bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcium Balance in Dialysis Is Best Managed by Adjusting Dialysate Calcium Guided by Kinetic Modeling of the Interrelationship between Calcium Intake, Dose of Vitamin D Analogues and the Dialysate Calcium Concentration
Authors: Gotch Frank , Levin Nathan W. , Kotanko Peter
Published: January 2010

Calcium mass balance (CaMB) is determined by the difference between Ca absorbed between dialyses (CaAbs) and the Ca removed during dialysis (JdCa2+). A mathematical model to quantify (1) CaAbs as a function of Ca intake (CaINT) and the doses of vitamin D analogues, and (2) JdCa2+ as a function of Ca2+ dialysance, the mean plasma Ca2+ (MCpiCa2+) minus dialysate Ca2+ (CdiCa2+), ultrafiltration rate (Qf) and treatment time is developed in this paper. The model revealed a basic design flaw in clinical studies of Ca-based as opposed to non-Ca-based binders in that CdiCa2+ must be reduced with the Ca-based binders in order to avoid a positive CaMB relative to the non-Ca-based binders. The model was also used to analyze CaMB in 320 Renal Research Institute hemodialysis patients and showed that all patients irrespective of type of binder were in positive CaMB between dialyses (mean ± SD 160 ± 67 mg/day) with current doses of vitamin D analogues prescribed. Calculation of the optimal CdiCa2+ for the 320 Renal Research Institute patients revealed that in virtually all instances, the CdiCa2+ required for neutral CaMB, where Ca removal during dialysis was equal to Ca accumulation between dialyses, was less than 2.50 mEq/l and averaged about 2.00 mEq/l. This sharply contradicts the recent KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease – Mineral and Bone Disorder, that suggests a CdiCa2+ of 2.5–3.0 mEq/l. Review of the KDIGO work group discussions shows that this discrepancy stems from the unwarranted work group assumption that intradialytic CaMB is zero. We strongly believe that this guideline for dialysate Ca2+ is inappropriate and should be modified to more realistically reflect the needs of dialysis patients.
Water for Haemodialysis and Related Therapies: Recent Standards and Emerging Issues
Authors: Hoenich Nicholas A. , Levin Robert , Ronco Claudio
Published: January 2010

Dialysis is a well-established and widely used procedure. For a number of years, the focus has been on ensuring that water used in the preparation of dialysis fluid meets the required chemical and microbiological quality and complies with national or international standards which have recently been updated. Continued vigilance is required, in particular when new chemicals such as silver-stabilized hydrogen peroxide and chlorine dioxide are used to prevent growth of Legionella bacteria in hospital water systems, since residues are harmful to patients receiving dialysis. To achieve the required quality, large volumes of water are processed, and a substantial portion is sent to waste via the municipal sewer systems with little attempt to reuse such water on site. In view of concern about global warming and climate change, there is a need to adopt a more environmentally conscious attitude requiring dialysis providers to focus on this aspect of water usage.
Laparoscopic Surgery for Transverse and Descending Colon Carcinomas Has Comparable Safety to Laparoscopic Surgery for Colon Carcinomas at Other Sites
Authors: Yamamoto Seiichiro , Fujita Shin , Akasu Takayuki , Yamaguchi Tomohiro , Moriya Yoshihiro
Published: January 2010

Background/Aims: Many randomized clinical trials have been performed to treat colon carcinoma with the exclusion of transverse colon carcinoma or descending colon carcinoma. The aim of the present study was to investigate the difference in surgical outcomes between laparoscopic surgery for transverse/descending colon carcinomas and that for other colon carcinomas. Methods: A total prospective registry of 455 patients with colon carcinoma, who initially underwent laparoscopic surgery between June 2001 and December 2008, were reviewed. Surgical outcomes were compared between laparoscopic surgery for transverse/descending colon carcinoma (transverse/descending group, n = 89) and laparoscopic surgery for other colon carcinomas (other group, n = 366). Results: There was no perioperative mortality. Preoperative clinical characteristics were similar between the two groups. Regarding operative and postoperative results, the surgical duration and intraoperative blood loss were significantly greater in the transverse/descending group. However, there were no significant differences in the postoperative course between groups, and the complication rates between the groups were similar. Conclusion: Laparoscopic surgery for transverse/descending carcinoma can be performed safely, and shows short-term benefits comparable to those in patients who underwent laparoscopic surgery for other colon carcinomas.
Massive Hemoptysis: An Update on the Role of Bronchoscopy in Diagnosis and Management
Authors: Sakr L. , Dutau H.
Published: January 2010

Hemoptysis is frequently encountered in clinical practice, and may be the presenting symptom of a number of diseases. Although massive hemoptysis accounts for only 5–15% of episodes, it should always be considered as a life-threatening condition that warrants effective assessment and management. In this article, we review the literature with regard to the definition, etiology, epidemiology, pathophysiology, diagnosis and treatment of massive hemoptysis, with special emphasis on the role of bronchoscopy as a diagnostic and therapeutic tool. We briefly present the circumstances under which the use of rigid bronchoscopy should be preferred for controlling massive bleeding. Moreover, we address the crucial importance of multidisciplinary collaboration by illustrating the roles of endovascular therapy and surgery in the optimal management of massive hemoptysis.
GnRH-Induced [Ca2+]i-Signalling Patterns in Mouse Gonadotrophs Recorded from Acute Pituitary Slices in vitro
Authors: Sánchez-Cárdenas Claudia , Hernández-Cruz Arturo
Published: January 2010

In this study we used [Ca2+]i imaging to monitor GnRH-induced intracellular Ca2+ signalling from dozens of gonadotrophs in mouse male pituitary slices. Responses of individual cells vary in magnitude, latency, duration and frequency of oscillation. Approximately 20% of gonadotrophs in situ display Ca2+ oscillations of increasing frequency at higher [GnRH] and biphasic (peak-plateau) responses at saturating [GnRH]. Nevertheless, this orderly progression, reported in cultured cells, is less well organized in 55% of cells. Furthermore, approximately 30% cells display non-oscillatory GnRH responses, reminiscent of immature gonadotrophs. Dose-response curves of slices from different animals suggest inter-individual differences in GnRH sensitivity. When the same dose of GnRH is applied repeatedly, individual cell responses are almost identical both in latency, oscillatory pattern and duration resembling the ‘Ca2+ fingerprint’ phenomenon. In addition, gonadotrophs in situare arranged in small clusters with similar GnRH-induced intracellular Ca2+-signalling patterns. Neighbouring gonadotrophs within clusters often display synchronized GnRH-induced responses with high correlation indices (>0.75). Nevertheless, synchronized responses between pairs of gonadotrophs are unaffected by incubation with blockers of gap-junction channels or P2X receptor channels, suggesting that they are not mediated by gap junctions or ATP. Alternative explanations are discussed, including pseudo-synchronization. In summary, while gonadotrophs in situ display GnRH-induced responses similar to those observed in cultured cells, different patterns and novel aspects of functional organization were found which deserve further investigation. This study on GnRH-induced Ca2+ signalling in the acute mice pituitary gland might be of potential relevance for characterizing GnRH actions in gonadotrophs in transgenic and knockout animals.
Influence of Aging on Movement of the Hyoid Bone and Epiglottis during Normal Swallowing: A Motion Analysis
Authors: Kang Bo-Sung , Oh Byung-Mo , Kim Il Soo , Chung Sun Gun , Kim Sang Jun , Han Tai Ryoon
Published: January 2010

Background: The age-related effects on various aspects of swallowing have been reported in studies on the temporal relationship between hyolaryngeal movement and bolus location, as well as the extent of hyolaryngeal movement. However, few studies have described the temporal and spatial relationships concurrently. Objective: The main purpose of this study was to define the kinematics of the hyoid bone and epiglottis, during swallowing, on the temporal and spatial relationships concurrently in healthy subjects, and to investigate the influence of aging on hyolaryngeal movement. Methods: We performed a two-dimensional motion analysis of the hyoid bone and epiglottis using videofluoroscopy images in 69 normal subjects. The trajectories of the hyolaryngeal movement and passage of a bolus were superimposed to form one plot. Temporal measurements included initiation and duration of the hyoid bone and epiglottis movement compared to their movement with the bolus. The spatial measurements included vertical and horizontal excursion of the hyoid bone, and the rotational angle of the epiglottis. Results: The duration of supraglottis closure, and the maximal vertical excursion of the hyoid bone were increased in older subjects, more than 65 years of age, compared to younger subjects (p < 0.05). Other temporal and spatial measurements were not statistically significant in the comparisons among the age groups. The vertical distance of the cervical vertebra was related to vertical excursion of the hyoid bone (p = 0.002), and the horizontal distance from the chin to the cervical vertebra was related to the horizontal excursion of the hyoid bone (p = 0.003). Conclusion: This paper describes a method for assessing temporal and spatial relationships of hyolaryngeal movement, and the passage of a bolus during swallowing. The two-dimensional kinematic swallowing motion analyses that were developed provided useful data that changed with age.
ANRIL
Expression Is Associated With Atherosclerosis Risk at Chromosome 9p21
Authors: Holdt Lesca M. , Beutner Frank , Scholz Markus , Gielen Stephan , Gäbel Gábor , Bergert Hendrik , Schuler Gerhard , Thiery Joachim , Teupser Daniel
Published: January 2010

Objective—

We tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this locus and associated with atherosclerosis risk.

Methods and Results—

We replicated the locus for coronary artery disease (
P
=0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque (
P
=0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts
EU741058
and
NR_003529
of
antisense noncoding RNA in the INK4 locus
(
ANRIL
) were significantly increased in carriers of the risk haplotype (
P
=2.1×10
−12
and
P
=1.6×10
−5
, respectively). In contrast, transcript
DQ485454
remained unaffected, suggesting differential expression of
ANRIL
transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of
ANRIL
transcripts was directly correlated with severity of atherosclerosis (
EU741058
and
NR_003529
;
P
=0.02 and
P
=0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as
CDKN2A
,
CDKN2B
,
C9orf53
, and
MTAP
.

Conclusion—

Our data provide robust evidence for an association of
ANRIL
but not
CDKN2A, CDKN2B, C9orf53
, and
MTAP
, with atherosclerosis and Chr9p21 genotype in a large cohort.
Loss of the Serum Response Factor Cofactor, Cysteine-Rich Protein 1, Attenuates Neointima Formation in the Mouse
Authors: Lilly Brenda , Clark Kathleen A. , Yoshigi Masaaki , Pronovost Stephen , Wu Meng-Ling , Periasamy Muthu , Chi Mei , Paul Richard J. , Yet Shaw-Fang , Beckerle Mary C.
Published: January 2010

Objective—

Cysteine-rich protein (CRP) 1 and 2 are cytoskeletal lin-11 isl-1 mec-3 (LIM)-domain proteins thought to be critical for smooth muscle differentiation. Loss of murine CRP2 does not overtly affect smooth muscle differentiation or vascular function but does exacerbate neointima formation in response to vascular injury. Because CRPs 1 and 2 are coexpressed in the vasculature, we hypothesize that CRPs 1 and 2 act redundantly in smooth muscle differentiation.

Methods and Results—

We generated
Csrp1
(gene name for CRP1) null mice by genetic ablation of the
Csrp1
gene and found that mice lacking CRP1 are viable and fertile. Smooth muscle–containing tissues from
Csrp1
-null mice are morphologically indistinguishable from wild-type mice and have normal contractile properties. Mice lacking CRPs 1 and 2 are viable and fertile, ruling out functional redundancy between these 2 highly related proteins as a cause for the lack of an overt phenotype in the
Csrp1
-null mice.
Csrp1
-null mice challenged by wire-induced arterial injury display reduced neointima formation, opposite to that seen in
Csrp2
-null mice, whereas
Csrp1/Csrp2
double-null mice produce a wild-type response.

Conclusion—

Smooth muscle CRPs are not essential for normal smooth muscle differentiation during development, but may act antagonistically to modulate the smooth muscle response to pathophysiological stress.
An Autocrine Linkage Between Matrix Metalloproteinase-14 and Tie-2 Via Ectodomain Shedding Modulates Angiopoietin-1–Dependent Function in Endothelial Cells
Authors: Onimaru Mitsuho , Yonemitsu Yoshikazu , Suzuki Hanako , Fujii Takaaki , Sueishi Katsuo
Published: January 2010

Objective—

The angiopoietin (Ang)–Tie-2 system plays a critical role during fetal and adult angiogenesis. Herein, we explored the Tie-2 shedding–related molecular mechanisms and the pathophysiological significance.

Methods and Results—

By using a mouse hindlimb ischemia model, we observed dissociated expression between the full-length Tie-2 (fTie-2) protein and Tie-2 mRNA in thigh muscles 1 day after an ischemic operation, suggesting that fTie-2 expression was modified through the posttranscriptional regulation in vivo. A soluble form of Tie-2 produced in human umbilical vein endothelial cells was dramatically suppressed by treatment with siRNA–matrix metalloproteinase (MMP) 14 or tissue inhibitor of metalloproteinase 3, resulting in an increase in cellular fTie-2 and thereby enhancing Ang-1–dependent Akt phosphorylation and Akt-dependent endothelial functions, such as Ang-2 downregulation or an increase of endothelial viability. Phorbol-12-myristate-13 acetate (PMA) upregulates MMP-14 mRNA via protein kinase C–extracellular signal–regulated kinase pathways, and enhanced soluble Tie-2 production in an MMP-14–dependent manner, resulting in a reduction of cellular fTie-2. In addition, the PMA-induced soluble Tie-2 was mediated by the protein kinase C–extracellular signal–regulated kinase signaling pathways. Finally, downregulation of tissue inhibitor of metalloproteinase 3 and upregulation of MMP-14 mRNA were confirmed in ischemic thigh muscles 1 day after the operation.

Conclusion—

An autocrine linkage between the endothelial protein kinase C–MMP-14 axis and Tie-2 shedding was shown to be a novel regulatory mechanism for the Ang–Tie-2 system and may play a role in modulating endothelial function during angiogenesis.
Propionyl-
l
-Carnitine Improves Postischemic Blood Flow Recovery and Arteriogenetic Revascularization and Reduces Endothelial NADPH-Oxidase 4–Mediated Superoxide Production
Authors: Stasi Maria Antonietta , Scioli Maria Giovanna , Arcuri Gaetano , Mattera Giovan Giuseppe , Lombardo Katia , Marcellini Marcella , Riccioni Teresa , De Falco Sandro , Pisano Claudio , Spagnoli Luigi Giusto , Borsini Franco , Orlandi Augusto
Published: January 2010

Objective—

The beneficial effect of the natural compound propionyl-
l
-carnitine (PLC) on intermittent claudication in patients with peripheral arterial disease is attributed to its anaplerotic function in ischemic tissues, but inadequate information is available concerning action on the vasculature.

Methods and Results—

We investigated the effects of PLC in rabbit hind limb collateral vessels after femoral artery excision, mouse dorsal air pouch, chicken chorioallantoic membrane, and vascular cells by angiographic, Doppler flow, and histomorphometrical and biomolecular analyses. PLC injection accelerated hind limb blood flow recovery after 4 days (
P
<0.05) and increased angiographic quadriceps collateral vascularization after 7 days (
P
<0.001) Histomorphometry confirmed the increased vascular area (
P
<0.05), with unchanged intramuscular capillary density. PLC-induced dilatative adaptation, and growth was found associated with increased inducible nitric oxide synthase and reduced arterial vascular endothelial growth factor and intracellular adhesion molecule-1 expression. PLC also increased vascularization in air pouch and chorioallantoic membrane (
P
<0.05), particularly in large vessels. PLC increased endothelial and human umbilical vascular endothelial cell proliferation and rapidly reduced inducible nitric oxide synthase and NADPH-oxidase 4–mediated reactive oxygen species production in human umbilical vascular endothelial cells; NADPH-oxidase 4 also regulated NF-κB–independent intracellular adhesion molecule-1 expression.

Conclusion—

Our results provided strong evidence that PLC improves postischemic flow recovery and revascularization and reduces endothelial NADPH-oxidase–related superoxide production. We recommend that PLC should be included among therapeutic interventions that target endothelial function.
FTY720 Stimulates 27-Hydroxycholesterol Production and Confers Atheroprotective Effects in Human Primary Macrophages
Authors: Blom Tomas , Bäck Nils , Mutka Aino-Liisa , Bittman Robert , Li Zaiguo , de Lera Angel , Kovanen Petri T. , Diczfalusy Ulf , Ikonen Elina
Published: January 2010

Rationale
:

The synthetic sphingosine analog FTY720 is undergoing clinical trials as an immunomodulatory compound, acting primarily via sphingosine 1-phosphate receptor activation. Sphingolipid and cholesterol homeostasis are closely connected but whether FTY720 affects atherogenesis in humans is not known.

Objective
:

We examined the effects of FTY720 on the processing of scavenged lipoprotein cholesterol in human primary monocyte-derived macrophages.

Methods and Results
:

FTY720 did not affect cholesterol uptake but inhibited its delivery to the endoplasmic reticulum, reducing cellular free cholesterol cytotoxicity. This was accompanied by increased levels of Niemann–Pick C1 protein (NPC1) and ATP-binding cassette transporter (ABC)A1 proteins and increased efflux of endosomal cholesterol to apolipoprotein A-I. These effects were not dependent on sphingosine 1-phosphate receptor activation. Instead, FTY720 stimulated the production of 27-hydroxycholesterol, an endogenous ligand of the liver X receptor, leading to liver X receptor–induced upregulation of ABCA1. Fluorescently labeled FTY720 was targeted to late endosomes, and the FTY720-induced upregulation of ABCA1 was NPC1-dependent, but the endosomal exit of FTY720 itself was not.

Conclusions
:

We conclude that FTY720 decreases cholesterol toxicity in primary human macrophages by reducing the delivery of scavenged lipoprotein cholesterol to the endoplasmic reticulum and facilitating its release to physiological extracellular acceptors. Furthermore, FTY720 stimulates 27-hydroxycholesterol production, providing an explanation for the atheroprotective effects and identifying a novel mechanism by which FTY720 modulates signaling.
The Benefits of Intravenous Thrombolysis Relate to the Site of Baseline Arterial Occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET)
Authors: De Silva Deidre A. , Brekenfeld Caspar , Ebinger Martin , Christensen Søren , Barber P. Alan , Butcher Kenneth S. , Levi Christopher R. , Parsons Mark W. , Bladin Christopher F. , Donnan Geoffrey A. , Davis Stephen M.
Published: January 2010

Background and Purpose—

In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET).

Methods—

EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator (tPA) in the 3- to 6-hour time window. Arterial obstruction site and degree were rated on magnetic resonance angiography blinded to treatment allocation and outcomes.

Results—

In 101 EPITHET patients, 87 had adequate quality magnetic resonance angiography, of whom 54 had baseline arterial obstruction. Infarct growth attenuation was greater in those with tPA treatment compared to placebo among patients with middle cerebral artery (MCA) obstruction (
P
=0.037). The treatment benefit of tPA over placebo in attenuating infarct growth was greater for MCA than internal carotid artery (ICA) obstruction (
P
=0.060). With tPA treatment, good clinical outcome was more likely with MCA than with ICA obstruction (
P
=0.005). Most patients with ICA obstruction did not achieve good clinical outcome, whether treated with tPA (100%) or placebo (77%). The study was underpowered to prove any treatment benefit of tPA among patients with any or severe degree of arterial obstruction.

Conclusions—

Arterial obstruction site strongly predicts outcomes. ICA obstruction carries a uniformly poor prognosis, whereas good outcomes with MCA obstruction are associated with tPA therapy.
Enlarged Perivascular Spaces on MRI Are a Feature of Cerebral Small Vessel Disease
Authors: Doubal Fergus N. , MacLullich Alasdair M.J. , Ferguson Karen J. , Dennis Martin S. , Wardlaw Joanna M.
Published: January 2010

Background and Purpose—

Enlarged perivascular spaces in the brain are common but generally overlooked and of uncertain pathophysiology. They may reflect underlying cerebral small vessel disease. We determined whether enlarged perivascular spaces were associated with lacunar stroke subtype and white matter hyperintensities, markers of established small vessel disease.

Materials and Methods—

We prospectively recruited patients with acute ischemic lacunar or cortical stroke. Age-matched nonstroke control subjects were also recruited. We rated basal ganglia and centrum semiovale enlarged perivascular spaces 0 to 4 (0=none, 4=>40) on T2-weighted MRI and white matter hyperintensities. We compared enlarged perivascular spaces between stroke subtypes and control subjects and assessed associations with vascular risk factors and white matter hyperintensities.

Results—

We recruited 350 patients; 129 lacunar, 124 cortical stroke, and 97 age-matched control subjects. Adjusting for vascular risk factors and white matter hyperintensities, total enlarged perivascular spaces were associated with lacunar stroke subtype (
P
=0.04) in the acute stroke group (n=253); basal ganglia enlarged perivascular spaces were associated with lacunar stroke subtype (
P
=0.003), deep (
P
=0.02) and periventricular white matter hyperintensities (
P
=0.01); in all 350 subjects, total enlarged perivascular spaces were associated with deep (
P
<0.001) and periventricular (
P
<0.001) white matter hyperintensities.

Conclusions—

Although prevalent in patients with vascular risk factors and stroke, enlarged perivascular spaces are specifically associated with lacunar ischemic stroke and white matter hyperintensities. Further studies should determine the mechanism of this association while including adequate controls to account for stroke and vascular risk factors. Enlarged perivascular spaces should not be overlooked in studies of small vessel disease.
Assessment and Improvement of Figures to Visually Convey Benefit and Risk of Stroke Thrombolysis
Authors: Gadhia Jigneshkumar , Starkman Sidney , Ovbiagele Bruce , Ali Latisha , Liebeskind David , Saver Jeffrey L.
Published: January 2010

Background and Purpose—

Deciding whether to use intravenous fibrinolytic therapy for acute cerebral ischemia within 3 hours of onset is challenging for patients, family members, and health care providers. Visual displays can permit individuals to rapidly understand response patterns to therapy. This study sought to evaluate, refine, and improve existing visual aids for stroke fibrinolytic decision-making.

Methods—

Existing visual aids were identified by Medline search and querying of national guideline organizations, pharmaceutical manufacturers, and stroke specialists, and were rated on a formal 8-point quality rating scale (0, lowest; 8, highest). Based on available instruments, new visual displays were developed to improve informed decision-making in routine practice.

Results—

Two existing visual aids were identified, one from an emergency medicine society and one from a pharmaceutical company. Both were comparison visual displays of outcomes with and without treatment; no decision matrix visual aid was found. Both scored 4.0 on the quality scale, showing defects of effect size distortion, privileging less salient outcomes, dissimilar representation by treatment group, and limited stakeholder participation in generation. Revised versions of these graphics were developed with higher quality scores (6.75 and 7.75). In addition, a new decision matrix display with quality score 8.0 was developed that complements the numeric text of a national patient education tool developed jointly by US neurology, emergency medicine, and stroke patient organizations.

Conclusion—

Existing visual aids for stroke fibrinolysis decision-making have deficiencies. New visual displays are now available to convey the health benefits and risks of fibrinolytic stroke therapy efficiently and informatively to patients and family members.
An Imbalance Between CD36 and ABCA1 Protein Expression Favors Lipid Accumulation in Stroke-Prone Ulcerated Carotid Plaques
Authors: Isoviita Pia M. , Nuotio Krista , Saksi Jani , Turunen Riitta , Ijäs Petra , Pitkäniemi Janne , Soinne Lauri , Kaste Markku , Kovanen Petri T. , Lindsberg Perttu J.
Published: January 2010

Background—

CD36 is a macrophage scavenger receptor mediating the uptake of modified lipoproteins, whereas the ABCA1 transporter counteracts this effect by mediating cellular lipid efflux. Based on a DNA microarray, we previously found that the
CD36
and
ABCA1
genes were overexpressed in symptom-causing carotid plaques (CP) compared with nonsymptom-causing CP. To evaluate their role in CP destabilization, we conducted detailed immunohistochemical studies on the localization of lipids, CD36 and ABCA1 proteins, extravasated red blood cells, and atheromatous/necrotic tissue.

Methods—

Ninety-two high-grade (>70%) stenosing CP obtained from carotid endarterectomy were Oil-red-O–stained for evaluation of neutral lipids. Subgroups of nonsymptom-causing and symptom-causing CP (n=42) were further analyzed by immunostaining adjacent histological sections against CD36 and ABCA1 and examining them microscopically.

Results—

When compared with nonsymptom-causing CP, the amount of extracellular lipid and the expression of CD36 protein were elevated in symptom-causing CP, but no difference was found in ABCA1 expression. These observations were also confirmed when ulcerated and nonulcerated CP were compared. In ulcerated CP, CD36 protein expression was higher than that of ABCA1, and the opposite was true in nonulcerated CP. CD36 colocalized with extravasated red blood cells and atheromatous or necrotic areas in the various types of CP.

Conclusions—

Our results suggest that an imbalance between lipid influx (CD36) and efflux (ABCA1) favors lipid accumulation in macrophages of ulcerated CP, thus contributing to plaque destabilization. Furthermore, colocalization of CD36 protein with red blood cells suggests that intraplaque hemorrhages may contribute to the lipid load and thus the stability of CP.
The Utility of Evolving Simulated Robot Morphology Increases with Task Complexity for Object Manipulation
Authors: Bongard Josh
Published: January 2010

Embodied artificial intelligence argues that the body and brain play equally important roles in the generation of adaptive behavior. An increasingly common approach therefore is to evolve an agent's morphology along with its control in the hope that evolution will find a good coupled system. In order for embodied artificial intelligence to gain credibility within the robotics and cognitive science communities, however, it is necessary to amass evidence not only for how to co-optimize morphology and control of adaptive machines, but why. This work provides two new lines of evidence for why this co-optimization is useful: Here we show that for an object manipulation task in which a simulated robot must accomplish one, two, or three objectives simultaneously, subjugating more aspects of the robot's morphology to selective pressure allows for the evolution of better robots as the number of objectives increases. In addition, for robots that successfully evolved to accomplish all of their objectives, those composed of evolved rather than fixed morphologies generalized better to previously unseen environmental conditions.
Acute Effects of Atorvastatin on Glomerular Filtration Rate, Tubular Function, Blood Pressure, and Vasoactive Hormones in Patients With Type 2 Diabetes
Authors: Paulsen L. , Matthesen S. K. , Bech J. N. , Starklint J. , Pedersen E. B.
Published: January 2010

Statins improve cardiovascular survival in both nondiabetic and diabetic patients, but diabetic patients benefit more, in both primary and secondary prevention. Statins seem to have multiple effects beyond cholesterol lowering, that is, pleiotropic effects that may include changes in renal function. This study tests the hypothesis that acute treatment with atorvastatin may change glomerular filtration rate, tubular function, vasoactive hormones, blood pressure, and pulse rate in patients with type 2 diabetes. In an acute, randomized, placebo‐controlled, double‐blinded, crossover trial, the effects of atorvastatin on renal function, vasoactive hormones, blood pressure, and pulse rate are measured in 21 patients with type 2 diabetes. Patients are randomized to either 2 doses of atorvastatin 80 mg or placebo before 2 different study days. Treatment with atorvastatin induces a significant reduction in fractional sodium excretion compared with placebo, and sodium clearance tends to be reduced. No significant differences in glomerular filtration rate, albumin/creatinine ratio, vasoactive hormones, and blood pressure by acute treatment with atorvastatin are found in diabetic patients. Acute treatment with atorvastatin reduces renal fractional sodium excretion in patients with type 2 diabetes. No changes are measured in glomerular filtration rate, albumin/creatinine ratio, vasoactive hormones, and blood pressure.
Single‐Dose Pharmacokinetics and Pharmacodynamics of Sergliflozin Etabonate, a Novel Inhibitor of Glucose Reabsorption, in Healthy Volunteers and Patients With Type 2 Diabetes Mellitus
Authors: Hussey Elizabeth K. , Clark Richard V. , Amin Dipti M. , Kipnes Mark S. , O'Connor‐Semmes Robin L. , O'Driscoll Eilis C. , Leong Jenny , Murray Sharon C. , Dobbins Robert L. , Layko Debbi , Nunez Derek J. R.
Published: January 2010

Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium‐dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5–500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at ∼30 to 45 minutes postdose (tmax), and had a plasma elimination half‐life (t1/2) of ∼0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose‐related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings.
Urban Neighborhood Context and Mortality in Late Life
Authors: Wight Richard G. , Cummings Janet R. , Karlamangla Arun S. , Aneshensel Carol S.
Published: January 2010

Objective: To examine the contextual effects of urban neighborhood characteristics on mortality among older adults. Method: Data are from the Study of Assets and Health Dynamics Among the Oldest Old (AHEAD). Death is assessed between the baseline assessment (1993) and the first follow-up interview (1995). Neighborhood data are from the 1990 Census. Results: The log odds of dying between the two time points are higher in high proportion Hispanic neighborhoods, net of individual-level sociodemographic variables, but this effect is partly mediated by individual-level health. The log odds of dying are significantly ( p < .05) lower in affluent neighborhoods, controlling for all individual-level variables and neighborhood proportion Hispanic. Discussion: There are survival-related benefits of living in an affluent urban neighborhood, which we posit may be manifested through the diffusion of innovations in health care and health-promotion activities.
On Magnetorheologic Elastomers for Vibration Isolation, Damping, and Stress Reduction in Mass-varying Structures
Authors: Collette Christophe , Kroll Gregory , Saive Gregory , Guillemier Vincent , Avraam More
Published: January 2010

This article considers two devices based on a magnetorheological elastomer (MRE): an MRE isolator under a frequency-varying harmonic excitation and a MRE Dynamic Vibration Absorber (DVA) mounted on a frequency-varying structure under a random excitation. In the first case, it is shown that the commandability of the elastomer improves the reduction of the RMS value of the body displacement by 10%. In the second case, it is shown on a simple example that a MRE DVA, while not optimal, can reduce the stress in the structure about 50% better than a classical DVA when the mass of the structure changes 35%. This makes them suitable to avoid high stress in mass-varying structures, and delay some damage mechanisms like the emergence of cracks and fatigue.
Perioperative Coagulopathy, Bleeding, and Hemostasis During Cardiac Surgery
Authors: Makar Moody , Taylor Jamie , Zhao Maxnu , Farrohi Ali , Trimming Michael , D’Attellis Nicola
Published: January 2010

Cardiac surgery patients use 10%-25% of the blood products transfused annually in the United States. The transfusion of red blood cells or blood products has been the subject of intense scrutiny over the past 10 years. Bleeding after cardiac surgery can be surgical or nonsurgical and lead to hemodynamic compromise and surgical reexploration. Because hemorrhage and blood product transfusions are associated with multiple negative outcomes, including increased mortality, it is prudent to understand the mechanisms responsible for nonsurgical bleeding. This review focuses on the physiology of the normal coagulation and fibrinolysis, risk factors associated with patients presenting for cardiac surgery, impairments of normal hemostasis associated with cardiac surgery and cardiopulmonary bypass (CPB), and potential interventions to reduce perioperative blood loss and blood transfusion.
Mechanism of attenuation of leptin signaling under chronic ligand stimulation
Authors: Knobelspies Holger , Zeidler Julia , Hekerman Paul , Bamberg-Lemper Simone , Becker Walter
Published: January 2010

Background

Leptin is an adipocyte-derived hormone that acts via its hypothalamic receptor (LEPRb) to regulate energy balance. A downstream effect essential for the weight-regulatory action of leptin is the phosphorylation and activation of the latent transcription factor STAT3 by LEPRb-associated Janus kinases (JAKs). Obesity is typically associated with chronically elevated leptin levels and a decreased ability of LEPRb to activate intracellular signal transduction pathways (leptin resistance). Here we have studied the roles of the intracellular tyrosine residues in the negative feedback regulation of LEPRb-signaling under chronic leptin stimulation.

Results

Mutational analysis showed that the presence of either Tyr985 and Tyr1077 in the intracellular domain of LEPRb was sufficient for the attenuation of STAT3 phosphorylation, whereas mutation of both tyrosines rendered LEPRb resistant to feedback regulation. Overexpression and RNA interference-mediated downregulation of suppressor of cytokine signaling 3 (SOCS3) revealed that both Tyr985 and Tyr1077 were capable of supporting the negative modulatory effect of SOCS3 in reporter gene assays. In contrast, the inhibitory effect of SOCS1 was enhanced by the presence of Tyr985 but not Tyr1077. Finally, the reduction of the STAT-phosphorylating activity of the LEPRb complex after 2 h of leptin stimulation was not accompanied by the dephosphorylation or degradation of LEPRb or the receptor-associated JAK molecule, but depended on Tyr985 and/or Tyr1077.

Conclusions

Both Tyr985 and Tyr1077 contribute to the negative regulation of LEPRb signaling. The inhibitory effects of SOCS1 and SOCS3 differ in the dependence on the tyrosine residues in the intracellular domain of LEPRb.
Analysis of the heat shock response in mouse liver reveals transcriptional dependence on the nuclear receptor peroxisome proliferator-activated receptor α (PPARα)
Authors: Vallanat Beena , Anderson Steven P , Brown-Borg Holly M , Ren Hongzu , Kersten Sander , Jonnalagadda Sudhakar , Srinivasan Rajagopalan , Corton J Christopher
Published: January 2010

Background

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. Many of these genes are also transcriptionally regulated by heat shock (HS) through activation by HS factor-1 (HSF1). We hypothesized that there are interactions on a genetic level between PPARα and the HS response mediated by HSF1.

Results

Wild-type and PPARα-null mice were exposed to HS, the PPARα agonist WY-14,643 (WY), or both; gene and protein expression was examined in the livers of the mice 4 or 24 hrs after HS. Gene expression profiling identified a number of Hsp family members that were altered similarly in both mouse strains. However, most of the targets of HS did not overlap between strains. A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARα-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARα-null mice that are known targets of PPARγ co-activator-1 (PGC-1) family members. Pretreatment of PPARα-null mice with WY increased expression of PGC-1β and target genes and prevented the down-regulation of the mitochondrial genes by HS. A comparison of HS genes regulated in our dataset with those identified in wild-type and HSF1-null mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARα and HSF1, a number require both factors for HS responsiveness.

Conclusions

These findings demonstrate that the PPARα genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARα in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.
Risk of incident or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the German biologics register RABBIT
Authors: Strangfeld Anja , Hierse Franka , Rau Rolf , Burmester Gerd-Ruediger , Krummel-Lorenz Brigitte , Demary Winfried , Listing Joachim , Zink Angela
Published: January 2010

Introduction

We used the data of the German biologics register RABBIT, a nationwide prospective cohort study, to investigate the risk of new or recurrent malignancy in patients with rheumatoid arthritis (RA) receiving biologics compared to conventional disease modifying anti-rheumatic drugs (DMARDs).

Methods

The analysis was based on patients with RA enrolled in RABBIT at the start of a biologic or conventional DMARD therapy between 01 May 2001 and 31 December 2006. Incidences of first or recurrent malignancies were analysed separately. A nested case-control design was used to investigate the risk of developing a first malignancy. Matching criteria were: age, gender, follow-up time, disease activity score based on 28 joint counts (DAS28) at study entry, smoking status, and selected chronic co-morbid conditions (obstructive or other lung disease, kidney, liver or gastrointestinal disease, psoriasis).

Results

A prior malignancy was reported in 122 out of 5,120 patients. Fifty-eight of these patients had received anti-TNFα agents, 9 anakinra, and 55 conventional DMARDs at study entry. In 14 patients (ever exposed to anti-TNFα: eight, to anakinra: one) 15 recurrent cancers were observed. The average time period since the onset of the first malignancy was nine years. Crude recurrence rates per 1,000 patient-years (pyrs) were 45.5 for patients exposed to anti-TNFα agents, 32.3 for anakinra patients and 31.4 for patients exposed to DMARDs only (Incidence rate ratio anti-TNFα vs. DMARD = 1.4, P = 0.6.). In patients without prior cancer, 74 patients (70% female, mean age: 61.3) developed a first malignancy during the observation. This corresponds to an incidence rate (IR) of 6.0/1,000 pyrs. Forty-four of these patients were ever exposed to anti-TNFα treatment (IR = 5.1/1,000 pyrs). In a nested case-control study comparing cancer patients to cancer-free controls, 44 of the cancer patients and 44 of the cancer-free controls were ever exposed to anti-TNFα agents (P = 1.0).

Conclusions

No significant differences in the overall incidence of malignancies in patients exposed or unexposed to anti-TNFα or anakinra treatment were found. The same applied to the risk of recurrent malignancies. However, in particular this last finding needs further validation in larger data sets.
Recent breast cancer incidence trends according to hormone therapy use: the California Teachers Study cohort
Authors: Marshall Sarah F , Clarke Christina A , Deapen Dennis , Henderson Katherine , Largent Joan , Neuhausen Susan L , Reynolds Peggy , Ursin Giske , Horn-Ross Pamela L , Stram Daniel O , Templeman Claire , Bernstein Leslie
Published: January 2010

Introduction

Recent, international declines in breast cancer incidence are unprecedented, and the causes remain controversial. Few data sources can address breast cancer incidence trends according to pertinent characteristics like hormone therapy use history.

Methods

We used the prospective California Teachers Study to evaluate changes in self-reported use of menopausal hormone therapy (HT) between 1995 to 1996 and 2005 to 2006 and age-adjusted breast cancer incidence among 74,647 participants aged 50 years or older. Breast cancer occurrence was determined by linkage with the California Cancer Registry.

Results

During 517,286 woman years of follow up, 565 in situ and 2,668 invasive breast cancers were diagnosed. In situ breast cancer incidence rates in this population did not change significantly from 2000 to 2002 to 2003 to 2005, whereas rates of invasive breast cancer declined significantly by 26.0% from 528.0 (95% confidence intervals (CI) = 491.1, 564.9) per 100,000 women in 2000 to 2002 to 390.6 (95% CI = 355.6, 425.7) in 2003 to 2005. The decline in invasive breast cancer incidence rates was restricted to estrogen receptor-positive tumors. In 1996 to 1999 and 2000 to 2002 invasive breast cancer incidence was higher for women who reported current HT use especially estrogen-progestin (EP) use at baseline than for never or past users; but by 2003 to 2005 rates were comparable between these groups. For women who were taking EP in 2001 to 2002,75% of whom had stopped use by 2005 to 2006, incidence had declined 30.6% by 2003 to 2005 (P = 0.001); whereas incidence did not change significantly for those who never took HT (P = 0.33).

Conclusions

Few data resources can examine prospectively individual HT use and breast cancer diagnosis. Stable in situ breast cancer rates imply consistent levels of screening and suggest recent declines in invasive breast cancer to be explained predominantly by changes in HT use.
Effects of Estradiol on Cerebrospinal Fluid Levels of Agouti-Related Protein in Ovariectomized Rhesus Monkeys
Authors: Xiao Ennian , Kim Andrea J. , Dutia Roxanne , Conwell Irene , Ferin Michel , Wardlaw Sharon L.
Published: January 2010

Hypothalamic proopiomelanocortin (POMC)-derived MSH peptides and the melanocortin receptor antagonist, agouti-related protein (AgRP), interact to regulate energy balance. Both POMC and AgRP neurons express estrogen receptors, but little is known about estrogen regulation of the melanocortin system in the primate. We have therefore examined the effects of physiological doses of estradiol (E2) on POMC and AgRP in lumbar cerebrospinal fluid (CSF) of ovariectomized monkeys. POMC prohormone was measured by ELISA. AgRP was measured by RIA (sensitive for the more biologically active C-terminal AgRP83-132 but also detects full-length AgRP) and by ELISA (measures primarily full length AgRP). In the first experiment, 14 animals were studied before and after 3 wk of E2. CSF POMC did not change, but AgRP(RIA) decreased from 7.9 ± 1.2 to 4.7 ± 1.2 fmol/ml after E2 (P = 0.03) and the POMC/AgRP(RIA) ratio increased from 4.2 ± 0.89 to 6.8 ± 1.04 (P = 0.04). AgRP(ELISA) did not change, but the ratio of AgRP(RIA) compared with AgRP(ELISA) was reduced after E2 (P = 0.02). In the second experiment, 11 animals were studied after 6 wk of E2, and similar changes were noted. The degree of AgRP(RIA) suppression with E2 was inversely related to body mass index (r = 0.569; P = 0.03). These results show for the first time that E2 suppresses AgRP(C-terminal) in CSF, increases the POMC to AgRP ratio, and may decrease AgRP processing, thus leading to increased melanocortin signaling. Furthermore, obesity was associated with resistance to the suppressive effects of E2 on AgRP, analogous to what is seen with obesity and leptin resistance.