bluuebunny/crossref_metadata_2025 huggingface dataset:
PPARγLigands Regulate Noncontractile and Contractile Functions of Airway Smooth Muscle: Implications for Asthma Therapy
Authors: Donovan Chantal , Tan Xiahui , Bourke Jane Elizabeth
Published: August 2012

In asthma, the increase in airway smooth muscle (ASM) can contribute to inflammation, airway wall remodeling and airway hyperresponsiveness (AHR). Targetting peroxisome proliferator-activated receptorγ(PPARγ), a receptor upregulated in ASM in asthmatic airways, may provide a novel approach to regulate these contributions. This review summarises experimental evidence that PPARγligands, such as rosiglitazone (RGZ) and pioglitazone (PGZ), inhibit proliferation and inflammatory cytokine production from ASMin vitro. In addition, inhaled administration of these ligands reduces inflammatory cell infiltration and airway remodelling in mouse models of allergen-induced airways disease. PPARγligands can also regulate ASM contractility, with acute treatment eliciting relaxation of mouse tracheain vitrothrough a PPARγ-independent mechanism. Chronic treatment can protect against the loss of bronchodilator sensitivity toβ2-adrenoceptor agonists and inhibit the development of AHR associated with exposure to nicotinein uteroor following allergen challenge. Of particular interest, a small clinical trial has shown that oral RGZ treatment improves lung function in smokers with asthma, a group that is generally unresponsive to conventional steroid treatment. These combined findings support further investigation of the potential for PPARγagonists to target the noncontractile and contractile functions of ASM to improve outcomes for patients with poorly controlled asthma.
Mullerian Adenosarcoma of Uterus with Sarcomatous Overgrowth and Heterologous Component Associated with Stromal Deposit in Omentum: A Case Report and Review of the Literature
Authors: Sinha Anuradha , Phukan Jyoti Prakash , Sengupta Sanjay , Guha Paulami
Published: August 2012

Background. Mullerian adenosarcoma with sarcomatous overgrowth (MASO) is a very rare variant of uterine sarcomas first described by Clement et al. as early as 1974. The presence of heterologous sarcomatous components is associated with aggressive biological behavior.Case Presentation. This is a case report of a 62-year female (P2 + 0) presenting with postmenopausal vaginal bleeding. Her preoperative USG revealed subserosal fibroid with adherent omentum. She underwent abdominal hysterectomy with bilateral oophorectomy. Histopathological diagnosis of resected specimen was Mullerian adenosarcoma with sarcomatous overgrowth and presence of heterologous elements involving body of the uterus. The whole thickness of the myometrium was involved along with the presence of serosal nodules and omental deposits of sarcomatous component.Conclusion. MA is considered as a low-grade malignant tumor, but MASO is a high-grade tumor frequently associated with invasion and metastasis with poor treatment outcome. Because of its rarity, correct identification of these tumors and distinction from other uterine sarcomas are a challenging job and hence its morphological features merits attention.
Surface and Internal Waves due to a Moving Load on a Very Large Floating Structure
Authors: Kakinuma Taro , Yamashita Kei , Nakayama Keisuke
Published: August 2012

Interaction of surface/internal water waves with a floating platform is discussed with nonlinearity of fluid motion and flexibility of oscillating structure. The set of governing equations based on a variational principle is applied to a one‐ or two‐layer fluid interacting with a horizontally very large and elastic thin plate floating on the water surface. Calculation results of surface displacements are compared with the existing experimental data, where a tsunami, in terms of a solitary wave, propagates across one‐layer water with a floating thin plate. We also simulate surface and internal waves due to a point load, such as an airplane, moving on a very large floating structure in shallow water. The wave height of the surface or internal mode is amplified when the velocity of moving point load is equal to the surface‐ or internal‐mode celerity, respectively.
Improved Pressure Distribution in Elliptic Elastic Contacts between High-Order Surfaces
Authors: Glovnea Marilena , Spinu Sergiu , Diaconescu Emanuel
Published: August 2012

The improvement of mechanical contacts or microcontacts seeks a nearly uniform current density over most of contact area. When microtopography is homogeneous, this aim is achieved if nominal shape of contacting surfaces yields a nearly uniform central pressure which decreases monotonously to zero in contour points. These authors derived recently this shape for circular contacts by employing high-order surfaces. This paper extends this result to elliptical contacts. Some results are used to this end, derived for elliptical elastic contacts between high-order surfaces. As homogeneous high order surfaces lead to a highly nonuniform pressure distribution, central pressure is flattened by making the first derivatives of pressure vanish in contact center. Then, the contacts between fourth, sixth, and eighth, order surfaces are analyzed and recurrence relations for pressure distribution and contact parameters are proposed.
Further Research on the M/G/1 Retrial Queueing Model with Server Breakdowns
Authors: Kasim Ehmet , Gupur Geni
Published: August 2012

We study spectral properties of the operator which corresponds to the M/G/1 retrial queueing model with server breakdowns and obtain that all points on the imaginary axis except zero belong to the resolvent set of the operator and 0 is not an eigenvalue of the operator. Our results show that the time‐dependent solution of the model is probably strongly asymptotically stable.
An Image-Based Model of the Whole Human Heart with Detailed Anatomical Structure and Fiber Orientation
Authors: Deng Dongdong , Jiao Peifeng , Ye Xuesong , Xia Ling
Published: August 2012

Many heart anatomy models have been developed to study the electrophysiological properties of the human heart. However, none of them includes the geometry of the whole human heart. In this study, an anatomically detailed mathematical model of the human heart was firstly reconstructed from the computed tomography images. In the reconstructed model, the atria consisted of atrial muscles, sinoatrial node, crista terminalis, pectinate muscles, Bachmann’s bundle, intercaval bundles, and limbus of the fossa ovalis. The atrioventricular junction included the atrioventricular node and atrioventricular ring, and the ventricles had ventricular muscles, His bundle, bundle branches, and Purkinje network. The epicardial and endocardial myofiber orientations of the ventricles and one layer of atrial myofiber orientation were then measured. They were calculated using linear interpolation technique and minimum distance algorithm, respectively. To the best of our knowledge, this is the first anatomically-detailed human heart model with corresponding experimentally measured fibers orientation. In addition, the whole heart excitation propagation was simulated using a monodomain model. The simulated normal activation sequence agreed well with the published experimental findings.
Update on Ppar and Nonalcoholic Fatty Liver Disease
Authors: Ables Gene P.
Published: August 2012

Nonalcoholic fatty liver disease (NAFLD) is the most common initial presentation of obesity and insulin resistance. Uninterrupted progression of hepatic lipid accumulation often leads to fatty liver disease and eventually cirrhosis. Insulin resistance is one of the characteristics of type 2 diabetes. Several types of treatment have been employed against type 2 diabetes some of which ameliorate NAFLD. The frequent line of treatment to improve insulin sensitivity is the use of thiazolidinediones (TZD) which activate the nuclear receptor, peroxisome proliferator activated receptor gamma (Pparγ). Although TZDs are proven to be very effective in promoting insulin sensitivity, its actions onPparγhave been complicated, specifically on NAFLD. According to studies in different models,Pparγmanifests both beneficial and undesirable effects on NAFLD. This paper will focus on the current knowledge ofPparγand its effect on NAFLD.
Experiences in Developing and Implementing Health Clubs to Reduce Hypertension Risk among Adults in a South African Population in Transition
Authors: Puoane Thandi R. , Tsolekile Lungiswa , Igumbor Ehimario U. , Fourie Jean M.
Published: August 2012

Chronic noncommunicable diseases (NCDs) are increasing substantially as a cause of death and disability in all strata of the South African society, particularly among the urbanised poor. Hypertension is a risk factor for many of these diseases and becoming a burden in a growing population in a Cape Town township, Khayelitsha. To alleviate healthcare demands at clinics in this area, a health club was initiated and community health workers (CHWs) were trained to empower community members about NCDs and create public awareness. After training, a health club was initiated. Three months after initiation of the health club, 76 participants had been recruited of whom 22 were regular attenders. New members joined the health club weekly. Anthropometric and blood pressure measurements were taken, and various hypertension topics were covered at the club meetings which included healthy behaviours, such as the benefits of being physically active and eating healthy. Nutrition education sessions based on the South African food-based dietary guidelines were also held. Consequent to the initial group that was established, two more clubs were formed in the area. Health clubs are sustainable and culturally appropriate when facilitated by local people who have an insight and deeper understanding of the culture and environment of the people they serve.
Directed Evolution of Proteins throughIn VitroProtein Synthesis in Liposomes
Authors: Nishikawa Takehiro , Sunami Takeshi , Matsuura Tomoaki , Yomo Tetsuya
Published: August 2012

Directed evolution of proteins is a technique used to modify protein functions through “Darwinian selection.”In vitrocompartmentalization (IVC) is anin vitrogene screening system for directed evolution of proteins. IVC establishes the link between genetic information (genotype) and the protein translated from the information (phenotype), which is essential for all directed evolution methods, by encapsulating both in a nonliving microcompartment. Herein, we introduce a new liposome-based IVC system consisting of a liposome, the protein synthesis using recombinant elements (PURE) system and a fluorescence-activated cell sorter (FACS) used as a microcompartment,in vitroprotein synthesis system, and high-throughput screen, respectively. Liposome-based IVC is characterized byin vitroprotein synthesis from a single copy of a gene in a cell-sized unilamellar liposome and quantitative functional evaluation of the synthesized proteins. Examples of liposome-based IVC for screening proteins such as GFP andβ-glucuronidase are described. We discuss the future directions for this method and its applications.
Asymptotic Behavior for a Nondissipative and Nonlinear System of the Kirchhoff Viscoelastic Type
Authors: Tatar Nasser-Eddine
Published: August 2012

A wave equation of the Kirchhoff type with several nonlinearities is stabilized by a viscoelastic damping. We consider the case of nonconstant (and unbounded) coefficients. This is a nondissipative case, and as a consequence the nonlinear terms cannot be estimated in the usual manner by the initial energy. We suggest a way to get around this difficulty. It is proved that if the solution enters a certain region, which we determine, then it will be attracted exponentially by the equilibrium.
Thyroid Surgery for Elderly Patients: Are They at Increased Operative Risks?
Authors: Ng Sze-How , Wong Kai-Pun , Lang Brian Hung-Hin
Published: August 2012

An increasing elderly population, a rising incidence of differentiated thyroid carcinoma (DTC), and a rising incidence of benign nodular disease with age are all contributing to a rise in thyroid operations for the elderly. Literature review on the outcome and safety of thyroid surgery in elderly patients has been filled with conflicting results and this subject remains controversial. Although most single-institution studies conducted by high-volume surgeons did not find significant differences of complication rates in elderly when compared with younger cohorts, they often lacked the power necessary to identify subtle differences and suffered from various selection and referral biases. Recent evidence from large population-based studies concluded that thyroid surgery in the elderly was associated with higher complication rates. One of the major contributing factors for the increased complication rate was because most elderly patients suffered from many preexisting comorbidities. Therefore, elderly patients who have abnormal thyroid findings should complete a thorough preoperative workup and better postoperative care after undergoing any thyroid surgery. Furthermore, these high-risk patients would benefit if they could be referred to high-volume, specialized surgical units early. In this systemic review, we aimed to evaluate different issues and controversies in thyroidectomy for elderly patients.
Preparation of Novel Chitosan‐Starch Blends as Thickening Agent and Their Application in Textile Printing
Authors: Abdou E. S. , El-Hennawi H. M. , Ahmed K. A.
Published: August 2012

Chitosan, a naturally available biopolymer which is now increasingly used as a functional finish on textile substrates to impart antimicrobial characteristics and increase dye uptake of fabrics, was blended with different ratios of gelatinized starch. The chitosan was extracted and characterized by IR, 1H‐NMR, and X‐ray powder diffraction. These blends were tested as thickeners in textile screen printing using Curcuma tinctoria as natural dye. The rheological properties and the viscosity of the printing paste were measured. The effect of chitosan on the printing properties of different fabrics (natural, blends, and synthetic fabrics) was studied by measuring the color strength value (K/S) and related color parameters of the printed fabrics. The antimicrobial properties of printed fabrics were assessed. The results proved that the printed fabrics using these new thickeners showed increase in the color strength value (K/S) giving darker color which means that chitosan increased the dye uptake on fabrics. Fastness properties of the printed fabrics to washing, rubbing, perspiration, and light have also been improved. The treated fabrics were found to be antimicrobial.
Citrus Limonin Lacks the Antichemotherapeutic Effect in Human Models of Breast Cancer
Authors: Somasundaram Siva , Price Janet , Pearce Karen , Shuck Ryan , Jayaprakasha G.K. , Patil Bhimanagouda
Published: August 2012

Background/Aims: Chemicals that interfere with reactive oxygen species metabolism can act as potential candidates for the treatment of cancer. Some of the glucosides of citrus limonin inhibit the endogenously generated reactive oxygen species. The aim is to study the interactions of limonin with chemotherapy. Methods: Breast cancer cell lines MCF-7 (p53 wild type) and MDA-MB-231 (p53 mutant) as well as the nontumorigenic epithelial cell line MCF-10 were used to screen the effect of limonin at 1-, 5- and 10-µM concentrations with camptothecin for apoptosis and NFĸB, p38 and ERK-MAPK signaling kinase assays. The effect of cyclophosphamide and limonin on MDA MB 231 xenografts was also studied. Results: Our results indicate that limonin did not inhibit camptothecin-induced apoptosis in human breast cancer cells in vitro through noninterference of camptothecin-induced phosphorylation of p38 MAPK and ERK-MAPK. Using an in vivo model of human breast cancer, limonin in combination with cyclophosphamide was not found to inhibit the cyclophosphamide-induced tumor regression through a reduced mitotic index of tumor xenograft cells when compared to treatment with cyclophosphamide alone. Conclusion: Both in vitro and in vivo results suggest that limonin could be beneficial for breast cancer patients undergoing chemotherapy.
Identification of a Novel Heterozygous IGF1 Splicing Mutation in a Large Kindred with Familial Short Stature
Authors: Fuqua John S. , Derr Michael , Rosenfeld Ron G. , Hwa Vivian
Published: August 2012

Background/Aims: Insulin-like growth factor (IGF)-I is critical for normal human growth. Extremely rare homozygous mutations of the IGF1 gene severely impair intrauterine growth, intellectual development and postnatal growth. Case/Method: A young male presented with postnatal growth retardation (–4.0 height SDS). His serum IGF-I concentration was low (115 µg/l, –2.21 SDS) and increased minimally to 130 µg/l (–1.82 SDS) on GH therapy, and he was analyzed for defect(s) in the GH-IGF-I axis. Severe short stature could be traced back several generations. Results: From the proband and 4 other severely short-statured family members, two novel, heterozygous, variants were identified in the IGF1 gene: c.207G>A in exon 3 and c.402+1G>C in the donor splice site of intron 4. The IGF1 gene was normal in 11 normal stature family members, and, interestingly, in 5 other short-statured family members. Study of IGF1 mRNA indicated c.402+1G>A induced splicing out of exon 4, leading to a predicted frameshift and protein truncation. Conclusions: A novel heterozygous IGF1 splicing variant is associated with familial short stature in an extended family. Although it remains unclear whether this heterozygous mutation is the cause of the growth failure, the extreme rarity of IGF1 gene defects makes these cases of considerable interest.
In vivo Evaluation of the Chitosan-Based Haemostatic Agent Omni-stat® in Porcine Liver Resection and in Liver Injury
Authors: Jegatheeswaran S. , Bhanot U. , Siriwardena A.K.
Published: August 2012

Background: Omni-stat®, a polysaccharide made by de-acetylation of chitin, is currently in use as a battlefield topical haemostat. This experimental study undertakes the first evaluation of Omni-stat in an in vivo porcine hepatectomy and liver trauma model. Methods: A model of sequential liver resection was employed: following liver resection, further resections were undertaken in the same animal provided that there was cessation of bleeding from the earlier resection and that haemodynamic stability was maintained. An additional liver trauma injury was undertaken after completion of all resections. Data were collected on heart rate, blood pressure, haematocrit, resection volumes, blood loss and the efficacy of Omni-stat in haemostasis. Results: Eight minor resections and 12 major resections were undertaken. Topical application of Omni-stat to raw post-transection surfaces immediately upon completion of resection achieved complete haemostasis with a single application in 14 of 15 (93%) resections. There was no recurrence of bleeding during the 5-hour protocol. The median time for cessation of bleeding after resection in the Omni-stat group was 3 min (range 3–6). This was not significantly different from time to cessation of bleeding in 5 control resections. There was no difference in blood loss or haemodynamic parameters. Respiratory rate was significantly faster after application of Omni-stat. In 2 liver lacerations, Omni-stat was effective in achieving cessation of haemorrhage. Conclusion: Omni-stat is an effective haemostat in experimental in vivo porcine liver resection and liver trauma. Further evaluation is required to assess its physiological absorption profile in man and its comparative efficacy against commercially established agents.
Brain Structure in Preclinical Huntington's Disease: A Multi-Method Approach
Authors: Wolf Robert Christian , Thomann Philipp Arthur , Thomann Anne Kerstin , Vasic Nenad , Wolf Nadine Donata , Landwehrmeyer G. Bernhard , Orth Michael
Published: August 2012

Background: Structural magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). So far, structural changes have been found mainly in preHD approaching the estimated motor onset of the disease (i.e. less than 15 years from onset), whereas structural findings in preHD far from the estimated motor onset have been inconclusive. Objectives: The aims of this study were to investigate the sensitivity of different methodological approaches to structural data in far-from-onset preHD (mean estimated time to motor onset = 21.4 years) and to explore the relationship between brain structure, clinical variables and cognition. Methods: High-resolution MRI data at 3 T were obtained from 20 preHD individuals and 20 healthy participants and subsequently analyzed using voxel-based morphometry (VBM), cortical surface modeling and subcortical segmentation analysis techniques. Results: VBM analyses did not reveal significant between-group differences, whereas cortical surface modeling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls. Significant correlations were found between striatal structure, estimated time to motor onset and executive performance, whereas cortical changes were not significantly correlated with these parameters. Conclusion: These data suggest that a combined methodological approach to structural MRI data could increase the sensitivity for detecting subtle neurobiological changes in early preHD. As consistently shown across different methods, the association between striatal structure and clinical measures supports the notion that changes in striatal volume could represent a more robust marker of disease progression than cortical changes.
The Disparity in Long-Term Survival after a First Stroke in Patients with and without Diabetes Persists: The Northern Sweden MONICA Study
Authors: Eriksson Marie , Carlberg Bo , Eliasson Mats
Published: August 2012

Background: Diabetes is an established risk factor for stroke. Compared to nondiabetic patients, diabetic patients also have an increased risk of new vascular events and death after stroke. We analyzed how differences in long-term survival between diabetic and nondiabetic stroke patients have changed over time, and if differences varied with respect to sex and age. Methods: This population-based study included 12,375 first-ever stroke patients, 25–74 years old, who were registered in the Northern Sweden MONICA Stroke Registry 1985–2005. Uniform diagnostic criteria for stroke case ascertainment were used throughout the study period. The diagnosis of diabetes was based on medical records or diabetes diagnosed during the acute stroke event. Patients were separated into four cohorts according to year of stroke and followed for survival until August 30, 2008. Results: The diabetes prevalence at stroke onset was 21%, similar in men and women, and remained stable throughout the study period. The diabetic patients were an average of 2 years older, more often nonsmokers and more likely to have antihypertensive treatment, antithrombotics, atrial fibrillation, and a history of myocardial infarction or transient ischemic attack than the nondiabetic patients. The total follow-up time was 86,086 patient-years during which a total of 1,930 (75.7%) of the diabetic patients and 5,744 (58.5%) of the nondiabetic patients died (p < 0.001). Median survival was 60 months (95% CI: 57–64) in diabetic patients and 117 months (113–120) in the nondiabetic patients. Survival improved significantly in both groups (p < 0.001). A Cox regression, adjusting for possible confounders (age, sex, antihypertensive medication, antithrombotics or other thrombolytic agents, history of myocardial infarction, type of stroke, diabetes, cohort and the diabetes-by-sex, diabetes-by-age and diabetes-by-cohort interactions), showed a hazard ratio of 1.67 (1.58–1.76) comparing survival in diabetic versus nondiabetic patients. The reduced survival in diabetic stroke patients was more pronounced in women (p = 0.02) and younger patients (p < 0.001). There was a tendency that the difference in survival decreased between the earlier cohorts and the 2000–2005 cohort, but the test for interaction did not reach statistical significance (p = 0.08). Conclusion: Long-term survival after a first stroke has improved in both diabetic and nondiabetic patients. Survival is markedly lower in diabetics, especially in women and younger patients, and the disparity persisted over 24 years. Decreasing the disparity in stroke survival is a challenge for stroke and diabetes care. New treatment methods in combination with intense secondary prevention in diabetic patients, especially in younger women, are needed.
Experimental First-Pass Method for Testing and Comparing Sorbent Polymers Used in the Clearance of Iodine Contrast Materials
Authors: Angheloiu George O. , Hänscheid Heribert , Wen Xiaoyan , Capponi Vincent , Anderson William D. , Kellum John A.
Published: August 2012

Background: Sorbents have been shown to adsorb iodinated radiocontrast media. Objective: In this study we describe a simple method to compare various sorbents in terms of capacity to adsorb radiocontrast media. Methods: Iodixanol solution was injected into columns filled with three types of sorbent at filtration velocities of increasing magnitude. Two variables of interest – contrast removal rate and matched iodine retention (MIR) – were calculated to measure the adsorption efficiency and the mass of contrast iodine adsorbed versus sorbent used, respectively. Results: The highest contrast removal and MIR for Porapak Q, CST 401 and Amberlite XAD4 were 41, 38 and 16% (p = 0.22 and 0.0005 for comparisons between Porapak Q-CST 401 and CST 401-Amberlite XAD4) and 0.060, 0.055 and 0.024, respectively (p = 0.18 and 0.0008). Extrapolation to a clinical scenario may suggest that removal of 8 ml iodixanol could be achieved by masses of sorbents of 43, 47 and 107 g, respectively. Conclusion: In this study we set a benchmark for comparing the radiocontrast-adsorbing efficiency of polymer sorbents during first-pass experiments, using a readily available methodology.
Insulin Sensitivity Modulates the Growth Response during the First Year of High-Dose Growth Hormone Treatment in Short Prepubertal Children Born Small for Gestational Age
Authors: Gies Inge , Thomas Muriel , Tenoutasse Sylvie , De Waele Kathleen , Lebrethon Marie-Christine , Beckers Dominique , Francois Inge , Maes Marc , Rooman Raoul , de Beaufort Carine , Massa Guy , De Schepper Jean
Published: August 2012

Aim: To study the relationship between insulin sensitivity and growth response in short children born small for gestational age (SGA) treated with growth hormone (GH). Methods: Randomized, open-label, 24-month intervention study in 40 short prepubertal SGA children [age (mean ± SD) 5.3 ± 1.5 years], who either remained untreated (n = 20) or were treated with GH (66 µg/kg/day; n = 20). Changes in fasting glucose, insulin, quantitative insulin sensitivity check index (QUICKI), IGF-1 and leptin after 1 and 2 years were studied. Results: Mean height SDS increased from –3.3 ± 0.7 to –2.3 ± 0.7 after 1 year, and to –1.9 ± 0.7 after 2 years of treatment. QUICKI decreased significantly (p = 0.008) in the first year of GH treatment and stabilized in the second year. Baseline QUICKI was positively associated (r = 0.40; p < 0.05) with the change in height SDS in the first year. Conclusion: Higher insulin sensitivity at the start of GH therapy is associated with greater first-year growth response to GH, and could be a promising parameter in selecting prepubertal short SGA children for GH treatment. However, this finding needs to be confirmed in larger studies.
A Case of Compound Mutations in the MYBPC3 Gene Associated with Biventricular Hypertrophy and Neonatal Death
Authors: Marziliano Nicola , Merlini Piera Angelica , Vignati Gabriele , Orsini Francesco , Motta Valentina , Bandiera Laura , Intrieri Mariano , Veronese Silvio
Published: August 2012

Hypertrophic cardiomyopathy (HCM) is a familial, genetically determined, primary cardiomyopathy caused by mutations in genes coding for proteins of the sarcomere, or, less frequently, genes involved in storage diseases. In pediatric settings, pure HCM has an estimated incidence of 4.7 per million children. The disease is often sub-clinical and goes unrecognized mainly because most patients with HCM have only mild symptoms, if any. However, sudden cardiac death, the most dramatic clinical occurrence and the primary concern for patients and physicians alike, may be the first manifestation of the disease. We describe a case of compound heterozygosity in the MYBPC3 gene (p.Glu258Lys and IVS25-1G>A) associated with biventricular hypertrophy, atrial enlargement and subsequent neonatal death 33 days postpartum. Other studies have reported compound and/or double heterozygosis in the same or different sarcomeric genes during childhood and adulthood, and neonatal presentations have also been described. Our observations show that the combination of a missense (p.Glu258Lys) and a splice-site mutation (IVS25-1G>A) profoundly affects the clinical course. In families in which parental mutations are known, preimplantation (where ethically and legally feasible) or prenatal genetic screening should be adopted because: (1) neonatal HCM in genetic heterozygosity is potentially lethal and (2) heart disease is the most common developmental malformation and the leading cause of neonatal mortality and morbidity.
Challenges of Disorders of Sex Development: Diverse Perceptions across Stakeholders
Authors: Kogan Barry A. , Gardner Melissa , Alpern Adrianne N. , Cohen Laura M. , Grimley Mary Beth , Quittner Alexandra L. , Sandberg David E.
Published: August 2012

Background/Aims: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or anatomic sex development is atypical. Optimal management is patient- and family-centered and delivered by interdisciplinary teams. The present pilot study elicits concerns held by important stakeholders on issues affecting young patients with DSD and their families. Methods: Content from focus groups with expert clinicians (pediatric urologists (n = 7), pediatric endocrinologists (n = 10), mental health professionals (n = 4), DSD patient advocates (n = 4), and interviews with parents of DSD-affected children (newborn to 6 years; n = 11) was coded and content-analyzed to identify health-related quality of life issues. Results: Key stressors varied across stakeholder groups. In general, family-centered issues were noted more than child-centered. In the child-centered domain, providers worried more about physical functioning; family and advocates emphasized gender concerns and body image. In the family-centered domain, parental concerns about medication management outweighed those of providers. Advocates reported more stressors regarding communication/information than other stakeholders. Conclusion: Variability exists across stakeholder groups in the key concerns affecting young children/families with DSD. Interdisciplinary DSD healthcare team development should account for varying perspectives when counseling families and planning treatment.
Subcortical and Cortical Structural Central Nervous System Changes and Attention Processing Deficits in Preschool-Aged Children with Prenatal Methamphetamine and Tobacco Exposure
Authors: Derauf Chris , Lester Barry M. , Neyzi Nurunisa , Kekatpure Minal , Gracia Luis , Davis James , Kallianpur Kalpana , Efird Jimmy T. , Kosofsky Barry
Published: August 2012

Objective: To examine the independent contributions of prenatal methamphetamine exposure (PME) and prenatal tobacco exposure (PTE) on brain morphology among a sample of nonalcohol-exposed 3- to 5-year-old children followed prospectively since birth. Study Design: The sample included 20 children with PME (19 with PTE) and 15 comparison children (7 with PTE), matched on race, birth weight, maternal education and type of insurance. Subcortical and cortical volumes and cortical thickness measures were derived through an automated segmentation procedure from T1-weighted structural magnetic resonance images obtained on unsedated children. Attention was assessed using the computerized Conners’ Kiddie Continuous Performance Test Version 5 (K-CPT™ V.5). PME effects on subcortical and cortical brain volumes and cortical thickness were tested by general linear model with type III sum of squares, adjusting for PTE, prenatal marijuana exposure, age at time of scan, gender, handedness, pulse sequence and total intracranial volume (for volumetric outcomes). A similar analysis was done for PTE effects on subcortical and cortical brain volumes and thickness, adjusting for PME and the above covariates. Results: Children with PME had significantly reduced caudate nucleus volumes and cortical thickness increases in perisylvian and orbital-frontal cortices. In contrast, children with PTE showed cortical thinning in perisylvian and lateral occipital cortices and volumetric increases in frontal regions and decreases in anterior cingulate. PME was positively related and caudate volume was inversely related to K-CPT reaction time by inter-stimulus interval, a measure of the ability to adjust to changing task demands, suggesting that children with PME may have subtle attentional deficits mediated by caudate volume reductions. Conclusions: Our results suggest that PME and PTE may have distinct differential cortical effects on the developing central nervous system. Additionally, PME may be associated with subtle deficits in attention mediated by caudate volume reductions.
Sexually Dimorphic Effects of Melatonin on Brain Arginine Vasotocin Immunoreactivity in Green Treefrogs (Hyla cinerea)
Authors: Lutterschmidt Deborah I. , Wilczynski Walter
Published: August 2012

Arginine vasotocin (AVT) and its mammalian homologue, arginine vasopressin (AVP), regulate a variety of social and reproductive behaviors, often with complex species-, sex- and context-dependent effects. Despite extensive evidence documenting seasonal variation in brain AVT/AVP, relatively few studies have investigated the environmental and/or hormonal factors mediating these seasonal changes. In the present study, we investigated whether the pineal hormone melatonin alters brain AVT immunoreactivity in green treefrogs (Hyla cinerea). Reproductively active male and female frogs were collected during the summer breeding season and a melatonin-filled or blank silastic capsule was surgically implanted subcutaneously. The duration of hormone treatment was 4 weeks, at which time frogs were eutha-nized and the brains and blood collected and processed for AVT immunohistochemistry and steroid hormone assay. We quantified AVT-immunoreactive (AVT-ir) cell bodies in the nucleus accumbens (NAcc), caudal striatum and amygda- la (AMG), anterior preoptic area, suprachiasmatic nucleus (SCN) and infundibular region of the ventral hypothalamus. Sex differences in AVT-ir cell number were observed in all brain regions except in the anterior preoptic area and ventral hypothalamus, with males having more AVT-ir cells than females in the NAcc, amygdala and SCN. Brain AVT was sensitive to melatonin signaling during the breeding season, and the effects of melatonin varied significantly with both region and sex. Treatment with melatonin decreased AVT immunoreactivity in both the NAcc and SCN in male H. cinerea. In contrast, brain AVT was relatively insensitive to melatonin signaling in females, indicating that the regulation of the AVT/AVP neuropeptide system by melatonin may be sexually dimorphic. Finally, melatonin did not significantly influence testosterone or estradiol concentrations of male or female frogs, respectively, suggesting that the effects of melatonin on AVT immunoreactivity are independent of changes in gonadal sex steroid hormones. Collectively, our results indicate that the AVT/AVP neuronal system may be an important target for melatonin in facilitating seasonal changes in reproductive physiology and social behavior.
Long-Term Follow-Up Evaluation of Results From Clinical Trial Using Hepatocyte Growth Factor Gene to Treat Severe Peripheral Arterial Disease
Authors: Makino Hirofumi , Aoki Motokuni , Hashiya Naotaka , Yamasaki Keita , Azuma Junya , Sawa Yoshiki , Kaneda Yasufumi , Ogihara Toshio , Morishita Ryuichi
Published: August 2012

Objective—

As angiogenic growth factors can stimulate the development of collateral arteries, a concept called therapeutic angiogenesis, we performed a phase I/IIa open-label clinical trial using intramuscular injection of naked plasmid DNA encoding hepatocyte growth factor (HGF). We reported long-term evaluation of 2 years after HGF gene therapy in 22 patients with severe peripheral arterial disease.

Methods and Results—

Twenty-two patients with peripheral arterial disease or Buerger disease staged by Fontaine IIb (n=7), III (n=4), and IV (n=11) were treated with HGF plasmid, either 2 mg or 4 mg ×2. Increase in ankle-branchial pressure index >0.1 was observed in 11 of 14 patients (79 %) at 2 years after gene therapy and in 11 of the 17 patients (65%) at 2 months. Reduction in rest pain (>2 cm in visual analog scale) was observed in 9 of 9 patients (100%) at 2 years and in 8 of 13 (62%) patients at 2 months. At 2 years, 9 of 10 (90%) ischemic ulcers reduced by >25%, accompanied by a reduction in the size of ulcer. Severe complications and adverse effects caused by gene transfer were not detected in any patient throughout the period up to 2 years.

Conclusion—

Overall, the present study demonstrated long-term efficacy of HGF gene therapy up to 2 years. These findings may be cautiously interpreted to indicate that intramuscular injection of naked HGF plasmid is safe, feasible, and can achieve successful improvement of ischemic limbs as sole therapy.
Moderate to High Concentrations of High-Density Lipoprotein From Healthy Subjects Paradoxically Impair Human Endothelial Progenitor Cells and Related Angiogenesis by Activating Rho-Associated Kinase Pathways
Authors: Huang Chun-Yao , Lin Feng-Yen , Shih Chun-Ming , Au Heng-Kien , Chang Yu-Jia , Nakagami Hironori , Morishita Ryuichi , Chang Nen-Chung , Shyu Kou-Gi , Chen Jaw-Wen
Published: August 2012

Objective—

Recent clinical evidence has failed to demonstrate the benefits of elevation of serum high-density lipoprotein (HDL), suggesting potential loss of protective effects of HDL at high concentrations. This study aimed to investigate the concentration-related effects of HDL on in vitro and in vivo functions of human endothelial progenitor cells (EPCs) and related angiogenesis.

Methods and Results—

Early and late outgrowth EPCs were generated from human circulating mononuclear cells. Oxidized low-density lipoprotein reduced viability of late outgrowth EPCs, which was reversed dose dependently by HDL. In the absence of oxidized low-density lipoprotein, HDL at low concentrations (5–50 μg/mL, equal to 0.5–5 mg/dL in human) enhanced EPC tube formation by activating phosphatidylinositol-3 kinase/Akt/endothelial NO synthase pathways. Moderate to high concentrations (400–800 μg/mL) of HDL paradoxically enhanced EPC senescence and impaired tube formation by activating Rho-associated kinase (ROCK) and inhibiting phosphatidylinositol-3 kinase/Akt and p38 mitogen-activated protein kinase pathways. Rho-associated kinase inhibitors, either Y27632 or statins, prevented high HDL–induced EPC senescence and improved in vitro tube formation, as well as in vivo capacity of angiogenesis of EPCs.

Conclusion—

While protecting EPCs from the injury of oxidized low-density lipoprotein, moderate to high concentrations of HDL paradoxically impaired EPCs and related angiogenesis in the absence of oxidized low-density lipoprotein by activating Rho-associated kinase pathways, providing mechanistic evidence of potential hazard effects of HDL.
Inhibition of Intrinsic Xase by Protein S
Authors: Chattopadhyay Rima , Sengupta Tanusree , Majumder Rinku
Published: August 2012

Objective—

Protein S is a vitamin K–dependent plasma protein that functions in the feedback regulation of thrombin generation. Our goal was to determine how protein S regulates the intrinsic pathway of blood coagulation.

Methods and Results—

We used plasma, including platelet-rich plasma, and in vitro methods to determine how the intrinsic pathway of blood coagulation is regulated by protein S. We obtained the following results: (1) activated partial thromboplastin time assays with protein S–supplemented plasma confirmed that protein S prolongs clotting time; (2) a modified activated partial thromboplastin time assay with factor IX (fIX)–deficient plasma confirmed that protein S affects fIX-initiated clotting; (3) a fIXa/factor VIIIa (fVIIIa)–mediated thrombin generation assay with either platelet-rich plasma or factor-deficient plasma, initiated with a limiting amount of tissue factor, was regulated by protein S; (4) in the presence of phosphatidylserine vesicles, protein S inhibited fIXa in the absence and presence of fVIIIa; and (5) protein S altered only the
K
M
for factor X activation by fIXa in the absence of fVIIIa and both
k
cat
and
K
M
in the presence of fVIIIa.

Conclusion—

From our findings, it can be concluded that protein S inhibits fIXa in the presence or absence of fVIIIa in an activated protein C–independent way.
A Disintegrin and Metalloproteinase 15 Contributes to Atherosclerosis by Mediating Endothelial Barrier Dysfunction via Src Family Kinase Activity
Authors: Sun Chongxiu , Wu Mack H. , Lee Eugene S. , Yuan Sarah Y.
Published: August 2012

Objective—

Endothelium dysfunction is an initiating factor in atherosclerosis. A disintegrin and metalloproteinase 15 (ADAM 15) is a multidomain metalloprotease recently identified as a regulator of endothelial permeability. However, whether and how ADAM15 contributes to atherosclerosis remains unknown.

Methods and Results—

Genetic ablation of ADAM15 in apolipoprotein E–deficient mice led to a significant reduction in aortic atherosclerotic lesion size (by 52%), plaque macrophage infiltration (by 69%), and smooth muscle cell deposition (by 82%). In vitro studies implicated endothelial-derived ADAM15 in barrier dysfunction and monocyte transmigration across mouse aortic and human umbilical vein endothelial cell monolayers. This role of ADAM15 depended on intact functioning of the cytoplasmic domain, as evidenced in experiments with site-directed mutagenesis targeting the metalloprotease active site (E349A), the disintegrin domain (Arginine-Glycine-Aspartic acid→Threonine-Aspartic acid-Aspartic acid), or the cytoplasmic tail. Further investigations revealed that ADAM15-induced barrier dysfunction was concomitant with dissociation of endothelial adherens junctions (vascular endothelial [VE]-cadherin/γ-catenin), an effect that was sensitive to Src family kinase inhibition. Through small interfering RNA-mediated knockdown of distinct Src family kinase members, c-Src and c-Yes were identified as important mediators of these junctional effects of ADAM15.

Conclusion—

These results suggest that endothelial cell-derived ADAM15, signaling through c-Src and c-Yes, contributes to atherosclerotic lesion development by disrupting adherens junction integrity and promoting monocyte transmigration.
Elevated CETP Activity Improves Plasma Cholesterol Efflux Capacity From Human Macrophages in Women
Authors: Villard Elise F. , El Khoury Petra , Duchene Emilie , Bonnefont-Rousselot Dominique , Clement Karine , Bruckert Eric , Bittar Randa , Le Goff Wilfried , Guerin Maryse
Published: August 2012

Objective—

We aim to identify the impact of endogenous cholesteryl ester transfer protein (CETP) activity on plasma capacity to mediate free cholesterol efflux from human macrophages.

Methods and Results—

Endogenous plasma CETP activity was measured in a population of 348 women. We defined a low CETP group corresponding to subjects displaying an endogenous plasma CETP activity within the first tertile and a high CETP group corresponding to subjects with an endogenous plasma CETP activity within the third tertile. Subjects from the high CETP activity group displayed a significant increase in the capacity of their plasma (+8.2%;
P
=0.001) to mediate cholesterol efflux from human acute monocytic leukemia cell line human macrophages and from ATP-binding cassette transporter A1-dependent pathway (+23.4%;
P
=0.0001) as compared with those from the low CETP activity group. Multivariate analyses revealed that the impact of CETP activity was independent of plasma lipids levels. Pre–β1-high-density lipoprotein concentrations were significantly elevated (+29.6%;
P
=0.01) in the high CETP activity group as compared with the low CETP activity group. A positive correlation between pre–β1-high-density lipoprotein levels and plasma efflux efficiency from human acute monocytic leukemia cell line human macrophages was observed (
r
=0.29,
P
=0.02).

Conclusion—

CETP leading to the improvement of plasma efflux capacity, as a result of efficient pre–β-high-density lipoprotein formation and ATP-binding cassette transporter A1 efflux, should be preserved to prevent lipid accumulation in human macrophages.
Cystatin C Identifies Patients With Stable Chronic Heart Failure at Increased Risk for Adverse Cardiovascular Events
Authors: Dupont Matthias , Wu Yuping , Hazen Stanley L. , Tang W. H. Wilson
Published: August 2012

Background—

Renal function is a strong predictor of adverse events in heart failure. Current renal function measures are imperfect, and cystatin C (CysC) is promoted as a better marker of glomerular filtration rate. This study compares the prognostic use of CysC and derived glomerular filtration rate estimates with other measures of renal function in patients with chronic heart failure.

Methods and Results—

We measured serum CysC levels in 823 patients with heart failure undergoing coronary angiography with follow-up of major adverse cardiovascular events (death, myocardial infarction, stroke). CysC levels strongly correlated with creatinine (
r
=0.73), blood urea nitrogen (
r
=0.70), and estimated glomerular filtration rate by the 4-variable modification of diet in renal disease equation (
r
=−0.62) (all
P
<0.001). However, the correlation was lower in estimated glomerular filtration rate ≥60 mL/min per 1.73 m
2
. CysC-based measures significantly improved areas under the receiver operating characteristic curve for the prediction of major adverse cardiovascular events, especially in estimated glomerular filtration rate ≥60 mL/min per 1.73 m
2
(
P
<0.01). Net reclassification improvement was 22.2% (
P
<0.001) in this group. CysC remained an independent predictor of major adverse cardiovascular events (
P
<0.001) after adjustment for traditional risk factors and brain natriuretic peptide.

Conclusions—

CysC is an independent predictor of adverse events in chronic heart failure. It adds prognostic value to creatinine, particularly in patients with preserved renal function.