bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings
Authors: Peterson Kevin , Jallow Sabelle , Rowland-Jones Sarah L. , de Silva Thushan I.
Published: February 2011

HIV-2 contributes approximately a third to the prevalence of HIV in West Africa and is present in significant amounts in several low-income countries outside of West Africa with historical ties to Portugal. It complicates HIV diagnosis, requiring more expensive and technically demanding testing algorithms. Natural polymorphisms and patterns in the development of resistance to antiretrovirals are reviewed, along with their implications for antiretroviral therapy. Nonnucleoside reverse transcriptase inhibitors, crucial in standard first-line regimens for HIV-1 in many low-income settings, have no effect on HIV-2. Nucleoside analogues alone are not sufficiently potent enough to achieve durable virologic control. Some protease inhibitors, in particular those without ritonavir boosting, are not sufficiently effective against HIV-2. Following review of the available evidence and taking the structure and challenges of antiretroviral care in West Africa into consideration, the authors make recommendations and highlight the needs of special populations.
Existence of Nontrivial Solutions and Sign‐Changing Solutions for Nonlinear Dynamic Equations on Time Scales
Authors: Xu Huiye
Published: February 2011

By using the topological degree theory and the fixed point index theory,
the existence of nontrivial solutions and sign‐changing solutions for a class of boundary value
problem on time scales is obtained. We should point out that the integral operator corresponding
to above boundary value problem is not assumed to be a cone mapping.
Present and Future: Pharmacologic Treatment of Obesity
Authors: Glandt Mariela , Raz Itamar
Published: February 2011

Obesity now presents one of the biggest health problems of our times. Diet and exercise are best for both prevention and treatment; unfortunately, both require much discipline and are difficult to maintain. Medications offer a possible adjunct, but their effect is modest, they are limited by side effects, and the weight loss lasts only as long as the drug is being taken, since as soon as treatment is stopped, the weight is regained. Sibutramine, a sympathomimetic medication which was available for long-term treatment, is the most recent of the drugs to be withdrawn from the market due to side effects; in this case it was an increased risk of cardiovascular events. This paper reviews those medications which are available for treatment of obesity, including many of those recently taken off the market. It also discusses some of the newer treatments that are currently being investigated.
Phase I Clinical Study of Seneca Valley Virus (SVV-001),a Replication-Competent Picornavirus, in Advanced Solid Tumors with Neuroendocrine Features
Authors: Rudin Charles M. , Poirier John T. , Senzer Neil N. , Stephenson Joseph , Loesch David , Burroughs Kevin D. , Reddy P. Seshidhar , Hann Christine L. , Hallenbeck Paul L.
Published: February 2011

Purpose: Seneca Valley Virus (SVV-001) is a novel naturally occurring replication-competent picornavirus with potent and selective tropism for neuroendocrine cancer cell types, including small cell lung cancer. We conducted a first-in-human, first-in-class phase I clinical trial of this agent in patients with cancers with neuroendocrine features, including small cell lung cancer.

Experimental Design: Clinical evaluation of single intravenous doses in patients with cancers with neuroendocrine features was performed across five log-increments from 107 to 1011 vp/kg. Toxicity, viral titers and clearance, neutralizing antibody development, and tumor response were assessed.

Results: A total of 30 patients were treated with SVV-001, including six with small cell carcinoma at the lowest dose of 107 vp/kg. SVV-001 was well tolerated, with no dose-limiting toxicities observed in any dose cohort. Viral clearance was documented in all subjects and correlated temporally with development of antiviral antibodies. Evidence of in vivo intratumoral viral replication was observed among patients with small cell carcinoma, with peak viral titers estimated to be >103-fold higher than the administered dose. One patient with previously progressive chemorefractory small cell lung cancer remained progression-free for 10 months after SVV-001 administration, and is alive over 3 years after treatment.

Conclusions: Intravenous SVV-001 administration in patients is well tolerated at doses up to 1011 vp/kg, with predictable viral clearance kinetics, intratumoral viral replication, and evidence of antitumor activity in patients with small cell lung cancer. Phase II clinical evaluation in small cell lung cancer is warranted, and has been initiated. Clin Cancer Res; 17(4); 888–95. ©2011 AACR.
Functional Roles ofSrcandFgrin Ovarian Carcinoma
Authors: Kim Hye-Sun , Han Hee Dong , Armaiz-Pena Guillermo N. , Stone Rebecca L. , Nam Eun Ji , Lee Jeong-Won , Shahzad Mian M. K. , Nick Alpa M. , Lee Sun Joo , Roh Ju-Won , Nishimura Masato , Mangala Lingegowda S. , Bottsford-Miller Justin , Gallick Gary E. , Lopez-Berestein Gabriel , Sood Anil K.
Published: February 2011

Purpose: Src is an attractive target because it is overexpressed in a number of malignancies, including ovarian cancer. However, the effect of Src silencing on other Src family kinases (SFKs) is not known. We hypothesized that other SFK members could compensate for the lack of Src activity.

Experimental Design: Cell viability after either Src or Fgr silencing was examined in ovarian cancer cell lines by MTT assay. Expression of SFKs after Src silencing in ovarian cancer cells was examined by real-time reverse transcriptase (RT)-PCR. Therapeutic effect of in vivo Src and/or Fgr silencing was examined using siRNA incorporated into chitosan nanoparticles (siRNA/CH-NP). Microvessel density, cell proliferation, and apoptosis markers were determined by immunohistochemical staining in ovarian tumor tissues.

Results: Src silencing enhanced cytotoxicity of docetaxel in both SKOV3ip1 and HeyA8 cells. In addition, Src silencing using siRNA/CH-NP in combination with docetaxel resulted in significant inhibition of tumor growth compared with control siRNA/CH-NP (81.8% reduction in SKOV3ip1, P = 0.017; 84.3% reduction in HeyA8, P < 0.005). These effects were mediated by decreased tumor cell proliferation and angiogenesis, and increased tumor cell apoptosis. Next, we assessed the effects of Src silencing on other SFK members in ovarian cancer cell lines. Src silencing resulted in significantly increased Fgr levels. Dual Src and Fgr silencing in vitro resulted in increased apoptosis that was mediated by increased caspase and AKT activity. In addition, dual silencing of Src and Fgr in vivo using siRNA/CH-NP resulted in the greatest reduction in tumor growth compared with silencing of either Src or Fgr alone in the HeyA8 model (68.8%, P < 0.05).

Conclusions: This study demonstrates that, in addition to Src, Fgr plays a biologically significant role in ovarian cancer growth and might represent an important target. Clin Cancer Res; 17(7); 1713–21. ©2011 AACR.
MHC Class I–Presented Tumor Antigens Identified in Ovarian Cancer by Immunoproteomic Analysis Are Targets for T-Cell Responses against Breast and Ovarian Cancer
Authors: Morse Michael A. , Secord Angeles A. , Blackwell Kimberly , Hobeika Amy C. , Sinnathamby Gomathinayagam , Osada Takuya , Hafner Julie , Philip Mohan , Clay Timothy M. , Lyerly H. Kim , Philip Ramila
Published: February 2011

Purpose: The purpose of this study is to test whether peptide epitopes chosen from among those naturally processed and overpresented within MHC molecules by malignant, but not normal cells, when formulated into cancer vaccines, could activate antitumor T-cell responses in humans.

Experimental Design: Mixtures of human leukocyte antigen A2 (HLA-A2)-binding ovarian cancer-associated peptides were used to activate naive T cells to generate antigen-specific T cells that could recognize ovarian and breast cancers in vitro. Combinations of these peptides (0.3 mg of each peptide or 1 mg of each peptide) were formulated into vaccines in conjunction with Montanide ISA-51 and granulocyte monocyte colony stimulating factor which were used to vaccinate patients with ovarian and breast cancer without evidence of clinical disease in parallel pilot clinical trials.

Results: T cells specific for individual peptides could be generated in vitro by using mixtures of peptides, and these T cells recognized ovarian and breast cancers but not nonmalignant cells. Patient vaccinations were well tolerated with the exception of local erythema and induration at the injection site. Nine of the 14 vaccinated patients responded immunologically to their vaccine by inducing peptide-specific T-cell responses that were capable of recognizing HLA-matched breast and ovarian cancer cells.

Conclusion: Mixtures of specific peptides identified as naturally presented on cancer cells and capable of activating tumor-specific T cells in vitro also initiate or augment immune responses toward solid tumors in cancer patients. Clin Cancer Res; 17(10); 3408–19. ©2011 AACR.
Population-Based Screening of Children for Specific Speech and Language Impairment in Germany: A Systematic Review
Authors: Kasper Jürgen , Kreis Julia , Scheibler Fülöp , Möller Delia , Skipka Guido , Lange Stefan , von dem Knesebeck Olaf
Published: February 2011

Objective: The study was aimed at evaluating the effectiveness of a systematic population-based screening programme for specific language impairment (SLI) in preschool children in Germany. Methods: The study question was divided into a review of (1) evidence from studies evaluating screening programmes, (2) diagnostic instruments in the German language, and (3) studies evaluating speech and language interventions. A systematic database search was conducted between June and October 2007 and was updated in January and again in May 2008. Relevant studies were identified by 2 independent reviewers based on screened titles/abstracts and full texts. Results: 4,806 studies were screened. The only existing controlled screening study did not provide data for SLI. No diagnostic study met the inclusion criteria. Sixteen randomized intervention studies were included, 3 studies contributed to the appraisal of earlier against later initiation of treatment. Most studies were of limited quality. We found indications of short-term positive effects from language therapies in children with SLI. Long-term outcomes were not investigated. No evidence supporting the advantage of earlier treatment initiation was identified. Conclusions: The benefit of population-based language screening of preschool children with SLI is not proven. Controlled screening studies are therefore necessary. For Germany, the accuracy of existing diagnostic instruments has not yet been sufficiently examined.
P-Glycoprotein Influence on the Brain Uptake of a 5-HT2A Ligand: [18F]MH.MZ
Authors: Schmitt Ulrich , Lee Dianne E. , Herth Matthias M. , Piel Markus , Buchholz Hans-Georg , Roesch Frank , Hiemke Christoph , Lueddens Hartmut , Debus Fabian
Published: February 2011

Background/Aims: The serotonergic system, especially the 5-HT2A receptor, is involved in various diseases and conditions. We have recently developed a new [18F]-5-HT2A receptor ligand using an analogue, MDL 100907, as a basis for molecular imaging with positron emission tomography. This tracer, [18F]MH.MZ, has been shown to be an adequate tool to visualize the 5-HT2A receptors in vivo. However, [18F]altanserin, similar in chemical structure, is a substrate of efflux transporters, such as P-glycoprotein (P-gp), of the blood-brain barrier, thus limiting its availability in the central nervous system. The aim of this study was to determine whether transport by P-gp influences the distribution ratio of [18F]MH.MZ in the frontal cortex. Methods: The approach was based on P-gp knockout mice which were compared with wild-type mice under several conditions. In vivo pharmacokinetic and microPET investigations were carried out. Results: All analyses showed that [18F]MH.MZ entered the brain and was sensitive to P-gp transport. In P-gp knockout mice, brain concentrations of MH.MZ were about 5-fold higher than in wild-type animals which is reflected by a 2-fold increase in standardized uptake values of [18F]MH.MZ in the frontal cortex of P-gp knockout mice. Conclusion: Our results give evidence for a functional role of transport mechanisms at the blood-brain barrier, specifically of P-gp, and its subregional distribution. Investigation of these mechanisms will benefit the development of more efficient radioligands and drugs for molecular imaging and pharmacotherapy of the mentally ill.
Hypoxemia during Moderate Sedation for Gastrointestinal Endoscopy: Causes and Associations
Authors: Qadeer Mohammed A. , Lopez A. Rocio , Dumot John A. , Vargo John J.
Published: February 2011

Background/Aims: Although prolonged hypoxemia (henceforth referred to as hypoxemia) is not uncommon during moderate sedation for endoscopy, there are only sparse data regarding its relationship with medications, endoscopic intubations and ventilation patterns. We aimed to study these relationships. Methods: 123 patients enrolled in the control arm of a randomized trial of ventilation monitoring during endoscopy were analyzed. Hypoxemia was defined as oxygen saturation of <90% for ≧15 s, and apnea as lack of respiratory activity for ≧15 s. Results: There were 132 hypoxemic events; 46 (35%) and 112 (85%) events occurred within 1 and 5 min of medication administration/endoscopic intubations, and conversely, 46/638 (7%) and 112/638 (18%) of all medication administration/endoscopic intubations led to hypoxemia in 1 and 5 min, respectively. Apnea, abnormal ventilation and normal ventilation were associated with 36, 30 and 34% of all hypoxemia events, respectively. However, only 101/268 (38%) apnea/abnormal ventilation events led to hypoxemia. Significant predictors of apnea were total dose of meperidine/fentanyl 1.3 (1.02–1.6) and total dose of midazolam 0.84 (0.71–0.99). Conclusions: Hypoxemia occurs typically within 5 min of medication administration or endoscope intubation and only one third of all apnea/abnormal ventilation events eventually lead to hypoxemia.
Comparison of Immunosorbent Assays for the Quantification of Biomarkers for Alzheimer’s Disease in Human Cerebrospinal Fluid
Authors: Schipke C.G. , Prokop S. , Heppner F.L. , Heuser I. , Peters O.
Published: February 2011

Background: The clinical diagnosis of Alzheimer’s disease in early stages may be substantiated by the quantification of the biomarkers Abeta42, Abeta40 and total-Tau (t-Tau) in cerebrospinal fluid (CSF). Different commercially available immunosorbent assays yield reliable results, yet the absolute values obtained may differ in between tests. Methods: We used CSF samples from patients that reported to our memory clinic. Enzyme-linked immunosorbent assays obtained from Innogenetics were used for the quantification of Abeta42 and t-Tau, test kits from IBL International were used to determine Abeta42 and Abeta40 concentrations. The multiplex assay system obtained from Mesoscale Discovery (MSD) Systems was used for the quantification of all three biomarkers. Results: For all biomarkers, the absolute values obtained with different test systems differ. However, the data sets highly correlate for all comparisons, with the MSD test system proving to be slightly more sensitive. Correlation coefficients (c) for the Abeta42 and Abeta40 quantifications lie between c = 0.80 and c = 0.87, and for the t-Tau quantifications we determined c = 0.99. Conclusion: We conclude that all assays evaluated give reliable results, yet absolute values obtained have to be assessed differently within the framework of diagnostic procedures, depending on the system used.
Insulin Resistance: Pathophysiology and Rationale for Treatment
Authors: Muntoni Sergio , Muntoni Sandro
Published: February 2011

After binding to its receptor and activating the β-subunit, insulin is faced with two divergent pathways: one is phosphatidylinositol 3-kinase (PI 3-K) dependent, while another is dependent upon activation of mitogen-activated protein kinase (MAP-K). The former is absolutely necessary for mediating most metabolic and antiapoptotic effects; the latter is linked to nonmetabolic, proliferative and mitogenic effects. In obese patients, especially with type 2 diabetes mellitus (DM2), only the PI 3-K, but not the MAP-K, is resistant to insulin stimulation: hence insulin resistance is better defined as metabolic insulin resistance. The resulting ‘compensatory hyperinsulinemia’ is an unsuccessful attempt to overcome the inhibition of the metabolic pathway at the price of unopposed stimulation of the MAP-K pathway, and the administration of exogenous insulin might worsen the metabolic dysfunction. As the preferential activation of the MAP-K pathway in insulin-resistant patients has atherogenic and mitogenic properties, this leads to atherosclerosis and cancer. Metformin may carry out direct protective action on human β cells, inasmuch as it improves both primary and secondary endpoints through selective inhibition of fatty acyl oxidation.
Woodhouse-Sakati Syndrome in an Israeli-Arab Family Presenting with Youth-Onset Diabetes Mellitus and Delayed Puberty
Authors: Rachmiel Marianna , Bistritzer Tzvy , Hershkoviz Eli , Khahil Auni , Epstein Orna , Parvari Ruth
Published: February 2011

Background and Objective: Woodhouse-Sakati syndrome (WSS) is a rare autosomal-recessive disorder characterized by a combination of hypogonadism, alopecia, diabetes mellitus (DM), mental retardation and extrapyramidal signs, not described previously in Israel. Our aim was to study the clinical and genetic characteristics of the extended family of a 16-year-old female who presented with new-onset DM and had delayed puberty on physical examination. Methods: The primary physician’s medical charts of 9 members of the proband’s consanguineous Israeli-Arab family were reviewed. Hormonal, metabolic and antibody profile, imaging studies and molecular analysis were performed in 4 phenotypically compatible members, including the proband. Results: Four subjects, 2 females and 2 males, had DM, absent pubertal development and similar appearance. None had extrapyramidal signs. The patients were homozygous for a one-base deletion mutation (c.436delC) in the C2orf37 gene. Conclusion: We describe the first Israeli-Arab family with phenotype and genotype of WSS, imitating autoimmune DM with gonadal failure.
Acute Renal Failure Caused by Imiquimod 5% Cream in a Renal Transplant Patient: Review of the Literature on Side Effects of Imiquimod
Authors: Santos-Juanes J. , Esteve A. , Mas-Vidal A. , Coto-Segura P. , Salgueiro E. , Gómez E. , Galache Osuna C.
Published: February 2011

Imiquimod is an immunomodulator of the imidazoquinoline group which possesses antiviral and antitumour activities. Although its mechanism of action has not been entirely elucidated yet, imiquimod 5% cream has been shown to be an efficient, long-lasting and safe therapy for multiple actinic keratoses in non-immunosuppressed patients and in transplant recipients. We report the case of a 44-year-old patient with a third renal transplant who developed an acute tubular necrosis confirmed by renal biopsy after the use of imiquimod 5% cream. The result of a literature search revealed a wide variety of side effects attributable to the use of imiquimod.
Caloric Restriction and Antiaging Effects
Authors: Xiang Lan , He Guoqing
Published: February 2011

Caloric restriction (CR) is widely used to study aging processes. It is a simple and highly reproducible method for delaying the aging process, preventing the onset of aging-related diseases and extending average or maximum lifespan. However, the mechanism underlying these effects of CR is still not clear. CR can inhibit growth, reduce body size and maintain a low body temperature. At the same time, there is a measurable decrease in the volume of adipose tissue, hyperglycemia and hyperinsulinemia, accompanied by modifications of lipid and energy metabolism and increased resistance to endogenous and extraneous stress. The metabolic changes induced by dietary restriction, the inhibition of fat deposition in nonadipose tissue and the effects on signal transduction are considered the most likely candidates for mechanisms underlying the effects of CR.
High Prevalence of Vitamin D Deficiency in Zahedan, Southeast Iran
Authors: Kaykhaei Mahmoud Ali , Hashemi Mohammad , Narouie Behzad , Shikhzadeh Abdolsamad , Rashidi Homeira , Moulaei Nezarali , Ghavami Saeid
Published: February 2011

Background: Several studies show a high prevalence of vitamin D deficiency in Asia. Data regarding the prevalence of vitamin D deficiency in southeast Iran are inadequate. Objectives: The purpose of this study was to determine the prevalence of vitamin D deficiency in Zahedan, a sunny area in southeast Iran. Subjects and Methods: This population-based cross-sectional study was performed on 993 apparently healthy subjects. Serum levels of 25-hydroxy vitamin D (25-OH vit D), parathyroid hormone, calcium, phosphate, and alkaline phosphatase activity were measured. Results: Inadequate vitamin D status was diagnosed in 94.7% of the subjects (25-OH vit D <30 ng/ml). The frequencies of deficiency (<20 ng/ml), insufficiency (20–30 ng/ml), sufficiency (30–150 ng/ml), and toxicity (>150 ng/ml) were 85.2, 9.5, 5.3, and 0.0%, respectively. Conclusion: The results indicate that vitamin D deficiency is common in the population of Zahedan. Based on our results, fortification of milk and the use of supplements is suggested in this region.
Aspirin Dose and Ticagrelor Benefit in PLATO: Fact or Fiction?
Authors: Serebruany Victor L.
Published: February 2011

Objectives: To summarize the available evidence regarding whether or not a higher aspirin maintenance dose inversely affects the ticagrelor benefit observed in the US cohort of the PLATO trial. Background: In the recent PLATO trial, the daily aspirin dosages in the USA were split between 81 and 325 mg while the vast majority of dosing outside of the USA was 75 or 100 mg. The FDA conducted exhaustive analyses of the aspirin dosage in a framework of primary clinical efficacy. Considering the post hoc, not prespecified nature of such analyses as well as multiple confounding problems with biologic plausibility, sensitivity to reclassification of small numbers of cases regarding loading versus maintenance aspirin dosing, and the distribution of events in high-dose aspirin observed outside of the USA, the FDA documents clearly suggest that aspirin dosing does not explain the disparate outcome results. In addition, the Advisory Committee members found no evidence to establish a reasonable link, and they uniformly rejected the hypothesis that aspirin dose affects the heterogeneity of outcomes in PLATO. Methods: Additional evidence driven from the FDA review on aspirin dose and PLATO outcomes is reassessed. Results: The wide distribution of outcomes differing from country to country, and inconsistency in European data despite identical aspirin doses, preclude the acceptance of the hypothesis that aspirin affects PLATO outcomes in general or adversely impacts the benefit of ticagrelor in the US cohort in particular. Differences in primary site monitoring by the study sponsor in most countries versus a third-party CRO in the USA represent an alternative explanation and deserve further attention. Conclusions: There is no solid evidence that aspirin dose affects outcomes after ticagrelor. Reevaluation of the overall endpoint differences, especially focusing on mortality, driven from sponsor-monitored sites versus outcomes observed by independent CROs is neccessary. The practice of self-monitoring in pivotal indication-seeking clinical trials should be avoided in the future.
Pituitary Stalk Dysgenesis-Induced Hypopituitarism in Adult Patients: Prevalence, Evolution of Hormone Dysfunction and Genetic Analysis
Authors: Fernandez-Rodriguez Eva , Quinteiro Celsa , Barreiro Jesus , Marazuela Mónica , Pereiro Inmaculada , Peinó Roberto , Cabezas-Agrícola Jose Manuel , Dominguez Fernando , Casanueva Felipe F. , Bernabeu Ignacio
Published: February 2011

Objectives: To investigate the prevalence of pituitary stalk dysgenesis (PSD) in adult hypopituitary patients by describing the chronology of hormone deficiencies and their potential correlation with traumatic delivery, mutations in genes required for pituitary development and function and pituitary stalk visibility on MRI. Design: Retrospective and prospective study involving 231 hypopituitary patients, including 26 diagnosed with PSD. Clinical, biochemical and radiological studies were reviewed. Molecular analyses of HESX1, LHX4,PROP1 and POU1F1 genes were performed prospectively. Results: PSD was present in 11.2% of hypopituitary patients. PSD was diagnosed before 14 years of age in 46.2% of cases, between 14 and 18 years of age in 23%, and in adulthood in 30.8%. Perinatal complications or gene mutations were present in 26.9 and 4.3% of patients, respectively. At first assessment, 92.3% of patients had growth hormone (GH) deficiency. 26.9% presented as combined pituitary deficiencies and 7.6% as panhypopituitarism. Hormone deficiencies were progressive during follow-up in 84.6%. 96% progressed to multiple deficiencies and 46% to panhypopituitarism. No significant association was found between hormonal dysfunction and previous perinatal damage or breech delivery (p = 0.17), PROP1 mutations (p = 0.26) or pituitary stalk visibility on MRI (p = 0.52). No mutations in POU1F1, HESX1 and LHX-4 genes were detected. Conclusion: In this study, PSD prevalence in adult hypopituitary patients was 11.2%. Typical clinical presentation includes isolated or combined pituitary hormone deficiencies during the pediatric age, which usually progress to combined or complete hypopituitarism in adulthood. Phenotype is highly variable depending on hormone profile and age at onset.
Impaired platelet function and peripartum bleeding in women with Gaucher disease
Authors: Simchen Michal , Oz Rotem , Shenkman Boris , Zimran Ari , Elstein Deborah , Kenet Gili
Published: February 2011

The risk of bleeding during delivery may be increased in women with Gaucher disease. We aimed to evaluate potential predictors for peripartum haemorrhage (PPH) during childbirth in these patients, while focusing upon coagulation tests and platelet function assays. Women with type 1 Gaucher disease who gave birth at Sheba Medical Center between 1999–2009 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, delivery and pregnancy outcome. PPH was defined as excessive bleeding during or immediately following delivery. Coagulation studies and platelet function tests, including aggregometry and cone and platelet (CPA) analyses, were performed on all women. We compared women with PPH (bleeders) and non-bleeders. Furthermore, women with abnormal CPA platelet function tests were compared with those with normal CPA platelet function with regards to the risk for PPH in at least one pregnancy. Forty-five pregnancies of 20 women were studied. Six women received enzyme replacement therapy during pregnancy. Mean platelet count prior to delivery was 83,000/μl ± 35,000/μl. Fourteen out of 45 (31%) deliveries were complicated by PPH. Neither thrombocytopenia nor enzyme therapy predicted PPH. Twelve out of 13 women with PPH (92.3%) versus 2/7 non-bleeders (28.6%) had impaired platelet aggregation (less than the 3rd percentile of normal average aggregate size values), when tested by CPA, (odds ratio [OR] 17.8, 95% confidence interval [CI] 2.5; 126.2; p=0.007). Notably, 78.6% of women with impaired CPA aggregation developed PPH during at least one delivery, as opposed to 16.7% of those with normal CPA platelet function tests (OR 11.6, 95% CI 1.7–77.7, p=0.018). In conclusion, women with type 1 Gaucher disease who have abnormal platelet function tests may have an increased risk of PPH.
Long-term secondary prophylaxis in children, adolescents and young adults with von Willebrand disease
Authors: Halimeh Susan , Krümpel Anne , Rott Hannelore , Bogdanova Nadja , Budde Ulrich , Manner Daniela , Faeser Britta , Mesters Rolf , Nowak-Göttl Ulrike
Published: February 2011

In patients with von Willebrand disease (VWD) replacement therapy with factor VIII/von Willebrand (VWF) concentrates is increasingly applied as prophylactic regimen. Since 2000, 82 consecutively enrolled patients with clinically relevant bleeding episodes (spontaneous, peri- or postoperative) were diagnosed with VWD [type 1: 42/82; type 2: 24/82; type 3: 13/82; acquired: 3/82]. In all patients, decision for initiating prophylaxis was based on a bleeding score > 2 prior to diagnosis, concomitant with recurrent bleeds associated with anaemia in patients with on-demand VWD therapy. We report results on secondary prophylactic VWF replacement therapy applied in 32 patients [children n=13; adolescents n=7; adults n=12] with VWD [type 1: 4; type 2: 15; type 3: 13], 15 of which were females, and nine of these at the reproductive period. Eight patients were treated with Humate P→ or Wilate→ (n=24). Median [min-max] dose [vWF:RCo] was 40 [20–47] IU/kg, 23 patients were given substitution therapy twice weekly, seven patients three times a week, and two children four times per week. Within a 12-month-period haemoglobin concentrations returned to normal values. Median duration of prophylaxis was three years. Recurrent bleeding episodes stopped in 31 of 32 patients, whereas inhibitors developed in one. Following a 12-month observation period the monthly bleeding frequency and the bleeding score was significantly reduced [3 vs. 0.07; 3 vs. 0: p< 0.001], compared to the preprophylaxis/pre-diagnostic values. The use of secondary prophylactic VWF replacement therapy is an effective tolerated treatment modality, highly beneficial for patients with VWD, who present with recurrent bleeding events during on-demand therapy.
The value of 64-detector row computed tomography for the exclusion of pulmonary embolism
Authors: Conti Giorgio de , Minotto Isabella , Filippi Lucia , Mongiat Marta , Faveri Daniele de , Maurizi Francesca , Valle Fabio Dalla , Piovella Chiara , Pagnan Antonio , Prandoni Paolo , Pesavento Raffaele ,   for the TACEP study
Published: February 2011

Recently, a diagnostic strategy using a clinical decision rule, D-dimer testing and spiral computed tomography (CT) was found to be effective in the evaluation of patients with clinically suspected pulmonary embolism (PE). However, the rate of venous thromboembolic complications in the three-month follow-up of patients with negative CT was still substantial and included fatal events. It was the objective to evaluate the safety of withholding anticoagulants after a normal 64-detector row CT (64-DCT) scan from a cohort of patients with suspected PE. A total of 545 consecutive patients with clinically suspected first episode of PE and either likely pre-test probability of PE (using the simplified Wells score) or unlikely pre-test probability in combination with a positive D-dimer underwent a 64-DCT. 64-DCT scanning was inconclusive in nine patients (1.6%), confirmed the presence of PE in 169 (31%), and ruled out the diagnosis in the remaining 367. During the three-month follow-up of the 367 patients one developed symptomatic distal deep-vein thrombosis (0.27%; 95%CI, 0.0 to 1.51%) and none developed PE (0 %; 95%CI, 0 to 1.0%). We conclude that 64-DCT scanning has the potential to safely exclude the presence of PE virtually in all patients presenting with clinical suspicion of this clinical disorder.
Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome
Authors: Wang Tracy Y. , White Jennifer A. , Tricoci Pierluigi , Giugliano Robert P. , Zeymer Uwe , Harrington Robert A. , Montalescot Gilles , James Stefan K. , Van de Werf Frans , Armstrong Paul W. , Braunwald Eugene , Califf Robert M. , Newby L. Kristin
Published: February 2011

Background—

In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non–ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use.

Methods and Results—

In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction
P
=0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (
P
=0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata.

Conclusions—

Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit–risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.

Clinical Trial Registration—

http://www.clinicaltrials.gov
. Unique identifier NCT00089895.
Remote Ischemic Preconditioning Protects the Brain Against Injury After Hypothermic Circulatory Arrest
Authors: Jensen Hanna A. , Loukogeorgakis Stavros , Yannopoulos Fredrik , Rimpiläinen Eija , Petzold Axel , Tuominen Hannu , Lepola Pasi , MacAllister Raymond J. , Deanfield John E. , Mäkelä Tuomas , Alestalo Kirsi , Kiviluoma Kai , Anttila Vesa , Tsang Victor , Juvonen Tatu
Published: February 2011

Background—

Ischemic preconditioning (IPC) is a mechanism protecting tissues from injury during ischemia and reperfusion. Remote IPC (RIPC) can be elicited by applying brief periods of ischemia to tissues with ischemic tolerance, thus protecting vital organs more susceptible to ischemic damage. Using a porcine model, we determined whether RIPC of the limb is protective against brain injury caused by hypothermic circulatory arrest (HCA).

Methods and Results—

Twelve piglets were randomized to control and RIPC groups. RIPC was induced in advance of cardiopulmonary bypass by 4 cycles of 5 minutes of ischemia of the hind limb. All animals underwent cardiopulmonary bypass followed by 60 minutes of HCA at 18°C. Brain metabolism and electroencephalographic activity were monitored for 8 hours after HCA. Assessment of neurological status was performed for a week postoperatively. Finally, brain tissue was harvested for histopathological analysis.

Study groups were balanced for baseline and intraoperative parameters. Brain lactate concentration was significantly lower (
P
<0.0001, ANOVA) and recovery of electroencephalographic activity faster (
P
<0.05, ANOVA) in the RIPC group. RIPC had a beneficial effect on neurological function during the 7-day follow-up (behavioral score;
P
<0.0001 versus control, ANOVA). Histopathological analysis demonstrated a significant reduction in cerebral injury in RIPC animals (injury score; mean [interquartile range]: control 5.8 [3.8 to 7.5] versus RIPC 1.5 [0.5 to 2.5],
P
<0.001,
t
test).

Conclusions—

These data demonstrate that RIPC protects the brain against HCA-induced injury, resulting in accelerated recovery of neurological function. RIPC might be neuroprotective in patients undergoing surgery with HCA and improve long-term outcomes. Clinical trials to test this hypothesis are warranted.
Health Behaviors and Racial Disparity in Blood Pressure Control in the National Health and Nutrition Examination Survey
Authors: Redmond Nicole , Baer Heather J. , Hicks LeRoi S.
Published: February 2011

Minorities have a higher prevalence of hypertension, a major risk factor for cardiovascular disease, which contributes to racial/ethnic disparities in morbidity and mortality in the United States. Many modifiable health behaviors have been associated with improved blood pressure control, but it is unclear how racial/ethnic differences in these behaviors are related to the observed disparities in blood pressure control. Cross-sectional analyses were conducted among 21 489 US adults aged >20 years participating in the National Health and Nutrition Examination Survey from 2001 to 2006. Secondary analyses were conducted among those with a self-reported diagnosis of hypertension. Blood pressure control was defined as systolic values <140 mm Hg and diastolic values <90 mm Hg (or <130 mm Hg and <80 mm Hg among diabetics, respectively). In primary analyses, non-Hispanic blacks had 90% higher odds of poorly controlled blood pressure compared with non-Hispanic whites after adjustment for sociodemographic and clinical characteristics (
P
<0.001). In secondary analyses among hypertensive subjects, non-Hispanic blacks and Mexican Americans had 40% higher odds of uncontrolled blood pressure compared with non-Hispanic whites after adjustment for sociodemographic and clinical characteristics (
P
<0.001). For both analyses, the racial/ethnic differences in blood pressure control persisted even after further adjustment for modifiable health behaviors, which included medication adherence in secondary analyses (
P
<0.001 for both analyses). Although population-level adoption of healthy behaviors may contribute to reduction of the societal burden of cardiovascular disease in general, these findings suggest that racial/ethnic differences in some health behaviors do not explain the disparities in hypertension prevalence and control.
A Single β-Amino Acid Substitution to Angiotensin II Confers AT
2
Receptor Selectivity and Vascular Function
Authors: Jones Emma S. , Del Borgo Mark P. , Kirsch Julian F. , Clayton Daniel , Bosnyak Sanja , Welungoda Iresha , Hausler Nicholas , Unabia Sharon , Perlmutter Patrick , Thomas Walter G. , Aguilar Marie-Isabel , Widdop Robert E.
Published: February 2011

Novel AT
2
R ligands were designed by substituting individual β-amino acid in the sequence of the native ligand angiotensin II (Ang II). Relative ATR selectivity and functional vascular assays (in vitro AT
2
R-mediated vasorelaxation and in vivo vasodepressor action) were determined. In competition binding experiments using either AT
1
R- or AT
2
R- transfected HEK-293 cells, only β-Asp
1
-Ang II and Ang II fully displaced [
125
I]-Ang II from AT
1
R. In contrast, β-substitutions at each position of Ang II exhibited AT
2
R affinity, with β-Tyr
4
-Ang II and β-Ile
5
-Ang II exhibiting ≈1000-fold AT
2
R selectivity. In mouse aortic rings, β-Tyr
4
-Ang II and β-Ile
5
-Ang II evoked vasorelaxation that was sensitive to blockade by the AT
2
R antagonist PD123319 and the nitric oxide synthase inhibitor L-NAME. When tested with a low level of AT
1
R blockade, β-Ile
5
-Ang II (15 pmol/kg per minute IV for 4 hours) reduced blood pressure (BP) in conscious spontaneously hypertensive rats (β-Ile
5
-Ang II plus candesartan, −24±4 mm Hg) to a greater extent than candesartan alone (−11±3 mm Hg, n=7,
P
<0.05), an effect that was abolished by concomitant PD123319 infusion. However, in an identical experimental protocol, β-Tyr
4
-Ang II had no influence on BP (n=10), and it was less stable than β-Ile
5
-Ang II in plasma stability assays. Thus, this study demonstrated that a single β-amino acid substitution resulted in a compound that demonstrated both in vitro vasorelaxation and in vivo depressor activity via AT
2
R. This approach to the design and synthesis of novel AT
2
R-selective peptidomimetics shows great potential to provide insight into AT
2
R function.
Teleconnection Pathways of ENSO and the IOD and the Mechanisms for Impacts on Australian Rainfall
Authors: Cai Wenju , van Rensch Peter , Cowan Tim , Hendon Harry H.
Published: February 2011

Impacts of El Niño–Southern Oscillation (ENSO) and the Indian Ocean dipole (IOD) on Australian rainfall are diagnosed from the perspective of tropical and extratropical teleconnections triggered by tropical sea surface temperature (SST) variations. The tropical teleconnection is understood as the equatorially trapped, deep baroclinic response to the diabatic (convective) heating anomalies induced by the tropical SST anomalies. These diabatic heating anomalies also excite equivalent barotropic Rossby wave trains that propagate into the extratropics. The main direct tropical teleconnection during ENSO is the Southern Oscillation (SO), whose impact on Australian rainfall is argued to be mainly confined to near-tropical portions of eastern Australia. Rainfall is suppressed during El Niño because near-tropical eastern Australia directly experiences subsidence and higher surface pressure associated with the western pole of the SO. Impacts on extratropical Australian rainfall during El Niño are argued to stem primarily from the Rossby wave trains forced by convective variations in the Indian Ocean, for which the IOD is a primary source of variability. These equivalent-barotropic Rossby wave trains emanating from the Indian Ocean induce changes to the midlatitude westerlies across southern Australia, thereby affecting rainfall through changes in mean-state baroclinicity, west–east steering, and possibly orographic effects. Although the IOD does not mature until austral spring, its impact on Australian rainfall during winter is also ascribed to this mechanism. Because ENSO is largely unrelated to the IOD during austral winter, there is limited impact of ENSO on rainfall across southern latitudes of Australia in winter. A strong impact of ENSO on southern Australia rainfall in spring is ascribed to the strong covariation of ENSO and the IOD in this season. Implications of this pathway from the tropical Indian Ocean for impacts of both the IOD and ENSO on southern Australian climate are discussed with regard to the ability to make seasonal climate predictions and with regard to the role of trends in tropical SST for driving trends in Australian climate.
A Cloud-Resolving 4DVAR Assimilation Experiment for a Local Heavy Rainfall Event in the Tokyo Metropolitan Area
Authors: Kawabata Takuya , Kuroda Tohru , Seko Hiromu , Saito Kazuo
Published: February 2011

A cloud-resolving nonhydrostatic four-dimensional variational data assimilation system (NHM-4DVAR) was modified to directly assimilate radar reflectivity and applied to a data assimilation experiment using actual observations of a heavy rainfall event. Modifications included development of an adjoint model of the warm rain process, extension of control variables, and development of an observation operator for radar reflectivity.

The responses of the modified NHM-4DVAR were confirmed by single-observation assimilation experiments for an isolated deep convection, using pseudo-observations of rainwater at the initial and end times of the data assimilation window. The results showed that the intensity of convection could be adjusted by assimilating appropriate observations of rainwater near the convection and that undesirable convection could be suppressed by assimilating small or no reflectivity.

An assimilation experiment using actual observations of a local heavy rainfall in the Tokyo, Japan, metropolitan area was conducted with a horizontal resolution of 2 km. Precipitable water vapor derived from global positioning system data was assimilated at 5-min intervals within 30-min assimilation windows, and surface and wind profiler data were assimilated at 10-min intervals. Doppler radial wind and radar-reflectivity data below the elevation angle of 5.4° were assimilated at 1-min intervals.

The 4DVAR assimilation reproduced a line-shaped rainband with a shape and intensity consistent with the observation. Assimilation of radar-reflectivity data intensified the rainband and suppressed false convection. The simulated rainband lasted for 1 h in the extended forecast and then gradually decayed. Sustaining the low-level convergence produced by northerly winds in the western part of the rainband was key to prolonging the predictability of the convective system.
Rotating Hydraulics and Upstream Basin Circulation*
Authors: Helfrich Karl R. , Pratt Lawrence J.
Published: February 2011

The flow in a source-fed f-plane basin drained through a strait is explored using a single-layer (reduced gravity) shallow-water numerical model that resolves the hydraulic flow within the strait. The steady upstream basin circulation is found to be sensitive to the nature of the mass source (uniform downwelling, localized downwelling, or boundary inflow). In contrast, the hydraulically controlled flow in the strait is nearly independent of the basin circulation and agrees very well with the Gill-theory solution obtained using the strait geometry and the numerically determined average potential vorticity in the strait entrance region. This Gill solution, however, gives a unique value of the upstream boundary layer flux splitting that does not agree with any of the full numerical solutions. The coupled basin–strait system is shown to select an average overflow potential vorticity corresponding to the Gill solution with maximum fluid depth on the strait boundaries. This state also corresponds to one of maximal upstream basin potential energy. This result is robust to changes in the basin geometry, strait characteristics, the dissipation parameter (linear drag), and the net mass flux. The nonunique relation between basin conditions and overflow transport is significant with regard to deep overflow transport monitoring. It is shown that the potential vorticity selection leads to overflow, or “weir,” transport relations that are well approximated by the zero potential vorticity theory. However, accurate estimates of the transport can only be obtained if conditions within the strait entrance region, and not the basin, are used.
Wind-Driven Recirculations and Exchange in the Labrador and Irminger Seas*
Authors: Spall Michael A. , Pickart Robert S.
Published: February 2011

It is demonstrated that recently observed cyclonic recirculation gyres in the Irminger and Labrador Seas may be forced by the strong cyclonic wind stress curl that develops each winter seaward of the east coast of Greenland. Idealized analytical and numerical models forced with such variable winds over a sloping bottom reproduce the essential aspects of the observed gyres (strength, location, and horizontal and vertical length scales). The communication between the forcing region in the Irminger Sea and the recirculation to the west is achieved by baroclinic topographic Rossby wave propagation along potential vorticity contours. The circulation is characterized as a time-dependent, stratified, topographic beta plume. For weak stratification, as found in the subpolar North Atlantic, the recirculation strength exhibits only weak seasonal variability, consistent with the observations, even though the forcing is active only during the winter. Baroclinic Rossby waves that develop when the wind forcing ceases in springtime interact with the bottom to provide a source of cyclonic vorticity that maintains the circulation until the wind strengthens again in the following winter.