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Journal of Cancer 2016The growing interest in enhancing and spreading colorectal cancer (CRC) screening has been stimulating the exploration of novel biomarkers with greater sensitivity and... (Review)
Review
The growing interest in enhancing and spreading colorectal cancer (CRC) screening has been stimulating the exploration of novel biomarkers with greater sensitivity and specificity than immunochemical faecal occult blood test (iFOBT). The present study provides i) a systematic review of the urinary biomarkers that have been tested to achieve early CRC diagnosis and assess the risk of colorectal adenoma and adenocarcinoma, and ii) a meta-analysis of the data regarding the urinary prostaglandin (PG) metabolite PGE-M. As regard to gene markers, we found significantly different percent methylation of the vimentin gene in CRC patients and healthy controls (HC) (p<0.0001). Respect to metabolism of nitrogenous bases, cytidine, 1-methyladenosine, and adenosine, have higher concentrations in CRC patients than in HC (respectively, p<0.01, p=0.01, and p<0.01). As regard to spermine we found that N1,N12 diacetyl spermine (DiAcSpm) and N1, N8 diacetylspermidine (DiAcSpd) were significantly higher in CRC than in HC (respectively p=0.01 and p<0.01). Respect to PGE-M, levels were higher in CRC than in those with multiple polyposis (p<0.006) and HC subjects (p<0.0004). PGE-M seems to be the most interesting and promising urinary marker for CRC and adenoma risk assessment and for CRC screening. In conclusion, evidence suggests that urinary biomarker could have a potential role as urinary biomarkers in the diagnosis of colorectal cancer. Particularly, PGE-M seems to be the most promising urinary marker for CRC early detection.
PubMed: 27877214
DOI: 10.7150/jca.16244 -
Chemistry & Biodiversity Nov 2016Due to the chemical structural diversity and various analgesic mechanisms, an increasing number of studies indicated that some flavonoids from medicinal plants could be... (Review)
Review
Due to the chemical structural diversity and various analgesic mechanisms, an increasing number of studies indicated that some flavonoids from medicinal plants could be promising candidates for new natural analgesic drugs, which attract high interests of advanced users and academic researchers. The aim of this systematic review is to report flavonoids and its derivatives as new analgesic candidates based on the pharmacological evidences. Sixty-four papers were found concerning the potential analgesic activity of 46 flavonoids. In this case, the evidence for analgesic activity of flavonoids and total flavonoids was investigated. Meanwhile, the corresponding analgesic mechanism of flavonoids was discussed by generalizing and analyzing the current publications. Based on this review, the conclusion can be drawn that some flavonoids are promising candidates for painful conditions and deserve particular attention in further research and development.
Topics: Analgesics; Biological Products; Brain; Calcium Channels; Central Nervous System; Flavonoids; Humans; Nitric Oxide; Prostaglandins; Serotonin
PubMed: 27449823
DOI: 10.1002/cbdv.201600060 -
The Cochrane Database of Systematic... Aug 2016Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric... (Review)
Review
BACKGROUND
Malabsorption of fat and protein contributes to poor nutritional status in people with cystic fibrosis. Impaired pancreatic function may also result in increased gastric acidity, leading in turn to heartburn, peptic ulcers and the impairment of oral pancreatic enzyme replacement therapy. The administration of gastric acid-reducing agents has been used as an adjunct to pancreatic enzyme therapy to improve absorption of fat and gastro-intestinal symptoms in people with cystic fibrosis. It is important to establish the evidence regarding potential benefits of drugs that reduce gastric acidity in people with cystic fibrosis. This is an update of a previously published review.
OBJECTIVES
To assess the effect of drug therapies for reducing gastric acidity for: nutritional status; symptoms associated with increased gastric acidity; fat absorption; lung function; quality of life and survival; and to determine if any adverse effects are associated with their use.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Trials Register: 12 May 2016.
SELECTION CRITERIA
All randomised and quasi-randomised trials involving agents that reduce gastric acidity compared to placebo or a comparator treatment.
DATA COLLECTION AND ANALYSIS
Both authors independently selected trials, assessed trial quality and extracted data.
MAIN RESULTS
The searches identified 39 trials; 17 of these, with 273 participants, were suitable for inclusion, but the number of trials assessing each of the different agents was small. Seven trials were limited to children and four trials enrolled only adults. Meta-analysis was not performed, 14 trials were of a cross-over design and we did not have the appropriate information to conduct comprehensive meta-analyses. All the trials were run in single centres and duration ranged from five days to six months. The included trials were generally not reported adequately enough to allow judgements on risk of bias.However, one trial found that drug therapies that reduce gastric acidity improved gastro-intestinal symptoms such as abdominal pain; seven trials reported significant improvement in measures of fat malabsorption; and two trials reported no significant improvement in nutritional status. Only one trial reported measures of respiratory function and one trial reported an adverse effect with prostaglandin E2 analogue misoprostol. No trials have been identified assessing the effectiveness of these agents in improving quality of life, the complications of increased gastric acidity, or survival.
AUTHORS' CONCLUSIONS
Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. Furthermore, due to the unclear risks of bias in the included trials, we are unable to make firm conclusions based on the evidence reported therein. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.
Topics: Abdominal Pain; Adult; Child; Cystic Fibrosis; Dietary Fats; Gastric Acid; Gastrointestinal Agents; Histamine H2 Antagonists; Humans; Intestinal Absorption; Pancreas; Proton Pump Inhibitors; Randomized Controlled Trials as Topic
PubMed: 27546383
DOI: 10.1002/14651858.CD003424.pub4 -
International Urology and Nephrology Nov 2016Lithium is an essential treatment in bipolar disorder and treatment-resistant depression; however, its use has been limited by concerns regarding its renal adverse... (Review)
Review
PURPOSE
Lithium is an essential treatment in bipolar disorder and treatment-resistant depression; however, its use has been limited by concerns regarding its renal adverse effects. An improved understanding of potential molecular mechanisms can help develop prevention and treatment strategies for lithium-associated renal disease.
METHODS
We conducted a systematic literature search using MEDLINE, Embase, and PsychINFO including English-language original research articles published prior to November 2015 that specifically investigated lithium's effects on nephrogenic diabetes insipidus (NDI) and chronic kidney disease (CKD), using molecular markers.
RESULTS
From a total of 3510 records, 71 pre-clinical studies and two relevant clinical studies were identified. Molecular alterations were reported in calcium signaling, inositol monophosphate, extracellular-regulated, prostaglandin, sodium/solute transport, G-protein-coupled receptors, nitric oxide, vasopressin/aquaporin, and inflammation-related pathways in lithium-associated renal disease. The majority of studies found that these mechanisms were implicated in NDI, while few studies had examined CKD.
DISCUSSION
Future studies will have to focus on (1) validating the present findings in human subjects and (2) examining CKD, which is the most clinically relevant lithium-associated renal effect. This will improve our understanding of lithium's biological effects, as well as inform a personalized medicine approach, which could lead to safer lithium prescribing and less renal adverse events.
Topics: Animals; Aquaporins; Calcium; Diabetes Insipidus, Nephrogenic; Humans; Lithium; Prostaglandins; Receptors, G-Protein-Coupled; Renal Insufficiency, Chronic; Signal Transduction; Sodium; Symporters; Vasopressins
PubMed: 27357223
DOI: 10.1007/s11255-016-1352-6 -
The Cochrane Database of Systematic... Mar 2016Supplementary oxygen is routinely administered to low-risk pregnant women during an elective caesarean section under regional anaesthesia; however, maternal and foetal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Supplementary oxygen is routinely administered to low-risk pregnant women during an elective caesarean section under regional anaesthesia; however, maternal and foetal outcomes have not been well established. This is an update of a review first published in 2013.
OBJECTIVES
The primary objective was to determine whether supplementary oxygen given to low-risk term pregnant women undergoing elective caesarean section under regional anaesthesia can prevent maternal and neonatal desaturation. The secondary objective was to compare the mean values of maternal and neonatal blood gas levels between mothers who received supplementary oxygen and those who did not (control group).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, issue 11), MEDLINE (1948 to November 2014) and EMBASE (1980 to November 2014). The original search was first performed in February 2012. We reran the search in CENTRAL, MEDLINE, EMBASE in February 2016. One potential new study of interest was added to the list of 'Studies awaiting Classification' and will be incorporated into the formal review findings during the next review update.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) of low-risk pregnant women undergoing an elective caesarean section under regional anaesthesia and compared outcomes with, and without, oxygen supplementation.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data, assessed methodological quality and performed subgroup and sensitivity analyses.
MAIN RESULTS
We found one new included study in this updated version. In total, our updated review includes 11 trials (with 753 participants). The low quality of evidence showed no significant differences in average Apgar scores at one minute (N = six trials, 519 participants; 95% confidence (CI) -0.16 to 0.31, P = 0.53) and at five minutes (N = six trials, 519 participants; 95% CI -0.06 to 0.06, P = 0.98). None of the 11 trials reported maternal desaturation. The very low quality of evidence showed that in comparison to room air, women in labour receiving supplementary oxygen had higher maternal oxygen saturation (N = three trials, 209 participants), maternal PaO2 (oxygen pressure in the blood; N = six trials, 241 participants), UaPO2 (foetal umbilical arterial blood; N = eight trials, 504 participants; 95% CI 1.8 to 4.9, P < 0.0001) and UvPO2 (foetal umbilical venous blood; N = 10 trials, 683 participants). There was high heterogeneity among these outcomes. A subgroup analysis showed no significant difference in UaPO2 between the two intervention groups in low-risk studies, whereas the high-risk studies showed a benefit for the neonatal oxygen group.
AUTHORS' CONCLUSIONS
Overall, we found no convincing evidence that giving supplementary oxygen to healthy term pregnant women during elective caesarean section under regional anaesthesia is either beneficial or harmful for either the mother or the foetus' short-term clinical outcome as assessed by Apgar scores. Although, there were significant higher maternal and neonatal blood gas values and markers of free radicals when extra oxygen was given, the results should be interpreted with caution due to the low grade quality of the evidence.
Topics: Anesthesia, Conduction; Anesthesia, Obstetrical; Apgar Score; Biomarkers; Cesarean Section; Dinoprost; Elective Surgical Procedures; Female; Fetal Blood; Humans; Malondialdehyde; Oxygen; Pregnancy; Randomized Controlled Trials as Topic
PubMed: 26982519
DOI: 10.1002/14651858.CD006161.pub3 -
The Journal of Maternal-fetal &... Jan 2017To conduct a meta-analysis of the association of platelet counts and pharmacotherapeutic failure in preterms with a patent ductus arteriosus (PDA). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To conduct a meta-analysis of the association of platelet counts and pharmacotherapeutic failure in preterms with a patent ductus arteriosus (PDA).
METHODS
MEDLINE, Embase, Science Citation Index, abstracts and conference proceedings were searched, and principal authors contacted. Included studies reported indomethacin or ibuprofen use for PDA closure, compared a group which failed treatment versus a group which did not and reported the association between platelet counts and indomethacin or ibuprofen failure. Two reviewers independently screened results and assessed methodological quality using the Newcastle-Ottawa Scale. Results are expressed as mean difference in platelet counts and summary odds ratios (OR) using a random effects model.
RESULTS
1105 relevant studies were identified; eight involving 1087 preterms were included. Platelet counts were significantly lower in infants who failed pharmacotherapy (Meandifference:-30.88 × 10/L; 95% CI:-45.69 × 10,-16.07 × 10/L; I2 = 24%; p=0.24). Similar results were obtained based on either pharmacotherapeutic agent. Treatment failure was also significantly associated with pre-treatment thrombocytopenia (summary OR:1.75; 95% CI:1.23-2.49, I2 = 36%, p=0.20).
CONCLUSIONS
Platelet counts are significantly lower in preterms who fail primary treatment for PDA. Pre-treatment thrombocytopenia is associated with higher odds of failure. Further cohort studies reporting platelet counts in prostaglandin inhibitor failure are needed for meta-analyses to firmly establish or refute a stronger association.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Platelets; Ductus Arteriosus, Patent; Humans; Ibuprofen; Indomethacin; Infant; Infant, Premature; Infant, Premature, Diseases; Odds Ratio; Platelet Count; Thrombocytopenia; Treatment Failure
PubMed: 26955892
DOI: 10.3109/14767058.2016.1163684 -
Nutrients Mar 2016Dietary advanced glycation end-products (AGEs) form during heating and processing of food products and are widely prevalent in the modern Western diet. Recent systematic... (Review)
Review
Dietary advanced glycation end-products (AGEs) form during heating and processing of food products and are widely prevalent in the modern Western diet. Recent systematic reviews indicate that consumption of dietary AGEs may promote inflammation, oxidative stress and insulin resistance. Experimental evidence indicates that dietary AGEs may also induce renal damage, however, this outcome has not been considered in previous systematic reviews. The purpose of this review was to examine the effect of consumption of a high AGE diet on biomarkers of chronic disease, including chronic kidney disease (CKD), in human randomized controlled trials (RCTs). Six databases (SCOPUS, CINHAL, EMBASE, Medline, Biological abstracts and Web of Science) were searched for randomised controlled dietary trials that compared high AGE intake to low AGE intake in adults with and without obesity, diabetes or CKD. Twelve dietary AGE interventions were identified with a total of 293 participants. A high AGE diet increased circulating tumour necrosis factor-alpha and AGEs in all populations. A high AGE diet increased 8-isoprostanes in healthy adults, and vascular cell adhesion molecule-1 (VCAM-1) in patients with diabetes. Markers of CKD were not widely assessed. The evidence presented indicates that a high AGE diet may contribute to risk factors associated with chronic disease, such as inflammation and oxidative stress, however, due to a lack of high quality randomised trials, more research is required.
Topics: Biomarkers; Diet; Dinoprost; Glycation End Products, Advanced; Humans; Inflammation; Inflammation Mediators; Oxidative Stress; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1
PubMed: 26938557
DOI: 10.3390/nu8030125 -
The Cochrane Database of Systematic... Jan 2016Oxytocin and prostaglandin are hormones responsible for uterine contraction during the third stage of labour. Receptors in the uterine muscles are stimulated by... (Review)
Review
BACKGROUND
Oxytocin and prostaglandin are hormones responsible for uterine contraction during the third stage of labour. Receptors in the uterine muscles are stimulated by exogenous or endogenous oxytocin leading to uterine contractions. Nipple stimulation or breastfeeding are stimuli that can lead to the secretion of oxytocin and consequent uterine contractions. Consequently, uterine contractions can reduce bleeding during the third stage of labour.
OBJECTIVES
To investigate the effects of breastfeeding or nipple stimulation on postpartum haemorrhage (PPH) during the third stage of labour.
SEARCH METHODS
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 July 2015) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials comparing breast stimulation, breastfeeding or suckling for PPH in the third stage of labour were selected for this review.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion in terms of risk of bias and independently extracted data. Disagreements were resolved by a third review author.
MAIN RESULTS
We included four trials (4608 women), but only two studies contributed data to the review's analyses (n = 4472). The studies contributing data were assessed as of high risk of bias overall. One of these studies was cluster-randomised and conducted in a low-income country and the other study was carried out in a high-income country. All four included studies assessed blood loss in the third stage of labour. Birth attendants estimated blood loss in two trials. The third trial assessed the hematocrit level on the second day postpartum to determine the effect of the bleeding. The fourth study measured PPH ≥ 500 mL. Nipple stimulation versus no treatmentOne study (4385 women) compared the effect of suckling versus no treatment. Blood loss was not measured in 114 women (59 in control group and 55 in suckling group). After excluding twin pregnancies, stillbirths and neonatal deaths, the main analyses for this trial were performed on 4227 vaginal deliveries. In terms of maternal death or severe morbidity, one maternal death occurred in the suckling group due to retained placenta (risk ratio (RR) 3.03, 95% confidence interval (CI) 0.12 to 74.26; one study, participants = 4227; very low quality evidence); severe morbidity was not mentioned. Severe PPH (≥ 1000 mL) was not reported in this study.The incidence of PPH (≥ 500 mL) was similar in the suckling and no treatment groups (RR 0.95, 95% CI 0.77 to 1.16; one study, participants = 4227; moderate quality). There were no group differences between nipple stimulation and no treatment regarding blood loss in the third stage of labour (mean difference (MD) 2.00, 95% CI -7.39 to 11.39; one study, participants = 4227; low quality). The rates of retained placenta were similar (RR 1.01, 95% CI 0.14 to 7.16; one study, participants = 4227; very low quality evidence), as were perinatal deaths (RR 1.06, 95% CI 0.57 to 1.98; one study, participants = 4271; low quality), and maternal readmission to hospital (RR 1.01, 95% CI 0.14 to 7.16; one study, participants = 4227; very low quality). We downgraded the evidence for this comparison for risk of bias concerns in the one included trial (inappropriate analyses for cluster design) and for imprecision (wide CIs crossing the line of no difference and, for some outcomes, few events).Many maternal secondary outcomes (including side effects) were not reported. Similarly, most neonatal secondary outcomes were not reported. Nipple stimulation versus oxytocinAnother study compared the effect of nipple stimulation (via a breast pump) with oxytocin. Eighty-seven women were recruited but only 85 women were analysed. Severe PPH ≥ 1000 mL and maternal death or severe morbidity were not reported.There was no clear effect of nipple stimulation on blood loss (MD 15.00, 95% CI -24.50 to 54.50; one study, participants = 85; low quality evidence), or on postnatal anaemia compared to the oxytocin group (MD -0.40, 95% CI -2.22 to 1.42; one study, participants = 85; low quality evidence). We downgraded evidence for this comparison due to risk of bias concerns in the one included trial (alternate allocation) and for imprecision (wide CIs crossing the line of no difference and small sample size).Many maternal secondary outcomes (including side effects) were not reported, and none of this review's neonatal secondary outcomes were reported.
AUTHORS' CONCLUSIONS
None of the included studies reported one of this review's primary outcomes: severe PPH ≥ 1000 mL. Only one study reported on maternal death or severe morbidity. There were limited secondary outcome data for maternal outcomes and very few secondary outcome data for neonatal outcomes.There was no clear differences between nipple stimulation (suckling) versus no treatment in relation to maternal death, the incidence of PPH (≥ 500 mL), blood loss in the third stage of labour, retained placenta, perinatal deaths or maternal readmission to hospital. Whilst these data are based on a single study with a reasonable sample size, the quality of these data are mostly low or very low.There is insufficient evidence to evaluate the effect of nipple stimulation for reducing postpartum haemorrhage during the third stage of labour and more evidence from high-quality studies is needed. Further high-quality studies should recruit adequate sample sizes, assess the impact of nipple stimulation compared to uterotonic agents such as syntometrine and oxytocin, and report on important outcomes such as those listed in this review.
Topics: Adult; Breast Feeding; Female; Hematocrit; Humans; Incidence; Labor Stage, Third; Nipples; Oxytocin; Physical Stimulation; Placenta, Retained; Postpartum Hemorrhage; Pregnancy; Randomized Controlled Trials as Topic
PubMed: 26816300
DOI: 10.1002/14651858.CD010845.pub2 -
PloS One 2016Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to assess the effect of marine-derived n-3 PUFA on prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and leukotriene B4 (LTB4) through systematic review and meta-analysis of randomized controlled trials.
METHOD AND FINDINGS
A structured search strategy on PubMed, Web of Science and Cochrane up to November 2015 was undertaken in this meta-analysis. Standard mean difference was used to calculate the effect size of marine-derived n-3 PUFA on PGE2, TXB2 and LTB4 in a random-effect model. A total of 18 RCTs with 826 subjects were included in this systematic review and meta-analysis. Supplementation of marine-derived n-3 PUFA significantly decreased concentrations of TXB2 in serum/plasma in subjects with high risk of cardiovascular diseases (SMD:-1.26; 95% CI: -1.65, -0.86) and LTB4 in neutrophils in unhealthy subjects (subjects with non-autoimmune chronic diseases or auto-immune diseases) (SMD:-0.59: 95% CI: -1.02, -0.16). Subgroup analyses showed a significant reduction of LTB4 in subjects with rheumatoid arthritis (SMD: -0.83; 95% CI: -1.37, -0.29), but not in non-autoimmune chronic disease patients (SMD: -0.33; 95% CI: -0.97, 0.31). No significant publication bias was shown in the meta-analysis.
CONCLUSIONS
Marine-derived n-3 PUFA had a beneficial effect on reducing the concentration of TXB2 in blood of subjects with high risk of CVD as well as LTB4 in neutrophils in unhealthy subjects, and that subjects with RA showed lower LTB4 content with supplementation of marine-derived n-3 PUFA.
Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Chronic Disease; Dietary Supplements; Dinoprostone; Dose-Response Relationship, Drug; Eicosanoids; Fatty Acids, Omega-3; Fish Oils; Humans; Leukotriene B4; Randomized Controlled Trials as Topic; Research Design; Thromboxane B2; Treatment Outcome
PubMed: 26808318
DOI: 10.1371/journal.pone.0147351 -
Inflammation Research : Official... Mar 2016A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells. (Review)
Review
OBJECTIVE AND DESIGN
A systematic review of all literature was done to assess the ability of the progestin dienogest (DNG) to influence the inflammatory response of endometriotic cells.
MAIN OUTCOME MEASURES
In vitro and in vivo studies report an influence of DNG on the inflammatory response in eutopic or ectopic endometrial tissue (animal or human).
RESULTS
After strict inclusion criteria were satisfied, 15 studies were identified that reported a DNG influence on the inflammatory response in endometrial tissue. These studies identified a modulation of prostaglandin (PG) production and metabolism (PGE2, PGE2 synthase, cyclo-oxygenase-2 and microsomal PGE synthase-1), pro-inflammatory cytokine and chemokine production [interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1 and stromal cell-derived factor-1], growth factor biosynthesis (vascular endothelial growth factor and nerve growth factor) and signaling kinases, responsible for the control of inflammation. Evidence supports a progesterone receptor-mediated inhibition of the inflammatory response in PR-expressing epithelial cells. It also indicated that DNG inhibited the inflammatory response in stromal cells, however, whether this was via a PR-mediated mechanism is not clear.
CONCLUSIONS
DNG has a significant effect on the inflammatory microenvironment of endometriotic lesions that may contribute to its clinical efficacy. A better understanding of the specific anti-inflammatory activity of DNG and whether this contributes to its clinical efficacy can help develop treatments that focus on the inhibition of inflammation while minimizing hormonal modulation.
Topics: Animals; Cytokines; Endometriosis; Epithelial Cells; Female; Hormone Antagonists; Humans; Immunologic Factors; Intercellular Signaling Peptides and Proteins; Nandrolone; Prostaglandins; Stromal Cells
PubMed: 26650031
DOI: 10.1007/s00011-015-0909-7