Large Interindividual Variability In Response Research Articles

Response to visual and mechano-acoustic predator cues is robust to ocean warming and acidification and is highly variable in European sea bass

Predator-prey interactions and, especially, the success of anti-predator responses are modulated by the sensory channels of vision, olfaction, audition and mechanosensation. If climate change alters fish sensory ability to avoid predation, community dynamics can be affected. We investigated whether mid-duration exposure to warming and/or acidification alters behavioural response to visual or mechano-acoustic predator cues in juvenile Dicentrarchus labrax. We measured kinematic variables before and after a visual or a mechano-acoustic challenge which mimicked an overflying bird shadow or a bird swoop attack, respectively. Due to large interindividual variability in responses before cue presentation, fish were categorized as slow and fast to account for baseline individual variability. Treatment did not impact kinematic variables as both slow and fast fish of every treatment elicited precautionary and escape responses. Interestingly, even slow fish swam as fast as fast fish after the cue, suggesting that regardless of initial category, fish managed to escape facing a danger. Anti-predator response varied according to the level of threat to survival with greater responses elicited after the swoop attack. Although wild juvenile sea bass aggregate in schools, school dynamics rely on single leaders which highlights the importance of the variability in individual behaviours. We demonstrated that anti-predator response in juvenile D. labrax is robust to mid-duration exposure to independent and combined effects of warming and acidification. If robustness is confirmed over long-duration, it could provide D. labrax with an evolutionary advantage in the future ocean, where cue transmission through changing environments can further modulate cue perception and predator-prey interactions.

Effects of Endurance Exercise and Vitamin D Supplementation on Insulin Resistance and Plasma Lipidome in Middle-Aged Adults with Type 2 Diabetes.

(1) Background: We investigated the effects of a 12-week exercise intervention with or without vitamin D supplementation on insulin resistance and the plasma lipidome of participants with type 2 diabetes. We further explored whether the effects of the intervention on glycemic parameters could be associated with the baseline lipidome. (2) Methods: Sixty-one participants were randomly allocated to control (Con), exercise (EX), vitamin D (VD), and EX + VD groups. Multiple glycemic and anthropometric parameters were evaluated before and after intervention. The homeostasis model assessment of insulin resistance (HOMA-IR) was the primary outcome. The plasma lipidome was analyzed before, after, and at an additional 12-week follow-up. Machine learning was applied to establish prediction models for responsiveness of glycemic control. (3) Results: Our interventions failed to improve the HOMA-IR index while fasting glucose was reduced in the EX + VD group (change%, -11.9%; effect size, 0.65; p < 0.05). Both EX and VD interventions altered the plasma lipidome, with EX + VD intervention considerably affecting levels of lyso-phosphatidylcholines and triglycerols containing long-chain unsaturated fatty acids. Such effects could last until 12 weeks after intervention. Notably, there was high inter-individual variability in glycemic parameters including HOMA-IR in response to the interventions, which could be predicted with great accuracy using an optimal panel of baseline lipid predictors alone or in combination with clinical indices, as assessed by an area under the receiver operating characteristic curve value of over 0.9. (4) Conclusions: Although substantial alterations were observed in the plasma lipidome related to glycemic control, our intervention failed to improve HOMA-IR scores, which may have been predominately due to the large inter-individual variability in responses. Basal plasma lipid levels could potentially predict an individual's response to intervention, highlighting the necessity of personalized nutrition.

Interaction between APOE, APOA1, and LPL Gene Polymorphisms and Variability in Changes in Lipid and Blood Pressure following Orange Juice Intake: A Pilot Study.

Chronic orange juice intake is associated with reduced risk of cardiovascular disease, however, a large inter-individual variability in response to orange juice for lipid profile and blood pressure has been observed. This heterogeneity in responsiveness could be associated with single nucleotide polymorphism (SNP), which has not been previously addressed. This study aims to investigate the influence of SNP in apolipoprotein E (APOE), apolipoprotein A1 (APOA1), mevalonate (MVK), and lipase lipoprotein (LPL) genes in the biological response after chronic orange juice intake. Forty-six volunteers ingested 500 mL daily for 60 days and blood pressure and biochemical parameters are measured. Also, SNPs in APOE, APOA1, MVK, and LPL genes are genotyped in the volunteers that are medium/high excretors of flavanone metabolites. GenotypesCC (APOA1), AA, and GG (LPL) are associated with positive health effects of orange juice and the CC (APOE), GG (APOA1), GG, and AA (LPL) genotypes are associated with no effects of orange juice consumption (p < 0.05). These results identify for the first-time SNP associated with effects of orange juice on lipid levels and blood pressure, results that may provide bases for future precise nutritional recommendations regarding this flavanone-rich food to lower the risk for cardiovascular disease.

Increasing Shoe Longitudinal Bending Stiffness Is Not Beneficial to Reduce Energy Cost During Graded Running

Carbon plates have been used to increase running shoes' longitudinal bending stiffness (LBS), leading to reductions in the energy cost of level running (Cr). However, whether or not this is true during uphill (UH) running remains unknown. The aim of our study was to identify the effect of LBS on Cr during UH running. Twenty well-trained male runners participated in this study. Cr was determined using gas exchange during nine 4-minute bouts performed using 3 different LBS shoe conditions at 2.22 and 4.44m/s on level and 2.22m/s UH (gradient: + 15%) running. All variables were compared using 2-way analyses of variance (LBS × speed/grade effects). There was no significant effect of LBS (F = 2.04; P = .14, ηp2=.11) and no significant LBS × grade interaction (F = 0.31; P = .87, ηp2=.02). Results were characterized by a very large interindividual variability in response to LBS changes. The current study contributes to a growing body of literature reporting no effect of LBS on Cr during level and UH running. Yet, the very large interindividual differences in response to changes in LBS suggest that increasing shoe LBS may be beneficial for some runners.

MRNA and small RNA gene expression changes in peripheral blood to detect internal Ra-223 exposure

Purpose Excretion analysis is the established method for detection of incorporated alpha-emitting radionuclides, but it is laborious and time consuming. We sought a simplified method in which changes in gene expression might be measured in human peripheral blood to detect incorporated radionuclides. Such an approach could be used to quickly determine internal exposure in instances of a radiological dispersal device or a radiation accident. Materials and methods We evaluated whole blood samples from five patients with castration-resistant prostate cancer and multiple bone metastases (without visceral or nodal involvement), who underwent treatment with the alpha emitting isotope Radium-223 dichloride (Ra-223, Xofigo®). Patients received about 4 MBq per cycle and, depending on survival and treatment tolerance, were followed for six months. We collected 24 blood samples approximately monthly corresponding to treatment cycle. Results Firstly, we conducted whole genome screening of mRNAs (mRNA seq) and small RNAs (small RNA seq) using next generation sequencing in one patient at eight different time points during all six cycles of Ra-223-therapy. We identified 1900 mRNAs and 972 small RNAs (222 miRNAs) that were differentially up- or down-regulated during follow-up after the first treatment with Ra-223. Overall candidate RNA species inclusion criteria were a general (≥|2|-fold) change or with peaking profiles (≥|5|-fold) at specific points in time. Next we chose 72 candidate mRNAs and 101 small RNAs (comprising 29 miRNAs) for methodologic (n = 8 samples, one patient) and independent (n = 16 samples, four patients) validation by qRT-PCR. In total, 15 mRNAs (but no small RNAs) were validated by methodologic and independent testing. However, the deregulation occurred at different time points, showing a large inter-individual variability in response among patients. Conclusions This proof of concept provides support for the applicability of gene expression measurements to detect internalized alpha-emitting radionuclides, but further work is needed with a larger sample size. While our approach has merit for internal deposition monitoring, it was complicated by the severe clinical condition of the patients we studied.

Pharmacogenomics-guided supportive oncology: A tale of two trials

Cancer-related symptoms, like depression, nausea, and pain, are common and negatively affect quality of life. Unfortunately, there is large inter-individual variability in response to supportive care medications for these symptoms. Pharmacogenomics may inform prescribing by identification of those genetically at risk for drug related adverse events or therapeutic failure. While such information can be applied to many drugs, there are specific oncology populations that could greatly benefit from pharmacogenomics-guided supportive care management due to high symptom burden, including those receiving palliative medicine and hematopoietic stem cell transplantation. The goal of this paper is to provide an overview of, and lessons learned from, the development of two prospective pharmacogenomics-guided interventional trials (“Supportive Care PGx Trial” and “Transplant PGx Trial”) across two different clinical settings at the Levine Cancer Institute: the Department of Supportive Oncology and the Transplant and Cellular Therapy section. Key considerations included the appropriate study design and endpoints (balancing study goals and resources), dissemination and application of individual pharmacogenetics results, technical details about assay development, and overall care coordination to minimize clinic disruption.

Distinct Effects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism: Lessons from Experimental Models and a Potential Role for Pharmacogenetics.

Personalized medicine strives to optimize drug treatment for the individual patient by taking into account both genetic and non-genetic factors for drug response. Inflammation is one of the non-genetic factors that has been shown to greatly affect the metabolism of drugs—primarily through inhibition of cytochrome P450 (CYP450) drug-metabolizing enzymes—and hence contribute to the mismatch between the genotype predicted drug response and the actual phenotype, a phenomenon called phenoconversion. This review focuses on inflammation-induced drug metabolism alterations. In particular, we discuss the evidence assembled through human in-vitro models on the effect of inflammatory mediators on clinically relevant CYP450 isoform levels and their metabolizing capacity. We also present an overview of the current understanding of the mechanistic pathways via which inflammation in hepatocytes may modulate hepatic functions that are critical for drug metabolism. Furthermore, since large inter-individual variability in response to inflammation is observed in human in-vitro models and clinical studies, we evaluate the potential role of pharmacogenetic variability in the inflammatory signaling cascade and how this can modulate the outcome of inflammation on drug metabolism and response.

Pharmacogenomic Response of Inhaled Corticosteroids for the Treatment of Asthma: Considerations for Therapy.

There is a large interindividual variability in response to ICSs in asthma. About 70% of the variance in ICS response is likely due at least partially to genetically determined characteristics of target genes. In this article, we examine the effects on the ICS response of gene variations in the corticosteroid pathway, and in the pharmacokinetics of corticosteroids, and also those outside the corticosteroid pathway, which have the potential to influence corticosteroid activity. Although the available evidence indicates that responses to ICSs in asthma are influenced by different genetic variants, there are still deep uncertainties as to whether a real association between these genetic variants and corticosteroid response could also possibly exist because there are difficulties in reproducing pharmacogenetic findings. This explains at least partly the insufficient use of pharmacogenomic data when treating asthmatic patients, which creates a real limitation to the proper use of ICSs in an era of precision medicine that links the right patient to the right treatment. Knowing and dealing with the genetic factors that influence the therapeutic ICS response is a fundamental condition for prescribing the right dose of ICS to the right patient at the right time.

Isometric Posterior Chain Peak Force Recovery Response Following Match-Play in Elite Youth Soccer Players: Associations with Relative Posterior Chain Strength.

The purpose of this study was to determine changes in two tests of lower limb isometric posterior chain force (IPC-F) following 90 min of match-play in elite youth soccer players and the interaction between relative strength and recovery profile. 14 players (age: 16 ± 2 years) performed 3 × 3 second IPC-F tests unilaterally at 30° and 90° of knee and hip flexion pre- and post-match, +24 h, +48 h, and +72 h post-match. Peak force was recorded for both limbs, combined and expressed relative to bodyweight (N/kg). A two-way repeated measures analysis of variance was performed to determine differences in force output between joint angles, time intervals and subjects. As there was no interaction between angle and time (p = 0.260), we report the change between timepoints as mean ∆ in 90° + 30° IPC-F. Relative to pre-match IPC-F, there were significant decreases post (∆ = −18%; p > 0.001) and at +24 h (∆ = −8%; p = 0.040), no significant difference at +48 h (∆ = 0%; p = 0.992) and a significant increase at +72 h (∆ = +12%; p = 0.005). There was a large inter-individual variability in recovery profile at both angles and substantial differences between post-match deficits at 90° (−10.8%) compared to 30° (−20.7%). Higher pre-match IPC-F was correlated with the magnitude of IPC-F deficits at both angles and all time points (r = 0.56 to 0.70, p = < 0.01) except for post-match 90°. Regular IPC-F monitoring to determine the magnitude of match-induced fatigue and track recovery may help inform decision-making regarding modifications to individual players training load, particularly as there is a large inter-individual variability in response to competition. Further research is warranted to better understand and address the finding that stronger players showed larger force deficits and slower recovery following match-play.

The Effects of Blood Flow Restricted Electrostimulation on Strength and Hypertrophy.

The combined effect of neuromuscular electrical stimulation (NMES) and blood flow restriction (BFR) on muscle mass and strength has not been thoroughly investigated. To examine the effects of combined and independent BFR and a low-intensity NMES on skeletal muscle adaptation. Exploratory study. Laboratory. Twenty recreationally active subjects. Subjects had each leg randomly allocated to 1 of 4 possible intervention groups: (1)cyclic BFR alone, (2)NMES alone, (3)BFR + NMES, or (4)control. Each leg was stimulated in its respective intervention group for 32minutes, 4days per week for 6weeks. Mean differences in size (in grams) and isometric strength (inkilograms), between week 0 and week 6, were calculated for each group. Leg strength increased 32 (19)kg in the BFR + NMES group, which differed from the 3 (11)kg change in the control group (P = .03). The isolated NMES and BFR groups revealed increases of 16 (28)kg and 18 (17)kg, respectively, but these did not statistically differ from the control, or one another. No alterations were statistically significant for leg size. Compared with a control that received no treatment, the novel combination of BFR and NMES led to increasing muscular strength of the knee extensors, but not muscle mass which had a large interindividual variability in response.

The effect of UGT1A9, CYP2B6 and CYP2C9 genes polymorphism on individual differences in propofol pharmacokinetics among Polish patients undergoing general anaesthesia

Propofol (2,6-diisopropylphenol) is one of the safest and most commonly used anaesthetic agents for intravenous general anaesthesia. However, in clinical practice, a large inter-individual variability in response to propofol is observed. To limit the risk of adverse effects, pharmacogenetic investigations are recommended. The aim of our study was to verify the impact of genetic changes c.516G>T in the CYP2B6, c.98T>C in the UGT1A9 and c.1075A>C in the CYP2C9 genes on the individual propofol pharmacokinetic profile in the Polish patients undergoing general anaesthesia. Eighty-five patients from the Department of Anaesthesiology and Intensive Therapy, Regional Hospital in Poznan, Poland, anaesthetised with propofol for surgery, were enrolled in the study. We have genotyped CYP2B6, UGT1A9 and CYP2C9 polymorphisms with the use of pyrosequencing. HPLC measurements of propofol plasma concentration were applied for a pharmacokinetic analysis of the anaesthetic. We identified poor (20), intermediate (42) and rapid (23) metabolisers of propofol, which constituted 24%, 49% and 27% of the group, respectively. Homozygotes c.516 T/T in the CYP2B6 gene were statistically more often found in the rapid metabolisers group (p < 0.05). However, polymorphisms c.98T>C in the UGT1A9 and c.1075A>C in the CYP2C9 genes did not affect the pharmacokinetic profile of propofol. The mean propofol retention time (MRT) correlated with the patient’s body mass index (BMI) (p < 0.05). From all the analysed changes, only polymorphism c.516G>T in the CYP2B6 gene and BMI affect the metabolism rate of propofol and may play an important role in the optimisation of propofol anaesthesia.

Changes in aerobic capacity and glycaemic control in response to reduced-exertion high-intensity interval training (REHIT) are not different between sedentary men and women.

Previously it has been reported that reduced-exertion high-intensity interval training (REHIT; total training time of 3 × 10 min per week) improves maximal aerobic capacity in both sedentary men and women, but improves insulin sensitivity in men only. The aim of the present study was to determine whether there is a true sex difference in response to REHIT, or that these findings can be explained by the large interindividual variability in response inherent to all exercise training. Thirty-five sedentary participants (18 women; mean ± SD age for men and women, respectively: age, 33 ± 9 and 36 ± 9 years; body mass index, 25.1 ± 2.1 and 24.1 ± 3.5 kg·m-2; maximal aerobic capacity, 38.6 ± 8.3 and 31.6 ± 4.6 mL·kg-1·min-1) completed a 6-week REHIT programme consisting of eighteen 10-min unloaded cycling sessions with 1 (first session) or 2 (all other sessions) "all-out" 10-20-s sprints against a resistance of 5% of body mass. Maximal aerobic capacity and oral glucose tolerance test-derived insulin sensitivity were determined before and after training. REHIT was associated with an increase in maximal aerobic capacity (2.54 ± 0.65 vs. 2.78 ± 0.68 L·min-1, main effect of time: p < 0.01), a trend toward reduced plasma insulin area-under-the-curve (AUC; 6.7 ± 4.8 vs. 6.1 ± 4.0 IU·min-1·mL-1, p = 0.096), but no significant change in plasma glucose AUC or the Cederholm index of insulin sensitivity. Substantial interindividual variability in response to REHIT was observed for all variables, but there was no significant effect of sex. In conclusion, REHIT improves the key health marker of aerobic capacity within a minimal total training time-commitment. There is large interindividual variability in responses to REHIT, but sex differences in the responses are not apparent.

Utility of patient-derived lymphoblastoid cell lines as an ex vivo capecitabine sensitivity prediction model for breast cancer patients.

Capecitabine is commonly used in treating breast cancer; however, therapeutic response varies among patients and there is no clinically validated model to predict individual outcomes. Here, we investigated whether drug sensitivity quantified in ex vivo patients' blood-derived cell lines can predict response to capecitabine in vivo. Lymphoblastoid cell lines (LCLs) were established from a cohort of metastatic breast cancer patients (n = 53) who were prospectively monitored during treatment with single agent capecitabine at 2000 mg/m2/day. LCLs were treated with increasing concentrations of 5′-DFUR, a major capecitabine metabolite, to assess patients' ex vivo sensitivity to this drug. Subsequently, ex vivo phenotype was compared to observed patient disease response and drug induced-toxicities. We acquired an independent cohort of breast cancer cell lines and LCLs derived from the same donors from ATCC, compared their sensitivity to 5′-DFUR. As seen in the patient population, we observed large inter-individual variability in response to 5′-DFUR treatment in patient-derived LCLs. Patients whose LCLs were more sensitive to 5′-DFUR had a significantly longer median progression free survival (9-month vs 6-month, log rank p-value = 0.017). In addition, this significant positive correlation for 5′-DFUR sensitivity was replicated in an independent cohort of 8 breast cancer cell lines and LCLs derived from the same donor. Our data suggests that at least a portion of the individual sensitivity to capecitabine is shared between germline tissue and tumor tissue. It also supports the utility of patient-derived LCLs as a predictive model for capecitabine treatment efficacy in breast cancer patients.

Nonsteroidal Anti-Inflammatory Drugs and the Heart

Aspirin has been on the market for 115 years. Beginning with the marketing of indomethacin for the treatment of rheumatoid arthritis in 1963, at least 20 other nonsteroidal anti-inflammatory drugs (NSAIDs) with aspirin-like actions have been developed over the past 50 years,1 culminating with the introduction of a new class of selective inhibitors of cyclooxygenase (COX)-2, the coxibs, approximately 15 years ago.2 The NSAIDs represent the single most crowded family of drugs sharing the same therapeutic activities and mechanism of action, perhaps reflecting the unmet therapeutic need in the area of pain management and the large interindividual variability in response to these agents. NSAIDs provide symptomatic relief of pain and inflammation associated with a variety of human disorders, including the rheumatic diseases. Their shared therapeutic actions (ie, analgesic, anti-inflammatory, and antipyretic) are usually accompanied by mechanism-based adverse effects that can, at least in part, be attenuated as a function of individual pharmacokinetic or pharmacodynamic properties.1 Nuances in the tolerability of different NSAIDs had been described in the precoxib era on the basis of clinical trials of a few hundred patients treated for up to a few months with soft end points. More recently, however, important differences in safety have been demonstrated in head-to-head randomized comparisons of individual coxibs and 1 or more traditional NSAIDs that involved tens of thousands of patients treated for up to a few years with hard end points. Even more significantly, the interpretation of the effects of NSAIDs has been greatly enhanced by the availability, for the first time, of large, placebo-controlled trials that aimed to assess the potential for chemoprevention of colorectal cancer by rofecoxib or celecoxib. As a result of these developments, the whole field of NSAIDs has been illuminated during the past 15 years. Although epidemiological studies had previously associated …

Platelet Rna As a Novel Biomarker for the Response to Antiplatelet Therapy

9 ISSN 1479-6678 10.2217/FCA.13.90 © 2014 Future Medicine Ltd Future Cardiol. (2014) 10(1), 9–12 Antiplatelet agents, such as aspirin, or P2Y 12 inhibitors, such as clopidogrel, prasugrel or ticagrelor, are widely prescribed to prevent ischemic events [1]. The combination of aspirin and a P2Y 12 inhibitor is endorsed by international guidelines in patients at high risk of ischemic events, while aspirin monotherapy is the backbone of preventative therapy for patients with established vascular disease [2–6]. Despite convincing evidence of its effectiveness, the efficacy of aspirin in certain individuals may vary and recurrence rates are high [2]. For example, in patients with established cardio vascular disease or multiple risk factors who use aspirin, 15–20% will suffer a future cardiovascular event (myocardial infarction [MI] or stroke), hospitalization for revascularization or death over 28 months [7]. Similarly, patients with Type 2 diabetes, a powerful magnifier of cardiovascular risk, are at equivalent risk of a first MI as nondiabetics with a prior MI (each 19–20% over 7 years) [8]. Consequently, aspirin is recommended in patients with Type 2 diabetes, especially if other cardiovascular risk factors are present [2,9]. However, two randomized trials of low-dose aspirin as primary prevention in more than 3000 diabetics each failed to significantly reduce MI or stroke [10,11], thereby suggesting that the benefits of aspirin are not uniform and may fail in certain high-risk individuals. Further more, antiplatelet agents are accompanied by an increase in bleeding events [2,12], which may offset any potential benefits, particularly in low-risk populations. Therefore, certain individuals may fail to benefit from aspirin, and others may be exposed to an increased risk of bleeding. The vast majority of clinicians and researchers lack reliable methods of identifying individuals with inadequate or unanticipated responses to antiplatelet drugs, and thus the tools for tailoring antiplatelet therapy. This need is greatest in the primary care setting where aspirin is widely used, but no method to assess drug response is accessible. Platelet function tests are available in certain settings and capture the large interindividual variability in response to aspirin, despite complete suppression of aspirin’s putative target, platelet COX-1 [13–16].

Role of VASP Phosphorylation Assay in Monitoring the Antiplatelet Therapy

Abstract Dual antiplatelet treatment with clopidogrel and aspirin represents standard regimen in prevention of thromboembolic events in patients with ischemic heart disease undergoing percutaneous coronary intervention (PCI). One of the greatest pitfalls of clopidogrel treatment is large inter-individual variability in response. Large amount of patients does not respond adequately and therefore are not „protected“ even in spite of receiving the therapy. Poor responders are exposed to three-fold increased risk of myocardial infarction, stent thrombosis and cardiac death. Clopidogrel is an antiplatelet prodrug, whose active metabolite inhibits platelet function by irreversible binding to the (adenosine diphosphate) platelet receptor P2Y12. Receptor P2Y12 plays primal role in ADP-mediated platelet activation, and also in mechanism of action of ADP inhibitors such as clopidogrel, prasugrel etc. Reasons stated above, raised the necessity for implementing reliable laboratory test in order to identify the unprotected patients. In an ideal scenario, such test would serve to adjust the dose and guide the individual tailored treatment. Vasodilator Stimulated Phosphoprotein (VASP) is an intracellular platelet protein which is non phosphorylated at basal state. Since its relation in cascade with P2Y12 receptor, VASP phosphorylation corerlates with inhibition of P2Y12 which is the receptor of prime importance in ADP mediated activation of platelets and as is primary target of ADP inhibitors action. Outcome of the assay is represented as the value of platelet reactivity index (PRI), where PRI values above 50% are considered inadequate response to treatment and signal exposure to increased risk of myocardial infarction, post-PCI stent thrombosis and cardiac death. VASP-P flow cytometric assay is emerging into the spotlight as the promising method, mostly for its specificity for ADP inhibitors, better outlook for standardising results and lesser sample manipulation compared to multiple electrode aggregometry.

Possible genetic implications in the response to cardiac resynchronisation therapy in a patient affected by heart failure

This report presents a case of a patient with idiopathic dilated cardiomyopathy and severe left ventricular systolic dysfunction who underwent cardiac resynchronisation therapy (CRT). During the follow-up a progressive increase in left ventricular ejection fraction was observed, as well as clinical improvement. No cardiovascular events occurred during the follow-up, except for appropriate Implantable Cardioverter Defibrillator (ICD) bursts for fast ventricular tachycardia. Genotyping for adrenoceptor gene polymorphisms detected that the patient was Glu27Glu homozygous carrier. There’s a large interindividual variability in response to CRT. Despite attempts to identify factors having an impact on this therapy, only QRS duration is accepted according to guidelines. Beta-adrenoceptors polymorphisms, modulating sympathetic drive in heart failure and left ventricular remodelling, may have a role in identifying patients with a better response to CRT, in order to target and individualise the patients’ treatment.

Biomarkers of therapy responsiveness in asthma: pitfalls and promises

Asthma is one of the most common chronic diseases worldwide. There is a large inter-individual variability in response to asthma treatment. Most patients respond well to standard therapy; however, a small proportion of the patients remain symptomatic despite treatment with high dosages of corticosteroids. Uncontrolled asthma leads to a decreased quality of life. Therefore, it is important to identify individuals who will respond poorly to standard asthma medication, especially to standard maintenance therapy with inhaled corticosteroids, at an early stage. Response to anti-inflammatory therapy is generally monitored by the assessment of clinical symptoms, which only partially correlates with underlying airway inflammation. The identification of specific inflammatory biomarkers might help to guide treatment or predict a corticosteroid response more accurately. Some inflammatory biomarkers are already finding their way into clinical practice (e.g. fraction of nitric oxide in exhaled breath), whereas others are predominantly used as a research tool (e.g. profiles of volatile organic compounds). Currently, there is no inflammatory biomarker used in routine clinical practice to predict a corticosteroid response. More knowledge on the underlying biological mechanism(s) of heterogeneous therapeutic responses could help to identify novel biomarkers. This review will focus on inflammatory patterns and genetic variations that may underlie differences in treatment response in patients with asthma, and will provide an overview of inflammatory biomarkers that could potentially serve as response predictors.

Immediate and long-term outcomes of corticosteroid therapy in pediatric crohnʼs disease patients

Although a mainstay of treatment of moderate to severe Crohn's disease (CD), corticosteroids use presents significant challenges because of large interindividual variability in response. Corticosteroid-dependence is of particular concern in children, where high rates have been reported. We examined the burden of corticosteroid-resistance and dependence in a well-characterized cohort of pediatric CD patients and investigated potential predictors of response. Children diagnosed with CD (<18 years), were recruited from two Canadian pediatric gastroenterology clinics. Immediate and long-term responses to corticosteroid therapy were retrospectively ascertained. Response rates (resistance and dependence) were estimated and potential predictors assessed using logistic regression analysis. Of the 645 CD patients, 364 (56.2%) received corticosteroids. The frequency of corticosteroid-resistance was (8.0%) (95% confidence interval [CI]: 5.0%-11%) and 40.9% (95% CI: 39.0%-46.0%) became dependent. In univariate analysis female gender (odds ratio [OR] = 2.49, 95% CI: 1.1-5.5, P = 0.025), disease severity (OR = 2.43, 95% CI: 1.10-5.38, P = 0.029), and complicated disease (OR = 2.75, 95% CI: 1.18-6.41, P = 0.019) were associated with resistance. In multivariate analysis lower age at diagnosis (OR = 1.34,95% CI: 1.03-3.01, P = 0.040), coexisting upper digestive tract involvement (OR = 1.35, 95% CI: 1.06-3.07, P = 0.031), and concomitant immunomodulator use (OR = 0.35, 95% CI: 0.16-0.75, P = 0.007) were significantly associated with steroid dependency. Our results demonstrate that steroid dependency is a frequent complication in children with CD. Children with an earlier age at diagnosis and coexisting upper digestive tract involvement could be potentially targeted for steroid-sparing therapy.

Impact of Genetic Polymorphisms and Drug – Drug Interactions on Clopidogrel and Prasugrel Response Variability

Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxo-clopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug-drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug-drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug-drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug-drug interaction affecting clopidogrel and prasugrel antiplatelet activity.