bluuebunny/crossref_metadata_2025 huggingface dataset:
Mucus Enhances Gut Homeostasis and Oral Tolerance by Delivering Immunoregulatory Signals
Authors: Shan Meimei , Gentile Maurizio , Yeiser John R. , Walland A. Cooper , Bornstein Victor U. , Chen Kang , He Bing , Cassis Linda , Bigas Anna , Cols Montserrat , Comerma Laura , Huang Bihui , Blander J. Magarian , Xiong Huabao , Mayer Lloyd , Berin Cecilia , Augenlicht Leonard H. , Velcich Anna , Cerutti Andrea
Published: September 2013

Guardian of the Gut

The intestine is able to tolerate continual exposure to large amounts of commensal bacteria and foreign food antigens without triggering an inappropriate inflammatory immune response. In the large intestine, this immunological tolerance is thought to occur via a physical separation between environment and host imposed by a continuous mucous layer built up from the secreted mucin protein, MUC2. However, in the small intestine, this mucous layer is porous, necessitating an additional layer of immune control.

Shan
et al.

(p.
447
, published online 26 September; see the Perspective by

Belkaid and Grainger

) now report that in the small intestine, MUC2 plays an active role in immunological tolerance by activating a transcription factor in resident dendritic cells, thereby selectively blocking their ability to launch an inflammatory response. This work identifies MUC2 as a central mediator of immune tolerance to maintain homeostasis in the gut and possibly at other mucosal surfaces in the body.
Real-Space Identification of Intermolecular Bonding with Atomic Force Microscopy
Authors: Zhang Jun , Chen Pengcheng , Yuan Bingkai , Ji Wei , Cheng Zhihai , Qiu Xiaohui
Published: September 2013

Imaging Hydrogen Bonds

The decoration of atomic force microscope tips with terminal CO molecules has afforded much higher resolution of the bonding of adsorbed molecules.

Zhang
et al.

(p.
611
, published online 26 September) show that this method, in combination with density function theory calculations, can image and characterize hydrogen-bonding contacts formed between 8-hydroxyquinoline molecules adsorbed on the (111) surface of copper under cryogenic conditions. At room temperature, a different bonding configuration was revealed that was the result of the molecules dehydrogenating on the copper surface and coordinating with surface copper atoms.
Draft Genome Sequence of Vancomycin-Heteroresistant Staphylococcus epidermidis Strain UC7032, Isolated from Food
Authors: Gazzola Simona , Pietta Ester , Bassi Daniela , Fontana Cecilia , Puglisi Edoardo , Cappa Fabrizio , Cocconcelli Pier Sandro
Published: September 2013

Staphylococcus epidermidis
strain UC7032 was isolated from ready-to-eat cured meat and is heteroresistant to glycopeptide antibiotics. The draft whole-genome analysis revealed that this strain shows common characteristics typical of strains that are involved in nosocomial infections.
Complete Genome Sequence of the Probiotic Strain Lactobacillus casei (Formerly Lactobacillus paracasei) LOCK919
Authors: Koryszewska-Bagińska Anna , Aleksandrzak-Piekarczyk Tamara , Bardowski Jacek
Published: September 2013

Lactobacillus casei
is usually regarded as a bacterium that lives naturally in the human intestinal tract, where it can contribute to host health and well-being. We describe here the complete genome sequence of
L. casei
LOCK919, a strain with probiotic properties isolated from child feces. The genome consists of a 3.11-Mb chromosome and a 29,768-bp plasmid.
Complete Genome Sequence of Vibrio anguillarum M3, a Serotype O1 Strain Isolated from Japanese Flounder in China
Authors: Li Guiyang , Mo Zhaolan , Li Jie , Xiao Peng , Hao Bin
Published: September 2013

Vibrio anguillarum
is an important bacterial pathogen that causes vibriosis in marine fish. We present the complete genome sequence of
V. anguillarum
M3, a serotype O1 clinical strain isolated from Japanese flounder (
Paralichthys olivaceus
) in Shandong, China.
Draft Genome Sequences of Three Newly Identified Species in the Genus
Cronobacter
,
C. helveticus
LMG23732
T
,
C. pulveris
LMG24059, and
C
.
zurichensis
LMG23730
T
Authors: Masood Naqash , Moore Karen , Farbos Audrey , Hariri Sumyya , Paszkiewicz Konrad , Dickins Ben , McNally Alan , Forsythe Stephen
Published: September 2013

Cronobacter helveticus
,
Cronobacter pulveris
, and
Cronobacter zurichensis
are newly described species in the
Cronobacter
genus, which is associated with serious infections of neonates. This is the first report of draft genome sequences for these species.
Where to buy OTC medications? A cross-sectional survey investigating consumers’ confidence in over-the-counter (OTC) skills and their attitudes towards the availability of OTC painkillers
Authors: Brabers A E M , Van Dijk L , Bouvy M L , De Jong J D
Published: September 2013

Objective

To examine consumers’ confidence in their own, and also in other people's, over-the-counter (OTC) skills and to describe their attitude towards the availability of OTC painkillers. Moreover we examined the association between confidence in OTC skills and attitudes.

Design

Cross-sectional survey. Mixed methods (postal and electronic) self-administered questionnaire.

Participants

Members of the Dutch Health Care Consumer Panel.

Main outcome measures

Consumers’ confidence in their own, and in other people's, OTC skills was examined. Confidence was measured by three questions regarding obtaining information on, choosing and using OTC medication. Consumers’ attitudes towards availability were assessed using six safety profiles, by asking which channel consumers prefer for each profile.

Results

The response rate was 68% (n=972). Consumers feel confident about their own OTC skills (mean 3.74; 95% CI 3.69 to 3.79, on a 5-point Likert scale), but have less confidence in OTC skills of others (mean 2.92; 95% CI 2.88 to 2.96). Consumers are conservative in their attitudes towards the availability of OTC painkillers. Most consumers prefer painkillers to be available exclusively in pharmacies (41–71% per profile indicated pharmacy only). Moreover, there is an association between confidence in OTC skills and attitudes (p=0.005; β=−0.114). Consumers who are more confident about their own OTC skills prefer OTC painkillers to be more generally available.

Conclusions

Consumers feel confident about their own OTC skills. However, they would prefer painkillers with safety profiles resembling those currently available OTC, to be available as OTC in pharmacies exclusively. Consumers’ confidence in the OTC skills of others is more consistent with their attitudes towards availability of OTC painkillers. Until consumers themselves realise that they are also one of the others, they may overestimate their own OTC skills, which may entail health risks.
Impact on cardiovascular risk follow-up from a shift to the CKD-EPI formula for eGFR reporting: a cross-sectional population-based primary care study
Authors: van Gelder Vincent A , Scherpbier-de Haan Nynke D , de Grauw Wim J C , O'Callaghan Christopher A , Wetzels Jack F M , Lasserson Daniel S
Published: September 2013

Objective

To assess the impact on cardiovascular risk factor management in primary care by the introduction of chronic kidney disease epidemiological collaboration (CKD-EPI) for estimated-glomerular filtration rate (eGFR) reporting.

Design and setting

Cross-sectional study of routine healthcare provision in 47 primary care practices in The Netherlands with Modification of Diet and Renal Disease Study eGFR reporting.

Methods

eGFR values were recalculated using CKD-EPI in patients with available creatine tests. Patients reclassified from CKD stage 3a to CKD stage 2 eGFR range were compared to those who remained in stage 3a for differences in demographic variables, blood pressure, comorbidity, medication usage and laboratory results.

Results

Among the 60 673 adult patients (37% of adult population) with creatine values, applying the CKD-EPI equation resulted in a 16% net reduction in patients with CKD stage 3 or worse. Patients reclassified from stage 3a to 2 had lower systolic blood pressure (139.7 vs 143.3 mm Hg p<0.0001), higher diastolic blood pressure (81.5 vs 78.4 mm Hg p<0.0001) and higher cholesterol (5.4 vs 5.1 mmol/L p<0.0001) compared to those who remained in stage 3a. Of those reclassified out of a CKD diagnosis 463 (32%) had no comorbidities that would qualify for annual CVD risk factor assessment and 20 (12% of those with sufficient data) had a EuroSCORE CVD risk >20% within 10 years.

Conclusions

Use of the CKD-EPI equation will result in many patients being removed from CKD registers and the associated follow-up. Current risk factor assessment in this group may be lacking from routine data and some patients within this group are at an increased risk for cardiovascular events.
Critical care paramedics: where is the evidence? a systematic review
Authors: von Vopelius-Feldt Johannes , Wood John , Benger Jonathan
Published: September 2013

Objectives

Paramedic-delivered prehospital critical care is an established concept in a number of emergency medical services around the world and, more recently, has been introduced to the UK. This review identifies and describes the available evidence relating to paramedics who routinely provide prehospital critical care as primary scene response (critical care paramedics, or CCP).

Methods

A systematic search of electronic databases was performed: CENTRAL, EMBASE, MEDLINE (through EMBASE and Web of Knowledge) and Web of Science (through Web of Knowledge).

Results

The search identified 12 relevant publications, one of which was a randomised controlled trial. The remaining 11 were retrospective studies. Five studies compared CCPs with physician-led care. Three of these publications demonstrated improved outcomes with physician care, while two showed no difference. Four further publications examined CCPs versus non-physician-led care and found improved outcomes (two studies), mixed effects (one study) and no difference (one study) for CCPs. Finally, three publications addressed the addition of skills to CCP competencies. A randomised controlled trial of CCP rapid sequence induction (RSI) and tracheal intubation demonstrated improved neurologic outcomes. CCP tube thoracostomy was shown to have similar complication rates to the same procedure performed in the emergency department, while addition of a non-invasive ventilation protocol to CCP practice had no effect on long-term mortality.

Conclusions

There is limited evidence to support the concept of paramedic-delivered prehospital critical care. The best available evidence suggests a benefit from prehospital RSI carried out by CCPs in patients with severe traumatic brain injury, but the impact of CCPs remains unclear for many conditions. Further high-quality research in this area would be welcome.
Is the ATLS classification of hypovolaemic shock appreciated in daily trauma care? An online-survey among 383 ATLS course directors and instructors
Authors: Mutschler Manuel , Hoffmann Marzellus , Wölfl Christoph , Münzberg Matthias , Schipper Inger , Paffrath Thomas , Bouillon Bertil , Maegele Marc
Published: September 2013

Objective

For the early recognition and management of hypovolaemic shock, ATLS suggests four shock classes based upon an estimated blood loss in percent. The aim of this study was to assess the confidence and acceptance of the ATLS classification of hypovolaemic shock among ATLS course directors and instructors in daily trauma care.

Methods

During a 2-month period, ATLS course directors and instructors from the ATLS region XV (Europe) were invited to participate in an online survey comprising 15 questions.

Results

A total of 383 responses were received. Ninety-eight percent declared that they would follow the ‘A, B, C, D, E’ approach by ATLS in daily trauma care. However, only 48% assessed ‘C-Circulation’ according to the ATLS classification of hypovolaemic shock. One out of four respondents estimated that in daily clinical routine, less than 50% of all trauma patients can be classified according to the current ATLS classification of hypovolaemic shock. Additionally, only 10.9% considered the ATLS classification of hypovolaemic shock as a ‘good guide’ for fluid resuscitation and blood product transfusion, whereas 45.1% stated that this classification only ‘may help’ or has ‘no impact’ to guide resuscitation strategies.

Conclusions

Although the ‘A, B, C, D, E’ approach according to ATLS is widely implemented in daily trauma care, the use of the ATLS classification of hypovolaemic shock in daily practice is limited. Together with previous analyses, this study supports the need for a critical reassessment of the current ATLS classification of hypovolaemic shock.
Diagnosing paediatric myocarditis: what really matters
Authors: Chong Shu-Ling , Bautista Dianne , Ang Angelina Su-Yin
Published: September 2013

Objective

Paediatric myocarditis has remained a diagnostic challenge. We aim to identify distinct characteristics and derive a scoring system that will trigger further investigations to be performed among paediatric patients presenting to the emergency department (ED) with clinically suspected myocarditis.

Design

We performed an age-matched case-control study of children seen in a large tertiary institution. Cases and controls were patients less than 16 years’ old who presented to the ED over a 10-year period from Jan 2001 to Dec 2010. Cases were identified with a final discharge or postmortem diagnosis of acute myocarditis. Controls were those who presented to the ED in the same period and were initially diagnosed with acute myocarditis, but who were later found to have other diagnoses. We compared their vital signs, presenting symptoms, physical examination findings, electrocardiogram and chest radiograph findings.

Results

Based on domain-specific stepwise conditional logistic regression analyses, five characteristics were found to be potentially discriminating: respiratory distress, poor perfusion, hypotension, an abnormal chest radiograph and any electrocardiogram abnormalities. Satisfactory discrimination was attained using these five parameters. The estimated area under receiver operating characteristic curve was 90% (95% CI 0.83 to 0.97). A cut-off score of 3 would give a positive likelihood ratio of 13 (95% CI 3.31 to 51.06) and a negative likelihood ratio of 0.35 (95% CI 0.22 to 0.55).

Conclusions

A cut-off risk score of 3, though not yet validated, may be potentially useful in future to trigger further investigations for children with suspected myocarditis. It allows for the appropriate use of resources, while minimising on misdiagnosis.
Internal quality control: best practice
Authors: Kinns Helen , Pitkin Sarah , Housley David , Freedman Danielle B
Published: September 2013

There is a wide variation in laboratory practice with regard to implementation and review of internal quality control (IQC). A poor approach can lead to a spectrum of scenarios from validation of incorrect patient results to over investigation of falsely rejected analytical runs. This article will provide a practical approach for the routine clinical biochemistry laboratory to introduce an efficient quality control system that will optimise error detection and reduce the rate of false rejection. Each stage of the IQC system is considered, from selection of IQC material to selection of IQC rules, and finally the appropriate action to follow when a rejection signal has been obtained. The main objective of IQC is to ensure day-to-day consistency of an analytical process and thus help to determine whether patient results are reliable enough to be released. The required quality and assay performance varies between analytes as does the definition of a clinically significant error. Unfortunately many laboratories currently decide what is clinically significant at the troubleshooting stage. Assay-specific IQC systems will reduce the number of inappropriate sample-run rejections compared with the blanket use of one IQC rule. In practice, only three or four different IQC rules are required for the whole of the routine biochemistry repertoire as assays are assigned into groups based on performance. The tools to categorise performance and assign IQC rules based on that performance are presented. Although significant investment of time and education is required prior to implementation, laboratories have shown that such systems achieve considerable reductions in cost and labour.
p53 and hepatoma-derived growth factor expression and their clinicopathological association with Ewing family tumour
Authors: Yang Yang , Zhen Tiantian , Zhang Fenfen , Dai Sujuan , Kang Lili , Liang Yingjie , Xue Ling , Han Anjia
Published: September 2013

Purpose

To investigate p53 and hepatoma-derived growth factor (HDGF) expression and their association with clinicopathological features of Ewing family tumour (EFT).

Experimental design

A total of 108 cases of EFT were retrospectively analysed. p53 and HDGF expression were detected using immunohistochemistry, and the relationships between p53 expression and HDGF expression and clinicopathological features of EFT were analysed. Kaplan–Meier curves were applied to estimate overall survival, log-rank test was used to assess prognostic relevance of p53 expression with overall survival and Cox regression model was performed to evaluate HRs.

Results

p53 expression and high HDGF expression was found in 17 (15.7%) and 55 (50.9%) patients, respectively. p53 expression was significantly associated with metastatic stage at initial diagnosis (p=0.007) and tumour venous/nerve invasion (p=0.023). A significant positive correlation was found between p53 expression and HDGF expression in EFT (p=0.022). p53 expression was an independent prognostic factor for overall survival of patients with EFT (p<0.001). Patients with p53-positive/high HDGF expression had a significantly shorter overall survival than those with p53-positive/low HDGF expression or p53-negative/high HDGF expression or p53-negative/low HDGF expression. We first constructed a novel molecular staging system by combining p53 expression and HDGF expression, which significantly improved prognostic stratification for patients with EFT.

Conclusions

p53 expression was an independent prognostic factor for patients with EFT. Combining p53 expression and HDGF expression significantly improved prognostic stratification for patients with EFT.
Neighbourhood economic deprivation explains racial/ethnic disparities in overweight and obesity among children and adolescents in the USA
Authors: Rossen Lauren M
Published: September 2013

Background

Low-income and some racial and ethnic subpopulations are more likely to suffer from obesity. Inequities in the physical and social environment may contribute to disparities in paediatric obesity, but there is little empirical evidence to date. This study explored whether neighbourhood-level socioeconomic factors attenuate racial and ethnic disparities in obesity among youth in the USA and whether individual-level socioeconomic status (SES) interacts with neighbourhood deprivation.

Methods

This analysis used data from 17 100 youth ages 2–18 years participating in the 2001–2010 National Health and Nutrition Examination Survey linked to census tract-level socioeconomic characteristics. Multilevel logistic regression models were used to examine neighbourhood deprivation in association with odds of obesity (age-specific and sex-specific body mass index percentile ≥95).

Results

The unadjusted prevalence of obesity was 15% among non-Hispanic white children and 21% among non-Hispanic black and Mexican-American children. Adjustment for individual-level SES neighbourhood deprivation and the interaction between these two factors resulted in a 74% attenuation of the disparity in obesity between non-Hispanic black and non-Hispanic white children and a 49% attenuation of the disparity between Mexican-American and non-Hispanic white children. There was a significant interaction between individual-level SES and neighbourhood deprivation where higher individual-level income was protective for children living in low-deprivation neighbourhoods, but not for children who lived in high-deprivation areas. Conversely, area deprivation was associated with higher odds of obesity, but only among children who were above the poverty threshold.

Conclusions

Future research on disparities in obesity and other health outcomes should examine broader contextual factors and social determinants of inequities.
The big problem: battling companion animal obesity
Authors: Raffan Eleanor
Published: September 2013

Obesity in companion animals is not a new problem and research is suggesting that it is a complex physiological issue, with genetic and endocrine causes. Eleanor Raffan discusses why some individuals appear to be predisposed to becoming obese, the far‐reaching consequences of obesity and how veterinary clinicians can help owners to help their pets
Increased net muscle protein balance in response to simultaneous and separate ingestion of carbohydrate and essential amino acids following resistance exercise
Authors: Witard Oliver C. , Cocke Tara L. , Ferrando Arny A. , Wolfe Robert R. , Tipton Kevin D.
Published: September 2013

Relative to essential amino acids (EAAs), carbohydrate (CHO) ingestion stimulates a delayed response of net muscle protein balance (NBAL). We investigated if staggered ingestion of CHO and EAA would superimpose the response of NBAL following resistance exercise, thus resulting in maximal anabolic stimulation. Eight recreationally trained subjects completed 2 trials: combined (COMB — drink 1, CHO+EAA; drink 2, placebo) and separated (SEP — drink 1, CHO; drink 2, EAA) post-exercise ingestion of CHO and EAA. Drink 1 was administered 1 h following an acute exercise bout and was followed 1 h later by drink 2. A primed, continuous infusion of l-[ring-13C6]-phenylalanine was combined with femoral arteriovenous sampling and muscle biopsies for the determination of muscle protein kinetics. Arterial amino acid concentrations increased following ingestion of EAA in both conditions. No difference between conditions was observed for phenylalanine delivery to the leg (COMB: 167 ± 23 μmol·min−1·(100 mL leg vol)−1 × 6 h; SEP: 167 ± 21 μmol·min−1·(100 mL leg vol)−1 × 6 h, P > 0.05). In the first hour following ingestion of the drink containing EAA, phenylalanine uptake was 50% greater for the SEP trial than the COMB trial. However, phenylalanine uptake was similar for COMB (110 ± 19 mg) and SEP (117 ± 24 mg) over the 6 h period. These data suggest that whereas separation of CHO and EAA ingestion following exercise may have a transient physiological impact on NBAL, this response is not reflected over a longer period. Thus, separation of CHO and EAA ingestion is unnecessary to optimize post-exercise muscle protein metabolism.
SYMMETRIC AND ASYMMETRIC QUANTUM CODES
Authors: GUENDA KENZA , GULLIVER T. AARON
Published: September 2013

The asymmetric CSS construction is extended to the Hermitian dual case. New infinite families of quantum symmetric and asymmetric codes are constructed. In particular, new quantum codes are obtained from binary BCH codes and MDS codes. These codes have known minimum distances and thus the relationship between the rate gain and minimum distance is given explicitly. The codes obtained are shown to have parameters better than those of previous codes. A number of known codes are special cases of the codes given here.
Calculated phase equilibria for phengite-bearing eclogites from NW Spitsbergen, Svalbard Caledonides
Authors: Elvevold Synnøve , Ravna Erling J. K. , Nasipuri Pritam , Labrousse Loic
Published: September 2013

Phengite-bearing eclogites occur in the Richarddalen Complex of NW Spitsbergen, Arctic Caledonides. Phase equilibrium modelling and conventional geothermobarometry have been used to constrain the metamorphic evolution of these eclogites. Pseudosections are calculated for the peak-pressure assemblage garnet+omphacite+phengite+amphibole+dolomite quartz+rutile. Compositional isopleths for garnet and phengite constrain the pressure–temperature (
P–T
) conditions to 1.9–2.0 GPa and 720–730 °C, in good agreement with the results obtained from conventional thermobarometry (720–740 °C and 2.4–2.5 GPa). Further
P–T
pseudosection modelling of clinopyroxene+plagioclase±amphibole±clinozoisite symplectites after omphacite suggests that decompression to
c.
1.2 GPa occurred along a steep exhumation path. The eclogite-bearing Richarddalen Complex constitutes the uppermost unit of a simple stack of thrust sheets where the metamorphic grade is increasing structurally upwards in the pile. Thrusting is the favoured uplift mechanism for the initial syn-orogenic exhumation to lower crustal levels. Constrictional north–south stretching in a transpressional regime is interpreted to be responsible for the final exhumation of the assembled stack of thrust sheets. Late Silurian–Early Devonian conglomerates were deposited directly on the eclogite-bearing gneisses of the Richarddalen Complex, and mark the end of exhumation of the nappe stack.
Impact of reduced daily physical activity on conduit artery flow-mediated dilation and circulating endothelial microparticles
Authors: Boyle Leryn J. , Credeur Daniel P. , Jenkins Nathan T. , Padilla Jaume , Leidy Heather J. , Thyfault John P. , Fadel Paul J.
Published: September 2013

Physical inactivity promotes the development of cardiovascular diseases. However, few data exist examining the vascular consequences of short-term reductions in daily physical activity. Thus we tested the hypothesis that popliteal and brachial artery flow-mediated dilation (FMD) would be reduced and concentrations of endothelial microparticles (EMPs) would be elevated following reduced daily physical activity. To examine this, popliteal and brachial artery FMD and plasma levels of EMPs suggestive of apoptotic and activated endothelial cells (CD31+/CD42b− and CD62E+ EMPs, respectively) were measured at baseline and during days 1, 3, and 5 of reduced daily physical activity in 11 recreationally active men (25 ± 2 yr). Subjects were instructed to reduce daily physical activity by taking <5,000 steps/day and refraining from planned exercise. Popliteal artery FMD decreased with reduced activity (baseline: 4.7 ± 0.98%, reduced activity day 5: 1.72 ± 0.68%, P < 0.05), whereas brachial artery FMD was unchanged. In contrast, baseline (pre-FMD) popliteal artery diameter did not change, whereas brachial artery diameter decreased (baseline: 4.35 ± 0.12, reduced activity day 5: 4.12 ± 0.11 P < 0.05) following 5 days of reduced daily physical activity. CD31+/CD42b− EMPs were significantly elevated with reduced activity (baseline: 17.6 ± 9.4, reduced activity day 5: 104.1 ± 43.1 per μl plasma, P < 0.05), whereas CD62E+ EMPs were unaltered. Collectively, our results provide evidence for the early and robust deleterious impact of reduced daily activity on vascular function and highlight the vulnerability of the vasculature to a sedentary lifestyle.
Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of theSerca2gene
Authors: Hillestad Vigdis , Kramer Frank , Golz Stefan , Knorr Andreas , Andersson Kristin B. , Christensen Geir
Published: September 2013

In human heart failure (HF), reduced cardiac function has, at least partly, been ascribed to altered calcium homeostasis in cardiomyocytes. The effects of the calcium sensitizer levosimendan on diastolic dysfunction caused by reduced removal of calcium from cytosol in early diastole are not well known. In this study, we investigated the effect of long-term levosimendan treatment in a murine model of HF where the sarco(endo)plasmatic reticulum ATPase ( Serca) gene is specifically disrupted in the cardiomyocytes, leading to reduced removal of cytosolic calcium. After induction of Serca2 gene disruption, these mice develop marked diastolic dysfunction as well as impaired contractility. SERCA2 knockout (SERCA2KO) mice were treated with levosimendan or vehicle from the time of KO induction. At the 7-wk end point, cardiac function was assessed by echocardiography and pressure measurements. Vehicle-treated SERCA2KO mice showed significantly diminished left-ventricular (LV) contractility, as shown by decreased ejection fraction, stroke volume, and cardiac output. LV pressure measurements revealed a marked increase in the time constant (τ) of isovolumetric pressure decay, showing impaired relaxation. Levosimendan treatment significantly improved all three systolic parameters. Moreover, a significant reduction in τ toward normalization indicated improved relaxation. Gene-expression analysis, however, revealed an increase in genes related to production of the ECM in animals treated with levosimendan. In conclusion, long-term levosimendan treatment improves both contractility and relaxation in a heart-failure model with marked diastolic dysfunction due to reduced calcium transients. However, altered gene expression related to fibrosis was observed.
Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells
Authors: Khanna Anchit , Kauko Otto , Böckelman Camilla , Laine Anni , Schreck Ilona , Partanen Johanna I. , Szwajda Agnieszka , Bormann Stefanie , Bilgen Turker , Helenius Merja , Pokharel Yuba R. , Pimanda John , Russel Mike R. , Haglund Caj , Cole Kristina A. , Klefström Juha , Aittokallio Tero , Weiss Carsten , Ristimäki Ari , Visakorpi Tapio , Westermarck Jukka
Published: September 2013

Checkpoint kinase Chk1 is constitutively active in many cancer cell types and new generation Chk1 inhibitors show marked antitumor activity as single agents. Here we present a hitherto unrecognized mechanism that contributes to the response of cancer cells to Chk1-targeted therapy. Inhibiting chronic Chk1 activity in cancer cells induced the tumor suppressor activity of protein phosphatase protein phosphatase 2A (PP2A), which by dephosphorylating MYC serine 62, inhibited MYC activity and impaired cancer cell survival. Mechanistic investigations revealed that Chk1 inhibition activated PP2A by decreasing the transcription of cancerous inhibitor of PP2A (CIP2A), a chief inhibitor of PP2A activity. Inhibition of cancer cell clonogenicity by Chk1 inhibition could be rescued in vitro either by exogenous expression of CIP2A or by blocking the CIP2A-regulated PP2A complex. Chk1-mediated CIP2A regulation was extended in tumor models dependent on either Chk1 or CIP2A. The clinical relevance of CIP2A as a Chk1 effector protein was validated in several human cancer types, including neuroblastoma, where CIP2A was identified as an NMYC-independent prognostic factor. Because the Chk1–CIP2A–PP2A pathway is driven by DNA-PK activity, functioning regardless of p53 or ATM/ATR status, our results offer explanative power for understanding how Chk1 inhibitors mediate single-agent anticancer efficacy. Furthermore, they define CIP2A-PP2A status in cancer cells as a pharmacodynamic marker for their response to Chk1-targeted therapy. Cancer Res; 73(22); 6757–69. ©2013 AACR.
Efficacy of Oral Cytarabine Ocfosfate and Etoposide in the Treatment of Elderly Patients with Higher-Risk Myelodysplastic Syndromes Compared to That in Elderly Acute Myeloid Leukemia Patients
Authors: Horikoshi Akira , Iriyama Noriyoshi , Hirabayashi Yukio , Kodaira Hitomi , Matsukawa Yoshihiro , Uchino Yoshihito , Takahashi Hiromichi , Hatta Yoshihiro , Takeuchi Jin , Kobayashi Sumiko , Miura Katsuhiro
Published: September 2013

Background: Elderly acute myeloid leukemia (AML) patients and patients with higher-risk myelodysplastic syndromes (MDS) have a much poorer prognosis than younger patients despite intensive chemotherapy. Methods: Ten patients with higher-risk MDS and 12 patients with AML over 65 years of age were enrolled into this study and received oral induction therapy with cytarabine ocfosfate and etoposide. Results: The therapy response rates were 60% in the MDS group and 41.7% in the AML group. The difference in overall survival among MDS and AML patients was not statistically significant. The difference in the median survival times of the responsive and nonresponsive groups, which included MDS and AML patients, was statistically significant (790 and 174 days, respectively). Conclusions: Based on a comparison of the data of this therapy in elderly higher-risk MDS patients versus elderly AML patients, we conclude that this therapy is well tolerated and can be cost-effective and useful for higher-risk MDS in elderly patients.
Next-Generation Sequence Analysis of Genes Associated with Obesity and Nonalcoholic Fatty Liver Disease-Related Cirrhosis in Extreme Obesity
Authors: Gerhard Glenn S. , Chu Xin , Wood G. Craig , Gerhard Genevieve M. , Benotti Peter , Petrick Anthony T. , Gabrielsen Jon , Strodel William E. , Still Christopher D. , Argyropoulos George
Published: September 2013

Objectives: Genome-wide association studies (GWAS) have led to the identification of single nucleotide polymorphisms in or near several loci that are associated with the risk of obesity and nonalcoholic fatty liver disease (NAFLD). We hypothesized that missense variants in GWAS and related candidate genes may underlie cases of extreme obesity and NAFLD-related cirrhosis, an extreme manifestation of NAFLD. Methods: We performed whole-exome sequencing on 6 Caucasian patients with extreme obesity [mean body mass index (BMI) 84.4] and 4 obese Caucasian patients (mean BMI 57.0) with NAFLD-related cirrhosis. Results: Sequence analysis was performed on 24 replicated GWAS and selected candidate obesity genes and 5 loci associated with NAFLD. No missense variants were identified in 19 of the 29 genes analyzed, although all patients carried at least 2 missense variants in the remaining genes without excess homozygosity. One patient with extreme obesity carried 2 novel damaging mutations in BBS1 and was homozygous for benign and damaging MC3R variants. In addition, 1 patient with NAFLD-related cirrhosis was compound heterozygous for rare damaging mutations in PNPLA3. Conclusions: These results indicate that analyzing candidate loci previously identified by GWAS analyses using whole-exome sequencing is an effective strategy to identify potentially causative missense variants underlying extreme obesity and NAFLD-related cirrhosis.
The Positive Association of Obesity Variants with Adulthood Adiposity Strengthens over an 80-Year Period: A Gene-by-Birth Year Interaction
Authors: Demerath Ellen W. , Choh Audrey C. , Johnson William , Curran Joanne E. , Lee Miryoung , Bellis Claire , Dyer Thomas D. , Czerwinski Stefan A. , Blangero John , Towne Bradford
Published: September 2013

Objective: To test the hypothesis that the statistical effect of obesity-related genetic variants on adulthood adiposity traits depends on birth year. Methods: The study sample included 907 related, non-Hispanic White participants in the Fels Longitudinal Study, born between 1901 and 1986, and aged 25-64.99 years (474 females; 433 males) at the time of measurement. All had both genotype data from which a genetic risk score (GRS) composed of 32 well-replicated obesity-related common single nucleotide polymorphisms was created, and phenotype data [including body mass index (BMI), waist circumference, and the sum of four subcutaneous skinfolds]. Maximum likelihood-based variance components analysis was used to estimate trait heritabilities, main effects of GRS and birth year, GRS-by-birth year interaction, sex, and age. Results: Positive GRS-by-birth year interaction effects were found for BMI (p < 0.001), waist circumference (p = 0.007), and skinfold thickness (p < 0.007). For example, each one-allele increase in GRS was estimated to result in a 0.16 increase in BMI among males born in 1930 compared to a 0.47 increase among those born in 1970. Conclusions: These novel findings suggest the influence of common obesity susceptibility variants has increased during the obesity epidemic.
Identification of Pleiotropic Genetic Effects on Obesity and Brain Anatomy
Authors: Curran Joanne E. , McKay D. Reese , Winkler Anderson M. , Olvera Rene L. , Carless Melanie A. , Dyer Thomas D. , Kent Jr. Jack W. , Kochunov Peter , Sprooten Emma , Knowles Emma E. , Comuzzie Anthony G. , Fox Peter T. , Almasy Laura , Duggirala Ravindranath , Blangero John , Glahn David C.
Published: September 2013

Background/Aims: Obesity is a major contributor to the global burden of chronic disease and disability, though current knowledge of causal biologic underpinnings is lacking. Through the regulation of energy homeostasis and interactions with adiposity and gut signals, the brain is thought to play a significant role in the development of this disorder. While neuroanatomical variation has been associated with obesity, it is unclear if this relationship is influenced by common genetic mechanisms. In this study, we sought genetic components that influence both brain anatomy and body mass index (BMI) to provide further insight into the role of the brain in energy homeostasis and obesity. Methods: MRI images of brain anatomy were acquired in 839 Mexican American individuals from large extended pedigrees. Bivariate linkage and quantitative analyses were performed in SOLAR. Results: Genetic factors associated with an increased BMI were also associated with a reduced cortical surface area and subcortical volume. We identified two genome-wide quantitative trait loci that influenced BMI and the ventral diencephalon volume, and BMI and the supramarginal gyrus surface area, respectively. Conclusions: This study represents the first genetic analysis seeking evidence of pleiotropic effects acting on both brain anatomy and BMI. Our results suggest that a region on chromosome 17 contributes to the development of obesity, potentially through leptin-induced signaling in the hypothalamus, and that a region on chromosome 3 appears to jointly influence the food-related reward circuitry and the supramarginal gyrus.
Prescribing of Drugs for Attention-Deficit Hyperactivity Disorder in Opioid Maintenance Treatment Patients in Norway
Authors: Karlstad Øystein , Furu Kari , Skurtveit Svetlana , Selmer Randi
Published: September 2013

Background: Attention-deficit hyperactivity disorder (ADHD) is a risk factor for the development of substance use disorders. Treatment of ADHD with psychostimulants in patients on opioid maintenance treatment (OMT) has been restricted in Norway. We examined the use of prescribed drugs for ADHD in OMT patients and assessed co-medication with other psychotropics. Methods: Data were drawn from the nationwide Norwegian Prescription Database (NorPD), which includes all prescriptions filled at pharmacies. The study population included subjects ≥18 years on OMT during 2008-2010. Results: In 2010, 6,116 patients received OMT and 2.8% of these also received ADHD drugs. This percentage is seven times greater than that in the gender- and age-specific general population of Norway. The prevalence was higher in the youngest patients, while there was no gender difference. Methylphenidate was the most commonly used drug for ADHD in OMT patients, followed by atomoxetine. 60% of OMT patients filled at least one prescription for antidepressants, anxiolytics or hypnotics, and percentages were similar for users and non-users of ADHD drugs. Conclusion: Treatment with ADHD drugs was higher in OMT patients than expected from the general population, but was relatively low compared to the prevalence of ADHD in patients with substance use disorders reported in the literature.
Tramadol Abuse in a Binge Pattern in a Young Depressed Woman
Authors: Ferrari Anna , Tiraferri Ilaria , Palazzoli Federica , Licata Manuela
Published: September 2013

Background: Tramadol is a central analgesic with a unique pharmacological profile in that it is an opioid agonist and an inhibitor of serotonin and norepinephrine reuptake. We describe a case of abuse of tramadol in a binge pattern in a young woman who had initially received the prescription of tramadol as an analgesic as needed. Case Description: The patient had no history of drug or alcohol abuse, but suffered from depression. Over time, she had increased the doses up to 30 ml of tramadol 100 mg/ml oral solution a week. She took the drug in consecutive ‘pinches', from afternoon to evening. Tramadol improved her mood, gave her euphoria, but also caused constipation and urinary retention. Detoxification was carried out by partial replacement with tramadol 100 mg extended release and gradual reduction of the number of pinches. The patient found it hard to follow the program because of withdrawal symptoms of an opioid type and especially because of the worsening of depression. Conclusion: The action of tramadol on the monoaminergic system is believed to be a factor that limits abuse liability and gives advantageous antidepressant-like properties, but it also involves the risk of inducing abuse of the analgesic to improve mood as if it were a stimulant.
Combined Serum Creatinine and Cystatin C Schwartz Formula Predicts Kidney Function Better than the Combined CKD-EPI Formula in Children
Authors: Chehade H. , Cachat F. , Jannot A.-S. , Meyrat B.-J. , Mosig D. , Bardy D. , Parvex P. , Girardin E.
Published: September 2013

Background: The combined serum creatinine (SCreat) and cystatin C (CysC) CKD-EPI formula constitutes a new advance for glomerular filtration rate (GFR) estimation in adults. Using inulin clearances (iGFRs), the revised SCreat and the combined Schwartz formulas, this study aims to evaluate the applicability of the combined CKD-EPI formula in children. Method: 201 iGFRs for 201 children were analyzed and divided by chronic kidney disease (CKD) stages (iGFRs ≥90 ml/min/1.73 m2, 90 > iGFRs > 60, and iGFRs ≤59), and by age groups (<10, 10-15, and >15 years). Medians with 95% confidence intervals of bias, precision, and accuracies within 30% of the iGFRs, for all three formulas, were compared using the Wilcoxon signed-rank test. Results: For the entire cohort and for all CKD and age groups, medians of bias for the CKD-EPI formula were significantly higher (p < 0.001) and precision was significantly lower than the solely SCreat and the combined SCreat and CysC Schwartz formulas. We also found that using the CKD-EPI formula, bias decreased and accuracy increased while the child age group increased, with a better formula performance above 15 years of age. However, the CKD-EPI formula accuracy is 58% compared to 93 and 92% for the SCreat and combined Schwartz formulas in this adolescent group. Conclusions: The performance of the combined CKD-EPI formula improves in adolescence compared with younger ages. Nevertheless, the CKD-EPI formula performs more poorly than the SCreat and the combined Schwartz formula in pediatric population.
Validity of Addenbrooke's Cognitive Examination to Discriminate between Incipient Dementia and Depression in Elderly Patients of a Private Clinic in Lima, Peru
Authors: Herrera-Pérez Eder , Custodio Nilton , Lira David , Montesinos Rosa , Bendezu Liliana
Published: September 2013

Background/Aims: Dementia and depression are different clinical conditions, but share common features, and can be indistinguishable in the initial disease stages. We aimed to establish whether the Peruvian version of the Addenbrooke's Cognitive Examination (ACE-Peru) can distinguish between the cognitive profile in patients with incipient dementia and that in patients with depression. Methods: This was a cross-sectional study to assess the performance on the ACE-Peru of 193 elderly subjects (102 with dementia, 21 with depression, and 70 healthy controls). Depending on the diagnosis, there were two groups of cognitive impairment (CI) - the primary neurodegenerative (PN-CI) subtype and the secondary to depression (SD-CI) subtype - as well as a non-CI group. The area under the curve (AUC) of the receiver-operating characteristic curve was determined to compare the diagnostic performance, using the diagnosis of CI as the gold standard. Results: In our sample of elderly subjects aged 59-82 years with at least 7 years of education, the ACE-Peru showed a significantly better performance than the MMSE (AUC = 0.997 vs. AUC = 0.887; p < 0.05) for the discrimination between PN-CI and SD-CI. Conclusions: The ACE-Peru is able to distinguish between the cognitive profile in patients with incipient dementia and that in patients with depression.
Punctate Inner Choroidopathy: A Clinical Case Report
Authors: Campos Joana , Campos António , Beselga Diana , Mendes Sílvia , Neves Arminda , Sousa J.P. Castro
Published: September 2013

Purpose: To report an uncommon case of a 29-year-old Caucasian male diagnosed with unilateral choroidal neovascularization (CNV) secondary to punctate inner choroidopathy leading to visual impairment. Methods: This is a retrospective and descriptive case report based on data from clinical records, patient observation and analysis of ancillary diagnostic tests. Results: A 29-year-old Caucasian male presented to our emergency department with complaints of decreased central vision in his left eye (LE), detected a few hours before. Best-corrected visual acuity (BCVA) in the LE was counting fingers at 50 cm and BCVA in the right eye was 20/20. Fundoscopy of the LE evidenced multiple round and yellowish lesions in the macula and nasal to the optic nerve, without intraocular inflammation signs. Optical coherence tomography showed increased retinal thickness with detachment of the neuroepithelium and a slight retinal pigment epithelium detachment. Fluorescein angiography revealed hyperfluorescent lesions with blurred borders in the macula. An intravitreal injection of bevacizumab (1.25 mg/0.05 ml) was administered in the LE, which resulted in anatomic and visual improvement. Conclusion: We present a rare case of unilateral CNV secondary to punctate inner choroidopathy in a young, myopic male.
C-Reactive Protein, Fatal and Nonfatal Coronary Artery Disease, Stroke, and Peripheral Artery Disease in the Prospective EPIC-Norfolk Cohort Study
Authors: van Wijk Diederik F. , Boekholdt S. Matthijs , Wareham Nicholas J. , Ahmadi-Abhari Sara , Kastelein John J.P. , Stroes Erik S.G. , Khaw Kay-Tee
Published: September 2013

Objective—

Circulating levels of C-reactive protein (CRP) are associated with an increased risk of coronary artery disease (CAD), stroke, and peripheral artery disease (PAD). Observational and experimental evidence suggest that CRP might differentially predict fatal and nonfatal cardiovascular events. Here, we sought to determine the predictive value of CRP for fatal and nonfatal CAD, stroke, or PAD.

Approach and Results—

CRP levels were measured in 18 450 apparently healthy participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. Cox proportional hazards models were used to quantify the association between CRP levels and fatal and nonfatal CAD events, strokes, and PAD events. Bootstrapping was applied to test for significant differences between the risk of fatal and nonfatal events. During 208 485 person-years at risk, 2915 CAD events, 361 strokes, and 657 PAD events occurred. CRP was associated with fatal and nonfatal CAD events and nonfatal PAD events. When adding CRP to predictive risk models for fatal and nonfatal events corrected for known cardiovascular risk factors, the net reclassification index was 2.1% for fatal and 1.9% for nonfatal events. Multivariate adjusted hazard ratios for fatal CAD events (hazard ratio, 1.36; 95% confidence interval, 1.27–1.46) differed significantly (mean difference, 13%; 95% confidence interval, 5.1%–21.9%;
P
<0.001) from the multivariate adjusted hazard ratio for nonfatal CAD events (hazard ratio, 1.21; 95% confidence interval, 1.15–1.26).

Conclusions—

In the EPIC-Norfolk cohort, CRP was associated with fatal and nonfatal CAD events, as well as nonfatal PAD events. Adding CRP to risk stratification models resulted in a small improvement in classification for both fatal and nonfatal events. Importantly, CRP was significantly more strongly associated with fatal CAD events than with nonfatal CAD events.