various renal cells that ANG II modulates Morg1 expression and HIF-1α transcriptional activity via cell type-specific mechanisms, demonstrating a novel mechanism by which ANG II may contribute to renal disease.
Delayed Diagnosis of Potocki-Shaffer Syndrome in a Woman with Multiple Exostoses and Mental Retardation
Authors: Palka C. , Alfonsi M. , Mohn A. , Guanciali Franchi P. , Chiarelli F. , Calabrese G.
Published: April 2012

We describe the case of an adult patient affected by multiple exostoses, severe mental retardation, epilepsy and facial dysmorphisms with a deletion of ∼2.3 Mb on chromosome 11p11.21, correlated to Potocki-Shaffer syndrome (PSS). PSS is a rare contiguous gene deletion syndrome, mainly characterized by multiple exostoses and bilateral parietal foramina. Mental retardation and craniofacial dysmorphisms have often been reported, too. Although the patient showed many signs of PSS since early childhood, the diagnosis was suggested only when we examined her at adult age. This case highlights how frequently rare diseases remain undiagnosed till adulthood and is an excellent example of the need for a timely and correct diagnosis.
Predictors of thromboxane levels in patients with non-ST-elevation acute coronary syndromes on chronic aspirin therapy
Authors: Giubilato Simona , Leo Andrea , Cosentino Nicola , Fracassi Francesco , Cataneo Leonardo , Porto Italo , Leone Antonio , Burzotta Francesco , Trani Carlo , Biasucci Luigi , Narducci Maria , Pulcinelli Fabio , Crea Filippo , Niccoli Giampaolo
Published: April 2012

High levels of thromboxane A2 (TxA2), a key mediator of platelet activation and aggregation, are associated with an increased risk of cardiovascular events. We aimed at assessing the predictors of higher plasma levels of TxB2, the stable metabolite of TxA2, in consecutive patients presenting with non-ST-elevation acute coronary syndrome (NSTE-ACS) on previous aspirin (ASA) treatment undergoing coronary angiography. Ninety-eight consecutive patients (age 61 ± 11, 75% males) with NSTE-ACS, on previous chronic ASA treatment, were prospectively enrolled in this study. Coronary disease extent was assessed by angiography according to the Bogaty score. In all patients, admission plasma levels of TxB2 (pg/ml) were measured by enzyme-linked immunosorbent assay, and patients showing TxB2 levels in the fourth quartile were compared to patients showing TxB2 levels in the lower quartiles. Multivariable logistic regression analysis showed that platelet count (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.02–1.63, p=0.04), multivessel coronary disease (OR 1.37, 95% CI 1.13–3.67, p=0.03), and coronary atherosclerosis extent index (OR 1.91, 95% CI 1.45–6.79, p=0.001) were independent predictors of TxB2 level upper quartile. Of note, C-reactive protein serum levels were similar in patients with TxB2 levels in the upper quartile as compared to those in the lower quartiles (p=0.49). In conclusion, NSTE-ACS patients with severe coronary atherosclerosis may have incomplete suppression of TxA2 production despite chronic ASA therapy. This finding suggests that additional efforts should be made to lower TxA2 levels in patients with widespread coronary artery disease.
The HAS-BLED score predicts bleedings during bridging of chronic oral anticoagulation
Authors: Omran Heyder , Bauersachs Rupert , Rübenacker Siegfried , Goss Franz , Hammerstingl Christoph
Published: April 2012

Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective invasive procedure. Current guidelines allow bridging therapy with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Apart from the risk of embolism, bleeding is an important complication in this setting and the optimal perioperative management of such patients is still under discussion. The aims of this prospective, observational, multicentre registry of patients treated by cardiologists were: 1) to evaluate current practice of perioperative management of OAC in a large outpatient cohort, 2) to document embolic and haemorrhagic events, and 3) to identify risk factors predicting adverse events. In the years 2009 and 2010, 1,000 invasive procedures (cardiac catheterisation n=533, pacemaker implantation n = 128, surgery n = 194, other n = 145) were performed in patients with OAC. Sixty- one (6.1%) of those patients did not receive bridging therapy during interruption of OAC, 937 (93.7%) patients were treated with LMWH, two patients (0.2%) received UFH. In 22 patients (2.2%) LMWHs were given in prophylactic dose, 727 patients (72.7%) were treated with halved therapeutic (i.e. weight-adapted) LMWH doses and 188 (18.8%) received full therapeutic LMWH doses. Four thromboembolic complications were observed during 30 days of follow-up (two retinal embolisms, one stroke, one myocardial infarction; 0.4%). One major bleeding (0.1%) and 35 clinically relevant bleedings (3.5%) occurred. Rehospitalisation after bleedings was necessary in 20 patients. Independent predictors for bleedings were history of mechanical heart valve replacement (MVR) (p=0.0002) and the HAS-BLED score (<0.0001), with a cut off value ≥3 being the most predictive variable for haemorrhage (hazard ratio 11.8, 95% confidence interval 5.6–24.9, p<0.0001). A total of 527 patients with atrial fibrillation and a CHADS2 score ≤2 received halved therapeutic or full therapeutic dosages of LMWH despite a low embolic risk, whereas 49 of the patients with heart valve replacement (51%) did not receive dosages of bridging therapy as recommended in guidelines. In conclusion, in this registry of patients treated by cardiologists, 94% of patients who required interruption of OAC before invasive procedures received LMWH as a bridging therapy, of whom 73% were treated with halved therapeutic LMWH-dosages. Guideline recommendations were followed in only 31% of cases. Importantly, 69% of patients with AF were over-treated while 51% of patients with heart valve replacement were under-treated with LMWHs. A HASB-BLED score ≥3 was highly predictive of bleeding events.
Coagulation activation and microparticle-associated coagulant activity in cancer patients
Authors: van Doormaal Frederiek , Berckmans René , Mackman Nigel , Manly David , Kamphuisen Pieter , Richel Dick , Büller Harry , Sturk Auguste , Nieuwland Rienk , Kleinjan Ankie
Published: April 2012

Cancer increases the risk of venous thromboembolism (VTE). Here, we investigated the contribution of microparticle (MP)-dependent procoagulant activity to the prothrombotic state in these patients. In 43 cancer patients without VTE at study entry and 22 healthy volunteers, markers of in vivo and MP-dependent coagulation were measured and patients were prospectively followed for six months for the development of VTE. Procoagulant activity of MPs was measured in vitro using a tissue factor (TF)-independent phospholipid dependent test, a factor Xa-generation assay with and without anti-TF, and a fibrin generation test (FGT) with and without anti-factor VII(a). Markers of in vivo coagulation activation and total number of MPs at baseline were significantly elevated in cancer patients compared to controls (F1+2 246 vs. 156 pM, thrombin-antithrombin complexes 4.1 vs. 3.0 mg/l, D-dimer 0.76 vs. 0.22 mg/l and 5.53 x 106 vs. 3.37 x 106 MPs/ml). Five patients (11.6%) developed VTE. Patients with VTE had comparable levels of coagulation activation markers and phospholipid-dependent MP pro-coagulant activity. However, median TF-mediated Xa-generation (0.82 vs. 0.21 pg/ml, p=0.016) and median VIIa-dependent FGT (13% vs. 0%, p=0.036) were higher in the VTE group compared with the non-VTE group. In this exploratory study the overall hypercoagulable state in cancer patients was not associated directly with the MP phospholipid-dependent procoagulant activity. However, in the patients who developed VTE within six months when compared to those who did not, an increased MP procoagulant activity was present already at baseline, suggesting this activity can be used to predict VTE.
Biological efficacy of a 600 mg loading dose of clopidogrel in ST-elevation myocardial infarction
Authors: Berbis Julie , Laine Marc , Armero Sébastien , Bessereau Jacques , Jacquin Laurent , Bonello Caroline , Camillieri Elise , Barragan Paul , Dignat-George Françoise , Paganelli Franck , Camoin-Jau Laurence , Bonello Laurent
Published: April 2012

Optimal platelet reactivity (PR) inhibition is critical to prevent thrombotic events in primary percutaneous coronary intervention (PCI). We aimed to determine the relationship between high on-treatment platelet reactivity (HTPR) and ST-elevation myocardial infarction (STEMI) following a 600 mg loading dose (LD) of clopidogrel. We performed a prospective monocentre study enrolling patients on clopidogrel undergoing PCI. The VASP index was used to assess PR inhibition after clopidogrel LD. HTPR was defined according to the consensus as a VASP index ≥50%. The present study included 833 patients undergoing PCI. Most patients had PCI for an acute coronary syndrome (58.7%). The mean VASP index was 50 ± 23% with a large inter-individual variability (range: 1–94%). Patients with a VASP index ≥50% were significantly older (p= 0.03), with a higher body mass index (BMI) (p<0.001), more often diabetic (p=0.03), taking omeprazole (p=0.03), admitted for an acute coronary syndrome (ACS) and with a high fibrinogen level compared to good responders (VASP <50%). In multivariate analysis BMI, omeprazole use, ACS and high fibrinogen level (p<0.001) remained significantly associated with HTPR. Of importance, in this analysis STEMI was independently associated with HTPR when compared with the other forms of ACS (NSTEMI and unstable angina) with an odd ratio of 2.14 (95% CI: 1.3 –3.5; p=0.003). In conclusion, STEMI is associated with high on-treatment platelet reactivity following 600 mg of clopidogrel. The present results suggest that 600 mg of clopidogrel may not be able to achieve an optimal PR inhibition in STEMI patients undergoing PCI and more potent drugs may be preferred.
Meta-Analysis of Bleeding Complications Associated With Cardiac Rhythm Device Implantation
Authors: Bernard Michael L. , Shotwell Matthew , Nietert Paul J. , Gold Michael R.
Published: April 2012

Background—

Many patients receiving cardiac rhythm devices have conditions requiring antiplatelet (AP) and/or anticoagulant (AC) therapy. Current guidelines recommend a heparin-bridging strategy (HBS) for anticoagulated patients with moderate/high risk for thrombosis. Several studies reported lower bleeding risk with continued oral anticoagulation rather than HBS. The best strategy for perioperative management of patients on AP therapy is less clear. The present study was designed as a meta-analysis of device implantation-associated bleeding complications using different AC/AP therapies.

Methods and Results—

PubMed and Cochrane Database searches identified articles based on design, outcomes, and available data. Device recipients were grouped as follows: no therapy, aspirin only, AC held, AC continued, dual AP, and HBS. The primary outcome was defined as a bleeding complication including hematoma, transfusion, or prolonged hospital stay. Thirteen articles were identified for analysis including 5978 patients. The combined incidence of bleeding complications was 274 of 5978 (4.6%), ranging from 2.2% (no therapy) to 14.6% (HBS). The estimated odds of bleeding were increased by 8.3 (95% CI, 5.5–12.9) times in the HBS group, 5.0 (95% CI, 3.0–8.3) for dual AP therapy, 1.7 (95% CI, 1.0–3.1) for AC held, 1.6 (95% CI, 0.9–2.6) for AC continued, and 1.5 (95% CI, 0.9–2.3) for aspirin only relative to the no therapy group. HBS significantly increased bleeding events compared with holding or continuing AC. Continuing AC did not increase bleeding events compared with no therapy.

Conclusions—

Continuing AC appears safer than HBS for device implantation. Dual AP therapy but not continuing AC carries a significant risk of bleeding.
A Novel Role for Type 1 Angiotensin Receptors on T Lymphocytes to Limit Target Organ Damage in Hypertension
Authors: Zhang Jian-dong , Patel Mehul B. , Song Young-Soo , Griffiths Robert , Burchette James , Ruiz Phillip , Sparks Matthew A. , Yan Ming , Howell David N. , Gomez Jose A. , Spurney Robert F. , Coffman Thomas M. , Crowley Steven D.
Published: April 2012

Rationale:

Human clinical trials using type 1 angiotensin (AT
1
) receptor antagonists indicate that angiotensin II is a critical mediator of cardiovascular and renal disease. However, recent studies have suggested that individual tissue pools of AT
1
receptors may have divergent effects on target organ damage in hypertension.

Objective:

We examined the role of AT
1
receptors on T lymphocytes in the pathogenesis of hypertension and its complications.

Methods and Results:

Deficiency of AT
1
receptors on T cells potentiated kidney injury during hypertension with exaggerated renal expression of chemokines and enhanced accumulation of T cells in the kidney. Kidneys and purified CD4
+
T cells from “T cell knockout” mice lacking AT
1
receptors on T lymphocytes had augmented expression of Th1-associated cytokines including interferon-γ and tumor necrosis factor-α. Within T lymphocytes, the transcription factors T-bet and GATA-3 promote differentiation toward the Th1 and Th2 lineages, respectively, and AT
1
receptor-deficient CD4
+
T cells had enhanced T-bet/GATA-3 expression ratios favoring induction of the Th1 response. Inversely, mice that were unable to mount a Th1 response due to T-bet deficiency were protected from kidney injury in our hypertension model.

Conclusions:

The current studies identify an unexpected role for AT
1
receptors on T lymphocytes to protect the kidney in the setting of hypertension by favorably modulating CD4
+
T helper cell differentiation.
Orai1 Determines Calcium Selectivity of an Endogenous TRPC Heterotetramer Channel
Authors: Cioffi Donna L. , Wu Songwei , Chen Hairu , Alexeyev Mikhail , St. Croix Claudette M. , Pitt Bruce R. , Uhlig Stefan , Stevens Troy
Published: April 2012

Rationale:

Canonical transient receptor potential 4 (TRPC4) contributes to the molecular composition of a channel encoding for a calcium selective store-operated current,
I
SOC
, whereas Orai1 critically comprises a channel encoding for the highly selective calcium release activated calcium current,
I
CRAC
. However, Orai1 may interact with TRPC proteins and influence their activation and permeation characteristics. Endothelium expresses both TRPC4 and Orai1, and it remains unclear as to whether Orai1 interacts with TRPC4 and contributes to calcium permeation through the TPRC4 channel.

Objective:

We tested the hypothesis that Orai1 interacts with TRPC4 and contributes to the channel's selective calcium permeation important for endothelial barrier function.

Methods and Results:

A novel method to purify the endogenous TRPC4 channel and probe for functional interactions was developed, using TRPC4 binding to protein 4.1 as bait. Isolated channel complexes were conjugated to anti-TRPC protein antibodies labeled with cy3-cy5 pairs. Förster Resonance Energy Transfer among labeled subunits revealed the endogenous protein alignment. One TRPC1 and at least 2 TRPC4 subunits constituted the endogenous channel (TRPC1/4). Orai1 interacted with TRPC4. Conditional Orai1 knockdown reduced the probability for TRPC1/4 channel activation and converted it from a calcium-selective to a nonselective channel, an effect that was rescued on Orai1 reexpression. Loss of Orai1 improved endothelial cell barrier function.

Conclusion:

Orai1 interacts with TRPC4 in the endogenous channel complex, where it controls TRPC1/4 activation and channel permeation characteristics, including calcium selectivity, important for control of endothelial cell barrier function.
Apolipoprotein E Genotype Predicts Hematoma Expansion in Lobar Intracerebral Hemorrhage
Authors: Brouwers H. Bart , Biffi Alessandro , Ayres Alison M. , Schwab Kristin , Cortellini Lynelle , Romero Javier M. , Rost Natalia S. , Viswanathan Anand , Greenberg Steven M. , Rosand Jonathan , Goldstein Joshua N.
Published: April 2012

Background and Purpose—

Hematoma volume is the most potent predictor of outcome in spontaneous intracerebral hemorrhage (ICH), and hematoma expansion after hospital presentation occurs in up to 40% of individuals. Among patients with lobar ICH, the apolipoprotein E (APOE) ϵ2 allele predicts larger hematoma volumes at presentation. We investigated whether the ϵ2 allele also identifies individuals at increased risk of hematoma expansion.

Methods—

We analyzed 510 patients with primary ICH and genetic data available from an ongoing prospective cohort study. Baseline and follow-up CT scans were assessed for ICH location and volume using computer-assisted volumetric methods.

Results—

Individuals with lobar ICH who possessed APOE ϵ2 were at increased risk for hematoma expansion (OR, 2.72; 95% CI, 1.19–6.23;
P
=0.009). The highest odds of expansion were in patients who qualified for the diagnosis of cerebral amyloid angiopathy-related ICH and carried the APOE ϵ2 allele (OR, 6.02; 95% CI, 1.60–22.58;
P
=0.008). There was no effect of ϵ2 on hematoma expansion in deep ICH and APOE ϵ4 had no effect on hematoma expansion in lobar or deep ICH.

Conclusions—

Possession of APOE ϵ2 predisposes individuals with lobar ICH to hematoma expansion. This effect is even more pronounced in patients with amyloid angiopathy-related ICH, consistent with the ϵ2 allele's role in vascular amyloid deposition and vessel fragility.
Adverse Effect of Early Epileptic Seizures in Patients Receiving Endovascular Therapy for Acute Stroke
Authors: Jung Simon , Schindler Kaspar , Findling Oliver , Mono Marie-Luise , Fischer Urs , Gralla Jan , El-Koussy Marwan , Weck Anja , Galimanis Aekaterini , Brekenfeld Caspar , Schroth Gerhard , Mattle Heinrich P. , Arnold Marcel
Published: April 2012

Background and Purpose—

The aim of this study was to analyze epileptic seizures and their impact on outcome in patients with stroke treated with endovascular therapy.

Methods—

From December 1992 to December 2010 we managed 805 patients with stroke with endovascular therapy. Epileptic seizures, bleeding complications, and 3-month outcomes were recorded prospectively. Outcomes of patients with early seizures (within 24 hours of stroke onset) and patients with late seizures (>24 hours after stroke) were compared with outcomes of seizure-free patients using uni- and multivariable statistics.

Results—

Forty-four of 805 patients (5.5%) had seizures between stroke onset and 3-month follow-up, 26 patients early and 18 late. Outcome of patients with late seizures and seizure-free patients was similar (
P
=0.144 and 0.807). Patients with early seizures had higher baseline National Institutes of Health Stroke Scale (
P
=0.023) and were younger (
P
=0.021) than seizure-free patients. Their mortality rate was 50% compared with 22.3% of the seizure free-patients (
P
=0.003), and less patients reached a favorable outcome (modified Rankin Scale 0–2): 15.4% and 46.8%, respectively (
P
=0.001). Early seizures independently predicted an unfavorable outcome (
P
=0.014; OR, 4.749; 95% CI, 0.376–3.914) and increased mortality (
P
=0.001; OR, 5.861; 95% CI, 0.770–2.947) in multiregression analysis. Patients with early seizures had a 1.6-fold higher risk for unfavorable outcome and a 2.2-fold higher risk for death compared with seizure-free patients.

Conclusions—

Seizures within 24 hours of stroke onset were associated with worse outcome in patients with stroke undergoing endovascular therapy. Our findings confirm a need for trials for prophylactic anticonvulsive treatment in patients receiving endovascular therapy for acute stroke.
Challenges in Assessing Hospital-Level Stroke Mortality as a Quality Measure
Authors: Xian Ying , Holloway Robert G. , Pan Wenqin , Peterson Eric D.
Published: April 2012

Background and Purpose—

Public reporting efforts currently profile hospitals based on overall stroke mortality rates, yet the “mix” of hemorrhagic and ischemic stroke cases may impact this rate.

Methods—

Using the 2005 to 2006 New York state data, we examined the degree to which hospital stroke mortality rankings varied regarding ischemic versus hemorrhagic versus total stroke. Observed/expected ratio was calculated using the Agency for Healthcare Research and Quality Inpatient Quality Indicator software. The observed/expected ratio and outlier status based on stroke types across hospitals were examined using Pearson correlation coefficients (
r
) and weighted κ.

Results—

Overall 30-day stroke mortality rates were 15.2% and varied from 11.3% for ischemic stroke and 37.3% for intracerebral hemorrhage. Hospital risk-adjusted ischemic stroke observed/expected ratio was weakly correlated with its own intracerebral hemorrhage observed/expected ratio (
r
=0.38). When examining hospital performance group (mortality better, worse, or no different than average), disagreement was observed in 35 of 81 hospitals (κ=0.23). Total stroke mortality observed/expected ratio and rankings were correlated with intracerebral hemorrhage (
r
=0.61 and κ=0.36) and ischemic stroke (
r
=0.94 and κ=0.71), but many hospitals still switched classification depending on mortality metrics. However, hospitals treating a higher percent of hemorrhagic stroke did not have a statistically significant higher total stroke mortality rate relative to those treating fewer hemorrhagic strokes.

Conclusions—

Hospital stroke mortality ratings varied considerably depending on whether ischemic, hemorrhagic, or total stroke mortality rates were used. Public reporting of stroke mortality measures should consider providing risk-adjusted outcome on separate stroke types.