bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis of Mild Cognitive Impairment Revisited after One Year
Authors: Diniz Breno Satler , Nunes Paula Villela , Yassuda Mônica Sanches , Forlenza Orestes Vicente
Published: February 2009

Background/Aims: The diagnostic stability of mild cognitive impairment (MCI) on short-term follow-up is a key issue in the characterization of this clinical syndrome. We aim to determine the cognitive outcome after 1 year of follow-up in a cohort of older adults. Methods: Baseline clinical and neuropsychological assessments were carried out in older subjects recruited at a tertiary memory clinic. The subjects were reassessed after 1 year of follow-up with the same clinical and neuropsychological protocol. Results: A total of 115 older adults, including MCI (n = 54) and controls (n = 61), underwent baseline and follow-up evaluation. Ten subjects classified as MCI at baseline (23%) resumed normal cognitive function and 13 controls (21%) progressed to MCI upon follow-up (χ2 = 0.015, d.f. = 1, p = 0.90). The subjects diagnosed as having MCI on both assessments were older (p = 0.002) and had a worse global cognitive performance according to the Cambridge Cognitive Test (p = 0.014). Conclusion: The subjects who maintain the MCI status are older and have a worse baseline cognitive performance as well as multiple cognitive deficits.
Serum Phosphate and Left Ventricular Hypertrophy in Young Adults: The Coronary Artery Risk Development in Young Adults Study
Authors: Foley Robert N. , Collins Allan J. , Herzog Charles A. , Ishani Areef , Kalra Philip A.
Published: February 2009

Background/Aims: A relationship with vascular dysfunction in chronic kidney disease suggests a possible association of phosphate level with left ventricular hypertrophy development in people with normal kidney function. We aimed to determine whether such an association exists in community-dwelling young adults. Methods: This is a cohort study of participants in the ongoing, community-based, prospective Coronary Artery Risk Development in Young Adults study (n = 4,055). Phosphate levels were measured at year 0, and left ventricular hypertrophy assessed by echocardiography at year 5. Results: The mean age was 25.0 years. Mean values were: estimated glomerular filtration rate 118.5 ml/min/1.73 m2; phosphate 3.7 mg/dl; left ventricular mass indexed to body surface area 80.5 g/m2, and indexed to height2.7 35.2 g/m2.7. Left ventricular hypertrophy was present in 4.5% of the population. As a continuous variable, the phosphate level was associated with left ventricular hypertrophy (odds ratio per standard deviation 1.27; 95% confidence interval 1.09–1.47; p = 0.0020). This association persisted after covariate adjustment (odds ratio per standard deviation 1.30; 95% confidence interval 1.10–1.54; p = 0.0018), and was most pronounced for fifth quintile phosphate levels (>4.0 mg/dl). Conclusion: Phosphate level may be a risk factor for left ventricular hypertrophy in community-dwelling young adults. As phosphate levels may be modifiable, the causality of this association can be addressed with controlled trials.
Longitudinal Changes of Cardiothoracic Ratio and Vascular Pedicle Width as Predictors of Volume Status during One Year in Chinese Peritoneal Dialysis Patients
Authors: Gao Ni , Kwan Bonnie Ching-Ha , Chow Kai-Ming , Chung Kwok-Yi , Leung Chi-Bon , Li Philip Kam-Tao , Szeto Cheuk-Chun
Published: February 2009

Background: Volume overload is an important contributing factor of cardiovascular disease (CVD) in peritoneal dialysis (PD) patients. Vascular pedicle width (VPW) and cardiothoracic ratio (CTR) in routine chest radiograph are indicators of intravascular volume. Longitudinal changes of VPW and CTR may be important prognostic factors of PD patients. Method: We studied 212 PD patients. Longitudinal changes in VPW (ΔVPW) and CTR (ΔCTR) were calculated. The relationship between radiologic measurements and clinical outcome was analyzed. Results: During the 12 months prior to enrollment, VPW rose from 53.35 ± 5.66 to 55.40 ± 6.30 mm (p < 0.001) and CTR rose from 53.3 ± 7.1 to 56.0 ± 7.8% (p < 0.001). After adjusting for confounding variables by Cox regression model, ΔCTR is an independent predictor of hospitalization-free survival; 1% increase in CTR confers 2.9% higher risk of hospitalization (95% confidence interval 0.2–5.7%, p = 0.034). None of the radiologic measurements correlated with actuarial patient survival. Conclusions: In chronic PD patients, ΔCTR is an independent predictor of hospitalization-free survival. This simple radiological parameter may serve as an important parameter for the risk stratification of PD patients.
Cardiovascular Disease Risk Factors and Progression of Alzheimer’s Disease
Authors: Abellan van Kan Gabor , Rolland Yves , Nourhashémi Fati , Coley Nicola , Andrieu Sandrine , Vellas Bruno
Published: February 2009

Background/Aims: To assess if cardiovascular disease risk factors (CVDRF) are predictive factors for poorer evolution of Alzheimer’s disease (AD) patients in terms of cognitive decline. Methods: The Réseau de la maladie d’Alzheimer – France (REAL.FR) study is a prospective multicentre cohort which has recruited 686 community-dwelling patients presenting mild to moderate AD. The presence of CVDRF and associated treatments was recorded at baseline. The rate of cognitive decline of AD patients was assessed using the Mini Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale cognitive subscale (ADAS-Cog), after 2 years of follow-up. Results: Of the 629 patients at baseline, 268 (42.6%) had no CVDRF, 256 (40.7%) reported 1 CVDRF and 105 (16.7%) reported 2–3. At inclusion, hypertension was present in 44.1% of patients, hypercholesterolaemia in 22.6% and diabetes in 9.4%. No statistically significant differences (p values of 0.9 for MMSE and 0.8 for ADAS-Cog) in mean cognitive decline after 2 years of follow-up were found comparing different subgroups of patients with CVDRF to the non-CVDRF group. Conclusions: Although there is evidence that CVDRF contribute to the onset of AD, these results suggest that CVDRF may not be part of the underlying processes that affect progression of AD.
Risk Factors of Iris Posterior Synechia Formation after Phacovitrectomy with Three-Piece Acrylic IOL or Single-Piece Acrylic IOL
Authors: Kim Seong-Woo , Oh Jaeryung , Song Jong-Suk , Kim Yong Yeon , Oh In-kyung , Huh Kuhl
Published: February 2009

Aims: To identify the risk factors of posterior iris synechia formation after phacovitrectomy with posterior chamber single-piece acrylic intraocular lens (IOL; Acrysof® SA60AT) or 3-piece acrylic IOL (Acrysof® MA60BM) implantation. Methods: We selected 153 eyes of 153 patients treated by phacovitrectomy between March 2000 and August 2006 and retrospectively reviewed the relationship between iris posterior synechiae and various factors, such as IOL type, tamponade, preoperative iris posterior synechiae, major indications for surgery, axial length and preoperative anterior chamber (AC) depth. Results: IOL type (p = 0.0447), C3F8 gas tamponades (p = 0.0074), preoperative iris posterior synechiae (p = 0.0001) and postoperative AC fibrin deposition (p = 0.0303) were significantly associated with postoperative iris posterior synechiae by multiple logistic regression analysis. The odds ratio (OR) for single-piece IOL versus 3-piece IOL was 2.658 (95% confidence interval, CI: 1.010–6.993), the OR for C3F8 gas versus balanced salt solution was 4.051 (95% CI: 1.455–11.281), for the presence of preoperative iris posterior synechiae 12.868 (95% CI: 3.511–47.165), and the OR for postoperative AC fibrin deposition was 6.012 (95% CI: 1.186–30.468). Conclusion: Preoperative iris posterior synechiae, C3F8 gas tamponade, postoperative AC fibrin deposition and the single-piece IOL could increase the rates of iris posterior synechiae after phacovitrectomy.
Comparative Permeation Studies of Nondiluted and Diluted Betamethasone-17-Valerate Semisolid Formulations through Isolated Human Stratum Corneum and Artificial Skin Construct
Authors: Mitriaikina S. , Müller-Goymann C.C.
Published: February 2009

Purpose of the Study: This article deals with a comparative study of the permeation of the halogenated corticosteroid betamethasone-17-valerate (BM-17-V) through isolated human stratum corneum (SC) and artificial skin constructs (ASC) from different semisolid formulations described in the German Pharmacopoeia, i.e. wool fat alcohol ointment (WO), basis cream DAC (German Drug Code) and commercial products containing BM-17-V 0.1% weight such as Celestan-V® cream, Celestan-V® ointment, and Soderm® ointment. In this study, pharmacopoeial ointment and cream were loaded in each case with BM-17-V. Methods: In vitropermeation experiments of BM-17-V were carried out in Franz diffusion cells using isolated human SC and ASC. Permeation data from both systems were compared statistically and those data were linearly correlated to each other. The saturation concentrations of BM-17-V within the formulations were calculated based on microscopical examination. The BM-17-V was metabolized via BM-21-V into betamethasone (BM) as its hydrolization product during the permeation experiments across SC. Since ASC has a higher enzymatic activity and less barrier qualities than SC, furthering the course of the permeation experiment, not only BM permeates besides the noncatabolized drug BM-17-V, but also 9α-fluoro-prednisolone as another decomposition product. The detection of BM-17-V and its degradation product was performed by high-performance liquid chromatography. Results: It was observed that the permeation of BM across ASC from all the formulations tested was higher by factors 9.7–27.7 than that from the same formulations permeating through SC, while the permeation sequence of the tested formulations was almost the same for SC and ASC. Afterwards the effect of the dilution of the semisolid formulations containing BM-17-V 0.1% weight on their permeation through SC was examined by mixing them with different ointments and a cream base. The permeation rate of BM from the dilution of Soderm ointment with WO and from WO diluted with different formulations from the German Pharmacopoeia were very similar.
Subjective Benefits of Sequential Bilateral Cochlear Implantation in Young Children after 18 Months of Implant Use
Authors: Scherf Fanny , Van Deun Lieselot , van Wieringen Astrid , Wouters Jan , Desloovere Christian , Dhooge Ingeborg , Offeciers Erwin , Deggouj Naïma , De Raeve Leo , Wuyts Floris L. , Van de Heyning Paul
Published: February 2009

Objective: To investigate the subjective benefits of bilateral cochlear implantation in 33 young children after 18 months of second implant use. Method: The Würzburg questionnaire inquiring into a range of hearing functions was filled out by the parents. Additional data concerning the daily life and well-being of the children were gathered with an open-ended questionnaire and the Categories of Auditory Performance. Results were analyzed separately for children younger and older than 6 years at the time of the second implantation. Results: After 18 months of bilateral implant use 30% of the younger and 6% of the older children made the transition to an auditory-oral communication. In this period, 15% of all children switched to mainstream schools. The parents reported an evolution of their children’s auditory abilities, which included a better sound and speech perception. Multiregression analysis revealed that early hearing aid fitting and the age at the second cochlear implantation significantly contributed to the variance of the Würzburg results. Conclusions: The results indicate a wide range of positive subjective changes associated with bilateral cochlear implantation, even in older children. This progress led to a better and easier communication and a better integration in the normal-hearing world.
High Ambient Glucose Augments Angiotensin II-Induced Proinflammatory Gene mRNA Expression in Human Mesangial Cells: Effects of Valsartan and Simvastatin
Authors: Naito Masayo , Shenoy Ananth , Aoyama Isao , Koopmeiners Joseph S. , Komers Radko , Schnaper H. William , Bomsztyk Karol
Published: February 2009

Background: Hyperglycemia may potentiate the adverse renal effects of angiotensin II (AII). In the kidney, the major target of AII action is the glomerular mesangial cell, where its hemodynamic and proinflammatory action contributes to renal injury. AII action is mediated by several types of cell receptors. Among those, the AT1 receptor has been best studied using specific AII receptor blockers (ARBs). These agents have emerged as major new modalities in the prevention and amelioration of renal disease where the ARB renoprotective anti-inflammatory properties could be more important than previously appreciated. Like the ARBs, statins may also modulate inflammatory responses that are renoprotective and complement their cholesterol-lowering effects. Aim: The aim of this project was to (i) identify a repertoire of proinflammatory mesangial cell AII-inducible mRNAs; (ii) determine if the AII-induced proinflammatory mRNA responses depend on ambient glucose, and (iii) test the anti-inflammatory effectiveness of an ARB, valsartan, either alone or in combination with a statin, simvastatin. Results/Conclusions: Using high-density microarrays and real-time PCR we identified several AII-inducible proinflammatory mesangial genes that exhibited augmented mRNA responses in high-glucose milieu. Valsartan blocked the AII-induced mRNA expression of proinflammatory genes (i.e. MCP-1, LIF and COX-2) maintained in normal and high glucose. These observations add to the mounting evidence that ARBs have anti-inflammatory effects in the kidney, a beneficial effect that may be more important in protecting renal function in diabetic patients. While simvastatin inhibited expression of some mRNAs encoding chemokines/cytokines, it enhanced expression of mRNA encoding COX-2, a key mediator of inflammation. Thus, the non-cholesterol effects of statins on inflammatory responses appear complex.
M1 Protein Allows Group A Streptococcal Survival in Phagocyte Extracellular Traps through Cathelicidin Inhibition
Authors: Lauth Xavier , von Köckritz-Blickwede Maren , McNamara Case W. , Myskowski Sandra , Zinkernagel Annelies S. , Beall Bernard , Ghosh Partho , Gallo Richard L. , Nizet Victor
Published: February 2009

M1 protein contributes to Group A Streptococcus (GAS) systemic virulence by interfering with phagocytosis and through proinflammatory activities when released from the cell surface. Here we identify a novel role of M1 protein in the stimulation of neutrophil and mast cell extracellular trap formation, yet also subsequent survival of the pathogen within these DNA-based innate defense structures. Targeted mutagenesis and heterologous expression studies demonstrate M1 protein promotes resistance to the human cathelicidin antimicrobial peptide LL-37, an important effector of bacterial killing within such phagocyte extracellular traps. Studies with purified recombinant protein fragments mapped the inhibition of cathelicidin killing to the M1 hypervariable N-terminal domain. A survey of GAS clinical isolates found that strains from patients with necrotizing fasciitis or toxic shock syndrome were significantly more likely to be resistant to cathelicidin than GAS M types not associated with invasive disease; M1 isolates were uniformly resistant. We conclude increased resistance to host cathelicidin and killing within phagocyte extracellular traps contribute to the propensity of M1 GAS strains to produce invasive infections.
Ageing, Mate Preferences and Sexuality: A Mini-Review
Authors: Oberzaucher Elisabeth , Grammer Karl
Published: February 2009

The evolutionary constraints that lead to the evolution of sexual reproduction are framed by the better repair mechanisms that repair fatal mutations, as well as the need for variable immune systems imposed on large organisms by parasites, such as viruses and bacteria. Besides the evolution of sexual reproduction, these factors also affect mate choice, especially as regards the gene complex that encodes the immune system. The need to increase both the likelihood of gametes to encounter each other as well as sufficient provision of nutrition for the offspring then leads to the evolution of two sexes: large numbers of small mobile sperms ensure that gametes meet, whereas large egg cells full of energy provide for the zygote, thus leading to a developmental advantage. The asymmetric investment in the offspring then affects not only mate choice criteria, but also cognitive strategies. Men place more importance on youthfulness and fertility than women, who regard resource holding potential as a more relevant criterion. Consequently, female jealousy is connected to endangered access to resources, whereas male jealousy is rooted in paternal uncertainty. Cognitive adaptations developed to ensure reproductive success show sex differences, such as in error management. The most obvious function of sexual behavior is reproduction. To foster the benefits for the offspring, reproduction partners should also develop an emotional bond, which is mediated by hormones connected to sexual intercourse. With increasing age, reproduction loses importance, while pair bonding functions remain relevant. Therefore, sexuality never ceases to be part of a relationship.
Neutrophil Extracellular Traps: A Strategic Tactic to Defeat Pathogens with Potential Consequences for the Host
Authors: Medina Eva
Published: February 2009

Recent investigations have highlighted new roles for neutrophils in the biology of infection and inflammation. Neutrophils are one of the main players in the innate immune system and actively contribute to host defense by killing pathogens. Added to their ability to eliminate microorganisms by phagocytosis, neutrophils can also kill microbes by capturing them in extracellular structures consisting of granule proteins and DNA called neutrophil extracellular traps (NETs). This review summarizes the recent advancements regarding the structure, production and biological relevance of NETs.
Activation of the Human Contact System on Neutrophil Extracellular Traps
Authors: Oehmcke Sonja , Mörgelin Matthias , Herwald Heiko
Published: February 2009

Pattern recognition is an integral part of the innate immune system. The human contact system has been shown to interact with the surface of many bacterial and fungal pathogens, and once activated leads to the generation of antimicrobial peptides and the proinflammatory mediator bradykinin. Here we show that apart from these surfaces also neutrophil extracellular traps (NETs) provide a surface that allows the binding and activation of the contact system. In addition, we present evidence that M1 protein, a streptococcal surface protein, in concert with human fibrinogen triggers polymorphonuclear neutrophils to form NETs.
Parental Perspective of the Benefits of Genetic Testing in Children with Congenital Deafness
Authors: Geelhoed E.A. , Harrison K. , Davey A. , Walpole I.R.
Published: February 2009

Aim: The aim of the study was to assess the perceived value of genetic testing for congenital deafness in families attending a clinical genetic outpatients department at a children’s hospital. The major testing objective was to provide information regarding deafness etiology, although families were advised that changes in treatment as a result of the test were unlikely. Using a ‘willingness-to-pay’ approach in the form of a questionnaire developed by Ryan et al. [J Med Genet 2003;40:1–5], parents were surveyed for their attitudes and willingness to pay for genetic testing. Results: Forty-nine families provided data for analysis, representing 56% of clinic attendances throughout the period. Most of the parents were themselves unaffected by hearing loss (93%) and none were deaf, although almost a quarter (22%) reported a family member born deaf. Parents considered the major benefit gained from testing was to better achieve clarity of understanding arising from discussion and the possible ascertainment of etiology. The average sum parents were willing to pay for genetic testing was 200 Australian dollars (AUD, 2007) or approximately 123 euros (EUR), ranging from 150 to 295 AUD according to ability to pay (as measured by gross income). However, the amount that even the highest income level were willing to pay underestimated the full economic cost of genetic testing. Conclusion: Genetic testing for deafness is highly valued by affected families despite the current limited overall expectation of definitive genetic diagnosis or changes in treatment. Parents considered the major benefits to be a better understanding of congenital deafness and the potential for assignment of causality.
Transbronchial Cryobiopsy: A New Tool for Lung Biopsies
Authors: Babiak Alexander , Hetzel Jürgen , Krishna Ganesh , Fritz Peter , Moeller Peter , Balli Tahsin , Hetzel Martin
Published: February 2009

Background: Specimens from transbronchial lung biopsies lack sufficient quality due to crush artifact and are generally too small for diagnosis of diffuse lung diseases. Flexible cryoprobes have been shown to be useful in therapeutic bronchoscopy. We introduce a novel technique for obtaining lung biopsies bronchoscopically, using a flexible cryoprobe. Objectives: The purpose of this study was to show the feasibility of using a cryoprobe to obtain lung biopsies during flexible bronchoscopy. Methods: Forty-one patients with radiographic signs of diffuse lung disease were selected for transbronchial biopsy. During flexible bronchoscopy, conventional transbronchial biopsies using forceps were done first. Then a flexible cryoprobe was introduced into the selected bronchus under fluoroscopic guidance. Once brought into position, the probe was cooled and then retracted with the frozen lung tissue being attached on the probe’s tip. The tissue was processed for histology. After establishing a diagnosis, the specimen area was measured using a digital morphometry system. Results: We evaluated the biopsy samples of 41 patients. The mean specimen area was 5.82 mm2 (0.58–20.88 mm2) taken by forceps compared to 15.11 mm2 obtained using the cryoprobe (2.15–54.15 mm2, p < 0.01). Two patients had a pneumothorax which resolved with tube thoracostomy. Biopsy-associated bleeding did not require any intervention. Transbronchial cryobiopsy contributed in a substantial number of cases to a definitive diagnosis. Conclusions: Transbronchial cryobiopsy is a novel technique which allows to obtain large biopsy samples of lung parenchyma that exceed the size and quality of forceps biopsy samples. Prospective trials are needed to compare this technique with surgical lung biopsy for diagnosis of diffuse lung diseases.
Substantially Reduced Calcaneal Bone Ultrasound Parameters in Severe Untreated Asthma
Authors: Mainz Jochen G. , Kaiser Werner A. , Beck James F. , Mentzel Hans-Joachim
Published: February 2009

We report the case of a 9-year-old male patient with severe bronchial asthma, who had not received inhaled corticosteroids (ICS) despite persistent asthma symptoms and 2 life-threatening asthma attacks. ICS application had been avoided for fear of systemic side effects like bone density loss. Quantitative ultrasound (QUS) is a noninvasive and ionizing radiation-free method to assess bone characteristics. In our clinic, regional age-, sex-, weight- and height-related references for calcaneal QUS were generated from 3,299 children and adolescents. Ultrasonic bone parameters from our patient were substantially reduced at the initial measurement when the patient was 6 years of age by up to –3.75 standard deviation scores. At the same time, chronic pulmonary hyperinflation led to severe thoracic deformation. Only when a second life-threatening asthma attack almost required mechanical ventilation, the family was convinced to have ICS therapy initiated. This treatment led to clinical stabilization including normalization of the thoracic shape. In parallel, QUS values improved continuously up to the normal range. Our case report emphasizes the risks of omitting ICS in severe asthma for fear for systemic side effects. On the contrary, ICS in low to medium dosages may allow regular growth, bone development and normalization of previously severe effects of the disease itself.
Bronchoalveolar Lavage Fluid Eosinophils Are Correlated to Natural Killer Cells in Eosinophilic Pneumonias
Authors: Papakosta D. , Manika K. , Kyriazis G. , Kontakiotis T. , Gioulekas D. , Polyzoni T. , Bouros D. , Patakas D.
Published: February 2009

Background: Eosinophilic lung diseases comprise a group of heterogeneous pulmonary disorders linked by increased eosinophils in bronchoalveolar lavage fluid (BALF). There is supporting evidence that natural killer (NK) cells participate in the regulation of eosinophilic inflammation. Objective: Our aim was to investigate the relationship between eosinophils and NK cells in BALF in patients with different interstitial lung diseases (ILDs) focusing on eosinophilic pneumonias. Methods: Of 114 patients who presented with increased BALF eosinophils (>5%), 74 patients were classified into the following groups: 27 had eosinophilic pneumonia (EP), 17 had idiopathic pulmonary fibrosis (IPF), 16 had hypersensitivity pneumonitis (HSP) and 14 had cryptogenic organizing pneumonia (COP/BOOP). Total BALF cells, cell density and cell differential counts were assessed and lymphocyte subsets CD3+, CD4+, CD8+, CD19+, CD3–CD16/56+ (NK) and CD3+CD16/56+ (NKT) were determined by flow cytometry. Results: Significant differences were observed in the percentages of lymphocytes (p < 0.001) and CD3+CD16/56+ cells (p = 0.023) among patient groups. In patients with EP, the percentage of eosinophils correlated positively with the number of CD3–CD16/56+ cells (r = 0.522, p = 0.005), the percentage of CD3–CD16/56+ cells (r = 0.690, p < 0.001), and the absolute count of CD3+CD16/56+ absolute cells (r = 0.609, p = 0.001). However, in patients with IPF, HSP or COP/BOOP, no correlation between the percentage of eosinophils and CD3–CD16/56+ or CD3+CD16/56+ cells was observed. Conclusions: Eosinophil inflammation seems to develop through a different pathway in EP compared to other ILDs.
Low Aerobic Capacity and High-Fat Diet Contribute to Oxidative Stress and IRS-1 Degradation in the Kidney
Authors: Morris E. Matthew , Whaley-Connell Adam T. , Thyfault John P. , Britton Steven L. , Koch Lauren G. , Wei Yongzhong , Ibdah Jamal A. , Sowers James R.
Published: February 2009

Background/Aims: Insulin receptor (IR-α and IR-β) is reduced in the kidney of insulin-resistant rodents. It is unknown if there are also reductions in insulin receptor substrate (IRS)-1 or if these effects are due to metabolic injury. Thereby, we hypothesized intrinsically high aerobic fitness would protect against high-fat diet (HFD)-induced reactive oxygen species (ROS) and IRS-1 degradation. Methods: We investigated the effects of HFD on triglyceride content, ROS production and IRS-1 degradation in the kidney of high-capacity (HCR)/low-capacity (LCR) rats, a model of intrinsic high and low aerobic capacity. Eighteen-week-old HCR and LCR rats were placed on a HFD or normal chow diet for 7 weeks. Intraperitoneal glucose tolerance, ROS, IR-β, total IRS-1 and ubiquitination were measured. Results: The HCR displayed greater insulin sensitivity and were resistant to HFD-induced insulin resistance. In the LCR kidney, HFD increased ROS potential, and reduced total IR-β and IRS-1 without altering triacylglycerol content. IRS-1 ubiquitination was higher in the LCR than HCR kidney, increased after HFD. Conclusions: Our data support that HFD-mediated kidney ROS is associated with reductions in IRS-1 and systemic insulin resistance. Further, high intrinsic aerobic capacity protects against IRS-1 degradation in the kidney following exposure to HFD.
Pituitary Pars Intermedia of Male Viscacha (Lagostomus maximus maximus): A Morphometric Study of Seasonal and Age-Related Changes in Immunohistochemistry
Authors: Acosta Mariano , Mohamed Fabian
Published: February 2009

The aim of this work was to study the pituitary pars intermedia in seasonally captured adult male and immature viscachas by immunohistochemistry and image analysis. The pituitary pars intermedia exhibited a well-developed parenchyma with scarce connective tissue and vascularization. It was formed by a close association of melanotrophs and folliculostellate cells. The folliculostellate cells were stellate in shape with cytoplasmic processes, and they originated follicles with PAS-positive colloid inside. The morphometric parameters of melanotrophs, follicular colloid and folliculostellate cells (S-100-ir and GFAP-ir) varied seasonally and in relation to age. These parameters showed minimal values in the adult males captured in winter and in immature animals, and they were maximal in summer. The percentage of vimentin-positive area of the folliculostellate cells was maximal in immature animals, decreased in relation to age and did not vary seasonally in the adult animals. The greatest development of pars intermedia in the adult animals in relation to the immature ones is probably related to the adults’ adaptation to the semiarid environment. The expression of the tested proteins suggests a probable neuroectodermic origin for the folliculostellate cells of the viscacha pituitary pars intermedia. In addition, the cytoplasmic processes of folliculostellate cells might originate an intercellular communication network inside the pars intermedia. The decrease in the morphometric parameters melanotrophs, follicular colloid and folliculostellate cells in winter suggests a low endocrine activity of this zone. This fact might be due to the effect of the short photoperiod and high melatonin serum levels.
Iron Oxide Particles for Atheroma Imaging
Authors: Tang Tjun Y. , Muller Karin H. , Graves Martin J. , Li Zhi Y. , Walsh Stewart R. , Young Victoria , Sadat Umar , Howarth Simon P.S. , Gillard J.H.
Published: February 2009

The selection of patients for vascular interventions has been solely based on luminal stenosis and symptomatology. However, histological data from both the coronary and carotid vasculature suggest that other plaque features such as inflammation may be more important in predicting future thromboembolic events. Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation in humans. It has reached the stage of development to have been recently used in an interventional drug study to not only assess inflammatory progression but also select patients at high risk. This article reviews the basic science behind the use of USPIO contrast agents in atheroma MR imaging, experimental work in animals, and how this has led to the emergence of this promising targeted imaging platform for assessment of high risk carotid atherosclerosis in humans.
Monocytes in Acute Coronary Syndromes
Authors: Shantsila Eduard , Lip Gregory Y.H.
Published: February 2009

The aim of this overview is to summarize the available data on the involvement of monocytes in the pathological processes related to the development of acute coronary syndromes and the recovery of damaged areas, the prevention of excessive inflammatory and procoagulant response, and the restoration of microcirculation (angiogenesis).
CD146 and its Soluble Form Regulate Monocyte Transendothelial Migration
Authors: Bardin Nathalie , Blot-Chabaud Marcel , Despoix Nicolas , Kebir Abdeldjalil , Harhouri Karim , Arsanto Jean-Pierre , Espinosa Leon , Perrin Pierre , Robert Stéphane , Vely Frédéric , Sabatier Florence , Le Bivic André , Kaplanski Gilles , Sampol José , Dignat-George Françoise
Published: February 2009

Objectives—

During inflammation, cell adhesion molecules are modulated or redistributed for leukocyte transmigration. Among molecules at the interendothelial junction, CD146 is involved in cell–cell cohesion and permeability, but its role in monocyte transmigration is unknown.

Methods and Results—

TNF enhanced CD146 expression at the junction and apical membrane of human umbilical veins endothelial cells (HUVECs) through CD146 synthesis and intracellular store redistribution. In addition, TNF increased the release of a soluble form (sCD146) through a metalloproteinase-dependent mechanism. The redistribution of CD146 to the junction led us to investigate its role in monocyte transmigration using THP1 and freshly isolated monocytes. Evidence that CD146 contributes to monocyte transmigration was provided by inhibition experiments using anti-CD146 antibodies and CD146 siRNA in HUVECs. In addition, sCD146 specifically bound both monocytes and HUVECs and dose-dependently increased monocyte transmigration. Assessment of sCD146 binding on immobilized CD146 failed to evidence any homophilic interaction. Together, our data suggest endothelial CD146 binds heterophilically with a yet unknown ligand on monocytes.

Conclusions—

Our results demonstrate that CD146 is regulated by the inflammatory cytokine TNF and that CD146 and sCD146 are both involved in monocyte transendothelial migration during inflammation.
Human IL-8 Regulates Smooth Muscle Cell VCAM-1 Expression in Response to Endothelial Cells Exposed to Atheroprone Flow
Authors: Hastings Nicole E. , Feaver Ryan E. , Lee Monica Y. , Wamhoff Brian R. , Blackman Brett R.
Published: February 2009

Objective—

Interleukin-8 (IL-8) is a soluble human-specific chemokine implicated in the development of the chronic inflammatory disease atherosclerosis. Recently, we showed that atheroprone hemodynamics induced IL-8 secretion from endothelial cells (ECs) concurrent with increased EC/smooth muscle cell (SMC) VCAM-1 expression in a human hemodynamic coculture model. Despite an IL-8 association with inflammation, we show here that blocking IL-8 activity during atheroprone flow resulted in increased levels of EC/SMC VCAM-1 expression. We tested the hypothesis that IL-8 limits SMC VCAM-1 expression in response to inflammatory stimuli, either atheroprone flow or cytokine interleukin-1β (IL-1β) addition.

Methods and Results—

Atheroprone flow increased monocyte adhesion in both EC/SMCs, concurrent with the induction of VCAM-1 protein. VCAM-1 antisera attenuated this response. IL-1β upregulated VCAM-1 in SMCs by 3-fold, a response inhibited by the addition of IL-8 at 24 hours. Neither IL-1β nor IL-8 induced proliferation or migration. Neutralization of the IL-8 receptor, CXCR2, further induced VCAM-1 in the presence of IL-1β, and phospho-p38 was required for NF-κB activation and VCAM-1 expression. Additionally, IL-8 reduced p38 activation and NF-κB activity induced by IL-1β alone.

Conclusions—

Together, these findings provide evidence for a novel role whereby IL-8 limits the inflammatory response in ECs/SMCs via VCAM-1 modulation.
Mechanistic Insights Into Nitrite-Induced Cardioprotection Using an Integrated Metabolomic/Proteomic Approach
Authors: Perlman David H. , Bauer Selena M. , Ashrafian Houman , Bryan Nathan S. , Garcia-Saura Maria F. , Lim Chee C. , Fernandez Bernadette O. , Infusini Giuseppe , McComb Mark E. , Costello Catherine E. , Feelisch Martin
Published: February 2009

Nitrite has recently emerged as an important bioactive molecule, capable of conferring cardioprotection and a variety of other benefits in the cardiovascular system and elsewhere. The mechanisms by which it accomplishes these functions remain largely unclear. To characterize the dose response and corresponding cardiac sequelae of transient systemic elevations of nitrite, we assessed the time course of oxidation/nitros(yl)ation, as well as the metabolomic, proteomic, and associated functional changes in rat hearts following acute exposure to nitrite in vivo. Transient systemic nitrite elevations resulted in: (1) rapid formation of nitroso and nitrosyl species; (2) moderate short-term changes in cardiac redox status; (3) a pronounced increase in selective manifestations of long-term oxidative stress as evidenced by cardiac ascorbate oxidation, persisting long after changes in nitrite-related metabolites had normalized; (4) lasting reductions in glutathione oxidation (GSSG/GSH) and remarkably concordant nitrite-induced cardioprotection, which both followed a complex dose–response profile; and (5) significant nitrite-induced protein modifications (including phosphorylation) revealed by mass spectrometry-based proteomic studies. Altered proteins included those involved in metabolism (eg, aldehyde dehydrogenase 2, ubiquinone biosynthesis protein CoQ9, lactate dehydrogenase B), redox regulation (eg, protein disulfide isomerase A3), contractile function (eg, filamin-C), and serine/threonine kinase signaling (eg, protein kinase A R1α, protein phosphatase 2A A R1-α). Thus, brief elevations in plasma nitrite trigger a concerted cardioprotective response characterized by persistent changes in cardiac metabolism, redox stress, and alterations in myocardial signaling. These findings help elucidate possible mechanisms of nitrite-induced cardioprotection and have implications for nitrite dosing in therapeutic regimens.
Lipid Incorporation Inhibits Src-Dependent Assembly of Fibronectin and Type I Collagen by Vascular Smooth Muscle Cells
Authors: Frontini Matthew J. , O'Neil Caroline , Sawyez Cynthia , Chan Bosco M.C. , Huff Murray W. , Pickering J. Geoffrey
Published: February 2009

A vital role of vascular smooth muscle cells (SMCs) is to stabilize the artery wall by elaborating fibrils of type I collagen. This is especially important in atherosclerotic lesions. However, SMCs in these lesions can be laden with lipids and the impact of this modification on collagen fibril formation is unknown. To address this, we converted human vascular SMCs to a foam cell state by incubating them with either LDL or VLDL. Biochemical markers of a SMC phenotype were preserved. However, microscopic tracking revealed a profound perturbation in the ability of the cells to assemble collagen fibrils, reducing assembly by up to 79%. This dysfunction was mirrored by an inability of smooth muscle foam cells to assemble fibronectin. Lipid-loaded SMCs did not display a generalized defect in the actin cytoskeleton and the formation of vinculin-containing focal adhesion complexes was preserved. However, lipid-loaded SMCs were unable to assemble fibrillar adhesion complexes and clustering of tensin and α5β1 integrin was disordered. Moreover, phosphorylation of tensin, required for fibrillar adhesion complex formation, was suppressed by up to 57%, with a concomitant decrease in activation of Src and FAK and restriction of activated Src to the cell edges. Forced activation of Src-FAK signaling in lipid-engorged SMCs rescued both fibrillar adhesion formation and fibrillogenesis. We conclude that lipid accumulation by SMCs disables the machinery for collagen and fibronectin assembly. This previously unknown relationship between atherogenic lipids and integrin-based signaling could underlie plaque vulnerability.
Clinical and Imaging Data at 5 Days as a Surrogate for 90-Day Outcome in Ischemic Stroke
Authors: Johnston Karen C. , Barrett Kevin M. , Ding Yong Hong , Wagner Douglas P.
Published: February 2009

Background and Purpose—

A simple, easily measured surrogate outcome measure for use in early treatment trials for acute ischemic stroke therapies would be highly valued. We hypothesized that day-5 NIH stroke scale score (NIHSS) and day-5 diffusion weighted imaging (DWI) volume would predict clinical outcome better than either alone and could be considered as a possible surrogate outcome in early phase acute stroke trials.

Methods—

The prospective Acute Stroke Accurate Prediction (ASAP) trial included a prespecified subgroup evaluated for early outcome. Logistic regression analysis was used to assess the prediction of modified Rankin (mRankin) of 0 or 1.

Results—

A total of 204 subjects completed the substudy, and 116 (57%) had excellent outcome at 3 months. The area under the ROC curve (AUC) for day-5 NIHSS predicting 3-month excellent outcome was 0.84; for DWI volume predicting outcome was 0.76, and for the multivariable model combining both was 0.84.

Conclusions—

The results of the early outcome substudy of the ASAP trial suggest that early stroke severity and infarct volume measures are predictive of 3-month excellent outcome. In our data set the DWI volume does not add clinically relevant information in predicting 3-month outcome. Validation of these results is required.
Homocysteine-Lowering Therapy and Stroke Risk, Severity, and Disability
Authors: Saposnik Gustavo , Ray Joel G. , Sheridan Patrick , McQueen Matthew , Lonn Eva ,   the HOPE 2 Investigators
Published: February 2009

Background and Purpose—

Elevated total homocysteine is associated with a higher risk of cerebrovascular disease. It is not known whether lowering homocysteine impacts on stroke risk, both in terms of severity and ischemic vs hemorrhagic stroke subtypes. Our aim was to determine whether vitamin therapy reduces the risk of ischemic and hemorrhagic stroke, as well as stroke-related disability.

Methods—

We analyzed stroke outcomes among participants of the Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial that randomized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or matching placebo, for 5 years.

Results—

Among 5522 participants, stroke occurred in 258 (4.7%) individuals during a mean of 5 years of follow-up. The geometric mean homocysteine concentration decreased by 2.2 μmol/L in the vitamin therapy group and increased by 0.80 μmol/L in the placebo group. The incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group (hazard ratio [HR], 0.75; 95% CI, 0.59–0.97). Vitamin therapy also reduced the risk of nonfatal stroke (HR, 0.72; 95% CI, 0.54–0.95) but did not impact on neurological deficit at 24 hours (
P
=0.45) or functional dependence at discharge or at 7 days (OR, 0.95; 95% CI, 0.57–1.56). In subgroup analysis, patients aged younger than 69 years, from regions without folic acid food fortification, with higher baseline cholesterol and homocysteine levels, and those not receiving antiplatelet or lipid-lowering drugs at enrollment had a larger treatment benefit.

Conclusions—

Lowering of homocysteine with folic acid and vitamins B6 and B12 did reduce the risk of overall stroke, but not stroke severity or disability.
Responsiveness and Validity of Three Outcome Measures of Motor Function After Stroke Rehabilitation
Authors: Hsieh Yu-wei , Wu Ching-yi , Lin Keh-chung , Chang Ya-fen , Chen Chia-ling , Liu Jung-sen
Published: February 2009

Background and Purpose—

This study investigated and compared the responsiveness and validity of the Fugl-Meyer Assessment (FMA), the Action Research Arm Test (ARAT), and the Wolf Motor Function Test (WMFT) for patients after stroke rehabilitation.

Methods—

A total of 57 patients with stroke received 1 of 3 rehabilitation treatments for 3 weeks. At pretreatment and posttreatment, the 3 outcome measures, as well as the Functional Independence Measure (FIM) as the external criterion, were administered. The standardized response mean (SRM) and the Wilcoxon signed rank test were used to examine the responsiveness. Construct validity and predictive validity were examined by the Spearman correlation coefficient (ρ).

Results—

The responsiveness of the FMA, ARAT, and WMFT functional ability scores was large (SRM=0.95–1.42), whereas the WMFT performance time score was small (SRM=0.38). The responsiveness of the FMA was significantly larger than those of the ARAT and the WMFT-TIME, but not the WMFT functional ability scores. With respect to construct validity, correlations between the FMA and other measures were relatively high (ρ=0.42–0.76). The FMA and the WMFT performance time scores at pretreatment had moderate predictive validity with the FIM scores at posttreatment (ρ=0.42–0.47). In addition, the ARAT and the WMFT functional ability scores revealed a low predictive validity with the FIM (ρ=0.17–0.26).

Conclusions—

The results support the FMA and the WMFT-FAS are suitable to detect changes over time for patients after stroke rehabilitation. While simultaneously considering the responsiveness and validity attributes, the FMA may be a relatively sound measure of motor function for stroke patients based on our results. Further research based on a larger sample is needed to replicate the findings.
Incidence, Types, Risk Factors, and Outcome of Stroke in a Developing Country
Authors: Sridharan Sapna E. , Unnikrishnan J.P. , Sukumaran Sajith , Sylaja P.N. , Nayak S. Dinesh , Sarma P. Sankara , Radhakrishnan Kurupath
Published: February 2009

Background and Purpose—

Despite increasing burden of stroke in developing countries, population-based data are rare. Through the Trivandrum Stroke Registry, we intend to assess incidence, types, risk factors, and outcome of stroke among urban and rural dwellers of a South Indian community.

Methods—

We ascertained all first-ever strokes occurring among 741 000 urban and 185 000 rural inhabitants of Trivandrum, Kerala. In addition to Steps 1 and 2 of World Health Organization STEPS Stroke Manual, we used multiple supplementary methods to maximize ascertainment of nonfatal and nonhospitalized fatal stroke events in the community.

Results—

During a 6-month period, 541 strokes were registered, 431 in the urban and 110 in the rural communities. Stroke occurred at a median age of 67 years; only 3.8% of patients were aged ≤40 years. Adjusted annual incidence rates per 100 000 were 135 (95% confidence interval 123 to 146) for total, 135 (122–148) for urban, and 138 (112–164) for rural populations, and 74.8 (66.3 to 83.2), 10.1 (7.0 to 13.2), and 4.2 (2.2 to 6.1) for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, respectively. There was more stroke of undetermined type in the rural community. One or more modifiable risk factors were identified in 90% patients. More rural male patients smoked tobacco. The 28th day case fatality rate was 24.5% for urban and 37.1% for rural populations (
P
=0.011).

Conclusions—

There are more similarities than differences between developing and developed countries in the epidemiology of stroke. Compared to urban stroke patients, rural ones are less likely to be optimally investigated and treated.
Using Historical Lesion Volume Data in the Design of a New Phase II Clinical Trial in Acute Stroke
Authors: Whitehead John , Bolland Kim , Valdès-Márquez Elsa , Lihic Anela , Ali Myzoon , Lees Kennedy
Published: February 2009

Background and Purpose—

Clinical research into the treatment of acute stroke is complicated, is costly, and has often been unsuccessful. Developments in imaging technology based on computed tomography and magnetic resonance imaging scans offer opportunities for screening experimental therapies during phase II testing so as to deliver only the most promising interventions to phase III. We discuss the design and the appropriate sample size for phase II studies in stroke based on lesion volume.

Methods—

Determination of the relation between analyses of lesion volumes and of neurologic outcomes is illustrated using data from placebo trial patients from the Virtual International Stroke Trials Archive. The size of an effect on lesion volume that would lead to a clinically relevant treatment effect in terms of a measure, such as modified Rankin score (mRS), is found. The sample size to detect that magnitude of effect on lesion volume is then calculated. Simulation is used to evaluate different criteria for proceeding from phase II to phase III.

Results—

The odds ratios for mRS correspond roughly to the square root of odds ratios for lesion volume, implying that for equivalent power specifications, sample sizes based on lesion volumes should be about one fourth of those based on mRS. Relaxation of power requirements, appropriate for phase II, lead to further sample size reductions. For example, a phase III trial comparing a novel treatment with placebo with a total sample size of 1518 patients might be motivated from a phase II trial of 126 patients comparing the same 2 treatment arms.

Discussion—

Definitive phase III trials in stroke should aim to demonstrate significant effects of treatment on clinical outcomes. However, more direct outcomes such as lesion volume can be useful in phase II for determining whether such phase III trials should be undertaken in the first place.