bluuebunny/crossref_metadata_2025 huggingface dataset:
PIK3CA Mutations May Be Discordant between Primary and Corresponding Metastatic Disease in Breast Cancer
Authors: Dupont Jensen Jeanette , Laenkholm Anne-Vibeke , Knoop Ann , Ewertz Marianne , Bandaru Raj , Liu Weihua , Hackl Wolfgang , Barrett J. Carl , Gardner Humphrey
Published: October 2010

Purpose: PIK3CA mutations are frequent in breast cancer and activate the PI3K/Akt pathway. Unexpectedly, PIK3CA mutation appears in general to be associated with better outcome. In a cohort of patients where both primary and metastatic lesions were available, the objective was to assess changes in PIK3CA mutations. We wished to discern whether selective pressures occur and the influence of PIK3CA mutation on time to recurrence.

Experimental Design: Formalin-fixed paraffin-embedded tumor blocks were obtained from 104 patients with paired samples from primary tumors and corresponding asynchronous metastatic breast tumors. Samples were analyzed for PIK3CA mutations (exons 9 and 20) as well as immunohistochemical evaluation for PTEN, pAKT, Ki67, ER, and HER2.

Results: PIK3CA mutation was detected in 45% of the primary tumors. Overall, there was a net gain in mutation in metastatic disease, to 53%; nonetheless, there were instances where metastases were wild type in patients with PIK3CA mutant primary tumors. Laser capture microdissection on a subset of cases revealed microheterogeneity for PIK3CA mutational status in the primary tumor. PIK3CA mutants overall showed a significantly longer time to first recurrence than wild type cases (P = 0.03).

Conclusion: PIK3CA mutations occur at high frequency in primary and metastatic breast cancer; these may not necessarily confer increased aggressiveness as mutants had a longer time to recurrence. Because PIK3CA status quite frequently changes between primary and metastatic disease, it emphasizes the necessity of assessing the PIK3CA status in the metastatic lesion for selection of PIK3CA inhibitor therapy. Clin Cancer Res; 17(4); 667–77. ©2010 AACR.
Resistance May Not Be Futile: microRNA Biomarkers for Chemoresistance and Potential Therapeutics
Authors: Allen Kristi E. , Weiss Glen J.
Published: October 2010

Chemoresistance to many commercially available cancer therapeutic drugs is a common occurrence and contributes to cancer mortality as it often leads to disease progression. There have been a number of studies evaluating the mechanisms of resistance and the biological factors involved. microRNAs have recently been identified as playing a role in the regulation of key genes implicated as cancer therapeutic targets or in mechanisms of chemoresistance including EGFR, MDR1, PTEN, Bak1, and PDCD4 among others. This article briefly reviews chemoresistance mechanisms, discusses how microRNAs can play a role in those mechanisms, and summarizes current research involving microRNAs as both regulators of key target genes for chemoresistance and biomarkers for treatment response. It is clear from the accumulating literature that microRNAs can play an important role in chemoresistance and hold much promise for the development of targeted therapies and personalized medicine. This review brings together much of this new research as a starting point for identifying key areas of interest and potentials for future study. Mol Cancer Ther; 9(12); 3126–36. ©2010 AACR.
A Comprehensive Survey of Clonal Diversity Measures in Barrett's Esophagus as Biomarkers of Progression to Esophageal Adenocarcinoma
Authors: Merlo Lauren M.F. , Shah Najaf A. , Li Xiaohong , Blount Patricia L. , Vaughan Thomas L. , Reid Brian J. , Maley Carlo C.
Published: October 2010

Neoplastic progression is an evolutionary process driven by the generation of clonal diversity and natural selection on that diversity within a neoplasm. We hypothesized that clonal diversity is associated with risk of progression to cancer. We obtained molecular data from a cohort of 239 participants with Barrett's esophagus, including microsatellite shifts and loss of heterozygosity, DNA content tetraploidy and aneuploidy, methylation, and sequence mutations. Using these data, we tested all major diversity measurement methods, including genetic divergence and entropy-based measures, to determine which measures are correlated with risk of progression to esophageal adenocarcinoma. We also tested whether the use of different sets of loci and alterations to define clones (e.g., selectively advantageous versus evolutionarily neutral) improved the predictive value of the diversity indices. All diversity measures were strong and highly significant predictors of progression (Cox proportional hazards model, P < 0.001). The type of alterations evaluated had little effect on the predictive value of most of the diversity measures. In summary, diversity measures are robust predictors of progression to cancer in this cohort. Cancer Prev Res; 3(11); 1388–97. ©2010 AACR.
Retinal Vein Occlusion: Current Treatment
Authors: Lattanzio Rosangela , Torres Gimeno Ana , Battaglia Parodi Maurizio , Bandello Francesco
Published: October 2010

Retinal vein occlusion (RVO) is a pathology noted for more than 150 years. Although a lot has been written on the matter, it is still a frequent condition with multifactorial etiopathogenesis with many unclear aspects. The RVO pathogenesis has varied systemic and local implications that make it difficult to elaborate treatment guidelines. The management of the patient with RVO is very complex and a multidisciplinary approach is required in order to identify and correct the associated risk factors. Laser therapy remains the gold standard in RVO, but only modest functional improvement has been shown in branch retinal occlusion forms. Multicenter studies of intravitreal drugs present them as an option to combine with laser. Anti-vascular endothelial growth factor, corticosteroids and sustained-release implants are the future weapons to stop disease progression and get a better visual outcome. Consequently, it is useful to clarify some aspects of the pathology that allow a better patient management.
Incidence, Pattern and Management of Bile Duct Injuries during Cholecystectomy: Experience from a Single Center
Authors: Pottakkat Biju , Vijayahari Ranjith , Prakash Anand , Singh Rajneesh Kumar , Behari Anu , Kumar Ashok , Kapoor Vinay Kumar , Saxena Rajan
Published: October 2010

Background: The incidence and pattern of bile duct injury (BDI) may be underreported because of the heterogeneous referral from multiple institutions. Methods: Retrospective analysis of data from 5,782 cholecystectomies performed between 1989 and 2007 was done. BDI were categorized into Strasberg types. Results: Fifty-seven (1%) patients sustained BDI. Ten of 57 (18%) patients had minor BDI (type A-10), 25/57 (44%) had major BDI (type C-3, type D-14, type E-8) and BDI could not be classified in the remaining 22/57 (39%) patients. Twenty-one of 25 (84%) major BDI were detected at operation – 21/57 (37%) injuries were detected and repaired intra-operatively. The other 36/57 (63%) injuries were detected after operation – 11 were managed expectantly, 5 had endoscopic stenting, 3 underwent percutaneous drainage of bilioma, 1 had a laparoscopic clipping of the subvesical duct, 4 underwent laparotomy and 12 required a combination of interventions. Five of the 57 (9%) patients died. At follow-up, 1 patient developed bile duct stricture which was managed endoscopically. All other patients were doing well at the last follow-up. Conclusions: In experienced centers, most of the major BDI can be detected and managed during cholecystectomy. Good results can be achieved by judicious selection of a combination of interventions in the majority of patients.
School Teachers’ Vocal Use, Risk Factors, and Voice Disorder Prevalence: Guidelines to Detect Teachers with Current Voice Problems
Authors: Bermúdez de Alvear Rosa M. , Barón Francisco Javier , Martínez-Arquero Antonio Ginés
Published: October 2010

Teachers’ voice problems are widely recognized as a consequence of their work. The measurement of vocal demands and risk factors is essential for adjusting occupational safety and health services to this population’s needs. Objectives: To correlate vocal behavior and symptomatology with risk factors and voice disorders, and to further analyze gender influence on these variables. Subjects and Methods: 282 kindergarten and elementary education teachers were surveyed in a cross-sectional study using a self-administered questionnaire. For the purpose of this study, voice disorder prevalence was estimated based on the presence of a vocal effort plus 2 frequent symptoms. Results: 81.5% of teachers reported some degree of vocal effort; more than 60% of subjects evidenced frequent throat paresthesias or vocal fatigue at the end of a working day, and about 55% reported hoarseness. Voice disorder prevalence was 59%. Multivariate logistic regression analysis revealed that female gender, time required to alleviate vocal symptoms, perceived general state of health, prolonged use of the voice, and pupils’ indiscipline significantly increased the odds of having vocal problems. Conclusions: Voice disorders affected most teachers and had a multifactorial nature. Vocal health care is particularly necessary for those subjects reporting vocal effort and more than 2 frequent symptoms.
A Documentation System to Save Time and Ensure Proper Application of the Fiberoptic Endoscopic Evaluation of Swallowing (FEES®)
Authors: Hey Christiane , Pluschinski Petra , Stanschus Soenke , Euler Harald A. , Sader Robert A. , Langmore Susan , Neumann Katrin
Published: October 2010

A properly performed fiberoptic endoscopic evaluation of swallowing (FEES®) is comprehensive and time-consuming. Editing times of FEES protocols and attempts for efficiency maximization are unknown. Here, the protocol editing times of completed FEES examinations were determined. The present study reports the time savings and quality gains of a newly developed documentation system tailored to the FEES standard of Langmore. Four independent examiners analyzed twelve videos of FEES procedures, six without and six with the documentation system. Effectiveness of the documentation system was evaluated according to the times for total evaluation, interpretation, documentation, report writing, and for report completeness. The documentation system reduced editing times and increased report completeness with large effect sizes. Averaged total evaluation time decreased from 42 to 27 min, report completeness increased from 55 to 80%. The use of the documentation system facilitates and improves the assessment of the swallowing process.
The Impact of Rate Reduction and Increased Loudness on Fundamental Frequency Characteristics in Dysarthria
Authors: Tjaden Kris , Wilding Greg
Published: October 2010

Objective: This study examined the extent to which articulatory rate reduction and increased loudness were associated with adjustments in utterance-level measures of fundamental frequency (F₀) variability for speakers with dysarthria and healthy controls that have been shown to impact on intelligibility in previously published studies. More generally, the current study sought to compare and contrast how a slower-than-normal rate and increased vocal loudness impact on a variety of utterance-level F₀ characteristics for speakers with dysarthria and healthy controls. Patients and Methods: Eleven speakers with Parkinson’s disease, 15 speakers with multiple sclerosis, and 14 healthy control speakers were audio recorded while reading a passage in habitual, loud, and slow conditions. Magnitude production was used to elicit variations in rate and loudness. Acoustic measures of duration, intensity and F₀ were obtained. Results and Conclusions: For all speaker groups, a slower-than-normal articulatory rate and increased vocal loudness had distinct effects on F₀ relative to the habitual condition, including a tendency for measures of F₀ variation to be greater in the loud condition and reduced in the slow condition. These results suggest implications for the treatment of dysarthria.
Substance Use Disorders: Findings from a Longitudinal Study of Individuals with and without a History of Developmental Language Disorders
Authors: Mouridsen Svend Erik , Hauschild Karen-Marie
Published: October 2010

Objective: To study the prevalence and types of substance use disorders (SUDs) in adults diagnosed during childhood as having a developmental language disorder (DLD). Patients and Methods: The prevalence rates and types of SUDs in a clinical sample of 469 individuals diagnosed during childhood as having a DLD were compared with SUDs in 2,345 matched controls from the general population without a known history of DLD using data from the nationwide Danish Psychiatric Central Register (DPCR). The average observation time was 34.7 years, and the mean age at follow-up was 35.8 years. Results:Of the 469 individuals with DLD, 12 (2.6%) appeared in the DPCR with an SUD diagnosis, compared with 46 (2.0%) in the control group (p = 0.41; OR 1.3; 95% CI 0.7–2.5). Specific SUDs occurred with a low frequency in both groups. Only cocaine-related disorders were significantly associated with DLD (p = 0.03). Variables at assessment in childhood, i.e. gender, IQ, the presence of a receptive language disorder, and the degrees of receptive and expressive language disorders were not associated with an SUD diagnosis in the DPCR at follow-up. Conclusion: Our findings do not support the hypothesis that DLD is a risk factor for SUD in adulthood.
Advanced Neuroimaging in Children with Nonaccidental Trauma
Authors: Ashwal Stephen , Wycliffe Nathaniel D. , Holshouser Barbara A.
Published: October 2010

Physical abuse associated with nonaccidental trauma (NAT) affects approximately 144,000 children per year in the USA and, frequently, these injuries affect the developing brain. Most infants with suspected NAT are initially evaluated by skull X-rays and computed tomography to determine whether fractures are present, the severity of the acute injury and the need for urgent neurosurgical intervention. Increasingly, magnetic resonance imaging (MRI) is conducted as it provides additional diagnostic and prognostic information about the extent and nature of the injury. In this review, we examine 4 MRI techniques as they apply to children who present acutely after NAT. Susceptibility-weighted imaging is a 3-D high-resolution MRI technique that is more sensitive than conventional imaging in detecting hemorrhagic lesions that are often associated with diffuse axonal injury (DAI). Magnetic resonance spectroscopy acquires metabolite information reflecting neuronal integrity and function from multiple brain regions and provides a sensitive, noninvasive assessment of neurochemical alterations that offers early prognostic information regarding outcome. Diffusion-weighted imaging (DWI) is based on differences in the diffusion of water molecules within the brain and has been shown to be very sensitive in the early detection of ischemic injury. It is now being used to study the direct effects of traumatic injury as well as those due to secondary ischemia. Diffusion tensor imaging is a form of DWI and allows better evaluation of white matter fiber tracts by taking advantage of the intrinsic directionality (anisotropy) of water diffusion in the human brain. It has been shown to be useful in identifying white matter abnormalities after DAI when conventional imaging appears normal. Although these imaging methods have been studied primarily in adults and children with accidental traumatic brain injury, it is clear that they have the potential to provide additional value in the imaging and clinical evaluation of children with NAT.
Allometry and Evolution in the Galago Skull
Authors: Ravosa Matthew J. , Daniel Ashley N. , Costley Destiny B.
Published: October 2010

To probe the ontogenetic bases of morphological diversity across galagos, we performed the first clade-wide analyses of growth allometries in 564 adult and non-adult crania from 12 galagid taxa. In addition to evaluating if variation in galago skull form results from the differential extension/truncation of common ontogenetic patterns, scaling trajectories were employed as a criterion of subtraction to identify putative morphological adaptations in the feeding complex. A pervasive pattern of ontogenetic scaling is observed for facial dimensions across galagids, with 2 genera also sharing relative growth trajectories for masticatory proportions (Galago, Galagoides). As the facial growth series and adult data are largely coincidental, interspecific variation may result from character displacement and consequent selection for size differentiation among sister taxa. Derived configurations of the jaw joint and jaw muscle mechanical advantage in Otolemur and Euoticus appear to facilitate increased gape during scraping behaviors. Differences in aspects of masticatory growth and form characterizing these 2 genera highlight selection to uncouple shared ontogenetic patterns, which occurred via transpositions that retained ancestral scaling patterns. Due to the lack of increased robusticity of load-resisting mandibular elements in Otolemur and Euoticus, there is little evidence to suggest that exudativory in galagos results in correspondingly higher masticatory stresses.
Reversal of Hartmann’s Procedure after Perforated Diverticulitis through the Stomal Side without Additional Incisions: The SIR Procedure
Authors: Vermeulen J. , Leijtens J.W.A. , Mannaerts G.H.H.
Published: October 2010

Aims: Reversal of Hartmann’s procedure (HP) is a complex operation and only performed in 50–60% of the patients. Stomal incision reversal (SIR), a new minimally invasive procedure for HP reversal, was assessed and compared to the standard surgical approach. Methods: 16 patients who had undergone HP for perforated diverticulitis underwent HP reversal by SIR. The only incision in SIR is the one to release the end colostomy. Intra-abdominal adhesiolysis is done manually. A stapled end-to-end colorectal anastomosis is created. The 16 patients who underwent SIR were compared with 32 control patients who were matched according to gender, age, American Society of Anesthesiologists (ASA) classification and Hinchey stage. Results: The operation time was shorter after SIR than after reversal by laparotomy [75 min (58–208) vs. 141 min (85–276); p < 0.001]. Patients after SIR had a shorter hospital stay than patients after laparotomy [4 days (2–22) vs. 9 days (4–64); p < 0.001]. The numbers of total postoperative surgical complications (early and late) were not different (p = 0.13). The anastomotic leakage rate was similar in both groups (6%). The conversion rate in the SIR group was 19% (n = 3). Conclusion: SIR compared favorably with HP reversal by laparotomy in terms of operation time and hospital stay, without increasing the number of postoperative complications.
Effect of Combination Therapy with Angiotensin Receptor Blocker and 1,25-Dihydroxyvitamin D3 in Type 2 Diabetic Nephropathy in KK-Ay/Ta Mice
Authors: Ohara Ikko , Tanimoto Mitsuo , Gohda Tomohito , Yamazaki Takahiko , Hagiwara Shinji , Murakoshi Maki , Aoki Tatsuya , Toyoda Hitoe , Ishikawa Yuji , Funabiki Kazuhiko , Horikoshi Satoshi , Tomino Yasuhiko
Published: October 2010

Background: Although angiotensin II type 1 receptor blockers (ARB) have beneficial effects in patients with diabetic nephropathy, they may induce a compensatory increase in renin. Renin exhibits profibrotic actions independent of angiotensin II, which is regulated by extracellular signal-regulated kinase 1 and 2 (ERK1/2). Calcitriol (1,25(OH)2D3) is a negative inhibitor of the renin-angiotensin system and the present study examined the effects of combination therapy with an ARB and 1,25(OH)2D3 on diabetic nephropathy in KK-Ay/Ta mice. Methods: KK-Ay/Ta mice were divided into four groups: ARB group, 1,25(OH)2D3 group, combination group, and control group. The urinary albumin/creatinine ratio (ACR) was measured and the renal expression of renin, p-ERK1/2 and TGF-β1 protein determined. Results: The levels of urinary ACR in the combination group were significantly lower than those in the ARB or control group. Renal expression of renin in the ARB group was significantly increased compared with the control group but was significantly decreased in both the 1,25(OH)2D3 and combination group. Renal expression of p-ERK1/2 in the combination group was significantly decreased compared with the control or ARB group. Expression of TGF-β1 protein in the ARB and combination groups, especially the combination group, was significantly decreased compared with those in the control group. Conclusions: These data suggest that the addition of 1,25(OH)2D3 to therapy with ARB further reduced proteinuria by suppressing the compensatory increase in renin expression in type 2 diabetic nephropathy. These effects might relate to suppression of renin, ERK1/2 and TGF-β1 expression which may or may not depend on angiotensin II.
Prospective evaluation of three different diagnostic criteria for disseminated intravascular coagulation
Authors: Takemitsu Tetsushi , Hatada Tsuyoshi , Ohmori Yukinari , Ishikura Ken , Takeda Taichi , Sugiyama Takashi , Yamada Norikazu , Maruyama Kazuo , Katayama Naoyuki , Isaji Shuji , Shimpo Hideto , Kusunoki Masato , Nobori Tsutomu , Wada Hideo
Published: October 2010

There are three different diagnostic score systems for disseminated intravascular coagulation (DIC) established by the Japanese Ministry Health and Welfare (JMHW), the International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM). The JMHW criteria are still used in Japan. In the present study, all three diagnostic criteria were used to prospectively evaluate 413 patients with different underlying diseases of DIC who were treated at the Mie University Hospital (JMHW, n= 166; ISTH, n=143; JAAM, n=291). The odds ratio (95% confidence interval) for death was 1.88 (1.22 – 2.90) in JMHW, 2.55 (1.65 – 3.95) in ISHT and 1.99 (1.19 – 3.32) in JAAM. The platelet count, prothrombin time, fibrin and fibri-nogen degradation products and fibrinogen were significantly important for diagnosis of DIC by all three diagnostic criteria. Haemostatic molecular markers were significantly high in all patients and were useful for the diagnosis of DIC. The JAAM diagnostic criteria displayed a high sensitivity for DIC and the ISTH overt-DIC diagnostic criteria displayed a high specificity for DIC. All three diagnostic criteria for DIC were related to a poor patient outcome.
Megakaryocyte gene targeting mediated by restricted expression of recombinase Cre
Authors: Nowakowski Adam , Alonso-Martín Sonia , Arias-Salgado Elena , Fernández Darío , Vilar MariPaz , Ayuso Matilde , Parrilla Roberto
Published: October 2010

The availability of mice with tissue-specific expression of recombinase Cre is the limiting step for a successful gene targeting by the Cre-LoxP methodology. This work aimed at generating transgenic mice with restricted expression of recombinase Cre in megakaryocytes and platelets, driven by the promoter of the αIIb gene (mαIIb-cre). Mice oocytes were microinjected with a 4.1 Kb construct comprising a 2.7 Kb promoter fragment of the glycoprotein αIIb gene, linked to the CrecDNA and followed by the polyA tail of the SV40. We found four mice with positive DNA genotype and three probable sites of genomic integration of the transgene. Only two of the founders showed presence of Cre-mRNA and production of Cre protein, restricted to megakaryocytes. The activity of Cre in mediating gene targeting was assessed by crossing mαIIb-cre mice to Cre-reporter mice (ROSA26-lacZ). The activity of β-galactosidase, detected only in megakaryocytes, was sufficient to generate intense staining of X-Gal in hepatic haematopoietic islands of 14.5 dpc fetuses, in bone marrow megakaryocytes and platelets from adult mice as well as in vitro cultured megakaryocytes differentiated from bone marrow hematopoietic stem cells. Moreover, the recombinase activity was sufficient to produce the specific gene targeting of a floxed CD40L allele in megakaryocytes. The mαIIb-cre transgenic mice with restricted production of Cre in megakaryocytes, offers a selective, alternative, new tool for the genetic analysis of platelet pathophysiology.
Apixaban versus enoxaparin in patients with total knee arthroplasty
Authors: Huang Jiahao , Liao Cun , Wu Liucheng , Cao Yunfei , Gao Feng
Published: October 2010

It was the objective of this study to systematically compare the effects of apixaban versus enoxaparin in patients following total knee arthroplasty (TKA). A systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials was conducted. Eligible studies were prospective, randomised control trials (RCT) of apixaban therapy, comparing with enoxaparin, in patients who have a high risk of venous thromboembolism (VTE) after TKA. Three RCTs involving 7,337 individuals were identified, of whom 4,057 were treated with apixaban 2.5 mg once daily, and 3280 were subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Meta-analysis demonstrated the odds ratio (OR) for the composite of major VTE (proximal deep-vein thrombosis and pulmonary embolism) for apixaban versus enoxaparin was 0.47 (95% confidence interval [CI]: 0.27 to 0.82, 0.6% vs. 1.2%) and 2.09 (95%CI: 0.99 to 4.45, 0.6% vs. 0.3%), respectively. All-cause mortality occurred in 0.2% of the apixaban group versus 0.09% of the enoxaparin group (OR=1.74; 95%CI, 0.51 to 5.95). With respect to safety outcomes, apixaban was associated with a lower major bleeding rate than enoxaparin (OR=0.55, 95%CI: 0.32 to 0.96). No significant differences were detected between two strategies in other endpoints of safety profile analysed: clinically relevant non-major bleeding, raised hepatic transaminase enzyme or bilirubin concentrations and arterial thromboembolic events. In conclusion, apixaban is non-inferior to subcutaneous enoxaparin when used for the same duration, with considerable advantage regarding safety profile of major bleeding after TKA.
The IκB Kinase Inhibitor Nuclear Factor-κB Essential Modulator–Binding Domain Peptide for Inhibition of Injury-Induced Neointimal Formation
Authors: Grassia Gianluca , Maddaluno Marcella , Musilli Claudia , De Stefano Daniela , Carnuccio Rosa , Di Lauro Maria Vittoria , Parratt Christopher A. , Kennedy Simon , Di Meglio Paola , Ianaro Angela , Maffia Pasquale , Parenti Astrid , Ialenti Armando
Published: October 2010

Objective—

The activation of nuclear factor-κB (NF-κB) is a crucial step in the arterial wall’s response to injury. The identification and characterization of the NF-κB essential modulator–binding domain (NBD) peptide, which can block the activation of the IκB kinase complex, have provided an opportunity to selectively abrogate the inflammation-induced activation of NF-κB. The aim of the present study was to evaluate the effect of the NBD peptide on neointimal formation.

Methods and Results—

In the rat carotid artery balloon angioplasty model, local treatment with the NBD peptide (300 μg/site) significantly reduced the number of proliferating cells at day 7 (by 40%;
P
<0.01) and reduced injury-induced neointimal formation (by 50%;
P
<0.01) at day 14. These effects were associated with a significant reduction of NF-κB activation and monocyte chemotactic protein-1 expression in the carotid arteries of rats treated with the peptide. In addition, the NBD peptide (0.01 to 1 μmol/L) reduced rat smooth muscle cell proliferation, migration, and invasion in vitro. Similar results were observed in apolipoprotein E
−/−
mice in which the NBD peptide (150 μg/site) reduced wire-induced neointimal formation at day 28 (by 47%;
P
<0.01).

Conclusion—

The NBD peptide reduces neointimal formation and smooth muscle cell proliferation/migration, both effects associated with the inhibition of NF-κB activation.
Endothelial, Sympathetic, and Cardiac Function in Inherited (6
R
)-
l
-Erythro-5,6,7,8-Tetrahydro-
l
-Biopterin Deficiency
Authors: Mayahi Lila , Mason Lydia , Bleasdale-Barr Katherine , Donald Ann , Trender-Gerhard Iris , Sweeney Mary G. , Davis Mary B. , Wood Nicholas , Mathias Christopher J. , Watson Laura , Pellerin Denis , Heales Simon , Deanfield John E. , Bhatia Kailash , Murray-Rust Judith , Hingorani Aroon D.
Published: October 2010

Background—

(6
R
)-5,6,7,8-Tetrahydro-
l
-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by
GCH1
. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in
GCH1
in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans.

Methods and Results—

In 16 DOPA-responsive dystonia patients with mutations predicted to affect GTPCH-1 expression or function and in age- and sex-matched control subjects, we measured plasma biopterin and nitrogen oxides by high-performance liquid chromatography and the Griess reaction, respectively, endothelial function by brachial artery flow-mediated dilation (FMD), sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response. Cardiac function and structure were assessed by echocardiography. Plasma biopterin was lower in patients (5.76±0.53 versus 8.43±0.85 nmol/L,
P
=0.03), but plasma NO
2
−
/NO
3
−
(NOx) (median, 9.06 [interquartile range, 5.35 to 11.04] versus 8.40 [interquartile range, 5.28 to 11.44] μmol/L,
P
=1) and FMD were not lower (7.7±0.8% versus 7.9±0.9%,
P
=0.91). In patients but not control subjects, FMD was insensitive to nitric oxide synthase inhibition (FMD at baseline, 6.7±2.1%; FMD during
l
-NMMA infusion, 6.2±2.5,
P
=0.68). The heart rate at rest was higher in patients, but the heart rate and blood pressure response to sympathetic stimulation did not differ in patients and control subjects despite lower concentrations of norepinepherine (264±8 pg/mL versus 226±9 pg/mL,
P
=0.006) and epinephrine (33.8±5.2 pg/mL versus 17.8±4.6 pg/mL,
P
=0.03) in patients. There was also no difference in cardiac function and structure.

Conclusions—

Sympathetic, cardiac, and endothelial functions are preserved in patients with GCH1 mutations despite a neurological phenotype, reduced plasma biopterin, and norepinepherine and epinephrine concentrations. Lifelong endogenous BH4 deficiency may elicit developmental adaptation through mechanisms that are inaccessible during acquired BH4 deficiency in adulthood.
Geographic Variation and Trends in Carotid Imaging Among Medicare Beneficiaries, 2001 to 2006
Authors: Curtis Lesley H. , Greiner Melissa A. , Patel Manesh R. , Duncan Pamela W. , Schulman Kevin A. , Matchar David B.
Published: October 2010

Background—

Diagnostic imaging among Medicare beneficiaries is an important contributor to rising health care costs. We examined temporal trends and geographic variation in the use of carotid ultrasound, carotid magnetic resonance angiography (MRA), and carotid x-ray angiography.

Methods and Results—

Analysis of a 5% national sample of claims from the Centers for Medicare and Medicaid Services for 1999 through 2006. Patients were 65 years or older and underwent carotid ultrasound, carotid MRA, carotid x-ray angiography, or a carotid intervention. The main outcome measures were annual age-adjusted rates of carotid imaging and interventions and factors associated with the use of carotid imaging. Rates of imaging increased by 27%, from 98.2 per 1000 person-years in 2001 to 124.3 per 1000 in 2006. Rates of carotid ultrasound increased by 23%, and rates of MRA increased by 66%. Carotid intervention rates decreased from 3.6 per 1000 person-years in 2001 to 3.1 per 1000 person-years in 2006. In 2006, rates of carotid ultrasound were lowest in the New England, Mountain, and West North Central regions and highest in the Middle Atlantic and South Atlantic regions. Regional differences persisted after adjustment for patient demographic characteristics, history of vascular disease and other comorbid conditions, and study year.

Conclusions—

From 2001 through 2006, there was substantial growth and variation in the use of carotid imaging, including a marked increase in the use of MRA, and a decrease in the overall rate of carotid intervention.
High-Resolution Magnetic Resonance Imaging Enhanced With Superparamagnetic Nanoparticles Measures Macrophage Burden in Atherosclerosis
Authors: Morishige Kunio , Kacher Daniel F. , Libby Peter , Josephson Lee , Ganz Peter , Weissleder Ralph , Aikawa Masanori
Published: October 2010

Background—

Macrophages contribute to the progression and acute complications of atherosclerosis. Macrophage imaging may serve as a biomarker to identify subclinical inflamed lesions, to predict future risk, and to aid in the assessment of novel therapies.

Methods and Results—

To test the hypothesis that nanoparticle-enhanced, high-resolution magnetic resonance imaging (MRI) can measure plaque macrophage accumulation, we used 3-T MRI with a macrophage-targeted superparamagnetic nanoparticle preparation (monocrystalline iron oxide nanoparticles-47 [MION-47]) in cholesterol-fed New Zealand White rabbits 6 months after balloon injury. In vivo MRI visualized thickened abdominal aortas on both T1- and T2-weighted spin-echo images (T1 spin echo, 20 axial slices per animal; T2 spin echo, 28 slices per animal). Seventy-two hours after MION-47 injection, aortas exhibited lower T2 signal intensity compared with before contrast imaging (signal intensity ratio, aortic wall/muscle: before, 1.44±0.26 versus after, 0.95±0.22; 164 slices;
P
<0.01), whereas T1 spin echo images showed no significant change. MRI on ex vivo specimens provided similar results. Histological studies colocalized iron accumulation with immunoreactive macrophages in atheromata. The magnitude of signal intensity reduction on T2 spin echo in vivo images further correlated with macrophage areas in situ (150 slices;
r
=0.73). Treatment with rosuvastatin for 3 months yielded diminished macrophage content (
P
<0.05) and reversed T2 signal intensity changes (
P
<0.005). Signal changes in rosuvastatin-treated rabbits correlated with reduced macrophage burden (
r
=0.73). In vitro validation studies showed concentration-dependent MION-47 uptake by human primary macrophages.

Conclusion—

The magnitude of T2 signal intensity reduction in high-resolution MRI after administration of superparamagnetic phagocytosable nanoparticles can assess macrophage burden in atheromata, providing a clinically translatable tool to identify inflamed plaques and to monitor therapy-mediated changes in plaque inflammation.
Electropathological Substrate of Longstanding Persistent Atrial Fibrillation in Patients With Structural Heart Disease
Authors: de Groot Natasja M.S. , Houben Richard P.M. , Smeets Joep L. , Boersma Eric , Schotten Ulrich , Schalij Martin J. , Crijns Harry , Allessie Maurits A.
Published: October 2010

Background—

During persistent atrial fibrillation (AF), waves with a focal spread of activation are frequently observed. The origin of these waves and their relevance for the persistence of AF are unknown.

Methods and Results—

In 24 patients with longstanding persistent AF and structural heart disease, high-density mapping of the right and left atria was performed during cardiac surgery. In a reference group of 25 patients, AF was induced by rapid pacing. For data analysis, a mapping algorithm was developed that separated the fibrillatory process into its individual wavelets and identified waves with a focal origin. During persistent AF, the incidence of focal fibrillation waves in the right atrium was almost 4-fold higher than during acute AF (median, 0.46 versus 0.12 per cycle per 1 cm
2
(25th to 75th percentile, 0.40 to 0.77 and 0.01 to 0.27;
P
<0.0001). They were widely distributed over both atria and were recorded at 46±18 of all electrodes. A large majority (90.5) occurred as single events. Repetitive focal activity (>3) happened in only 0.8. The coupling interval was not more than 11 ms shorter than the average AF cycle length (
P
=0.04), and they were not preceded by a long interval. Unipolar electrograms at the site of origin showed small but clear R waves. These data favor epicardial breakthrough rather than a cellular focal mechanism as the underlying mechanism. Often, conduction from a site of epicardial breakthrough was blocked in 1 or more directions. This generated separate multiple wave fronts propagating in different directions over the epicardium.

Conclusions—

Focal fibrillation waves are due to epicardial breakthrough of waves propagating in deeper layers of the atrial wall. In patients with longstanding AF, the frequency of epicardial breakthroughs was 4 times higher than during acute AF. Because they provide a constant source of independent fibrillation waves originating over the entire epicardial surface, they offer an adequate explanation for the high persistence of AF in patients with structural heart disease.
Vascular Endothelial Growth Factor-B Acts as a Coronary Growth Factor in Transgenic Rats Without Inducing Angiogenesis, Vascular Leak, or Inflammation
Authors: Bry Maija , Kivelä Riikka , Holopainen Tanja , Anisimov Andrey , Tammela Tuomas , Soronen Jarkko , Silvola Johanna , Saraste Antti , Jeltsch Michael , Korpisalo Petra , Carmeliet Peter , Lemström Karl B. , Shibuya Masabumi , Ylä-Herttuala Seppo , Alhonen Leena , Mervaala Eero , Andersson Leif C. , Knuuti Juhani , Alitalo Kari
Published: October 2010

Background—

Vascular endothelial growth factor-B (VEGF-B) binds to VEGF receptor-1 and neuropilin-1 and is abundantly expressed in the heart, skeletal muscle, and brown fat. The biological function of VEGF-B is incompletely understood.

Methods and Results—

Unlike placenta growth factor, which binds to the same receptors, adeno-associated viral delivery of VEGF-B to mouse skeletal or heart muscle induced very little angiogenesis, vascular permeability, or inflammation. As previously reported for the VEGF-B
167
isoform, transgenic mice and rats expressing both isoforms of VEGF-B in the myocardium developed cardiac hypertrophy yet maintained systolic function. Deletion of the VEGF receptor-1 tyrosine kinase domain or the arterial endothelial Bmx tyrosine kinase inhibited hypertrophy, whereas loss of VEGF-B interaction with neuropilin-1 had no effect. Surprisingly, in rats, the heart-specific VEGF-B transgene induced impressive growth of the epicardial coronary vessels and their branches, with large arteries also seen deep inside the subendocardial myocardium. However, VEGF-B, unlike other VEGF family members, did not induce significant capillary angiogenesis, increased permeability, or inflammatory cell recruitment.

Conclusions—

VEGF-B appears to be a coronary growth factor in rats but not in mice. The signals for the VEGF-B–induced cardiac hypertrophy are mediated at least in part via the endothelium. Because cardiomyocyte damage in myocardial ischemia begins in the subendocardial myocardium, the VEGF-B–induced increased arterial supply to this area could have therapeutic potential in ischemic heart disease.
Anterior Mitral Leaflet Curvature During the Cardiac Cycle in the Normal Ovine Heart
Authors: Kvitting John-Peder Escobar , Bothe Wolfgang , Göktepe Serdar , Rausch Manuel K. , Swanson Julia C. , Kuhl Ellen , Ingels Neil B. , Miller D. Craig
Published: October 2010

Background—

The dynamic changes of anterior mitral leaflet (AML) curvature are of primary importance for optimal left ventricular filling and emptying but are incompletely characterized.

Methods and Results—

Sixteen radiopaque markers were sutured to the AML in 11 sheep, and 4-dimensional marker coordinates were acquired with biplane videofluoroscopy. A surface subdivision algorithm was applied to compute the curvature across the AML at midsystole and at maximal valve opening. Septal-lateral (SL) and commissure-commissure (CC) curvature profiles were calculated along the SL AML meridian (M
SL
)and CC AML meridian (M
CC
), respectively, with positive curvature being concave toward the left atrium. At midsystole, the M
SL
was concave near the mitral annulus, turned from concave to convex across the belly, and was convex along the free edge. At maximal valve opening, the M
SL
was flat near the annulus, turned from slightly concave to convex across the belly, and flattened toward the free edge. In contrast, the M
CC
was concave near both commissures and convex at the belly at midsystole but convex near both commissures and concave at the belly at maximal valve opening.

Conclusions—

While the SL curvature of the AML along the M
SL
is similar across the belly region at midsystole and early diastole, the CC curvature of the AML along the M
CC
flips, with the belly being convex to the left atrium at midsystole and concave at maximal valve opening. These curvature orientations suggest optimal left ventricular inflow and outflow shapes of the AML and should be preserved during catheter or surgical interventions.
Pre-Conviction Detention before the International Criminal Court: Compliance or Fragmentation?
Authors: Golubok Sergey
Published: October 2010

This article analyses nascent case law of the International Criminal Court on provisional detention at the investigation stage and in the course of trial (together referred to as “pre-conviction detention”) vis-à-vis the standards developed in the jurisprudence of the European Court of Human Rights, being a reflection of “internationally recognized human rights” to which the ICC, according to its Statute, must adhere. At least several instances of presumed inconsistencies are detected. It is argued that international criminal tribunals should above all comply with standards set by international human rights law for domestic criminal proceedings, in particular when the most fundamental and basic human right ‐ the right to personal liberty ‐ is affected. Failure to comply entails a serious risk of hazardous fragmentation.
Peacekeepers under Fire: Prosecuting the RUF for Attacks against the UN Assistance Mission in Sierra Leone
Authors: Sloan James
Published: October 2010

In the “RUF case”, the Special Court for Sierra Leone considered charges brought against senior officials of the Revolutionary United Front (RUF) in relation, inter alia, to a series of notorious attacks against the UN Assistance Mission in Sierra Leone (UNAMSIL) in May 2000. In finding the accused guilty of certain of the crimes charged, the Trial Chamber relied heavily on single-source evidence, hearsay evidence and circumstantial evidence. The Trial Chamber addressed a number of difficult factual and legal issues relating to the definition of peacekeeping and the status of robust peacekeepers for the first time; however, not all such findings appear to have been accurately grounded in fact and law.
An Inquiry into the ICC Appeals Chamber’s Exercise of the Power of Remand
Authors: Waite Prince Neto D.C.B.
Published: October 2010

The ICC’s Appeals Chamber (AC) has the authority to review, on appeal, judgments, decisions, orders and the exercise of power by the Pre-Trial and Trial Chambers. The Rome Statute and the Rules of Procedure and Evidence expressly provide that the AC may confirm, reverse or amend matters on appeal, and has the power of remand in Article 81 and Article 83 appeals against decisions of acquittal, conviction or sentence. There is no express power to remand an issue in Article 82 (interlocutory) appeals. This article discusses whether the AC has the power, generally, to remand a matter to Chambers below, thereby not coming to a determination itself. The article concludes by suggesting that the AC has the power of remand, and that it springs from two sources: (1) for appeals generally, the Court’s inherent powers and (2) for Article 81 and Article 83 appeals, the Court’s Statutory powers in Article 83(2). Therefore, the AC, under its inherent jurisdiction, may exercise the power of remand for Article 82 (interlocutory) appeals.
Multilayer Cloud Detection with the MODIS Near-Infrared Water Vapor Absorption Band
Authors: Wind Galina , Platnick Steven , King Michael D. , Hubanks Paul A. , Pavolonis Michael J. , Heidinger Andrew K. , Yang Ping , Baum Bryan A.
Published: October 2010

Data Collection 5 processing for the Moderate Resolution Imaging Spectroradiometer (MODIS) on board the NASA Earth Observing System (EOS) Terra and Aqua spacecraft includes an algorithm for detecting multilayered clouds in daytime. The main objective of this algorithm is to detect multilayered cloud scenes, specifically optically thin ice cloud overlying a lower-level water cloud, that present difficulties for retrieving cloud effective radius using single-layer plane-parallel cloud models. The algorithm uses the MODIS 0.94-μm water vapor band along with CO2 bands to obtain two above-cloud precipitable water retrievals, the difference of which, in conjunction with additional tests, provides a map of where multilayered clouds might potentially exist. The presence of a multilayered cloud results in a large difference in retrievals of above-cloud properties between the CO2 and the 0.94-μm methods. In this paper the MODIS multilayered cloud algorithm is described, results of using the algorithm over example scenes are shown, and global statistics for multilayered clouds as observed by MODIS are discussed. A theoretical study of the algorithm behavior for simulated multilayered clouds is also given. Results are compared to two other comparable passive imager methods. A set of standard cloudy atmospheric profiles developed during the course of this investigation is also presented. The results lead to the conclusion that the MODIS multilayer cloud detection algorithm has some skill in identifying multilayered clouds with different thermodynamic phases.
The Effective Static Stability Experienced by Eddies in a Moist Atmosphere
Authors: O’Gorman Paul A.
Published: October 2010

Water vapor directly affects the dynamics of atmospheric eddy circulations through the release of latent heat. But it is difficult to include latent heat release in dynamical theories because of the associated nonlinearity (precipitation generally occurs where there is upward motion). A new effective static stability is derived that fundamentally captures the effect of latent heat release on moist eddy circulations. It differs from the usual dry static stability by an additive term that depends on temperature and a parameter measuring the up–down asymmetry of vertical velocity statistics. Latent heat release reduces the effective static stability experienced by eddies but cannot reduce it to zero so long as there are nonprecipitating regions of the eddies. Evaluation based on reanalysis data indicates that the effective static stability in the lower troposphere ranges from ∼80% of the dry static stability at high latitudes to ∼25% in the tropics.

The effective static stability provides a solution to the longstanding problem of how to adapt dry dynamical theories to the moist circulations in the atmosphere. Its utility for climate change problems is illustrated based on simulations with an idealized general circulation model. It is shown to help account for changes in the thermal stratification of the extratropical troposphere, the extent of the Hadley cells, the intensity of extratropical transient eddies, and the extratropical eddy length.