bluuebunny/crossref_metadata_2025 huggingface dataset:
Costs of adverse events among patients with HIV infection treated with nonnucleoside reverse transcriptase inhibitors
Authors: Simpson KN , Chen S‐Y , Wu AW , Boulanger L , Chambers R , Nedrow K , Tawadrous M , Pashos CL , Haider S
Published: March 2014

Objectives

The aim of the study was to assess the incidence and costs of adverse events (AEs) among patients with HIV infection treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) from the health care system perspective.

Methods

US medical and pharmacy claims during 2004−2009 were examined to select adult new NNRTI users with HIV infection. The incidence of selected AEs and time to occurrence were assessed during the first year. Episodes of care for each AE were identified using claims associated with AE management. For each AE, a propensity score model was used to match patients with an AE to those without (1:4) based on the propensity of having an AE. Mean total health care costs, AE‐associated costs and incremental costs per episode, and annual total health care costs per patient were calculated.

Results

Of the 2548 NNRTI‐treated patients, 29.3% experienced AEs. The incidence ranged from 0.4 episodes/1000 person‐years for suicide/self‐injury to 14.9 episodes/1000 person‐years for dizziness, 49.8 episodes/1000 person‐years for depression and 150.3 episodes/1000 person‐years for lipid disorder. The mean AE‐associated cost (duration) per episode ranged from $586 (88 days) for lipid disorder to $975 (33 days) for rash, $2760 (73 days) for sleep‐related symptoms and $4434 (41 days) for nausea/vomiting. The mean incremental cost per episode ranged from $1580 for rash to $2032 for lipid disorder, $8307 for sleep‐related symptoms and $12 833 for nausea/vomiting. During the 12 months following NNRTI initiation, the mean annual total health care cost was $27 299 (efavirenz: $26 185; other NNRTIs: $34 993) and AE‐associated costs were $608 (efavirenz: $554; other NNRTIs: $979) among all NNRTI users.

Conclusions

With treatment increasing patient survival, comparisons of therapeutic regimens should consider treatment‐associated AEs. Findings from this study could be informative for clinicians and payers in managing HIV infection with NNRTIs.
The rate of recovery in renal function when patients with HIV infection discontinue treatment with tenofovir
Authors: Young J , Wang Q , Fux CA , Bernasconi E , Furrer H , Vernazza P , Calmy A , Cavassini M , Weber R , Battegay M , Bucher HC ,   Swiss HIV Cohort Study
Published: March 2014

Objectives

Tenofovir is associated with reduced renal function. It is not clear whether patients can be expected to fully recover their renal function if tenofovir is discontinued.

Methods

We calculated the estimated glomerular filtration rate (eGFR) for patients in the Swiss HIV Cohort Study remaining on tenofovir for at least 1 year after starting a first antiretroviral therapy regimen with tenofovir and either efavirenz or the ritonavir‐boosted protease inhibitor lopinavir, atazanavir or darunavir. We estimated the difference in eGFR slope between those who discontinued tenofovir after 1 year and those who remained on tenofovir.

Results

A total of 1049 patients on tenofovir for at least 1 year were then followed for a median of 26 months, during which time 259 patients (25%) discontinued tenofovir. After 1 year on tenofovir, the difference in eGFR between those starting with efavirenz and those starting with lopinavir, atazanavir and darunavir was – 0.7 [95% confidence interval (CI) −2.3 to 0.8], −1.4 (95% CI −3.2 to 0.3) and 0.0 (95% CI −1.7 to 1.7) mL/min/1.73 m2, respectively. The estimated linear rate of decline in eGFR on tenofovir was −1.1 (95% CI −1.5 to −0.8) mL/min/1.73 m2 per year and its recovery after discontinuing tenofovir was 2.1 (95% CI 1.3 to 2.9) mL/min/1.73 m2 per year. Patients starting tenofovir with either lopinavir or atazanavir appeared to have the same rates of decline and recovery as those starting tenofovir with efavirenz.

Conclusions

If patients discontinue tenofovir, clinicians can expect renal function to recover more rapidly than it declined.
Influence of kidney bean, field pea and amaranth protein isolates on the characteristics of starch‐based gluten‐free muffins
Authors: Shevkani Khetan , Singh Narpinder
Published: March 2014

This study was undertaken to see the effect of kidney bean (KB), field pea (FP) and amaranth (AM) protein isolates on the viscoelasticity and gluten‐free muffin‐making properties of starch‐based batter. The characteristics of gluten‐free muffins were also compared to those prepared with wheat gluten (WG). The incorporation of different protein isolates enhanced batter viscoelasticity (increased storage and loss modulus and decreased tan δ) and resulted in muffins with higher specific volume, springiness and cohesiveness. Firmness of the muffins varied with the source of protein isolate. KB protein isolates resulted in firmer muffins compared to those made from FP, AM and WG. The crust colour became more reddish‐brown on incorporation of protein isolates, while crumb colour varied with the source of protein. Overall, the results revealed that KB, FP and AM protein isolates can be successfully used to prepare gluten‐free muffins with characteristics comparable to those made from wheat gluten.
Restoring the glycosaminoglycans layer in recurrent cystitis: Experimental and clinical foundations
Authors: Cicione Antonio , Cantiello Francesco , Ucciero Giuseppe , Salonia Andrea , Madeo Immacolata , Bava Ilaria , Aliberti Antonio , Damiano Rocco
Published: March 2014

Restoring the bladder glycosaminoglycans layer has recently been introduced as prophylactic treatment for recurrent urinary tract infections. Herein, we analyze the latest main clinical and experimental studies to support this therapeutic option. An electronic research was carried out in the most common databases in order to identify any published studies. Retrieved studies were categorized as experimental or clinical according to their setting. For the clinical studies, the evidence level was assigned. A total of 13 laboratory studies showed how bladder glycosaminoglycans instillations act: attenuation of the inflammation process, reduction of bladder contraction amplitude and frequency, reduction of epithelium damage, and lower bacterial growth in urine and tissue samples. Likewise, two randomized clinical trials with grade 2 evidence level and two case series with grade 4 evidence level reported glycosaminoglycans as an alternative to reduce episodes and to prolong recurrence time in patients with recurrent urinary tract infections. At least 12 months of follow up was completed. No serious adverse events were reported. Compared with a placebo, in one randomized study a significantly higher maximum cystometric capacity was obtained, whereas in the other study a significant increase in quality of life scores was reported too. An improvement in the urinary symptoms score was reported by the two randomized trials. Although the clinical use of glycosaminoglycans replacement therapy for recurrent urinary tract infections is supported by a small number of clinical studies with different evidence levels, the laboratory studies show that glycosaminoglycans could have a protective role against inflammatory factors, supporting the idea “to restore the glycosaminoglycans bladder layer to prevent chronic disease course”.
Climate change and annual survival in a temperate passerine: partitioning seasonal effects and predicting future patterns
Authors: Gullett Philippa , Evans Karl L. , Robinson Robert A. , Hatchwell Ben J.
Published: March 2014

Predicting climate change impacts on population size requires detailed understanding of how climate influences key demographic rates, such as survival. This knowledge is frequently unavailable, even in well‐studied taxa such as birds. In temperate regions, most research into climatic effects on annual survival in resident passerines has focussed on winter temperature. Few studies have investigated potential precipitation effects and most assume little impact of breeding season weather. We use a 19‐year capture–mark–recapture study to provide a rare empirical analysis of how variation in temperature and precipitation throughout the entire year influences adult annual survival in a temperate passerine, the long‐tailed tit Aegithalos caudatus. We use model averaging to predict longer‐term historical survival rates, and future survival until the year 2100. Our model explains 73% of the interannual variation in survival rates. In contrast to current theory, we find a strong precipitation effect and no effect of variation in winter weather on adult annual survival, which is correlated most strongly to breeding season (spring) weather. Warm springs and autumns increase annual survival, but wet springs reduce survival and alter the form of the relationship between spring temperature and annual survival. There is little evidence for density dependence across the observed variation in population size. Using our model to estimate historical survival rates indicates that recent spring warming has led to an upward trend in survival rates, which has probably contributed to the observed long‐term increase in the UK long‐tailed tit population. Future climate change is predicted to further increase survival, under a broad range of carbon emissions scenarios and probabilistic climate change outcomes, even if precipitation increases substantially. We demonstrate the importance of considering weather over the entire annual cycle, and of considering precipitation and temperature in combination, in order to develop robust predictive models of demographic responses to climate change.

Synthesis

Prediction of climate change impacts demands understanding of how climate influences key demographic rates. In our 19‐year mark‐recapture study of long‐tailed tits Aegithalos caudatus, weather explained 73% of the inter‐annual variation in adult survival; warm springs and autumns increased survival, wet springs reduced survival, but winter weather had little effect. Robust predictions thus require consideration of the entire annual cycle and should not focus solely on temperature. Unexpectedly, survival appeared not to be strongly density‐dependent, so we use historical climate data to infer that recent climate change has enhanced survival over the four decades in which the UK long‐tailed tit population has more than doubled. Furthermore, survival rates in this species are predicted to further increase under a wide range of future climate scenarios.
Anatomy of a Municipal Triumph: New York City's Upsurge in Life Expectancy
Authors: Preston Samuel H. , Elo Irma T.
Published: March 2014

Over the period 1990–2010, the increase in life expectancy for males in New York City was 6.0 years greater than for males in the United States. The female relative gain was 3.9 years. Male relative gains were larger because of extremely rapid reductions in mortality from HIV/AIDS and homicide, declines that reflect effective municipal policies and programs. Declines in drug‐ and alcohol‐related deaths also played a significant role in New York City's advance, but every major cause of death contributed to its relative improvement. By 2010, New York City had a life expectancy that was 1.9 years greater than that of the US. This difference is attributable to the high representation of immigrants in New York's population. Immigrants to New York City, and to the United States, have life expectancies that are among the highest in the world. The fact that 38 percent of New York's population consists of immigrants, compared to only 14 percent in the United States, accounts for New York's exceptional standing in life expectancy in 2010. In fact, US‐born New Yorkers have a life expectancy below that of the United States itself.
Period‐Based Mortality Change: Turning Points in Trends since 1950
Authors: Ouellette Nadine , Barbieri Magali , Wilmoth John R.
Published: March 2014

We investigate a major turning point in mortality trends at adult ages that occurred for many low‐mortality countries in the late 1960s or early 1970s. We analyze patterns of total and cause‐specific mortality over the past 60 years using data from the Human Mortality Database and the World Health Organization. We focus on four broad categories of causes of death: heart diseases, cerebrovascular diseases, smoking‐related cancers, and all other cancers. We use a two‐slope regression model to assess the timing and magnitude of turning points in mortality trends over this era, making separate analyses by sex, age, and cause of death. The age pattern of temporal changes is given particular attention. Our results demonstrate convincingly that period‐based factors were very significant in the onset of the “cardiovascular revolution” in the years around 1970. In general, although cohort processes cannot be ruled out as a driver of mortality change in recent decades (especially for mortality due to smoking‐related cancers), the evidence reviewed here suggests that period factors have been the dominant force behind the mortality trends of high‐income countries during this era.
The Recent Mortality Decline in Russia: Beginning of the Cardiovascular Revolution?
Authors: Grigoriev Pavel , Meslé France , Shkolnikov Vladimir M. , Andreev Evgeny , Fihel Agnieszka , Pechholdova Marketa , Vallin Jacques
Published: March 2014

The health situation in Russia has often been characterized as a long‐running crisis. From the 1960s until the beginning of the 2000s, the declining life expectancy trend was substantially interrupted only twice: once in the mid‐1980s as a result of Gorbachev's anti‐alcohol campaign, and again at the end of the 1990s as a result of the “rebound” effect following the dramatic rise in mortality associated with the acute socioeconomic crisis. In both cases, the progress made proved to be short‐lived. A third mortality decline in Russia began in 2003 and is still ongoing. We investigate the components and driving forces of this new development, in particular the role played by cardiovascular diseases. Using cause‐specific mortality data, we identify the main features of the recent improvements and compare these features with those observed in selected European countries, specifically France, Poland, and Estonia. Our aim is to gauge whether the features of the improvements in these countries are similar to those of the recent advancements made in Russia. Although the recent improvements in Russia have features in common with initial stages of prior mortality declines in other countries and may support optimism about the future, a return to mortality stagnation cannot be ruled out.
Elder Care and Migrant Labor in Europe: A Demographic Outlook
Authors: Cangiano Alessio
Published: March 2014

This article examines the demand for migrant labor in older‐adult care as one of the key aspects of the aging and migration nexus. It reviews the demographic determinants that have shaped demand for and provision of older‐adult care across Europe. Using the EU Labour Force Survey, new comparative estimates are generated on the employment of migrants in care occupations and the channels of entry into the European labor market. Projections on demand for and supply of care to the older population reveal a future gap in both formal and informal provision. It is shown that, owing to institutional, economic, and social constraints, the significant growth of the care workforce that will be required to meet the future needs of Europe's aging populations is unlikely to be achieved by relying exclusively on EU labor supply. The conclusions outline some implications for future immigration policies.
Genetic parameters for chronic progressive lymphedema in Belgian Draught Horses
Authors: De Keyser K. , Janssens S. , Peeters L.M. , Foqué N. , Gasthuys F. , Oosterlinck M. , Buys N.
Published: March 2014

Genetic parameters for chronic progressive lymphedema (CPL)‐associated traits in Belgian Draught Horses were estimated, using a multitrait animal model. Clinical scores of CPL in the four limbs/horse (CPLclin), skinfold thickness and hair samples (hair diameter) were studied. Due to CPLclin uncertainty in younger horses (progressive CPL character), a restricted data set (D_3+) was formed, excluding records from horses under 3 years from the complete data set (D_full). Age, gender, coat colour and limb hair pigmentation were included as fixed, permanent environment and date of recording as random effects. Higher CPLclin certainty (D_3+) increased heritability coefficients of, and genetic correlations between traits, with CPLclin heritabilities (SE) for the respective data sets: 0.11 (0.06) and 0.26 (0.05). A large proportion of the CPLclin variance was attributed to the permanent environmental effect in D_full, but less in D_3+. Date of recording explained a proportion of variance from 0.09 ± 0.03 to 0.61 ± 0.08. Additive genetic correlations between CPLclin and both skinfold thickness and hair diameter showed the latter two traits cannot be used as a direct diagnostic aid for CPL. Due to the relatively low heritability of CPLclin, selection should focus on estimated breeding values (from repeated clinical examinations) to reduce CPL occurrence in the Belgian Draught Horse.
Pilot Study of the Korean Parent Training Program Using a Partial Group‐Randomized Experimental Study
Authors: Kim Eunjung , Cain Kevin , Boutain Doris , Chun Jin‐Joo , Kim Sangho , Im Hyesang
Published: March 2014

Problem

Korean American (KA) parents need a culturally tailored parent training that helps them bridge the Korean and American cultures and divergent parenting practices.

Methods

The Korean Parent Training Program (KPTP) was pilot tested with 48 KA mothers of children between 3 and 8 years old using a partial group‐randomized controlled experimental study design. Researchers gathered self‐report survey and observation data.

Findings

Analyses, which used generalized estimating equations, indicated the intervention group mothers increased use of effective parenting practices and their children decreased behavioral problems and reported less acculturation conflict with their mothers.

Conclusion

The KPTP is a promising way to promote effective parenting and increase positive child mental health in KA families.
Circulating Endothelial Progenitor Cells in Hypertensive Patients With Increased Arterial Stiffness
Authors: Marketou Maria E. , Kalyva Athanasia , Parthenakis Fragiskos I. , Pontikoglou Charalampos , Maragkoudakis Spyros , Kontaraki Joanna E. , Chlouverakis Gregory , Zacharis Evangelos A. , Patrianakos Alexandros , Papadaki Helen A. , Vardas Panos E.
Published: March 2014

The potential association between arterial stiffening and circulating endothelial progenitor cells (EPCs) in patients with essential hypertension was investigated. Pulse wave velocity (PWV) was used to evaluate arterial stiffness in 24 patients with essential hypertension and 19 healthy controls. Blood samples were taken and immunostained with antibodies against the cell surface markers CD34, CD45, and CD133. Using flow cytometry, EPCs as a population of CD45−/CD34+/CD133+ cells were measured. Hypertensive patients were not found to have higher levels of circulating CD45−/CD34+/CD133+ compared with the control group (0.0026%±0.0031% vs 0.0023%±0.0023%, respectively; P=.7). Correlation analysis revealed a strong association between the number of CD45−/CD34+/CD133+ cells and PWV (r=0.58, P<.001), indicating that hypertensive patients with increased PWV have a greater percentage of CD45−/CD34+/CD133+ cells. Data showed a correlation between the number of circulating CD45−/CD34+/CD133+ cells and arterial stiffness, suggesting that those cells might have a role in arterial remodeling.
Efficacy of periodontal plastic procedures in the treatment of multiple gingival recessions
Authors: Graziani Filippo , Gennai Stefano , Roldán Silvia , Discepoli Nicola , Buti Jacpop , Madianos Phoebus , Herrera David
Published: March 2014

Objective

To systematically review the efficacy of periodontal plastic procedures (PPP) in the treatment of multiple gingival recessions (MGR).

Methods

Randomized clinical trials (RCT) on MGR treatment with at least 6 months duration were identified through electronic databases and hand‐searched journals. Primary outcomes were complete root coverage (CRC) and percentage of root coverage (PRC). Weighted means and forest plots were calculated for all PPP. Subgroup analysis was performed according to the type of flap. A Bayesian network meta‐analysis (NM) on secondary outcomes was also performed.

Results

Nine trials including 208 subjects and 858 recessions were identified. CRC after PPP was 24–89%. Mean weighted PRC was 86.27% (95% CI 80.71–91.83; p < 0.01). Heterogeneity of the literature prevented inter‐techniques comparison. Coronally advanced flap (CAF) shows the higher variability in terms of CRC. Modified CAF and tunnel approaches show higher level of CRC. The NM suggests that CAF plus graft showed the higher probability of being the best treatment.

Conclusions

Limited evidence is available for MGR coverage. PPP are associated with high level of efficacy, in terms of PRC, and high variability of CRC. Indirect evidence indicates that CAF may benefit from newer variations of the technique and by the additional use of grafting.
Fundamental principles in periodontal plastic surgery and mucosal augmentation – a narrative review
Authors: Burkhardt Rino , Lang Niklaus P.
Published: March 2014

Aim

To provide a narrative review of the current literature elaborating on fundamental principles of periodontal plastic surgical procedures.

Methods

Based on a presumptive outline of the narrative review, MESH terms have been used to search the relevant literature electronically in the PubMed and Cochrane Collaboration databases. If possible, systematic reviews were included. The review is divided into three phases associated with periodontal plastic surgery: a) pre‐operative phase, b) surgical procedures and c) post‐surgical care. The surgical procedures were discussed in the light of a) flap design and preparation, b) flap mobilization and c) flap adaptation and stabilization.

Results

Pre‐operative paradigms include the optimal plaque control and smoking counselling. Fundamental principles in surgical procedures address basic knowledge in anatomy and vascularity, leading to novel appropriate flap designs with papilla preservation. Flap mobilization based on releasing incisions can be performed up to 5 mm. Flap adaptation and stabilization depend on appropriate wound bed characteristics, undisturbed blood clot formation, revascularization and wound stability through adequate suturing.

Conclusion

Delicate tissue handling and tension free wound closure represent prerequisites for optimal healing outcomes.
Surgical techniques on periodontal plastic surgery and soft tissue regeneration: Consensus Report of Group 3 of the 10th European Workshop on Periodontology
Authors: Sanz Mariano , Simion Massimo ,   Working Group 3 of the European Workshop on Periodontology
Published: March 2014

Background

The scope was to review the three main clinical indications in periodontal plastic surgical procedures.

Aims

To review the fundamental principles in periodontal plastic surgery, the main surgical designs in flap surgery applied to the treatment of recessions, peri‐implant soft tissue deficiencies and soft tissue ridge augmentation, as well as the surgical principles of using autologous connective tissue grafts and soft tissue substitutes.

Fundamental Principles in Plastic Surgery

In the pre‐operative phase, the key elements are the control of prognostic factors affecting the patient, namely oral hygiene, tobacco smoking cessation and systemic disease control. In the operative phase, the principles of flap design, mobilization, advancement, adaptation and stabilization. In the post‐operative phase infection control, including effective oral hygiene measures, antiseptic treatment and other medications.

Critical Elements in Flap Design and Surgical Execution

In single recession defects, the most widely used flap technique is the coronally advanced flap and in specific clinical situations the laterally positioned flap. In multiple recession defects, the number of defects and their location and depth guide the surgical design, being one design with and the other without vertical releasing incisions. When flaps are used in combination with grafts the tunnel flap is also used extensively.

Critical Elements in the Use of Soft Tissue Replacement Grafts

The key elements are the donor site selection and harvesting technique, its tissue integration and volume stability.

Clinical Recommendations

Given the current evidence, various clinical recommendations on the use of flaps and grafts are provided.
Clinical efficacy of periodontal plastic surgery procedures: Consensus Report of Group 2 of the 10th European Workshop on Periodontology
Authors: Tonetti Maurizio S. , Jepsen Søren ,   Working Group 2 of the European Workshop on Periodontology
Published: March 2014

Aim

The scope of the discussions of this consensus report was to assess the strength of the scientific evidence and make clinical and research recommendations for surgical interventions to cover exposed root surfaces and enhance soft tissues at implants.

Methods

Discussions were informed by three systematic reviews covering single recessions, multiple recessions and soft‐tissue deficiencies at implants. The strength of the evidence was assessed using a modification in GRADE. The group also emphasized the need to report the experience of the surgeon and the performance of the control intervention (CONSORT guidelines for non‐pharmacological treatment).

Results

A moderate strength of evidence supported the following statements for single (moderately deep, mostly maxillary) recessions without inter‐dental attachment loss: (i) The addition of a connective tissue graft (CTG) improved outcomes of coronally advanced flaps (CAF). (ii) The addition of enamel matrix derivative (EMD) improved the outcomes of CAF. For multiple recessions, preliminary data indicate that flaps specifically designed to treat this condition are worthy of additional attention. Emerging data indicate that it is possible to obtain complete root coverage at sites with some inter‐dental attachment loss. With regards to soft‐tissue deficiencies at implants, several procedures are available, but great heterogeneity among studies does not allow drawing conclusions at this time.

Conclusions

The group highlighted that periodontal plastic procedures are complex, technique‐sensitive interventions that require advanced skills and expertise. At single recessions, the addition of autologous CTG or EMD under CAF improves complete root coverage and may be considered the procedure of choice at maxillary anterior and premolar teeth. The adjunctive benefit needs to be put in the context of increased morbidity of the donor area or increased cost. Additional research is needed to: (i) assess the role of alternatives to autologous soft‐tissue grafting in combination with CAF; (ii) identify the optimal surgical design and the need for additional soft‐tissue grafting (or alternatives) at multiple recessions, recessions with inter‐dental attachment loss and soft‐tissue deficiencies at implants.
Effects of a green tea extract, Polyphenon E, on systemic biomarkers of growth factor signalling in women with hormone receptor‐negative breast cancer
Authors: Crew K. D. , Ho K. A. , Brown P. , Greenlee H. , Bevers T. B. , Arun B. , Sneige N. , Hudis C. , McArthur H. L. , Chang J. , Rimawi M. , Cornelison T. L. , Cardelli J. , Santella R. M. , Wang A. , Lippman S. M. , Hershman D. L.
Published: March 2014

Background

Observational and experimental data support a potential breast cancer chemopreventive effect of green tea.

Methods

We conducted an ancillary study using archived blood/urine from a phase IB randomised, placebo‐controlled dose escalation trial of an oral green tea extract, Polyphenon E (Poly E), in breast cancer patients. Using an adaptive trial design, women with stage I–III breast cancer who completed adjuvant treatment were randomised to Poly E 400 mg (n = 16), 600 mg (n = 11) and 800 mg (n = 3) twice daily or matching placebo (n = 10) for 6 months. Blood and urine collection occurred at baseline, and at 2, 4 and 6 months. Biological endpoints included growth factor [serum hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], lipid (serum cholesterol, triglycerides), oxidative damage and inflammatory biomarkers.

Results

From July 2007‐August 2009, 40 women were enrolled and 34 (26 Poly E, eight placebo) were evaluable for biomarker endpoints. At 2 months, the Poly E group (all dose levels combined) compared to placebo had a significant decrease in mean serum HGF levels (−12.7% versus +6.3%, P = 0.04). This trend persisted at 4 and 6 months but was no longer statistically significant. For the Poly E group, serum VEGF decreased by 11.5% at 2 months (P = 0.02) and 13.9% at 4 months (P = 0.05) but did not differ compared to placebo. At 2 months, there was a trend toward a decrease in serum cholesterol with Poly E (P = 0.08). No significant differences were observed for other biomarkers.

Conclusions

Our findings suggest potential mechanistic actions of tea polyphenols in growth factor signalling, angiogenesis and lipid metabolism.
Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects
Authors: Vassar Robert , Kuhn Peer‐Hendrik , Haass Christian , Kennedy Matthew E. , Rajendran Lawrence , Wong Philip C. , Lichtenthaler Stefan F.
Published: March 2014

The β‐site APP cleaving enzymes 1 and 2 (BACE1 and BACE2) were initially identified as transmembrane aspartyl proteases cleaving the amyloid precursor protein (APP). BACE1 is a major drug target for Alzheimer's disease because BACE1‐mediated cleavage of APP is the first step in the generation of the pathogenic amyloid‐β peptides. BACE1, which is highly expressed in the nervous system, is also required for myelination by cleaving neuregulin 1. Several recent proteomic and in vivo studies using BACE1‐ and BACE2‐deficient mice demonstrate a much wider range of physiological substrates and functions for both proteases within and outside of the nervous system. For BACE1 this includes axon guidance, neurogenesis, muscle spindle formation, and neuronal network functions, whereas BACE2 was shown to be involved in pigmentation and pancreatic β‐cell function. This review highlights the recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism‐based liabilities, in particular for BACE inhibitors in Alzheimer's disease.

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The protease BACE1 is a major drug target in Alzheimer disease. Together with its homolog BACE2, both proteases have an increasing number of functions within and outside of the nervous system. This review highlights recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism‐based liabilities, in particular for BACE inhibitors in Alzheimer disease.
Relationships between serotonergic and cannabinoid system in depressive‐like behavior: a PET study with [11C]‐DASB
Authors: Burokas Aurelijus , Martín‐García Elena , Gutiérrez‐Cuesta Javier , Rojas Santiago , Herance José Raúl , Gispert Juan Domingo , Serra Miquel‐Ángel , Maldonado Rafael
Published: March 2014

Chronic stress represents a major environmental risk factor for mood disorders in vulnerable individuals. The neurobiological mechanisms underlying these disorders involve serotonergic and endocannabinoid systems. In this study, we have investigated the relationships between these two neurochemical systems in emotional control using genetic and imaging tools. CB1 cannabinoid receptor knockout mice (KO) and wild‐type littermates (WT) were exposed to chronic restraint stress. Depressive‐like symptoms (anhedonia and helplessness) were produced by chronic stress exposure in WT mice. CB1 KO mice already showed these depressive‐like manifestations in non‐stress conditions and the same phenotype was observed after chronic restraint stress. Chronic stress similarly impaired long‐term memory in both genotypes. In addition, brain levels of serotonin transporter (5‐HTT) were assessed using positron emission tomography. Decreased brain 5‐HTT levels were revealed in CB1 KO mice under basal conditions, as well as in WT mice after chronic stress. Our results show that chronic restraint stress induced depressive‐like behavioral alterations and brain changes in 5‐HTT levels similarly to those revealed in CB1 KO mice in non‐stressed conditions. These results underline the relevance of chronic environmental stress on serotonergic and endocannabinoid transmission for the development of depressive symptoms.

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Chronic restraint stress induces depressive‐like behavior and reduced 5‐HTT levels in WT mice similar to those revealed in non‐stressed CB1‐KO mice. Reduced 5‐HTT in both genotypes increases synaptic 5‐HT concentration. The 5‐HT release is modulated through CB1 receptors and the absence of inhibitory CB1 receptor causes decreased inhibition of 5‐HT release resulting in high synaptic 5‐HT concentration that are not further enhanced by stress.
A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity
Authors: Hashimoto Yuichi , Matsuoka Masaaki
Published: March 2014

Expression of a familial Alzheimer's disease (AD)‐linked mutant of amyloid β precursor protein (APP) or the binding of transforming growth factor β2 to wild‐type (wt)‐APP causes neuronal death by activating an intracellular death signal (a APP‐mediated intracellular death signal) in the absence of the involvement of amyloid β (Aβ) toxicity in vitro. These neuronal death models may therefore be regarded as Aβ‐independent neuronal death models related to AD. A recent study has shown that the A673T mutation in the APP isoform APP770, corresponding to the A598T mutation in the most prevalent neuronal APP isoform APP695 (an AD‐protective mutant of APP), is linked to a reduction in the incidence rate of AD. Consistent with this, cells expressing the AD‐protective mutant of APP produce less Aβ than cells expressing wt‐APP. In this study, transforming growth factor β2 caused death in cultured neuronal cells expressing wt‐APP, but not in those expressing the AD‐protective mutant of APP. This result suggests that the AD‐protective mutation of APP reduces the incidence rate of AD by attenuating the APP‐mediated intracellular death signal. In addition, a mutation that causes hereditary cerebral hemorrhage with amyloidosis‐Dutch type also attenuated the APP‐mediated intracellular death signal.

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The A598T mutation of amyloid precursor protein APP is linked to a reduction in the incidence rate of Alzheimer's disease (AD). This study shows that TGFβ2 causes death in neuronal cells expressing wild‐type APP, but not in those expressing the AD‐protective mutant of APP, suggesting that the AD‐protective mutation of APP reduces the incidence rate of AD by attenuating the APP‐mediated intracellular death signal.
PI3K‐p110‐alpha‐subtype signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2
Authors: Wahane Shalaka Dhanraj , Hellbach Nicole , Prentzell Mirja Tamara , Weise Stefan Christopher , Vezzali Riccardo , Kreutz Clemens , Timmer Jens , Krieglstein Kerstin , Thedieck Kathrin , Vogel Tanja
Published: March 2014

Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGFβ) and insulin‐like growth factor 1 (IGF1) have a central role. The TGFβ‐ and IGF1‐pathways cross‐talk and share signalling molecules, but in the central nervous system putative points of intersection remain unknown. We studied the biological effects and down‐stream molecules of TGFβ and IGF1 in cells derived from the mouse cerebral cortex at two developmental time points, E13.5 and E16.5. IGF1 induces PI3K, AKT and the mammalian target of rapamycin complexes (mTORC1/mTORC2) primarily in E13.5‐derived cells, resulting in proliferation, survival and neuronal differentiation, but has small impact on E16.5‐derived cells. TGFβ has little effect at E13.5. It does not activate the PI3K‐ and mTOR‐signalling network directly, but requires its activity to mediate neuronal differentiation specifically at E16.5. Our data indicate a central role of mTORC2 in survival, proliferation as well as neuronal differentiation of E16.5‐derived cortical cells. mTORC2 promotes these cellular processes and is under control of PI3K‐p110‐alpha signalling. PI3K‐p110‐beta signalling activates mTORC2 in E16.5‐derived cells but it does not influence cell survival, proliferation and differentiation. This finding indicates that different mTORC2 subtypes may be implicated in cortical development and that these subtypes are under control of different PI3K isoforms.

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Within developing cortical cells TGFβ‐ and IGF‐signalling activities are timely separated. TGFβ dominates in E16.5‐derived cells and drives neuronal differentiation. IGF influences survival, proliferation and neuronal differentiation in E13.5‐derived cells. mTORC2‐signalling in E16.5‐derived cells influences survival, proliferation and differentiation, activated through PI3K‐p110‐alpha. PI3K‐p110‐beta‐signalling activates a different mTORC2. Both PI3K/mTORC2‐signalling pathways are required but not directly activated in TGFβ‐mediated neuronal differentiation.
Governing the Organic Cocoa Network from Ghana: Towards Hybrid Governance Arrangements?
Authors: Glin Laurent C. , Oosterveer Peter , Mol Arthur P.J.
Published: March 2014

In this paper, we examine the processes of initiation, construction and transformation of the organic cocoa network from Ghana. We address in particular how the state responded to and engaged with civil‐society actors in the organic cocoa network and to what extent state involvement reshaped state–business–civil society relations? While most of the literature argues that globalization and liberalization processes weakened the state's position as key player in the development and management of agro‐food networks, the case of the (organic) cocoa sector in Ghana is often depicted as an exception because of the strong position the state still occupies in it. Employing a global commodity network perspective to analyse the Ghanaian organic cocoa case, this paper demonstrates that although the state is still a major player in the contemporary (organic) cocoa network, some hybrid governance arrangements, involving state, transnational and national NGO networks, and businesses, are emerging. The organic cocoa network also prompted a double process of ‘dis‐ and re‐embedding’ at the local level that helped shape and strengthen the organic cocoa network.
Risk of falls and bleeding in elderly patients with acute venous thromboembolism
Authors: Kämpfen P. , Méan M. , Limacher A. , Righini M. , Jaeger K. , Beer H‐J. , Osterwalder J. , Frauchiger B. , Matter C. M. , Kucher N. , Cornuz J. , Banyai M. , Egloff M. , Aschwanden M. , Bounameaux H. , Rodondi N. , Aujesky D.
Published: March 2014

Objective

Whether or not a high risk of falls increases the risk of bleeding in patients receiving anticoagulants remains a matter of debate.

Methods

We conducted a prospective cohort study involving 991 patients ≥65 years of age who received anticoagulants for acute venous thromboembolism (VTE) at nine Swiss hospitals between September 2009 and September 2012. The study outcomes were as follows: the time to a first major episode of bleeding; and clinically relevant nonmajor bleeding. We determined the associations between the risk of falls and the time to a first episode of bleeding using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time‐varying covariate.

Results

Four hundred fifty‐eight of 991 patients (46%) were at high risk of falls. The mean duration of follow‐up was 16.7 months. Patients at high risk of falls had a higher incidence of major bleeding (9.6 vs. 6.6 events/100 patient‐years; P = 0.05) and a significantly higher incidence of clinically relevant nonmajor bleeding (16.7 vs. 8.3 events/100 patient‐years; P < 0.001) than patients at low risk of falls. After adjustment, a high risk of falls was associated with clinically relevant nonmajor bleeding [subhazard ratio (SHR) = 1.74, 95% confidence interval (CI) = 1.23–2.46], but not with major bleeding (SHR = 1.24, 95% CI = 0.83–1.86).

Conclusion

In elderly patients who receive anticoagulants because of VTE, a high risk of falls is significantly associated with clinically relevant nonmajor bleeding, but not with major bleeding. Whether or not a high risk of falls is a reason against providing anticoagulation beyond 3 months should be based on patient preferences and the risk of VTE recurrence.
Inactivation of MYC reverses tumorigenesis
Authors: Li Y. , Casey S. C. , Felsher D. W.
Published: March 2014

The MYC proto‐oncogene is an essential regulator of many normal biological programmes. MYC, when activated as an oncogene, has been implicated in the pathogenesis of most types of human cancers. MYC overexpression in normal cells is restrained from causing cancer through multiple genetically and epigenetically controlled checkpoint mechanisms, including proliferative arrest, apoptosis and cellular senescence. When pathologically activated in the correct epigenetic and genetic contexts, MYC bypasses these mechanisms and drives many of the ‘hallmark’ features of cancer, including uncontrolled tumour growth associated with DNA replication and transcription, cellular proliferation and growth, protein synthesis and altered cellular metabolism. MYC also dictates tumour cell fate by enforcing self‐renewal and by abrogating cellular senescence and differentiation programmes. Moreover, MYC influences the tumour microenvironment, including activating angiogenesis and suppressing the host immune response. Provocatively, brief or even partial suppression of MYC back to its physiological levels of activation can lead to the restoration of intrinsic checkpoint mechanisms, resulting in acute and sustained tumour regression associated with tumour cells undergoing proliferative arrest, differentiation, senescence and apoptosis, as well as remodelling of the tumour microenvironment, recruitment of an immune response and shutdown of angiogenesis. Hence, tumours appear to be addicted to the MYC oncogene because of both tumour cell intrinsic and host‐dependent mechanisms. MYC is important for the regulation of both the initiation and maintenance of tumorigenesis.
High‐Resolution MRI Visualization of Aneurysmal Thrombosis after Flow Diverter Stent Placement
Authors: Gory Benjamin , Sigovan Monica , Vallecilla Carolina , Courbebaisse Guy , Turjman Francis
Published: March 2014

Flow‐diverter stents are the new promising tools in the treatment of intracranial aneurysms allowing progressive aneurysm occlusion. Here, we report a case where high‐resolution magnetic resonance imaging showed thrombus at fundus of the aneurysm sac, indicating a progressive intraaneurysmal thrombosis after flow‐diverter placement.
Monitoring of Cortical Activity Postreperfusion. A Powerful Tool for Predicting Clinical Response Immediately After Recanalization
Authors: Flores Alan , Ribó Marc , Rubiera Marta , Gonzalez‐Cuevas Montserrat , Pagola Jorge , Rodriguez‐Luna David , Muchada Marián , Kallas Julia , Meler Pilar , Sanjuan Estela , Alvarez‐Sabin Jose , Montaner Joan , Molina Carlos A.
Published: March 2014

BACKGROUND

In acute ischemic stroke, although early recanalization predicts rapid neurological recovery, in some cases early reperfusion does not immediately correlate to clinical improvement as “stunned brain” patients. The cortical activity monitoring in stroke patients is usually performed to evaluate epileptic activity through electroencephalogram. Bispectral index (BIS) monitor the cortical activity by fronto‐temporal electrodes and is currently used for monitoring level of conscious on sedo‐analgesia patients. Some studies have shown certain sensibility to detect cerebrovascular events during carotid revascularization. We aimed to evaluate the impact of BIS monitoring before and shortly after reperfusion on early and delayed clinical improvement on stroke patients.

METHODS

Consecutive patients with acute anterior circulation ischemic stroke who received reperfusion therapies were monitored with bicortical BIS during the first 6 hours of admission. We registered initial and final BIS value on the affected and contralateral side and determined asymmetry and changes in relation to recanalization and other clinical variables as sedation and perprocedure complications. We defined major clinical improvement decrease ≥8 points at discharge or 5 day at admission. Infarct volume was measure on 24‐hour CT scan. Modified Rankin score at 3 months was evaluated.

RESULTS

A total of 53 patients were monitored with BIS. Median age was 73 years, median baseline National Institutes of Health Stroke Scale (NIHSS) 16. We observed an inverse correlation between final BIS score and NIHSS at discharge (P < .001; r = −.538) and infarct volume at 24 hours (P = .031; r = −.430).

A receiver–operator characteristic curve identified a final BIS score of >81 as the value that better predicted further clinical improvement. After adjusting for recanalization, posttreatment NIHSS and age, final BIS emerged as the only independent predictor of clinical improvement(OR 1.21; CI 95%:1.01–1.28; P = .024).

Among patients without improvement at 24 hours, after adjusting for recanalization, posttreatment NIHSS and age, final BIS value >81 emerged as the only independent predictor of clinical improvement(OR 11.6; CI 95%:1.112–122.3; P = .04).

CONCLUSION

BIS value is associated with clinical and radiological variables in acute stroke patients. The final BIS value is a powerful independent predictor of further clinical improvement. Larger studies are needed to assess the value of post reperfusion cortical activity measured by BIS.
Comparison of the biological activity of two different isolates from mangosteen
Authors: Moongkarndi Primchanien , Jaisupa Nattapon , Samer Jutima , Kosem Nuttavut , Konlata Julaporn , Rodpai Ekkarat , Pongpan Narongchai
Published: March 2014

Objective

Mangosteen has been used in traditional medicine for treatment of many diseases. Recent studies have reported the active constituents isolated from this plant. In this study, purified α-mangostin, a major component and partially purified water-soluble fraction found in fruit pericarps, was carefully isolated, and their biological activity was compared, i.e. antioxidative activity and cytotoxic effect in breast cancer cells: SKBR3.

Methods

Antioxidative activity was determined using the 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH) assay and reactive oxygen species (ROS) assay, whereas the cytotoxic effect was evaluated by the MTT assay and morphological changes by fluorescence staining.

Key finding

The DPPH scavenging capacities of α-mangostin and water-soluble extract were obtained, the IC50 at 183.95 and 54.57 μg/ml, respectively. Meanwhile, the intracellular ROS level was significantly decreased after treatment with α-mangostin and water-soluble extraction at 20 and 200 μg/ml, respectively. α-mangostin exhibited the cytotoxicity at ED50 8.21 μg/ml, while the water-soluble extract was non-toxic to cells at ED50 higher than 160 μg/ml. Both constituents showed antioxidative activity by chemical assay and in cells, but α-mangostin expressed strong cytotoxicity and showed apoptotic bodies.

Conclusion

The different isolated constituents would be further studied for future possible use as chemotherapy in cancer and chemoprevention in Alzheimer's disease.