bluuebunny/crossref_metadata_2025 huggingface dataset:
Timing of complementary feeding and the risk of atopic eczema
Authors: Niinivirta Katri , Isolauri Erika , Nermes Merja , Laitinen Kirsi
Published: October 2013

Aim

To find out whether there was an association between when complementary feeding was introduced and the appearance of atopic eczema in children with a family history of allergy.

Methods

This prospective study followed 256 mother and child pairs until the child was four‐years‐old. Repeated skin prick testing was performed and a clinical diagnosis of eczema made by a physician. The mothers kept a continuous diary about the introduction of complementary feeding. To control the possible reverse causation of delaying complementary food introduction due to presumed child allergy, parental suspicions of allergic reactions were recorded.

Results

The introduction of cereals and fish after seven‐months‐of‐age was associated with an increased risk of atopic eczema. However, when the parents' suspicions that their child might be exhibiting symptoms of allergic disease were taken into account, this effect was no longer significant.

Conclusion

We found no evidence that the timing of the introduction of complementary feeding increased the risk of atopic eczema in a high‐risk cohort, when parental suspicions were taken into account. Therefore, it seems that families with a history of allergy can safely comply with current feeding recommendations, although confirmation in further studies is warranted.
Physiology and analysis of the electrocardiographic T wave in mice
Authors: Speerschneider T. , Thomsen M. B.
Published: October 2013

Aim

The murine electrocardiogram (ECG) is a valuable tool in cardiac research, although the definition of the T wave has been a matter of debate for several years potentially leading to incomparable data. By this study, we seek to make a clear definition of the murine T wave. Moreover, we investigate the consequences of performing QT interval correction in anaesthetized mice.

Methods

Electrocardiograms from conscious mice were recorded by implanted telemetry devices. Surface ECGs were recorded from anaesthetized mice before and during pharmacological interventions, ventricular ischaemia and heart failure. Right atrial pacing was performed to evaluate the relationship between heart rate and QT intervals.

Results

Electrocardiogram traces of conscious and anaesthetized mice (lead II) showed separable positive J waves and negative T waves. The end of the T wave was determined as the point where the T wave returned to the isoelectric line. Atrial pacing revealed that the duration of the QT interval is independent of heart rate in anaesthetized mice. The calcium channel blocker, verapamil, prolonged the PR interval; however, the polarities of the J and T waves were not changed. Local cardiac ischaemia and β‐adrenergic stimulation caused indistinguishable positive J and T waves. In contrast, chronic heart failure caused entirely negative J and T waves. In every case, the end of the T wave was clearly distinguishable on the ECG.

Conclusion

The end of the T wave is readily available from conscious and anaesthetized mice. Heart rate correction of QT interval duration in the anaesthetized mouse is not recommended.
Review article: newer optical and digital chromoendoscopy techniques vs. dye‐based chromoendoscopy for diagnosis and surveillance in inflammatory bowel disease
Authors: Tontini G. E. , Vecchi M. , Neurath M. F. , Neumann H.
Published: October 2013

Background

Recent innovations in gastrointestinal endoscopy have changed our traditional approach to diagnosis and therapy in patients with inflammatory bowel diseases (IBD). While traditionally used dye‐based chromoendoscopy (DBC) techniques suffer from several limitations that reduce their utility in daily routine practice, newer ‘dye‐less’ chromoendoscopy (DLC) techniques offer a great potential to overcome most of these limitations.

Aim

To review available optical and digital chromoendoscopy techniques, by critically discussing their potential for diagnostic and surveillance colonoscopy in patients with IBD.

Methods

A literature search on the use of dye‐less and dye‐based chromoendoscopy in IBD patients was performed.

Results

In long‐standing IBD, DBC improves detection of dysplasia (diagnostic odds ratio = 17.5, 95% CI = 1.2–247.1) as well as prediction of inflammatory disease activity and extent of disease compared with standard video‐colonoscopy. Narrow band imaging (NBI) shows no improvement in dysplasia detection rates compared with white‐light endoscopy and DBC (P = 0.6). Moreover, NBI results in a suboptimal differentiation of dysplastic from nondysplastic lesions. No data regarding digital DLC techniques (i.e. FICE, i‐scan) for dysplasia detection in IBD are yet available. Both NBI and i‐scan are superior to white‐light endoscopy in assessing the activity and extent of colorectal IBD.

Conclusions

Although the potential benefits of newer optical and digital dye‐less chromoendoscopy techniques over traditionally used DBC are substantial, only DBC can currently be recommended to improve dysplasia detection in long‐standing IBD. In contrast, DLC has the potential to quantify disease activity and mucosal healing in IBD.
Biochemical criteria at 1 year are not robust indicators of response to ursodeoxycholic acid in early primary biliary cirrhosis: results from a 29‐year cohort study
Authors: Papastergiou V. , Tsochatzis E. A. , Rodriquez‐Peralvarez M. , Thalassinos E. , Pieri G. , Manousou P. , Germani G. , Rigamonti C. , Arvaniti V. , Karatapanis S. , Burroughs A. K.
Published: October 2013

Background

In primary biliary cirrhosis (PBC), biochemical criteria at 1 year are considered surrogates of response to ursodeoxycholic acid (UDCA). However, due to the slow natural history of PBC, evaluation at 1 year may be suboptimal to assess the therapeutic response, particularly in early disease.

Aim

To determine whether evaluation of biochemical criteria at 1 year is a reliable surrogate of UDCA response in early PBC.

Methods

We analysed the prospectively collected data of 215 patients (untreated = 129; UDCA‐treated = 86) with early PBC (normal baseline bilirubin/albumin) and a median follow‐up of 8 years (range: 1–29.1). The 1‐year attainment rates of the Barcelona, Paris‐I, Paris‐II and Toronto definitions, and their predictive relevance for a poor outcome (death, transplantation, complications of cirrhosis), were assessed either as a result of UDCA or no treatment. Independent associations with attaining each UDCA response definition were identified by multivariate analysis.

Results

Untreated patients displayed 1‐year biochemical features compatible with ‘treatment response’ at rates (Barcelona: 36.4%, Paris‐I: 66.7%, Toronto: 59.7%, Paris‐II: 40.3%) similar to those obtained under UDCA. Depending on the definition, baseline ALP≤3xULN (OR: 4.80–35.90), AST≤2xULN (OR: 5.63–9.34) and early histological stage (OR: 3.67–3.87) were the stronger predictors for attaining the criteria. UDCA treatment was associated with attaining Barcelona (OR = 2.16) and Paris‐II (OR = 2.84), but not Paris‐I, and not Toronto definition when excluding late histological cases. Paris‐I criteria were significantly predictive of long‐term outcomes (HR = 2.83) in untreated patients.

Conclusions

In early PBC, biochemical criteria at 1 year reflect severity of the disease rather than the therapeutic response to UDCA.
Portable X‐Ray Fluorescence Spectroscopy of Pictographs: A Case Study From the Lower Pecos Canyonlands, Texas
Authors: Koenig C. W. , Castañeda A. M. , Boyd C. E. , Rowe M. W. , Steelman K. L.
Published: October 2013

We evaluate the effectiveness of non‐destructive portable X‐ray fluorescence spectroscopy (pXRF) for elemental analysis of pictographs at 10 sites in the Lower Pecos Canyonlands of Texas. Considerations and limitations of pXRF analysis are discussed to inform future research. We found that manganese and iron minerals were the main constituents of black and red paints, respectively. However, 40 pXRF measurements from 31 images tested at 41VV75 and 41VV76 did not contain manganese, suggesting charcoal pigment—the first widespread documentation of charcoal figures in the area. The identification of charcoal‐based pigments is important for rock‐art and radiocarbon studies in the region.
Examining Americans’ Attitudes toward Drone Strikes on the Eve of the 2012 Presidential Election
Authors: Crawford Jarret T. , Wiley Shaun , Ventresco Nina
Published: October 2013

On the eve of the 2012 U.S. Presidential election, we conducted an initial investigation into the determinants of people's attitudes toward the U.S. military's use of drone strikes in Pakistan. Drawing on existing research and theory in social and political psychology, we examined the effects of political ideology, framing effects (national security vs. human costs), value orientations, and the salience of Presidential candidate endorsement (Obama vs. Romney) on attitudes toward drone policy. The perceived relevance of security values and universalism values to judgments of drone policy mediated the relationship between ideology and drone policy attitudes. Additionally, a human costs frame increased the relevance of universalism values and decreased the relevance of security values to drone policy attitudes relative to a national security frame, and, through these values, decreased support for drone strikes. Neither of these effects was moderated by candidate salience. We discuss the theoretical and practical implications of these findings, and identify several avenues for future research on this important and controversial policy.
Covariate effects and population pharmacokinetics of lamivudine in HIV‐infected children
Authors: Piana Chiara , Zhao Wei , Adkison Kimberly , Burger David , Jacqz‐Aigrain Evelyne , Danhof Meindert , Della Pasqua Oscar
Published: October 2013

Aim

Lamivudine is used as first line therapy in HIV‐infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and Cmax).

Methods

Data from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non‐linear mixed effects approach. A stepwise procedure was used for covariate model building.

Results

A one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance (CL) and volume of distribution (V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6 kg), CL and V were 16.5 (95% CI 15.2, 17.7) l h−1 and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12 h) after twice daily doses of 4 mg kg−1 ranged from 4.44 mg l−1 h for children <14 kg to 7.25 mg l−1 h for children >30 kg.

Conclusions

The use of meta‐analysis is critical to identify the correct covariate‐parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered.
Clinical implementation of pharmacogenetics in kidney transplantation: calcineurin inhibitors in the starting blocks
Authors: Elens Laure , Bouamar Rachida , Shuker Nauras , Hesselink Dennis A. , van Gelder Teun , van Schaik Ron H. N.
Published: October 2013

Pharmacogenetics has generated many expectations for its potential to individualize therapy proactively and improve medical care. However, despite the huge amount of reported genetic associations with either pharmacokinetics or pharmacodynamics of drugs, the translation into patient care is still slow. In fact, strong evidence for a substantial clinical benefit of pharmacogenetic testing is still limited, with a few exceptions. In kidney transplantation, established pharmacogenetic discoveries are being investigated for application in the clinic to improve efficacy and to limit toxicity associated with the use of immunosuppressive drugs, especially the frequently used calcineurin inhibitors (CNIs) tacrolimus and ciclosporin. The purpose of the present review is to picture the current status of CNI pharmacogenetics and to discuss the most promising leads that have been followed so far.
The Effect of Intraspinal Bupivacaine versus Levobupivacaine on the QTc Intervals during Caesarean Section: A Randomized, Double‐blind, Prospective Study
Authors: Dogan Zafer , Yildiz Huseyin , Akcay Ahmet , Coskuner Ismail , Arikan Deniz C. , Silay Emin , Akbudak Ilknur H. , Kaya Hakan , Oksuz Hafize
Published: October 2013

The aim of this study was to describe whether or not spinal anaesthesia with bupivacaine versus levobupivacaine has any effects on the QTc interval during caesarean section. Sixty healthy pregnant women scheduled for elective caesarean section were randomized to spinal anaesthesia with either bupivacaine (the bupivacaine group) or levobupivacaine (the levobupivacaine group). ECG recordings were performed prior to spinal anaesthesia at baseline (T1), 5 min. after spinal anaesthesia, but before uterine incision (T2), and after skin closure (T3). QT intervals were calculated and corrected with the patients' heart rate according to the Bazett formula. Compared with baseline values, mean maximum QTc intervals at T2 and T3 were significantly longer in the levobupivacaine group, but only at T2 in the bupivacaine group. In addition, compared with the bupivacaine group, the QTc maximum interval at T3 was significantly longer in the levobupivacaine group. At T2, the QTc maximum intervals were longer than baseline in both groups. By the end of the surgery, the prolongation of the QTc interval had disappeared in the bupivacaine group but not in the levobupivacaine group.
Naringin Inhibits ROS‐activated MAPK Pathway in High Glucose‐induced Injuries in H9c2 Cardiac Cells
Authors: Chen Jingfu , Guo Runmin , Yan Hai , Tian Lihong , You Qiong , Li Shanghai , Huang Ruina , Wu Keng
Published: October 2013

Naringin, an active flavonoid isolated from citrus fruit extracts, exhibits biological and pharmacological properties, such as antioxidant activity and antidiabetic effect. Mitogen‐activated protein kinase (MAPK) signalling pathway has been shown to participate in hyperglycaemia‐induced injury. The present study tested the hypothesis that naringin protects against high glucose (HG)‐induced injuries by inhibiting MAPK pathway in H9c2 cardiac cells. To examine this, the cells were treated with 35 mM glucose (HG) for 24 hr to establish a HG‐induced cardiomyocyte injury model. The cells were pre‐treated with 80 μM naringin for 2 hr before exposure to HG. The findings of this study showed that exposure of H9c2 cells to HG for 24 hr markedly induced injuries, as evidenced by a decrease in cell viability, increases in apoptotic cells and reactive oxygen species (ROS) production, as well as dissipation of mitochondrial membrance potential (MMP). These injuries were significantly attenuated by the pre‐treatment of cells with either naringin or SB203580 (a selective inhibitor of p38 MAPK) or U0126 (a selective inhibitor of extracellular signal regulated kinase 1/2, ERK1/2) or SP600125 (a selective inhibitor of c‐jun N‐termanal kinase, JNK) before exposure to HG, respectively. Furthermore, exposure of cells to HG increased the phosphorylation of p38 MAPK, ERK1/2 and JNK. The increased activation of MAPK pathway was ameliorated by pre‐treatment with either naringin or N‐acetyl‐L‐cysteine (NAC), a ROS scavenger, which also reduced HG‐induced cytotoxicity and apoptosis, leading to increase in cell viability and decrease in apoptotic cells. In conclusion, our findings provide new evidence for the first time that naringin protects against HG‐induced injuries by inhibiting the activation of MAPK (p38 MAPK, ERK1/2 and JNK) and oxidative stress in H9c2 cells.
The Neuro‐Immune Axis: Prospect for Novel Treatments for Mental Disorders
Authors: Kraneveld Aletta D. , de Theije Caroline G.M. , van Heesch Floor , Borre Yuliya , de Kivit Sander , Olivier Berend , Korte Mechiel , Garssen Johan
Published: October 2013

Disturbed bidirectional pathways between the (central) nervous system and immune system have been implicated in various mental disorders, including depressive and neurodevelopmental disorders. In this minireview, the role of the neuro‐immune axis and its targetability in relation to major depression and autism spectrum disorder will be discussed. All together, the management of these and possibly other multi‐factorial mental disorders needs a new and integrated therapeutic approach. Pharmacologically bioactive molecules as well as medical nutrition targeting the (gut)–immune–brain axis could be such an approach.
In Vitro Assessment of 36 CYP2C9 Allelic Isoforms Found in the Chinese Population on the Metabolism of Glimepiride
Authors: Dai Da‐Peng , Wang Shuang‐Hu , Geng Pei‐Wu , Hu Guo‐Xin , Cai Jian‐Ping
Published: October 2013

Of the 57 reported CYP2C9 alleles, to date, 36 of them have been identified in the Chinese population. The aim of this study was to assess the catalytic characteristics of these allelic isoforms and their effects on the metabolism of glimepiride in vitro. Baculovirus‐mediated expressing system was used to highly express wild‐type and the 35 CYP2C9 allelic variants in insect cell microsomes. Then, the enzymatic characteristics of each variant were evaluated using glimepiride as the substrate. Reactions were performed at 37°C with the insect microsomes and 0.125–10 μM glimepiride for 40 min. After termination, the products were extracted and used for signal collection by LC‐MS/MS. Of the 36 tested CYP2C9 allelic isoforms, only four variants (CYP2C9.40, CYP2C9.47, CYP2C9.51 and CYP2C9.54) exhibited similar relative clearance values to that of wild‐type CYP2C9.1. In addition, one variant (CYP2C9.36) showed a higher intrinsic clearance value than the wild‐type protein, while the remaining 30 CYP2C9 allelic isoforms exhibited significantly decreased clearance values (from 0.1% to 87.2%) compared to CYP2C9.1. This study provided the most comprehensive data on the enzymatic activities of all reported CYP2C9 variants in the Chinese population with regard to the commonly used antidiabetic drug, glimepiride. Our results indicate that most of the tested rare alleles significantly decrease the catalytic activity of CYP2C9 variants towards glimepiride hydroxylation in vitro.
Abnormalities of brain response during encoding into verbal working memory among euthymic patients with bipolar disorder
Authors: McKenna Benjamin S , Sutherland Ashley N , Legenkaya Anna P , Eyler Lisa T
Published: October 2013

Objectives

Individuals with bipolar disorder (BD) have trait‐like deficits in attention and working memory (WM). A fundamental dissociation for most verbal WM theories involves the separation of sensory‐perceptual encoding, reliant upon attention, from the maintenance of this information in WM proper. The present study examined if patients with BD demonstrate differential neural changes in encoding and maintenance WM processes that underlie cognitive impairment.

Methods

Event‐related functional magnetic resonance imaging during a delayed match‐to‐sample WM paradigm was employed in 23 inter‐episode medicated patients with BD and 23 demographically similar healthy comparison participants. We examined brain regions during encoding and maintenance task intervals to identify regions that demonstrated differential effects between groups. Medication effects and functional connectivity between prefrontal cortex and basal ganglia/thalamus were examined during the encoding interval due to the importance of these regions and the connection among them for encoding into WM.

Results

Patients with BD exhibited deficits in task accuracy and attenuated brain response during the encoding interval in areas of the prefrontal cortex, caudate, thalamus, and posterior visual regions. In contrast, patients with BD exhibited hyperactivation in posterior sensory regions during the maintenance interval. Among the BD group, those with greater medication load exhibited the greatest brain response within the prefrontal cortex.

Conclusions

Reduction in activation during the encoding interval suggests that attentional deficits underlie WM deficits in patients with BD. These deficits appear to be trait‐like in so far as they were observed during periods of euthymia in patients with BD. Medication effects remain to be further explored as there was evidence of prefrontal changes dependent on medication load.
An empirical evaluation of the MATRICS Consensus Cognitive Battery in bipolar disorder
Authors: Van Rheenen Tamsyn E , Rossell Susan L
Published: October 2013

Objectives

There is a large body of evidence to indicate that neurocognitive impairments in bipolar disorder (BD) may represent viable endophenotypes; however, a standard consensus‐based battery of cognitive tests used to measure them is yet to appear. There is potential for a neurocognitive battery which was developed for use in the related disorder, schizophrenia – the MATRICS Consensus Cognitive Battery (MCCB) – to provide a consistent measurement tool with a standard to which the cognitive capacity of BD can be compared to other disorders. However, its suitability for capturing neurocognitive impairment in BD cohorts is not well established. Moreover, neurocognitive tests recently recommended by the International Society for Bipolar Disorders (ISBD) for inclusion in a consensus neurocognitive battery for BD have not been evaluated in the context of the MCCB. An evaluation of (i) the clinical efficacy of the MCCB and (ii) the tests recommended by the ISBD in a BD cohort were the aims of the current study.

Methods

A total of 50 patients with BD (mean age = 38 years) and 52 healthy controls (mean age = 34 years) completed all of the MCCB subtests, in addition to the well‐recognized Trail Making Test–Part B and the Colour–Word Stroop.

Results

Multivariate analyses of variance of the MCCB domains revealed a significant group effect for overall cognition, and significantly reduced patient performance on speed of processing, working memory, and visual and verbal learning. A second multivariate analysis of variance using a newly created composite score called executive function, comprising scores on an existing MCCB subtest in addition to TMT‐B and Colour–Word Stroop, revealed significant differences on this domain as well. Subgroup analysis indicated that there were no differences in any domain score performance between symptomatic and euthymic patients, or bipolar I and II disorder patient groups.

Conclusions

Our findings suggest that the MCCB and two additionally recommended ISBD executive function measures form a promising consensus‐based research tool for examining neurocognition in BD.
A Neglected Aspect of Conscience: Awareness of Implicit Attitudes
Authors: Fitzgerald Chloë
Published: October 2013

The conception of conscience that dominates discussions in bioethics focuses narrowly on private regulation of behaviour resulting from explicit attitudes. It neglects to mention implicit attitudes and the role of social feedback in becoming aware of one's implicit attitudes. But if conscience is a way of ensuring that a person's behaviour is in line with her moral values, it must be responsive to all aspects of the mind that influence behaviour. There is a wealth of recent psychological work demonstrating the influence of implicit attitudes on behaviour. A necessary part of having a well‐functioning conscience must thus be awareness and regulation of one's implicit attitudes in addition to one's explicit attitudes; this cannot be done by an individual in isolation. On my revised conception of conscience, heeding social feedback, being emotionally self‐aware and engaging in self‐monitoring are important for the possession of a well‐functioning conscience. Health professionals may need specific training to help them develop and maintain a well‐functioning conscience, which should involve cultivation of awareness of implicit attitudes, emphasis on social feedback and techniques to enable better control over them.
Standard of Care, Institutional Obligations, and Distributive Justice
Authors: MacKay Douglas
Published: October 2013

The problem of standard of care in clinical research concerns the level of treatment that investigators must provide to subjects in clinical trials. Commentators often formulate answers to this problem by appealing to two distinct types of obligations: professional obligations and natural duties. In this article, I investigate whether investigators also possess institutional obligations that are directly relevant to the problem of standard of care, that is, those obligations a person has because she occupies a particular institutional role. I examine two types of institutional contexts: (1) public research agencies – agencies or departments of states that fund or conduct clinical research in the public interest; and (2) private‐for‐profit corporations. I argue that investigators who are employed or have their research sponsored by the former have a distinctive institutional obligation to conduct their research in a way that is consistent with the state's duty of distributive justice to provide its citizens with access to basic health care, and its duty to aid citizens of lower income countries. By contrast, I argue that investigators who are employed or have their research sponsored by private‐for‐profit corporations do not possess this obligation nor any other institutional obligation that is directly relevant to the ethics of RCTs. My account of the institutional obligations of investigators aims to contribute to the development of a reasonable, distributive justice‐based account of standard of care.
Phase I, multicentre, dose‐escalation trial of monotherapy with milatuzumab (humanized anti‐CD74 monoclonal antibody) in relapsed or refractory multiple myeloma
Authors: Kaufman Jonathan L. , Niesvizky Ruben , Stadtmauer Edward A. , Chanan‐Khan Asher , Siegel David , Horne Heather , Wegener William A. , Goldenberg David M.
Published: October 2013

CD74, expressed in multiple myeloma (MM), was evaluated as a target for immunotherapy with milatuzumab (a humanized anti‐CD74 antibody). In a multicentre dose escalation study, 25 patients with advanced MM received milatuzumab doses of 1·5 (N = 8), 4·0 (N = 9), 8·0 (N = 4) or 16·0 mg/kg (N = 4) administered twice weekly x 4. They had a median of 5 prior treatments (17 post ≥1 stem cell transplantation) and were refractory (N = 7) or relapsed (N = 18) with generally short‐lived responses to last treatment (median 4·0 months). After increasing prophylactic medications and slowing administration, infusions were well tolerated (National Cancer Institute‐Common Terminology Criteria v3 toxicity Grades 1–2) with no dose‐limiting toxicity at higher doses. Only one patient developed borderline positive human anti‐milatuzumab antibody titres of uncertain clinical significance. Although milatuzumab was rapidly cleared from circulation with little serum accumulation and low trough levels, B‐cell levels were moderately decreased with treatment (median decrease, 34%). There were no objective responses by European Group for Blood and Marrow Transplantation criteria, but 5 of 19 patients (26%) who completed treatment in this heavily pretreated and generally refractory group had stable disease for ≥3 months post‐treatment (one continuing for 17 months). Disease stabilization and evidence of pharmacodynamic activity support further development for use in combination with other agents or as a drug conjugate. (Clinicaltrials.gov identifier: NCT00421525)
Erythroid‐extrinsic regulation of normal erythropoiesis by retinoic acid receptors
Authors: Dewamitta Sita R. , Joseph Chacko , Purton Louise E. , Walkley Carl R.
Published: October 2013

Vitamin A and its derivatives (retinoids) are important regulators of haematopoiesis, acting via retinoic acid receptors (RARs). Epidemiological studies indicated an association of vitamin A deficiency with anaemia in humans. To define the requirements of RARs in erythropoiesis, we evaluated erythroid parameters in RAR germ‐line deficient and conditional knock out mice with erythroid specific deletion of RARs. Adult RARγ−/− mice were anaemic, however, Epor‐Cre Rarafl/fl, Epor‐Cre Rargfl/fl and Epor‐Cre Rarafl/flgfl/fl mice were normal, indicating a lack of an erythroid intrinsic RAR function. Therefore, erythroid‐specific RAR function is dispensable for erythropoiesis and RARγ plays an erythroid extrinsic role in erythropoiesis.
Chronic myeloproliferative neoplasms and risk of osteoporotic fractures; a nationwide population‐based cohort study
Authors: Farmer Sarah , Horváth‐Puhó Erzsébet , Vestergaard Hanne , Hermann Anne Pernille , Frederiksen Henrik
Published: October 2013

Patients with systemic mastocytosis have an increased risk of osteoporosis, however, the risk of osteoporotic fractures among the classic chronic myeloproliferative neoplasms (CMPN), including essential thrombocythaemia (ET), polycythaemia vera (PV) and chronic myeloid leukaemia (CML), is unknown. We conducted a population‐based cohort study to determine the risk of osteoporotic fractures among three cohorts of patients with newly diagnosed ET, PV, and CML. Patients were identified in medical registers including all Danish hospitals during 1980–2010 and were followed until first osteoporotic fracture. Fracture risk was compared to cohorts from the general population matched on age, sex and calendar year. We followed 7595 CMPN patients and 338 974 comparison cohort members. We found that the risk of femoral fracture after 5 years was consistently higher than the general population, being 3·01% (95% confidence interval (CI): 2·20–4·10), 4·74% (95%CI: 4·06–5·52) and 4·64% (95%CI: 3·29–6·53) among ET, PV, and CML patients respectively. Adjusted hazard ratio for femoral fracture was increased 1·19‐fold (95% CI: 0·94–1·51) for ET patients, 1·82‐fold (95% CI: 1·62–2·04) for PV patients, and 2·67‐fold (95% CI: 1·97–3·62) for CML patients. We conclude that CMPN patients are at higher risk of osteoporotic fractures than the general population.
How I treat children and adolescents with acute promyelocytic leukaemia
Authors: Abla Oussama , Ribeiro Raul C.
Published: October 2013

Acute promyelocytic leukaemia (APL) is a rare subtype of acute myeloid leukaemia. The outcome of paediatric APL has improved substantially over the past 20 years; cure rates above 80% are expected when all‐trans retinoic acid (ATRA) is given with anthracycline‐based regimens. The presenting features of paediatric APL may include severe bleeding and thrombotic complications, which contribute to the high early death rate. The incidence of leucocytosis and the microgranular subtype is greater in paediatric than adult APL, and children experience greater ATRA‐related toxicity. It is crucial to begin ATRA therapy and intensive platelet and fibrinogen replacement on first suspicion of APL. Recent risk‐adapted therapeutic trials have shown that patients at greater risk of relapse benefit from the introduction of high‐dose cytarabine during consolidation. Combination therapy with ATRA and arsenic trioxide provides very effective frontline treatment and may reduce the need for subsequent anthracycline therapy.
Impact of glucose‐6‐phosphate dehydrogenase deficiency on sickle cell anaemia expression in infancy and early childhood: a prospective study
Authors: Benkerrou Malika , Alberti Corinne , Couque Nathalie , Haouari Zinedine , Ba Aissatou , Missud Florence , Boizeau Priscilla , Holvoet Laurent , Ithier Ghislaine , Elion Jacques , Baruchel André , Ducrocq Rolande
Published: October 2013

In patients with sickle cell anaemia (SCA), concomitant glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is usually described as having no effect and only occasionally as increasing severity. We analysed sequential clinical and biological data for the first 42 months of life in SCA patients diagnosed by neonatal screening, including 27 G6PD‐deficient patients, who were matched on sex, age and parents' geographic origin to 81 randomly selected patients with normal G6PD activity. In the G6PD‐deficient group, steady‐state haemoglobin was lower (−6·2 g/l, 95% confidence interval (CI), [−10·1; −2·3]) and reticulocyte count higher (247 × 109/l, 95%CI, [97; 397]). The acute anaemic event rate was 3 times higher in the G6PD‐deficient group (P < 10−3). A higher proportion of G6PD‐deficient patients required blood transfusion (20/27 [74%] vs. 37/81 [46%], P < 10−3), for acute anaemic events, and also vaso‐occlusive and infectious events. No significant between‐group differences were found regarding the rates of vaso‐occlusive, infectious, or cerebrovascular events. G6PD deficiency in babies with SCA worsens anaemia and increases blood transfusion requirements in the first years of life. These effects decrease after 2 years of age, presumably as the decline in fetal haemoglobin levels leads to increased sickle cell haemolysis and younger red blood cells with higher G6PD activity.
A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia
Authors: Grinfeld Jacob , Gerrard Gareth , Alikian Mary , Alonso‐Dominguez Juan , Ale Sakuntala , Valgañon Mikel , Nteliopoulos Georgios , White Deborah , Marin David , Hedgley Corinne , O'Brien Stephen , Clark Richard , Goldman John M. , Milojkovic Dragana , Apperley Jane F. , Foroni Letizia
Published: October 2013

Approximately one‐third of patients with chronic myeloid leukaemia will fail to achieve or maintain responses to imatinib. Changes in solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also termed OCT1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed SLC22A1 mRNA levels and single nucleotide polymorphisms (SNPs) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of SLC22A1 expression did not significantly correlate with imatinib failure or achievement of molecular remission. The SNP 408V>M (g.1222G>A) was present in 65% of patients and was associated in all cases with an eight base‐pair insertion (8+ allele) at the 3′ end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M420del was found in 33% of patients and never in cis with 8+ (the 3− allele). Significantly longer times to 1% and 0·1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8+8+ or 8+N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8+ and 3− (NN, 18%) showed the best outcomes overall. Thus, while SLC22A1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so.
Secondary cancers among children with acute lymphoblastic leukaemia treated by the Tokyo Children's Cancer Study Group protocols: a retrospective cohort study
Authors: Ishida Yasushi , Maeda Miho , Urayama Kevin Y. , Kiyotani Chikako , Aoki Yuki , Kato Yoko , Goto Shoko , Sakaguchi Sachi , Sugita Kenichi , Tokuyama Mika , Nakadate Naoya , Ishii Eizaburo , Tsuchida Masahiro , Ohara Akira ,   The QOL committee of Tokyo Children's Cancer Study Group (TCCSG)
Published: October 2013

With improvement in survival, it is important to evaluate the impact of treatment on secondary cancers in acute lymphoblastic leukaemia (ALL) survivors. A retrospective cohort study comprising 2918 children diagnosed with ALL and enrolled on Tokyo Children's Cancer Study Group (TCCSG) protocols between 1984 and 2005 was conducted to evaluate the incidence of secondary cancers and associated factors including treatment protocol, cranial irradiation and other characteristics of the primary ALL. Thirty‐seven patients developed secondary cancers, including acute myeloid leukaemia (n = 11), myelodysplastic syndrome (n = 5), non‐Hodgkin lymphoma (n = 2), brain tumours (n = 13) and other solid carcinomas (n = 6) within a median follow‐up duration of 9·5 years. The cumulative incidence of any secondary cancers was 1·0% (95% confidence interval (CI), 0·7–1·4%) at 10 years and 2·4% (95% CI, 1·5–3·7%) at 20 years, respectively. Standardized incidence rate ratio of secondary cancers was 9·3 (95% CI, 6·5–12·8). Multivariate analyses showed an increased risk of secondary cancers associated with the recent treatment protocol and cranial irradiation. There was no evidence of a reduction in secondary cancer incidence despite marked decreases in cranial irradiation use in the recent protocols.
Concerns about unintended negative consequences of informing the public about multifactorial risks may be premature for young adult smokers
Authors: Waters Erika A. , Kincaid Caroline , Kaufman Annette R. , Stock Michelle L. , Peterson Laurel M. , Muscanell Nicole L. , Guadagno Rosanna E.
Published: October 2013

Background

Many health risks are associated with both genetic and behavioural factors. Concerns have been raised that learning about such multifactorial risks might have detrimental effects on health‐related beliefs, cognitions, and affect. However, experimental evidence is sparse.

Objective

To explore the effects of reading an online news article about the discovery of a genetic basis for nicotine addiction.

Methods

Smokers (N = 333) were recruited from the psychology subject pools of two major universities. Participants were randomly assigned to read one of three news articles: one describing a genetic basis for nicotine addiction and lung cancer obtained from a national news source, one altered to indicate no genetic basis for nicotine addiction and lung cancer, or one unrelated attention control. Participants then completed an online questionnaire, which assessed smoking‐related cognitions and affect, and beliefs about nicotine addiction, quitting smoking, and whether the harms of tobacco use are delayed.

Results

There was no statistically significant influence of experimental condition on smoking‐related cognitions/affect (ps > .05, η2 < .002), beliefs about addiction and quitting (Wilks' λ = .98, p = .66, η2 = .01), or delayed harm (ps > .05, η2 < .002).

Conclusion

Reading an online news article about the presence or absence of a genetic basis for nicotine addiction was not found to change smoking‐related cognitions/affect or beliefs among young adult smokers. Concerns about negative effects of multifactorial risk information on health beliefs may be premature. Nevertheless, to effectively translate basic genomics research into effective public health practice, further research should investigate these issues in different populations, via different communication modalities, and for different health outcomes.

Statement of contribution

What is already known on this subject?

Information about the health implications of the interaction between genetics and behaviour is becoming prevalent.

Learning about these interactions may reduce perceived risk and intentions to engage in health behaviours.

What does this study add?

Informing young adult smokers about the genetic basis for nicotine addiction does not affect health beliefs negatively.

Responses are not moderated by endorsing the idea of genetic causation or current/experimenter smoking status.
An exploratory assessment of theory of mind and psychological impairment in patients with bulimia nervosa
Authors: Laghi Fiorenzo , Cotugno Armando , Cecere Francesco , Sirolli Arianna , Palazzoni David , Bosco Francesca M.
Published: October 2013

This study aimed to investigate psychosocial functioning and different dimensions of theory of mind (ToM) in people with bulimia nervosa (BN) and Eating Disorder Not Otherwise Specified‐BNtype (EDNOS‐BN). Psychosocial functioning and ToM were assessed in a sample of young adult females, 16BNand 16EDNOS‐BNoutpatients and 16 healthy controls (HCs). They were assessed using the Eating Disorder Inventory‐Symptom Checklist‐2 (EDI‐2SC) for evaluating psychological traits associated with eating disorders; the Symptom Checklist‐90‐Revised (SCL‐90‐R) for evaluating psychopathological status; and the Theory of Mind Assessment Scale (Th.o.m.a.s.), a semi‐structured interview aimed at assessing a person's different dimensions of ToM. TheBNandEDNOS‐BNgroups exhibited worse performance than the control group on all dimensions of theSCL‐90‐R, and on all dimensions of theEDI‐2SC. The only difference for perfectionism was thatBNobtained higher scores thanEDNOS‐BNgroup. Our results also revealed an impairment of third‐person and second‐order ToM in patients with bulimia (BNandEDNOS‐BN) with respect to control subjects. These preliminary data have important implications for future empirical work, in that they provide valuable information regarding the importance of investigating the various facets of ToM ability separately, in order to provide a more detailed profile of ToM functioning in the clinical samples.
The protective role of coenzyme Q10 in renal injury associated with extracorporeal shockwave lithotripsy: a randomised, placebo‐controlled clinical trial
Authors: Carrasco Julia , Anglada Francisco J. , Campos Juan P. , Muntané Jordi , Requena Maria J. , Padillo Javier
Published: October 2013

Objective

To determine the efficacy of coenzyme Q10 (CoQ10) in preventing renal injury in patients with lithiasis undergoing extracorporeal shockwave lithotripsy (ESWL).

Patients and Methods

Prospective, randomised, double‐blind, placebo‐controlled clinical trial of 100 patients with renal lithiasis who were treated with ESWL.

The patients were distributed randomly into two groups receiving either placebo or CoQ10 (200 mg/day), a powerful antioxidant with vasoactive properties, orally administered during the week before ESWL and for 1 week after.

Renal dysfunction markers, vasoactive hormones, oxidative stress, plasma levels of several interleukins and vascular resistance index (VRI) using Doppler ultrasound were evaluated the week before ESWL, 2 h before ESWL and at 2 h, 24 h and 7 days after ESWL.

Results

There was a significant increase in glomerular filtration (P = 0.013), as well as a decrease in the albumin/creatinine ratio and the β2‐microglobulin level (P = 0.02) after 1 week of treatment in the CoQ10 group. These changes were maintained at the follow‐up after ESWL.

The administration of CoQ10 was associated with improvement in vasoactive hormone parameters, VRI and interleukin levels. These improvements were maintained until the end of the follow‐up period.

However, the administration of CoQ10 was not associated with significant changes in the oxidative stress parameters.

Conclusion

Our results indicate that CoQ10 administration improves renal function and vasoactive and inflammation parameter values, allowing for preconditioning before the tissue insult caused by ESWL.
Cadmium disorganises the scaffolding of gap and tight junction proteins in the hepatic cell line WIF B9
Authors: Boucherie Sylviane , Decaens Catherine , Verbavatz Jean‐Marc , Grosse Brigitte , Erard Marie , Merola Fabienne , Cassio Doris , Combettes Laurent
Published: October 2013

Background Information

Hepatocytes, which perform the main functions of the liver, are particularly vulnerable to toxic agents such as cadmium, an environmental pollutant. To identify the molecular targets for cadmium in hepatocytes, we have studied the effects of CdCl2 on the hybrid cell line WIF‐B9 that exhibits stable structural and functional hepatocytic polarity.

Results

We showed that the toxicity of CdCl2 (1 µM, 24 h) resulted in a reduction in direct intercellular communication (via gap junctions) and in an increase in paracellular permeability (decrease in the sealing of tight junctions). These effects were not related to changes in the expression of the key proteins involved, Cx32 and claudin 2, the first being constitutive of gap junctions and the second of tight junctions in this cell line. Using immunofluorescence experiments, we observed a change in the location of Cx32 and claudin 2: these two proteins were less often found in the tight junction network that closes the bile canaliculi (BC). In control cells, ‘Proximity Ligation Assay’ (PLA Duolink®) has confirmed in situ that molecules of claudin 2 and Cx32 are very close to each other at the BC (probably less than 16 nm). This was no longer the case after treatment with CdCl2. Localisation of occludin and Cx32 relative to each other was not modified by CdCl2, but CdCl2 increased the PLA signal between molecules of JAM‐A and Cx32. Finally, examination of freeze‐fracture replicas obtained from cultures treated with CdCl2 showed the disruption of the network of tight junctions and the depletion or the disintegration of the junctional plaques associated with tight junctions.

Conclusions

This study demonstrates in situ the changes induced by cadmium on the organisation of cell–cell junctions and points out the importance of the association Cx32/claudin 2 for the maintenance of normal hepatocyte functions.
Panencephalopathic Creutzfeldt‐Jakob Disease with Distinct Pattern of Prion Protein Deposition in a Patient with D178N Mutation and Homozygosity for Valine at Codon 129 of the Prion Protein Gene
Authors: Marcon Gabriella , Indaco Antonio , Di Fede Giuseppe , Suardi Silvia , Finato Nicoletta , Moretti Valentino , Micoli Sandro , Fociani Paolo , Zerbi Pietro , Pincherle Alessandro , Redaelli Veronica , Tagliavini Fabrizio , Giaccone Giorgio
Published: October 2013

Prion diseases include sporadic, acquired and genetic forms linked to mutations of the prion protein (PrP) gene (PRNP). In subjects carrying the D178N PRNP mutation, distinct phenotypes can be observed, depending on the methionine/valine codon 129 polymorphism. We present here a 53‐year‐old woman with D178N mutation in the PRNP gene and homozygosity for valine at codon 129. The disease started at age 47 with memory deficits, progressive cognitive impairment and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years and the disease course was 6 years. The neuropathologic examination demonstrated severe diffuse cerebral atrophy with neuronal loss, spongiosis and marked myelin loss and tissue rarefaction in the hemispheric white matter, configuring panencephalopathic Creutzfeldt‐Jakob disease. PrP deposition was present in the cerebral cortex, basal ganglia and cerebellum with diffuse synaptic‐type pattern of immunoreactivity and clusters of countless, small PrP deposits, particularly evident in the lower cortical layers, in the striatum and in the molecular layer of the cerebellum. Western blot analysis showed the presence of type 1 PrPSc (Parchi classification). These findings underline the clear‐cut distinction between the neuropathological features of Creutzfeldt‐Jakob disease associated with D178N PRNP mutation and those of fatal familial insomnia.