bluuebunny/crossref_metadata_2025 huggingface dataset:
Translating human genetics into mouse: The impact of ultra‐rapid in vivo genome editing
Authors: Aida Tomomi , Imahashi Risa , Tanaka Kohichi
Published: November 2013

Gene‐targeted mutant animals, such as knockout or knockin mice, have dramatically improved our understanding of the functions of genes in vivo and the genetic diversity that characterizes health and disease. However, the generation of targeted mice relies on gene targeting in embryonic stem (ES) cells, which is a time‐consuming, laborious, and expensive process. The recent groundbreaking development of several genome editing technologies has enabled the targeted alteration of almost any sequence in any cell or organism. These technologies have now been applied to mouse zygotes (in vivo genome editing), thereby providing new avenues for simple, convenient, and ultra‐rapid production of knockout or knockin mice without the need for ES cells. Here, we review recent achievements in the production of gene‐targeted mice by in vivo genome editing.
The ecological consequences of megafaunal loss: giant tortoises and wetland biodiversity
Authors: Froyd Cynthia A. , Coffey Emily E. D. , van der Knaap Willem O. , van Leeuwen Jacqueline F. N. , Tye Alan , Willis Katherine J.
Published: November 2013

The giant tortoises of the Galápagos have become greatly depleted since European discovery of the islands in the 16th Century, with populations declining from an estimated 250 000 to between 8000 and 14 000 in the 1970s. Successful tortoise conservation efforts have focused on species recovery, but ecosystem conservation and restoration requires a better understanding of the wider ecological consequences of this drastic reduction in the archipelago's only large native herbivore. We report the first evidence from palaeoecological records of coprophilous fungal spores of the formerly more extensive geographical range of giant tortoises in the highlands of Santa Cruz Island. Upland tortoise populations on Santa Cruz declined 500–700 years ago, likely the result of human impact or possible climatic change. Former freshwater wetlands, a now limited habitat‐type, were found to have converted to Sphagnum bogs concomitant with tortoise loss, subsequently leading to the decline of several now‐rare or extinct plant species.
Visit‐to‐visit systolic blood pressure variability predicts all‐cause and cardiovascular mortality after lacunar infarct
Authors: Lau K. K. , Wong Y. K. , Chang R. S. K. , Teo K. C. , Hon S. F. K. , Chan K. H. , Wat K. L. , Cheung R. T. F. , Li L. S. W. , Siu C. W. , Ho S. L. , Tse H. F.
Published: November 2013

Background and purpose

Both blood pressure (BP) and its variability (BPV) are established risk factors for development of atherosclerotic disease and are associated with an increased risk for cardiovascular and all‐cause mortality. The prognostic implications of outpatient clinic visit‐to‐visit BPV amongst patients with lacunar infarction are nevertheless unknown.

Methods

The clinical outcome of 281 patients with lacunar infarction was prospectively followed up. The average BP and BPV, as determined by the standard deviation of the systolic and diastolic BP, were recorded during a mean 13 ± 6 outpatient clinic visits.

Results

The mean age of the population was 70 ± 10 years. After a mean 78 ± 18 months follow‐up, 65 patients died (23%), 31% (20/65) due to cardiovascular causes; 14% and 7% developed recurrent stroke and acute coronary syndrome. After adjusting for age, sex, mean systolic and diastolic BP, cardiovascular risk factors and comorbidities, patients with a systolic BPV of the third tertile had significantly higher risk of all‐cause mortality [hazard ratio (HR) 1.97, 95% confidence interval (CI) 1.02–3.80, P = 0.04) and cardiovascular mortality (HR 7.64, 95% CI 1.65–35.41, P < 0.01) than those with systolic BPV of the first tertile. Nevertheless, systolic BPV did not predict recurrent stroke or acute coronary syndrome. Diastolic BPV did not predict various adverse clinical outcomes.

Conclusions

Visit‐to‐visit systolic BPV predicts long‐term all‐cause and cardiovascular mortality after lacunar infarct, independent of conventional risk factors including average BP control.
Influence of pH on inhibition of Streptococcus mutans by Streptococcus oligofermentans
Authors: Liu Ying , Chu Lei , Wu Fei , Guo Lili , Li Mengci , Wang Yinghui , Wu Ligeng
Published: November 2013

Streptococcus oligofermentans is a novel strain of oral streptococcus that can specifically inhibit the growth of Streptococcus mutans. The aims of this study were to assess the growth of S. oligofermentans and the ability of S. oligofermentans to inhibit growth of Streptococcus mutans at different pH values. Growth inhibition was investigated in vitro using an interspecies competition assay. The 4‐aminoantipyine method was used to measure the initial production rate and the total yield of hydrogen peroxide in S. oligofermentans. S. oligofermentans grew best at pH 7.0 and showed the most pronounced inhibitory effect when it was inoculated earlier than S. mutans. In terms of the total yield and the initial production rate of hydrogen peroxide by S. oligofermentans, the effects of the different culture pH values were as follows: pH 7.0 > 6.5 > 6.0 > 7.5 > 5.5 = 8.0 (i.e. there was no significant difference between pH 5.5 and pH 8.0). Environmental pH and the sequence of inoculation significantly affected the ability of S. oligofermentans to inhibit the growth of S. mutans. The degree of inhibition may be attributed to the amount of hydrogen peroxide produced.
Goodbye van Gend en Loos, Hello Bosman? Using Network Analysis to Measure the Importance of Individual CJEU Judgments
Authors: Derlén Mattias , Lindholm Johan
Published: November 2013

It is generally agreed that some judgments by the Court of Justice are more important than others, but the ability of traditional legal methods to identify such judgments is inherently limited. In this article, we apply various tools developed in network analysis to identify which judgments are the most important as legal precedents. The study reveals that certain well‐known judgments, like van Gend en Loos, have limited importance as precedents, while other judgments, like Bosman, PreussenElektra and Schumacker, are likely overlooked.
Patterns in CH4 and CO2 concentrations across boreal rivers: Major drivers and implications for fluvial greenhouse emissions under climate change scenarios
Authors: Campeau Audrey , del Giorgio Paul A.
Published: November 2013

It is now widely accepted that boreal rivers and streams are regionally significant sources of carbon dioxide (CO2), yet their role as methane (CH4) emitters, as well as the sensitivity of these greenhouse gas (GHG) emissions to climate change, are still largely undefined. In this study, we explore the large‐scale patterns of fluvial CO2 and CH4 partial pressure (pCO2, pCH4) and gas exchange (k) relative to a set of key, climate‐sensitive river variables across 46 streams and rivers in two distinct boreal landscapes of Northern Québec. We use the resulting models to determine the direction and magnitude of C‐gas emissions from these boreal fluvial networks under scenarios of climate change. River pCO2 and pCH4 were positively correlated, although the latter was two orders of magnitude more variable. We provide evidence that in‐stream metabolism strongly influences the dynamics of surface water pCO2 and pCH4, but whereas pCO2 is not influenced by temperature in the surveyed streams and rivers, pCH4 appears to be strongly temperature‐dependent. The major predictors of ambient gas concentrations and exchange were water temperature, velocity, and DOC, and the resulting models indicate that total GHG emissions (C‐CO2 equivalent) from the entire network may increase between by 13 to 68% under plausible scenarios of climate change over the next 50 years. These predicted increases in fluvial GHG emissions are mostly driven by a steep increase in the contribution of CH4 (from 36 to over 50% of total CO2‐equivalents). The current role of boreal fluvial networks as major landscape sources of C is thus likely to expand, mainly driven by large increases in fluvial CH4 emissions.
Fibrolytic enzymes and a ferulic acid esterase‐producing bacterial additive applied to alfalfa hay at baling: effects on fibre digestibility, chemical composition and conservation characteristics
Authors: Lynch J. P. , Jin L. , Church J. S. , Baah J. , Beauchemin K. A.
Published: November 2013

This study evaluated the effect of two fibrolytic enzyme products, applied at baling, on the chemical composition and digestibility of alfalfa hay. Three replicate bales of alfalfa hay (82% dry matter) were produced with the application of one of five treatments including an untreated control and one of two fibrolytic enzyme products (DYC and ECO), either applied alone or in combination with a ferulic acid esterase‐producing bacterial additive. The enzyme products were applied on the basis of endoglucanase activity. The neutral detergent fibre (NDF) concentration and accumulated temperature after storage of hay produced using DYC‐ or ECO‐based treatments were greater (P < 0·05) than untreated hay, except for hay bales produced using ECO alone. Bales produced using ECO‐based treatments had a greater (P < 0·05) in vitro NDF digestibility compared with untreated bales. The application of fibrolytic enzymes at baling may potentially improve NDF digestibility without negatively affecting chemical composition or increasing aerobic deterioration. However, the effects of fibrolytic enzymes varied depending on the product applied. Combining ferulic acid esterase‐producing bacterial additives with fibrolytic enzymes did not improve the nutritive value of hay after storage.
Virtual tissue microarrays: a novel and viable approach to optimizing tissue microarrays for biomarker research applied to ductal carcinoma in situ
Authors: Quintayo Mary Anne , Starczynski Jane , Yan Fu Jian , Wedad Hanna , Nofech‐Mozes Sharon , Rakovitch Eileen , Bartlett John M S
Published: November 2013

Aims

Tissue microarrays (TMAs) are effective tools for performing high‐throughput standardization analyses of biomarkers, but evidence indicating the core number required to be representative of the whole tumour is lacking. Ductal carcinoma in situ (DCIS) is a non‐obligate precursor of invasive breast cancer. The number and size of cores that can best represent a DCIS lesion are unknown. Rather than performing extensive experiments using several variants of physical TMAs, the aim of this study was to develop a ‘virtual TMA’ approach that is effective at optimizing biomarker discovery and validation.

Methods and results

Whole DCIS sections from 95 patients were evaluated by immunohistochemistry for oestrogen receptor (ER), progesterone receptor (PgR), HER2, and Ki67. Histoscores were generated manually for ER, PgR, and HER2, as well as percentage positivity for Ki67. Slides were scanned using the FDA‐approved Ariol SL50 Image Analysis system, and the virtual array (V‐Array) module was used. Virtual cores created virtual TMAs, and our validated scoring classifiers were applied. Automated histoscores and percentage positivity were determined, and compared against increasing numbers of cores. The optimal number of cores was based on concordant results between virtual TMAs and corresponding whole sections.

Conclusions

We have shown that virtual arrays constitute an important tool in digital pathology in both research and clinical settings.
Supplier–retailer inventory coordination with credit term for inventory‐dependent and linear‐trend demand
Authors: Wu Chengfeng , Zhao Qiuhong
Published: November 2013

In this paper, a nonintegrated and collaborative replenishment policy is considered, respectively, which incorporates varying demand depending on both inventory level and time during the finite planning horizon. For additional cost savings realized from coordination, the paper adopts trade credit as a cost‐saving shift means and introduces a brand new parameter, that is, credit period rate. Then, the equitable credit period rate is determined, and different values of the credit period rate reflect the allocation of additional cost savings between the supplier and retailer. Furthermore, the conditions for the existence and uniqueness of an optimal solution are proved for the nonintegrated and collaborative replenishment policy, and an efficient solution procedure is developed to determine the optimal results and coordination of the inventory model. Finally, several numerical examples are provided to illustrate the proposed strategy and algorithm, and the sensitivity analysis of the optimal solution with respect to each parameter is presented. The sensitivity analysis suggests that the size of the credit period rate has a strong relationship with the supplier's and retailer's inventory cost (including capital cost) and setup cost. In real‐life situations, this proposed strategy may be applied to some consumer products in the growth phase or best‐selling consumer goods, etc.
What's going on behind the screens?
Authors: Falloon G.
Published: November 2013

Since their introduction in 2010, much has been said and written about Apple's iPad (Apple Inc., Cupertino, CA, USA) and its potential to transform when and how students learn. Much of this hype has focused on attributes of the device such as its touch screen interface, light and portable form factor, easy‐to‐use operating system, and large array of apps. Emerging studies mainly report positive outcomes for students from using iPads in specific learning situations. These studies have cited enhanced motivation and learner engagement, often linking this with improved learning outcomes. However, there is a dearth of research exploring how students interact with these devices, and the factors that affect the quality and learning value from that interaction.

This article reports on the use of an innovative recording solution to capture video and audio data of young students using iPads to develop literacy, numeracy and problem‐solving/decision‐making skills. The study offers insights into how students go about solving problems within apps, and highlights the importance of knowledge, affective and dispositional elements, and good app design to profitable interaction. It also flags considerations for teachers embarking on initiatives involving iPads, and suggests app developers need to work more closely with teachers to improve the learning value of their products.
Seborrheic dermatitis and hypertension in adults: a cross‐sectional study
Authors: Linder D. , Dreiher J. , Zampetti A. , Sampogna F. , Cohen A.D.
Published: November 2013

Background

Seborrheic dermatitis (SD) is a chronic inflammatory skin disease that shares some features with psoriasis. Previous reports have demonstrated an association between hypertension and psoriasis. Chronic skin inflammation may plays a role in the aetiology of hypertension in both disorders.

Objective

To evaluate the association between SD and hypertension in an adult large population sample.

Methods

A cross‐sectional study was carried out by utilizing the database of Clalit Health Services, a healthcare provider organization for over 4 million enrollees in Israel. All adult patients previously diagnosed with SD were compared with a sample of enrollees without SD regarding the prevalence of hypertension. Patients without SD were frequency matched to SD patients regarding age and sex. Data on other health‐related lifestyles and comorbidities were collected.

Results

The study included all 9255 patients with SD and 9246 age‐ and sex‐matched patients without SD. The prevalence of hypertension was significantly higher in patients with SD (27.1% vs. 24.7%, P < 0.001, OR = 1.13, 95% CI: 1.05–1.21). A multivariate logistic regression model demonstrated that SD was significantly associated with hypertension after controlling for confounders, including age, sex, socioeconomic status, smoking, diabetes and obesity (multivariate OR = 1.23, 95% CI: 1.12–1.35, P < 0.001).

Conclusions

In this study, an association between SD and hypertension was demonstrated in adults. Many factors can be advocated to explain this association. Genetic predisposition, psychological conditions, lipid abnormalities and chronic inflammation of the skin with a change in cytokine balance should be explored as potential mechanisms.
Comparative study of photodynamic therapy with 5%, 10% and 20% aminolevulinic acid in the treatment of generalized recalcitrant facial verruca plana: a randomized clinical trial
Authors: Li Q. , Jiao B. , Zhou F. , Tan Q. , Ma Y. , Luo L. , Zhai J. , Luan Q. , Li C. , Wang G. , Gao T.
Published: November 2013

Background

Generalised recalcitrant facial verruca plana responds poorly to current therapeutic options, including cryotherapy, topical drugs and carbon dioxide (CO2) laser. Case reports and uncontrolled studies suggested that topical photodynamic therapy (PDT) is effective choice of treatment free from potential complications associated with invasive therapies.

Aims

To investigate the efficacy and safety of PDT with different concentrations of photosensitiser in the treatment of verruca plana.

Materials & Methods

The two sides of a subject's face were separately randomized to receive aminolevulinic acid (ALA) of 5%, 10% or 20% concentration. All patients were irradiated with 633‐nm red light for 339 J/cm2 total dose. Complete response (CR) rate was assessed on Week 4, 8, and 16 respectively.

Results

The mean overall clearance rate was 74.1%, 68.8%, and 64.6% on Week 4, 8, and 12, respectively, in the 110 treated sides. The CR rate was lower in the 5%‐ALA group than in the 10%‐ALA group (14.3% vs. 33.3%, p < 0.05) and 20%‐ALA group (14.3% vs. 26.3%, p < 0.05) after 12 weeks. The mean severity of pain measured by visual analogue scale (VAS) scoring was 3.8 (range: 2 to 10, depending on the lesion location). The overall recurrence rate was 16.7% (4/24) on Week 12. Hyperpigmentation was observed in 61% (67/110) of all treated sides. On Week 4, 8, and 16, hyperpigmentation was more developed in the 20%‐ALA group than in the other two groups (p < 0.05).

Discussion

In terms of complete clearance rate, the 5% ALA‐PDT group was significantly inferior to the 10% and 20% ALA‐PDT groups at each follow‐up. In contrast, the 20% ALA group showed a higher incidence rate of transient hyperpigmentation than the other two groups.

Conclusions

This randomised clinical trial suggests that PDT with ALA of 10% concentration offers better efficacy and safety than 5% or 20% concentration for generalised recalcitrant facial verruca plana.
A Detailed Cost Evaluation of a Juvenile Drug Court that Follows the Juvenile Drug Court Model (16 Strategies)
Authors: Carey Shannon M. , Herrera Allen Theresa , Perkins Tamara , Waller Mark S.
Published: November 2013

Although juvenile drug courts (JDCs) have now been in operation for 17 years, there is still no definitive appraisal as to this model's cost effectiveness and in particular, no detailed cost analysis of a JDC program following the 16 strategies until this one. The cost data presented in this paper build on the process and outcome evaluations performed on the Clackamas County Juvenile Drug Court (CCJDC). The criminal justice costs incurred by participants in drug court are compared with the costs incurred by eligible non‐participants.

CCJDC participants had far more positive outcomes than those who did not participate in the program. In the two years after drug court entry, CCJDC participants cost the taxpayers $961 less per participant than similar individuals who did not attend the drug court program.
Burden of Sliding Scale Insulin Use in Elderly Long‐Term Care Residents with Type 2 Diabetes Mellitus
Authors: Pandya Naushira , Wei Wenhui , Meyers Juliana L. , Kilpatrick Brett S. , Davis Keith L.
Published: November 2013

Objectives

To examine prevalence, practice patterns, and associated burden of sliding scale insulin (SSI) therapy in elderly adults with type 2 diabetes (T2DM).

Design

A retrospective cross‐sectional study assessing merged medical chart data and the Minimum Data Set.

Setting

One hundred seventeen long‐term care (LTC) facilities in seven U.S. states.

Participants

Elderly adults with insulin‐treated T2DM (N = 2,096) admitted to a LTC facility after January 1, 2009, who had been in the facility for at least 3 months before chart abstraction and had received treatment with non‐SSI or SSI regimens. The latter were categorized into SSI‐only, basal–SSI, prandial–SSI, basal–prandial–SSI, and multiple regimens with SSI. Data were collected from September 2010 through September 2011.

Measurements

Demographic and clinical characteristics were recorded. Fingerstick burden was assessed as the average number of fingersticks per week and average number without subsequent insulin administration. Other measures included glycosylated hemoglobin (HbA1c) and hypoglycemia events.

Results

Overall, 73.8% of participants received SSI therapy. SSI‐treated participants were more likely to be younger (P = .01), non‐white (P = .002), and receiving sulfonylurea (P = .004) than non‐SSI treated participants. SSI therapy was associated with a mean ± standard deviation of 19.9 ± 7.9 fingersticks per week, of which 12.5 ± 7.6 were not followed by insulin administration. Fewer SSI‐treated participants than non‐SSI treated participants had one or more HbA1c measurements of 7.0% or less (48.8% vs 57.2%) or 8.5% or less (85.2% vs 87.6%, respectively). Rates of hypoglycemia were similar in both groups (15.0% vs 14.9%).

Conclusion

SSI therapy is widely used in LTC facilities and is associated with a high fingerstick burden. SSI regimens are associated with poorer glycemic control but a rate of hypoglycemia similar to that of non‐SSI regimens.
Prevalence, Awareness, Treatment, and Control of Hypertension in Elderly Adults with Chronic Kidney Disease: Results from the Survey of Prevalence, Awareness, and Treatment Rates in Chronic Kidney Disease Patients with Hypertension in China
Authors: Cai Guangyan , Zheng Ying , Sun Xuefeng , Chen Xiangmei ,   the Survey of Prevalence, Awareness, and Treatment Rates in Chronic Kidney Disease Patients with Hypertension in China Collaborative Group
Published: November 2013

Objectives

Data regarding hypertension in elderly adults with chronic kidney disease (CKD) remains limited. This study aimed to assess the epidemiological characteristics of hypertension in elderly adults with CKD using data from a nationwide survey.

Design

A nationwide, multicenter, cross‐sectional study with a large sample.

Setting

The Survey of Prevalence, Awareness, and Treatment Rates in Chronic Kidney Disease Patients with Hypertension in China (PATRIOTIC).

Participants

Participants in PATRIOTIC (aged ≥60; n = 2,414).

Measurements

Trained physicians measured blood pressure (BP) using a standard protocol with a mercury sphygmomanometer at the time of admission.

Results

The prevalence, awareness, and treatment of hypertension in elderly adults with CKD were 82.0%, 90.7%, and 87.3%, respectively. The control of hypertension at BP less than 140/90 mmHg was 29.6% and at BP less than 130/80 mmHg it was 12.1%. No significant differences were noted in the prevalence, awareness, treatment, or control of hypertension in individuals with CKD divided into the age groups of 60 to 69, 70 to 79, and 80 and older (P > .05). With increasing age, the proportion of isolated systolic hypertension in elderly adults with CKD with uncontrolled hypertension increased (P = .02). Obesity (P = .01), CKD Stages 4 and 5 (P < .001), and concomitant diabetes mellitus (P = .002) were significantly associated with uncontrolled hypertension in elderly adults with CKD, using the goal of BP less than 140/90 mmHg.

Conclusion

The prevalence of hypertension in elderly adults in China with CKD is high, and its control is poor. Most elderly adults with CKD with uncontrolled hypertension have systolic hypertension. Obesity, CKD Stages 4 and 5, and diabetes mellitus were adversely associated with greater uncontrolled hypertension in elderly adults with CKD.
When Credit Bites Back
Authors: JORDÀ ÒSCAR , SCHULARICK MORITZ , TAYLOR ALAN M.
Published: November 2013

Using data on 14 advanced countries between 1870 and 2008 we document two key facts of the modern business cycle: relative to typical recessions, financial crisis recessions are costlier, and more credit‐intensive expansions tend to be followed by deeper recessions (in financial crises or otherwise) and slower recoveries. We use local projection methods to condition on a broad set of macro‐economic controls to study how past credit accumulation impacts key macro‐economic variables such as output, investment, lending, interest rates, and inflation. The facts that we uncover lend support to the idea that financial factors play an important role in the modern business cycle.
Financial Crises and Recapitalizations
Authors: SANDRI DAMIANO , VALENCIA FABIÁN
Published: November 2013

We develop a dynamic stochastic general equilibrium model with financial frictions on both financial intermediaries and goods‐producing firms. Since financial intermediaries are highly leveraged, we show that the welfare gains from their recapitalization in response to large but rare net worth losses are as large as those from eliminating typical business cycle fluctuations. We also find that these gains are increasing in the size of the net worth loss, are larger when recapitalization funds are raised from the household rather than the real sector, and can be larger when lower idiosyncratic risk leads to higher leverage.
Financial Exposure and the International Transmission of Financial Shocks
Authors: KAMBER GÜNEŞ , THOENISSEN CHRISTOPH
Published: November 2013

This paper analyzes the transmission mechanism of banking sector shocks in an international real business cycle model with heterogeneous bank sizes. We examine to what extent the financial exposure of the banking sector affects the transmission of foreign banking sector shocks. In our model, the more exposed domestic banks are to the foreign economy via lending to foreign firms, the greater are the spillovers from foreign financial shocks to the home economy. The model highlights the role of openness to trade and the dynamics of the terms of trade in the international transmission mechanism of banking sector shocks: spillovers from foreign banking sector shocks are greater the more open the home economy is to trade and the less the terms of trade respond to foreign shocks.
Maternal obesity impairs brain glucose metabolism and neural response to hyperglycemia in male rat offspring
Authors: Chen Hui , Simar David , Morris Margaret J.
Published: November 2013

Hypothalamic appetite regulators neuropeptide Y (NPY) and pro‐opiomelanocortin (POMC) are modulated by glucose. This study investigated how maternal obesity disturbs glucose regulation of NPY and POMC, and whether this deregulation is linked to abnormal hypothalamic glucose uptake‐lactate conversion. As post‐natal high‐fat diet (HFD) can exaggerate the effects of maternal obesity, its additional impact was also investigated. Female Sprague Dawley rats were fed a HFD (20 kJ/g) to model maternal obesity. At weaning, male pups were fed chow or HFD. At 9 weeks, in vivo hypothalamic NPY and POMC mRNA responses to acute hyperglycemia were measured; while hypothalami were glucose challenged in vitro to assess glucose uptake‐lactate release and related gene expression. Maternal obesity dampened in vivo hypothalamic NPY response to acute hyperglycemia, and lowered in vitro hypothalamic glucose uptake and lactate release. When challenged with 20 mM glucose, hypothalamic glucose transporter 1, monocarboxylate transporters, lactate dehydrogenase‐b, NPY and POMC mRNA expression were down‐regulated in offspring exposed to maternal obesity. Post‐natal HFD consumption reduced in vitro lactate release and monocarboxylate transporter 2 mRNA, but increased POMC mRNA levels when challenged with 20 mM glucose. Overall, maternal obesity produced stronger effects than post‐natal HFD consumption to impair hypothalamic glucose metabolism. However, they both disturbed NPY response to hyperglycemia, potentially leading to hyperphagia.

image

Maternal obesity reduced hypothalamic glucose uptake‐lactate conversion, which disturbs glucose regulation of neuropeptide Y (NPY) and potentially leads to hyperphagia. The down‐regulation of hypothalamic glucose and lactate transporters and the synchronously decreased mammalian target of rapamycin (mTOR) expression in response to maternal obesity may be an underlying mechanism. Post‐weaning high‐fat diet (HFD) consumption also impaired hypothalamic NPY response to hyperglycemia, however less potently than maternal obesity, potentially because of its limited impact on glucose‐lactate conversion and transporter expression.
Transfer of omega‐3 fatty acids across the blood–brain barrier after dietary supplementation with a docosahexaenoic acid‐rich omega‐3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study
Authors: Freund Levi Y. , Vedin I. , Cederholm T. , Basun H. , Faxén Irving G. , Eriksdotter M. , Hjorth E. , Schultzberg M. , Vessby B. , Wahlund L.‐O. , Salem N. , Palmblad J.
Published: November 2013

Objective

Little is known about the transfer of essential fatty acids (FAs) across the human blood–brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega‐3 (n‐3) FAs would change the FA profile of the cerebrospinal fluid (CSF).

Methods

A total of 33 patients (18 receiving the n‐3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double‐blind, placebo‐controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n‐3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation.

Results

At 6 months, the n‐3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n‐3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n‐3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin‐1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers.

Conclusions

Oral supplementation with n‐3 FAs conferred changes in the n‐3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.
Meaningful Youth Engagement as a Protective Factor for Youth Suicidal Ideation
Authors: Armstrong Laura Lynne , Manion Ian G.
Published: November 2013

Youth suicide is a leading cause of mortality. Greater still is the prevalence of suicidal behavior and ideation. In this study with 813 secondary school students, we explored youth engagement in structured extracurricular activities as a possible protective factor for suicidal ideation. Personally meaningful youth engagement significantly moderated the relationships between depressive symptoms, risk behaviors, self‐esteem, and social support in the prediction of suicidal ideation. Specifically, the more meaning found in engagement, the less likely youth were to report suicidal thoughts in spite of risk factors. Acknowledging limitations, a focus on engaging youth in well‐selected activities of interest might represent a nonstigmatizing approach to universal prevention. Further research into the mechanisms of such an approach is warranted.
Expression and Activity of Collagenases in the Digital Laminae of Horses with Carbohydrate Overload‐Induced Acute Laminitis
Authors: Wang L. , Pawlak E.A. , Johnson P.J. , Belknap J.K. , Alfandari D. , Black S.J.
Published: November 2013

Background

Matrix metalloproteinases (MMP) are hypothesized to degrade structurally important components of the laminar extracellular matrix (ECM) in horses with laminitis.

Objective

To compare levels of expression of stromelysin‐1 (MMP‐3), collagenases (MMP‐1, ‐13), and membrane type‐MMPs (MMP‐14, ‐15, ‐16), and the distribution of theirECMsubstrates, in laminae of healthy horses and horses with carbohydrate overload laminitis.

Animals

Twenty‐five adult horses.

Methods

Gene and protein expression were determined in extracts of laminae using real‐time quantitative polymerase chain reaction and Western blotting after sodium dodecylsulfate polyacrylamide gel electrophoresis. Distribution of MMP‐13 andECMcomponents was determined using indirect immunofluorescent microscopy of nonfixed frozen sections.ECMmorphology was assessed by hematoxylin and eosin staining.

Results

Of the genes studied, only those encoding MMP‐1 and ‐13 were upregulated inCHO‐induced laminitis; MMP‐1 at Obel grade (OG)1 lameness and MMP‐13 at OG3 lameness. Laminar MMP‐1 was present as 52 kDa proenzyme only. MMP‐13 was present as pro‐ (61 kDa) and processed (48 kDa) enzyme. MMP‐13 localized to the basal epithelium of the secondary epidermal laminae and its increased expression were accompanied by the appearance in secondary dermal laminae (SDL) of multiple foci that were devoid of collagen I, fibronectin, chondroitin and keratan sulfate glycosaminoglycans, and eosin‐staining material.

Conclusions and Clinical Relevance

MMP‐13 is upregulated in laminae of horses withCHO‐inducedOG3 lameness and, by degrading components of theECM, may contribute to the formation ofECM‐free lesions (gaps or tears) that appear in theSDLwithOG3 lameness.
Iron Status in Blood Donor Dogs
Authors: Zaldívar‐López S. , Iazbik M.C. , Marín L.M. , Couto C.G.
Published: November 2013

Background

Despite the popularity of canine blood donor (BD) programs, there is scarce scientific information regarding iron status in this canine population of dogs.

Objective

To assess iron status in dogs used in a blood donor program.

Animals

A total of 130 healthy dogs (75 BD, 55 controls [C]) were included. A subset of dogs (n = 12) were used to evaluate the effects of repetitive donations by having a second and more recent sample analyzed.

Methods

Serum iron concentration (SI), unsaturated iron‐binding capacity (UIBC), total iron‐binding capacity (TIBC), and percentage transferrin saturation (%SAT) were obtained. Values were compared using a 2‐way ANOVA (factors: BD status, breed). For the subset of BD, the first sample (less frequent donors ‐LD‐, after a mean of 3.8 donations) was compared to a second sample (experienced donors ‐ED‐, mean 13.6 donations) using a paired t‐test.

Results

SI (183.7 ± 55.3 μg/dL) and %SAT (55.7 ± 17.4%) were higher and UIBC (152.6 ± 73.3 μg/dL) was lower in BD dogs than in C (153.9 ± 51.7 μg/dL, 43.8 ± 17.8%, and 224.1 ± 120.6 μg/dL, respectively). Also, UIBC and TIBC were lower, and %SAT higher in Greyhounds when compared with non‐Greyhounds. ED had decreased %SAT and increased UIBC and TIBC when compared with LD.

Conclusions and Clinical Importance

Our canine BD population did not have iron deficiency and had higher SI concentration than C. However, ED (~14 consecutive blood donations every ~8 weeks) developed a mild iron deficiency, although values were still within canine reference intervals. Greyhounds have higher %SAT than non‐Greyhounds, which might be a breed‐specific peculiarity.
Effects of Pioglitazone on Insulin Sensitivity and Serum Lipids in Obese Cats
Authors: Clark M. , Thomaseth K. , Dirikolu L. , Ferguson D. C. , Hoenig M.
Published: November 2013

Background

Pioglitazone is a thiazolidinedione (TZD) insulin sensitizer approved for use in human type 2 diabetes mellitus. Therapeutic options for diabetes in cats are limited.

Objective

To evaluate the effects of pioglitazone in obese cats, which are predisposed to insulin resistance, to assess its potential for future use in feline diabetes mellitus.

Animals

A total of 12 obese purpose‐bred research cats (6 neutered males and 6 spayed females, 5–7 years of age, weighing 5.4–9.8 kg).

Methods

Randomized, placebo‐controlled 3‐way crossover study. Oral placebo or pioglitazone (Actos™; 1 or 3 mg/kg) was administered daily for 7‐week periods, with IV glucose tolerance testing before and after each period.

Results

Three mg/kg pioglitazone significantly improved insulin sensitivity (geometric mean [95% CI] 0.90 [0.64–1.28] to 2.03 [1.49–2.78] min−1pmol−1L;P = .0014 versus change with placebo), reduced insulin area under the curve during IVGTT (geometric mean [range] 27 [9–64] to 18 [6–54] min∙nmol/L;P = .0031 versus change with placebo), and lowered serum triglyceride (geometric mean [range] 71 [29–271] to 48 [27–75] mg/dL;P = .047 versus change with placebo) and cholesterol (geometric mean [range] 187 [133–294] to 162 [107–249] mg/dL;P = .0042 versus change with placebo) concentrations in the obese cats. No adverse effects attributable to pioglitazone were evident in the otherwise healthy obese cats at this dosage and duration.

Conclusions and Clinical Importance

Results of this study support a positive effect of pioglitazone on insulin sensitivity and lipid metabolism in obese cats, and suggest that further evaluation of the drug in cats with diabetes mellitus or other metabolic disorders might be warranted.
Molecular and biochemical modifications of liver glutamine synthetase elicited by daytime restricted feeding
Authors: Vázquez‐Martínez Olivia , De Ita‐Pérez Dalia , Valdés‐Fuentes Marlen , Flores‐Vidrio Alejandra , Vera‐Rivera Gabriela , Miranda María I. , Méndez Isabel , Díaz‐Muñoz Mauricio
Published: November 2013

Background & Aims

The circadian clock system in the liver plays important roles in regulating metabolism and energy homeostasis. Restricted feeding schedules (RFS) become an entraining stimulus that promotes adaptations that form part of an alternative circadian clock known as the food entrained oscillator (FEO). The aim of this study was to evaluate the daily variations of glutamine synthetase (GS) in liver under a daytime RFS.

Methods

Hepatic GS properties were analysed at 3‐h intervals over a 24‐h period in adult male Wistar rats maintained in a 12:12 h light–dark cycle. RFS group: food access for 2‐h in light phase, during 3 weeks. AL group: feeding ad libitum. Fa group: acute fast (21 h). Fa–Re group: acute fast followed by refed 2 h. mRNA expression was measured by RT‐qPCR, protein presence by Western‐blot and immunohistochemistry, enzyme activity by a spectrophotometric assay, and glutamine by high pressure liquid chromatography.

Results and Conclusions

Restricted feeding schedule induced circadian rhythmicity in mRNA levels of GS and the loss of the rhythmic pattern in mitochondrial GS activity. GS activity in liver homogenates displayed a robust rhythmic pattern in AL that was not modified by RFS. The presence of GS and its zonal distribution did not show rhythmic pattern in both groups. However, acute Fa and Fa–Re diminished GS protein and activity in liver homogenates. Hepatic glutamine concentrations showed a 24‐h rhythmic pattern in both groups, in an antiphasic pattern. In conclusion, daytime RFS influences the liver GS system at different levels, that could be part of rheostatic adaptations associated to the FEO, and highlight the plasticity of this system.
Histological features of chronic hepatitis C in haemodialysis patients
Authors: Sakellariou Stratigoula , Boletis John N. , Sypsa Vana , Psichogiou Mina , Tiniakos Dina , Delladetsima Ioanna
Published: November 2013

Background & Aims

HCV infection in haemodialysis (HD) patients is still a matter of investigation. The aim of this study was to determine the histology of chronic hepatitis C (CHC) in HCV‐infected HD patients within the context of a comparative analysis including non‐uraemic patients with CHC. The relative importance of virological, demographic and clinical parameters on disease manifestation was examined.

Methods

Sixty‐one consecutive liver biopsies from HD patients and 326 from non‐uraemic patients with chronic HCV infection were comparatively evaluated.

Results

Haemodialysis patients with CHC were older than control subjects (P = 0.031), showing a similar HCV genotype distribution (P = 0.328) and lower viral load (P = 0.001). CHC in HD patients was significantly milder according to stage (P = 0.033), grade and its parameters (periportal activity, portal inflammation and lobular activity) (P < 0.001). The frequency of lymphoid aggregates (10.2% vs 50%, P < 0.001), bile duct lesions (1.7% vs 22.1%, P < 0.001) and extent of steatosis (P = 0.022) in HD group was significantly reduced. Multivariate analysis showed that non‐uraemic patients had 2.3 times higher risk of developing steatosis independently of genotype distribution and age. In HD group, genotype 3, longer HD duration and age at infection were significantly associated with steatosis, while older age at infection correlated with advanced fibrosis.

Conclusions

Chronic hepatitis C in HD patients is usually very mild, losing its diagnostic histological features while patient's age and age at infection retain their prognostic significance. The weak inflammatory response, probably because of immunocompromised status and low viral load, may present a beneficial factor in the natural course of the disease.
Induction of systemic oxidative stress leads to brain oedema in portacaval shunted rats
Authors: Bosoi Cristina R. , Tremblay Mélanie , Rose Christopher F.
Published: November 2013

Background & Aims

The pathogenesis of hepatic encephalopathy (HE) is multifactorial and often associated with the development of brain oedema. In addition to ammonia playing a central role, systemic oxidative stress is believed to aggravate the neuropsychological effects of ammonia in patients with chronic liver disease (CLD). The aim of this study was to (i) induce systemic oxidative stress in hyperammonaemic portacaval anastomosed (PCA) rats by inhibiting the antioxidant glutathione using Dimethyl maleate (DEM) and (ii) investigate whether a synergistic relationship between ammonia and oxidative stress contributes to the pathogenesis of brain oedema in CLD.

Methods

Four‐week PCA and sham‐operated rats received DEM (0.4–4 mg/kg/day) for the last 10 days before sacrifice when oxidative stress markers [reactive oxygen species (ROS) and malondialdehyde (MDA)] were assessed in blood and frontal cortex. Brain water content was measured using a specific gravimetric technique.

Results

Dimethyl maleate induced an increase in ROS and MDA in the blood, but not in the brain, of the PCA rats, compared with non‐treated PCA rats. This was accompanied with an increase in brain water content (PCA+DEM: 78.45 ± 0.13% vs. PCA: 77.38 ± 0.11%, P < 0.001). Higher doses of DEM induced systemic oxidative stress in sham‐operated controls, but brain oedema did not develop.

Conclusions

Dimethyl maleate provoked systemic, not central, oxidative stress in PCA rats, resulting in the development of brain oedema. Independently, hyperammonaemia and systemic oxidative stress do not precipitate brain oedema; therefore, our findings sustain that a synergistic effect between hyperammonaemia and systemic oxidative stress is responsible for the development of brain oedema in HE.
Pegylated interferon α‐2a plus ribavirin for decompensated hepatitis C virus‐related cirrhosis: relationship between efficacy and cumulative dose
Authors: Xu Yan , Qi Wenqian , Wang Xu , Zhao Ping , Zhang Yonggui , Zhang Qian , Qin Shaoyou , Wang Jiangbin
Published: November 2013

Background & Aims

A combination of pegylated interferon alpha‐2a (Peg‐IFNα‐2a) and ribavirin (RBV) achieves a sustained virological response (SVR) in 40–50% of patients infected with genotype 1 hepatitis C virus (HCV), but efficacy rates are significantly lower in patients with decompensated HCV‐induced cirrhosis. The efficacy and tolerability of Peg‐IFNα‐2a and RBV, the cumulative dose effect, time to achieve planned cumulative dose and role of HCV phenotype on treatment response were determined in patients with decompensated HCV‐induced cirrhosis.

Methods

In this case‐controlled study, 257 patients with decompensated HCV‐induced cirrhosis were enrolled, including patients treated with partial splenic embolization for leukopaenia. Of patients with sufficient blood cell counts, 130 patients opted for antiviral therapy (treatment group) consisting of 180 μg/kg Peg‐IFNα‐2a for 48 weeks with 800–1200 mg/day RBV; the remaining 127 were considered the control group. Primary endpoints were SVR and absence of relapse; the secondary end point was assessment of disease progression.

Results

Sustained virological response was highest and relapse rates were lowest when cumulative doses of Peg‐IFNα‐2a and RBV were both ≥80% of the prescribed dose. Patients achieving ≥80% of the planned cumulative doses in 48 weeks had a significantly higher SVR compared with patients achieving this in 72 weeks. Patients with HCV genotype 1 had significantly lower SVR compared with patients with HCV genotype 2 (19.7% vs. 42.9%, respectively; P = 0.008). Treatment group patients had a significantly lower rate of SVR‐independent liver disease‐related mortality.

Conclusions

Our findings provide additional evidence to support the use of Peg‐IFNα‐2a and RBV therapy for decompensated HCV‐induced cirrhosis.
Geographical and environmental gradients shape phenotypic trait variation and genetic structure in Populus trichocarpa
Authors: McKown Athena D. , Guy Robert D. , Klápště Jaroslav , Geraldes Armando , Friedmann Michael , Cronk Quentin C. B. , El‐Kassaby Yousry A. , Mansfield Shawn D. , Douglas Carl J.
Published: November 2013

Populus trichocarpa is widespread across western North America spanning extensive variation in photoperiod, growing season and climate. We investigated trait variation in P. trichocarpa using over 2000 trees from a common garden at Vancouver, Canada, representing replicate plantings of 461 genotypes originating from 136 provenance localities.

We measured 40 traits encompassing phenological events, biomass accumulation, growth rates, and leaf, isotope and gas exchange‐based ecophysiology traits. With replicated plantings and 29 354 single nucleotide polymorphisms (SNPs) from 3518 genes, we estimated both broad‐sense trait heritability (H2) and overall population genetic structure from principal component analysis.

Populus trichocarpa had high phenotypic variation and moderate/high H2 for many traits. H2 ranged from 0.3 to 0.9 in phenology, 0.3 to 0.8 in biomass and 0.1 to 0.8 in ecophysiology traits. Most traits correlated strongly with latitude, maximum daylength and temperature of tree origin, but not necessarily with elevation, precipitation or heat : moisture indices. Trait H2 values reflected trait correlation strength with geoclimate variables. The population genetic structure had one significant principal component (PC1) which correlated with daylength and showed enrichment for genes relating to circadian rhythm and photoperiod.

Robust relationships between traits, population structure and geoclimate in P. trichocarpa reflect patterns which suggest that range‐wide geographical and environment gradients have shaped its genotypic and phenotypic variability.