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This manuscript reviews sperm morphology and its disorders in the context of infertility. A new look into an old challenge is delivered, based on contemporary scientific and clinical evidence. We highlight the functional repercussions of sperm morphology aberrations and dissect the cause and effect of a variety of insults and pathogenic mechanisms focusing on the relationships among sperm shape, function, and compartmental analysis of cellular and subcellular structures. Different types of teratozoospermia are identified as a sequela of aberrant spermiogenesis, and their proven or speculated origins are discussed. In addition to known and suspected genetic causes, oxidative damage is highlighted as a major plausible pathogenic factor. The examination of sperm morphology with the use of strict criteria provides valuable information to guide the clinician to direct therapeutic management. We emphasize that sperm morphology is probably the most relevant parameter of the traditional semen evaluation and can be used as a valid biomarker of functional deficiencies, providing information about chances of conception. The information provided by the examination of sperm morphology as part of a complete semen analysis becomes more and more significant from a clinical point of view for infertility and perhaps men’s health.

MicroRNAs (miRNA) are recently discovered endogenous, small noncoding RNAs (of 22 nucleotides) that play pivotal roles in gene regulation. They are involved in post-transcriptional control of gene expression. miRNAs are emerging as important regulators of cell proliferation, development, cancer formation, stress responses, cell death and physiological conditions. Increasing evidence has demonstrated the human miRNAs bind to their target mRNA sequences with perfect or near-perfect sequence complementarily. This provides a powerful strategy for discovering potential type 2 diabetes mellitus (T2DM) targets and gives the probability to exploit them for diagnostic and therapeutic causes. About 6% of the world population is affected by T2DM, and it is recognized as a global epidemic by the World Health Organization. At present there is no valid biomarker to control or manage T2DM. Therefore, the present study applied a mature sequence of miRNAs from publicly accessible databases to identify the miRNA from T2DM expressed sequence tags, and the results are detailed and discussed below.

Background: Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing. Objective: The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS. Methods: In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures. Results: Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760–0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale ( r = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r = −0.553, respectively), ps Conclusion: Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS.

There is a growing interest in using endogenous compounds as drug transporter biomarkers to facilitate drug-drug interaction (DDI) risk assessment in early phase I clinical trials. Compared to other drug transporters, however, no valid biomarker for hepatic organic cation transporter (OCT) 1 has been described to date. The present work represents the first report of an endogenous compound, isobutyryl-l-carnitine (IBC), as a potential clinical OCT1 biomarker for DDI assessment. A hydrophilic interaction chromatography (HILIC)-mass spectrometry/high resolution mass spectrometry (MS/HRMS) assay with a simple sample preparation method was developed. The assay is capable of simultaneously quantifying multiple endogenous compounds, including IBC, thiamine, N1-methylnicotinamide (1-NMN), creatinine, carnitine, and metformin, which is a probe for OCT1 and OCT2 and MATE1 and MATE2K (multidrug and toxin extrusion proteins) in clinical studies. The HRMS assay was fit-for-purpose validated in human plasma and demonstrated good linearity, accuracy, and precision for all analytes. It was further applied to two phase I clinical trials to evaluate potential biomarkers for OCT1 and additional cation transporters (renal OCT2, MATE1, and MATE2K). The clinical data demonstrated that plasma IBC changes correlated well with in vitro data and supported its use as a liver OCT1 biomarker. The described HILIC-MS/HRMS assay can be used as a "biomarker cocktail" to simultaneously assess clinical DDI risk for the inhibition of OCT1/2 and MATEs in clinical studies with new drug candidates.

Epileptic seizure forecasting, combined with the delivery of preventative therapies, holds the potential to greatly improve the quality of life for epilepsy patients and their caregivers. Forecasting seizures could prevent some potentially catastrophic consequences such as injury and death in addition to several potential clinical benefits it may provide for patient care in hospitals. The challenge of seizure forecasting lies within the seemingly unpredictable transitions of brain dynamics into the ictal state. The main body of computational research on determining seizure risk has been focused solely on prediction algorithms, which involves a challenging issue of balancing sensitivity and false alarms. There have been some studies on identifying potential biomarkers for seizure forecasting; however, the questions of “What are the true biomarkers for seizure prediction” or even “Is there a valid biomarker for seizure prediction?” are yet to be fully answered. In this paper, we introduce a tool to facilitate the exploration of the potential biomarkers. We confirm using our tool that interictal slowing activities are a promising biomarker for epileptic seizure susceptibility prediction.

Routine quantitative electromyography is used for the assessment of the presence of lower motor neurone involvement and its consequences, including primary denervation and compensatory reinnervation of muscle fibres. However, it is not useful for the assessment of the motor unit number reserve. The need for a valid biomarker to evaluate lower motor neurone disease progression in such diseases as amyotrophic lateral sclerosis, and for use in clinical trials, has led to a number of studies of the methods that allow assessment of the number of motor units. In this review, motor unit number estimation (MUNE) methods with incremental stimulation and the recently developed motor unit number index (MUNIX) method, along with their technical and clinical aspects, are presented as methods which reflect motor unit loss in neurogenic processes. These electrodiagnostic tests may allow a valuable assessment of disease progression and the efficacy of new therapeutic methods in clinical trials in diseases with lower motor neurone degeneration.

Conditioned pain modulation (CPM) is a promising psychophysical biomarker of central pain mechanisms because it significantly discriminates patients with chronic pain from healthy controls. Nevertheless, it is unclear in what extent CPM assessed experimentally is correlated with clinical manifestations of pain. To assess the concurrent validity of CPM, we performed a systematic review of the literature reporting correlations between CPM responses and pain intensity, disability, duration, and area in patients with different chronic pain conditions. We included 32 studies that altogether encompassed data from 1958 patients and provided 62 correlations. The majority of the results (69%) reported nonsignificant correlations between CPM efficiency and clinical manifestations of pain, whereas the remaining results showed a correlation between CPM reduction and worse clinical symptoms of pain. The modality of stimulation, the type of pain, and the stimulation site appear to be critical variables that influenced the pattern of results. Given that most of the studies were conducted with highly heterogeneous methodologies and unclear risk of bias, the findings highlight the need for future studies using standardized measures of clinical and experimental pain before considering CPM as a valid biomarker of pain. We discuss some guidelines to overcome the constraints in this promising line of research.

The diagnostic process for autism spectrum disorders (ASD) is based on a behavioral analysis of the suspected individual. Despite intensive research, no specific and valid biomarker has been identified for ASD, but saliva, with its advantages such as non-invasive collection, could serve as a suitable alternative to other body fluids. As a source of nucleic acid of both human and microbial origin, protein and non-protein molecules, saliva offers a complex view on the current state of the organism. Additionally, the use of salivary markers seems to be less complicated not only for ASD screening but also for revealing the etiopathogenesis of ASD, since enrolling neurotypical counterparts willing to participate in studies may be more feasible. The aim of the presented review is to provide an overview of the current research performed on saliva in relation to ASD, mutual complementing, and discrepancies that result in difficulties applying the observed markers in clinical practice. We emphasize the methodological limitations of saliva collection and processing as well as the lack of information regarding ASD diagnosis, which is critically discussed.

The tumor microenvironment (TME) is composed mainly of tumor cells, tumorinfiltrating immune cells, and matrix components. Recent clinical studies have indicated that tumor immune cell infiltration (ICI) is related to the sensitivity of immunotherapy and the prognosis of patients with bladder cancer (BC). Nevertheless, up to now, the landscape of immune infiltration in BC has not been clearly defined. Here we present two algorithms to reveal the landscape of ICI in 277 cases of BC. Two kinds of ICI patterns were established, and ICI scores were based on the analysis of the main components. In sub-types with high ICI scores, we found highly expressed immunecheckpoint and activated transforming growth factor b and WNT signal pathways. These might be the cause of poor prognosis. A low ICI score indicated a better prognosis. Our study showed that ICI scores in immunotherapy could be a valid biomarker for the prognosis of patients and a predictive indicator. The evaluation of ICI patterns of a larger cohort of samples would expand our cognition of TME, and the present study might guide the strategies of immunotherapy for patients with BC.

[EN] The assessment of autism spectrum disorder (ASD) is based on semi-structured procedures addressed to children and caregivers. Such methods rely on the evaluation of behavioural symptoms rather than on the objective evaluation of psychophysiological underpinnings. Advances in research provided evidence of modern procedures for the early assessment of ASD, involving both machine learning (ML) techniques and biomarkers, as eye movements (EM) towards social stimuli. This systematic review provides a comprehensive discussion of 11 papers regarding the early assessment of ASD based on ML techniques and children¿s social visual attention (SVA). Evidences suggest ML as a relevant technique for the early assessment of ASD, which might represent a valid biomarker-based procedure to objectively make diagnosis. Limitations and future directions are discussed., The authors have no relevant financial or non-financial interests to disclose. This work was supported by the Spanish Ministry of Economy, Industry, and Competitiveness funded project "Immersive Virtual Environment for the Evaluation and Training of Children with Autism Spectrum Disorder: T Room" (IDI-20170912). This work was also supported by the Spanish Ministry of Science and Innovation funded project "T-EYE: Monitoring system for children with ASD based on artificial intelligence and physiological measures" (IDI-20201146)

In recent years, there has been attention focused on the value of salivary IgA (sIgA) as a potential biomarker for the identification of athletes who may be at increased risk of developing respiratory tract infection (RTI). The utility of sIgA, in this context, is based on biological plausibility and several observational studies revealing an apparent association between sIgA and RTI susceptibility. The overall published evidence evaluating the value of sIgA in this context is however conflicting, and there is currently a lack of clear guidance as to whether this marker has a place in the health surveillance and care of athletes. In this review, we critically appraise the literature assessing the potential for sIgA to be used in this context, evaluating it against 4 key biomarker characteristics, including its (1) practicality, (2) reproducibility, (3) specificity/sensitivity, and (4) potential clinical impact and relevance. This process reveals that although there is an apparent association between respiratory illness and sIgA in many studies, with some promising results, overall there remains a paucity of evidence supporting its overall value in this context. Key deficiencies in the metrics employed to endorse a valid biomarker are apparent, including a lack of reproducibility and low specificity and sensitivity in the detection of RTI susceptibility. The review outlines these issues and makes future recommendations.

The need for a valid biomarker for assessing disease progression and for use in clinical trials on amyotrophic lateral sclerosis (ALS) has stimulated the study of methods that could measure the number of motor units. Motor unit number index (MUNIX) is a newly developed neurophysiological technique that was demonstrated to have a good correlation with the number of motor units in a given muscle, even though it does not necessarily accurately express the actual number of viable motor neurons. Several studies demonstrated the technique is reproducible and capable of following motor neuron loss in patients with ALS and peripheral polyneuropathies. The main goal of this review was to conduct an extensive review of the literature using MUNIX. We conducted a systematic search in English medical literature published in two databases (PubMed and SCOPUS). In this review, we aimed to answer the following queries: Comparison of MUNIX with other MUNE techniques; the reproducibility of MUNIX; the utility of MUNIX in ALS and preclinical muscles, peripheral neuropathies, and other neurological disorders.

Huntington disease (HD) is an inherited neurodegenerative disorder most commonly manifesting in adulthood. Identification of biomarkers tracking neurodegeneration before the onset of motor symptoms is important for future interventional studies. Our study aimed to contribute in the phenotypic characterization of the premanifest HD phase.28 premanifest subjects (preHD), 25 age-matched controls, and 12 manifest HD patients were enrolled for the study. The participants underwent a multimodal protocol including cognitive evaluations, arithmetic ability test, posturography, composite cerebellar functional test (CCFS), and brain 3T-MRI. PreHD were divided at the group median for predicted years to expected onset into "far-from-onset" (15 years, PreHD-far), and "close-to-onset" (≤15 years, preHD-close). Basal ganglia volumes and cortical thickness were computed using FreeSurfer.PreHD-close showed significantly lower scores than controls in Symbol Digit Modalities Test (p = 0.017), Arithmetic subtraction task (p = 0.04), and MMSE (p 0.006). At posturography, preHD-close showed increased sway velocity (0.04) and distance (p 0.02) compared to controls. PreHD-close had reduced striatum and globus pallidus volumes and left occipital cortical thinning compared to controls. Compared to PreHD far-from-onset, PreHD-close showed bilateral cortical thinning in occipital and parahippocampal regions, inversely correlating with burden score and prognostic index for HD. CCFS only differed between controls and manifest HD. PreHD far-from-onset did not show significant differences in comparison with controls.We confirmed that quantitative brain MRI represents a valid biomarker of neurodegeneration in preHD. Posturography and Arithmentic tests seem promising tools for detecting early changes in premanifest HD, but need to be further confirmed in large cohorts.

Background: There is a great interest in developing biomarkers to enhance early detection and clinical management of tongue squamous cell carcinoma (TSCC). However, the developmental path towards a clinically valid biomarker remains extremely challenging. Ideally, the initial key step in moving a newly discovered biomarker towards clinical implementation is independent replication. Therefore, the focus of this review is on biomarkers that consistently showed clinical relevance in two or more publications. Methods: We searched PubMed database for relevant papers across different TSCC sample sources, i.e., body fluids (saliva, serum/plasma) and tissues. No restriction regarding the date of publication was applied except for immunohistochemistry (IHC); only studies published between 2010 and June 2017 were included. Results: The search strategy identified 1429 abstracts, of which 96 papers, examining 150 biomarkers, were eventually included. Of these papers, 66% were exploratory studies evaluating single or a panel of biomarkers in one publication. Ultimately, based on studies that had undergone validation for their clinical relevance in at least two independent studies, we identified 10 promising candidates, consisting of different types of molecules (IL-6, IL-8, and Prolactin in liquid samples; HIF-1α, SOX2, E-cadherin, vimentin, MALAT1, TP53, and NOTCH1 in tissue biopsies).Conclusions: Although more exploratory research is needed with newer methods to identify biomarkers for TSCC, rigorous validation of biomarkers that have already shown unbiased assessment in at least two publications should be considered a high priority. Further research on these promising biomarkers or their combination in multi-institutional studies, could provide new possibilities to develop a specific panel for early diagnosis, prognosis, and individualized treatments.

Background: According to the World Alzheimer Report 2019, an estimated 50 million people worldwide are living with dementia. The smell test is a method for early detection of Alzheimer's disease (AD) as an inexpensive, simple, and noninvasive screening tool. This study aimed to evaluate the accuracy of the Iran Smell Identification Test (Iran-SIT) in discriminating patients with AD, with mild cognitive impairment (MCI), and the healthy subjects.Methods: In this study, 42 patients with AD, 33 with MCI, and 32 healthy controls were recruited from the referral Memory Clinic of Tehran University of Medical Sciences. The olfactory function was examined with six odors through Iran-SIT.Results: We found a significant difference among the olfactory function in subjects with normal cognitive status, that of those with MCI and those with AD (p < 0.001). The cutoff point for the diagnosis of AD was (sensitivity and specificity were, respectively, 85.7 and 90.8%), and (Sensitivity and specificity were, respectively, 93.9 and 100%) for MCI.Conclusion: These results suggest that Iran-SIT is a valid biomarker and practical screening tool, with simple, inexpensive, and readily available for use in combination with neuropsychological tools and neuroimaging for early detection of AD.

Comprehensive understanding of the serological response to SARS-CoV-2 infection is important for both pathophysiologic insight and diagnostic development. Here, we generate a pan-human coronavirus programmable phage display assay to perform proteome-wide profiling of coronavirus antigens enriched by 98 COVID-19 patient sera. Next, we employ ReScan, a method to efficiently sequester phage expressing the most immunogenic peptides and print them onto paper-based microarrays using acoustic liquid handling, which isolates and identifies 9 candidate antigens, 8 of which are derived from the 2 proteins used for SARS-CoV-2 serologic assays: spike and nucleocapsid proteins. After deployment in a high-throughput assay amenable to clinical lab settings, these antigens show improved specificity over a whole protein panel. This proof-of-concept study demonstrates that ReScan will have broad applicability for other emerging infectious diseases or autoimmune diseases that lack a valid biomarker, enabling a seamless pipeline from antigen discovery to diagnostic using one recombinant protein source., Graphical Abstract, Highlights • ReScan is a whole proteome screen to isolate and identify serologic assay targets • Antibodies to linear peptides in COVID19 sera bind Spike and Nucleocapsid proteins • Rapid workflow that seamlessly translates biomarkers into a functional diagnostic • Multiplexing linear S and N SARS-CoV-2 peptides can increase diagnostic specificity, Rapid serologic assay development remains challenging in scenarios where antigens are unknown, and is particularly crucial during a pandemic. Zamecnik et al. employ ReScan, which combines paper-based microarrays and programmable phage display, to screen for and isolate the most immunogenic peptides for SARS-CoV-2 antibody diagnostics.

This review aims to validate hair antiretroviral concentration (HAC) as a measure for antiretroviral medication adherence. This review included 31 studies that analyzed a total of 11 ARV drugs in four different drug classes. The associations between HAC and non-pharmacokinetic measures were generally lower than the association between HAC and other pharmacokinetic measures: the correlation coefficients (r) ranged from − 0.20 to 0.38 for self-report or pill counts and 0.20 to 0.85 for electronic drug monitoring; HAC and other pharmacokinetic measures were positively correlated with the correlation coefficients (r) ranging from 0.20 to 0.72, 0.34 to 0.86, 0.50 to 0.85 for antiretroviral concentration in plasma, peripheral blood mononuclear cells, and dried blood spots, respectively. HAC was one of the strongest independent predictors of virologic responses. HAC of tenofovir was significantly associated with renal toxicity in large sample studies. This review suggests that HAC is a valid biomarker of antiretroviral medication adherence.

Parental Burnout (PB) is a chronic stress-related disorder experienced in the parental role. Recent studies have shown that PB is a serious condition with severe consequences for parents (e.g., suicidal ideations) and children (e.g., parental neglect and violence). However, PB’s biological correlates have not yet been examined. Numerous studies suggest that hair cortisol concentration (HCC) is a valid biomarker of a variety of chronic stress conditions. HCC has been shown to be related to job burnout, but no studies have looked at the association between HCC and parental burnout. Given that the two forms of burnout are only weakly related, it is important to fill this gap. In this study, we compared HCC of parents suffering from PB (N = 119) to that of control parents (N = 59). We also examined the correlation between PB scores and HCC levels, controlling for job burnout symptoms. The results showed that HCC was 213 % higher in parents suffering from PB (mean level: 99.90 pg/mg) compared to controls (mean level: 46.83 pg/mg). Moreover, HCC was significantly related to PB (r = 0.27). These findings suggested that HCC can be considered as a biomarker of PB (though with caution, as 36.1 % of the parents in PB had HCC values equal to or below the mean of the control parents) and reinforce the view that HCC is a biomarker of chronic stress conditions. The HCC levels observed in parents suffering from PB point to the importance of this condition as well as its potential harmful consequences for their health.

A valid biomarker is defined as ‘a characteristic that is measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention’.1 The advent and validation of biomarkers based on identification of organic mechanisms, pathogenesis or pathophysiology have the potential to introduce individualisation in management of disorders of lower gastrointestinal function. An actionable biomarker is a biomarker that is associated with a directed treatment to prevent or reverse symptoms or disease, and this has resulted in a paradigm shift in oncological treatment from a tumour type-focussed approach to a molecularly-directed agnostic one, exploring the role of biological agents targeted to the driver genomic alteration irrespective of the cancer histology.2 Such actionable biomarkers have been introduced in functional lower gastrointestinal disorders.3 Importantly, this approach also provides opportunity to provide patients with personalised approach to treatment. This article highlights the diverse methods to identify the organic pathogenesis (figure 1) and to choose treatments based on approved treatments, off-label treatment with approved medications or, in the future, experimental medications. The a priori criteria for inclusion was based on the evidence of pathobiological relevance, extensive data on normal values, performance characteristics of the biomarker, availability of treatment directed to the biomarker, as well as evidence of efficacy of treatment directed at the specific biomarker. For example, the normal value data in adults for cited measurements are based on the following numbers: gastric emptying (319 (214 females, 105 males));4 colonic transit (220 (145 females, 75 males); 5 colonic compliance (n = 40);6 anorectal manometry with normal balloon expulsion (143 (96 females and 47 males));7 gastric accommodation (354 (230 females, 120 males));8 48 hours faecal bile acid excretion (96 (60 females and 36 males))9 and serum 7αC4 for bile acid diarrhoea (184 …

Amyotrophic Lateral Sclerosis (ALS) currently lacks a robust and well-defined biomarker that can 1) assess the progression of the disease, 2) predict and/or delineate the various clinical subtypes, and 3) evaluate or predict a patient's response to treatments. The kynurenine Pathway (KP) of tryptophan degradation represent a promising candidate as it is involved with several neuropathological features present in ALS including neuroinflammation, excitotoxicity, oxidative stress, immune system activation and dysregulation of energy metabolism. Some of the KP metabolites (KPMs) can cross the blood brain barrier, and many studies have shown their levels are dysregulated in major neurodegenerative diseases including ALS. The KPMs can be easily analyzed in body fluids and tissue and as they are small molecules, and are stable. KPMs have a Janus face action, they can be either or both neurotoxic and/or neuroprotective depending of their levels. This mini review examines and presents evidence supporting the use of KPMs as a relevant set of biomarkers for ALS, and highlights the criteria required to achieve a valid biomarker set for ALS.

Cardiovascular disease (CVD) is the major cause of death globally; therefore, there is a need for the identification of valid biomarker that accurately predict the risk of developing cardiovascular disease, and novel therapeutic approaches for its treatment. Exosomes are very small extracellular vesicles containing protein, lipid, transcription factors, mRNAs, non-coding RNA and nucleic acid contents, that are important players in intercellular communication, and that act via long-range signals or cell-to-cell contact. The discovery of exosomes provides potential strategies for the diagnosis and treatment of cardiovascular disease. In the current review, we have explored the potential impact of exosomes on cardiovascular physiology, and their therapeutic potential in cardiovascular disorders with a emphasize on the existing preclinical studies.

Pancreatic cancer with its associated infaust prognosis urgently needs better early detection of disease, especially for screening of high risk individuals. Despite early promise and theoretical considerations, however, KRAS mutional analysis of cfDNA seems not a way forward here. A more multifaceted panel of mutational spectrum biomarkers study (KRAS, TP53, SMAD4, P16, EGFR GNAS, MENN1, DAXX, VHL and in combination of pancreatic cancer specific STR markers) along with epigenetic alterations in cfDNA in pancreatic cancer patients may still provide a successful prognostic and diagnostic avenue, but generally speaking cfDNA does not appear very promising direction. Hence focus should now be directed to alternative methodology.

The gold standard for the detection of urothelial carcinoma is represented by urethro-cystoscopy and biopsy. Both procedures are invasive and expensive and therefore cytology is often used as first approach to investigate on a possible neoplasia, being a safe and cost-effective diagnostic modality of evaluation. Because cytology alone is not highly sensitive for detection of low grade urothelial carcinoma and recurrence of the disease, several adjunct markers and urine based tests for urothelial carcinoma have been developed, which can help in the final diagnosis. In particular, ProEx C is an immunohistochemical cocktail containing antibodies direct against topoisomerase IIα (TOP2A) and minichromosome maintenance 2 (MCM2) proteins. It proved to be a valid biomarker especially in detecting squamous intraepithelial lesions in cervical liquid-based samples and in discerning these lesions from their mimickers, as well as in ovarian, endometrial, vulvar, primary and metastatic melanomas, breast, pancreatic and renal cell carcinomas. This brief review covers the effective utility of ProEx C as adjunct tool in assessing the urothelial lesions in urine cytology, also providing prognostic and therapeutic information to help in clinical decisions.

Scrapie is a fatal neurodegenerative disease of sheep and goats belonging to the group of Transmissible Spongiform Encephalopathy or prion diseases. The EU has adopted mandatory measures for scrapie surveillance to safeguard public and animal health because it is highly contagious and might decimate all genetic susceptible animals in affected flocks. Definite diagnosis of scrapie relies on the detection of the pathological prion protein in brain tissues and there are still no blood biomarkers available for making diagnosis in living animals that can be used for the screening of sheep in scrapie-affected flocks. Neurofilament light (NfL) protein, a valid biomarker for neuronal and axonal damages, can now be easily measured in blood by the ultra-sensitive single molecule array (Simoa) technology. Recent work reported that serum NfL is increased in neurodegenerative diseases, including human prion diseases, but no data are available for scrapie or other animal prion diseases. Here, we found that the median serum NfL concentration in scrapie animals (56.2, IQR 42.2–84.8, n = 9) was more than 15 times higher (p = 0.00084) than that found in control samples (3.4, IQR 3.0–26.3, n = 11). Moreover, serum NfL concentration in scrapie sheep with clinical signs (n = 2; 75.3, 15.7 pg/ml) did not significantly (p = 0.541; t-test) differ from scrapie animals without clinical signs (n = 7; 61.0, 10.7 pg/ml). The receiver operating characteristic (ROC) curve analysis estimated the cut-off value of 31 pg/ml serum NfL for distinguishing scrapie-infected sheep from controls. The application of this cut-off value gives an accuracy of the test of 95% (percent error of 5.23%). These data indicate that the Simoa test for serum NfL might be a useful screening method for detecting preclinical scrapie in living sheep. Finally, the preliminary data reported here need confirmation in large and more structured studies.

Tumor metastasis and anticancer drug resistance are the major causes of mortality in patients with colorectal cancer (CRC). Due to the limitations of conventional biomarkers, it is urgent to identify novel and valid biomarkers to predict the progression and prognosis of CRC. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect MAGT1 expression in CRC clinical samples or cell lines. Bioinformatics analysis was used to investigate the association between MAGT1 alteration and clinicopathological features of patients with CRC. The present study revealed that the transcription levels of magnesium transporter 1 (MAGT1) were significantly increased in CRC tissues compared with matched adjacent normal tissues. Overexpression of MAGT1 was associated with advanced tumor stage, N and M classification. In addition, for patients who underwent chemotherapy, patients in the MAGT1-low expression group exhibited a longer overall survival (OS) time than patients in the high-expression group. Patients with CRC treated with chemotherapy had a longer OS time than those treated without chemotherapy in the MAGT1-low expression group but not in the MAGT1-high expression group. Furthermore, MAGT1 was a valid but not an independent prognostic factor for CRC. Therefore, the present study highlighted that MAGT1 may serve as a valid biomarker for predicting the development, progression and poor prognosis of CRC.

Background: There are no clearly established clinical biochemical markers for cigarette smoking despite the knowledge that cigarette smoking is a risk factor for various diseases, especially cardiovascular complications of respiratory pathologies. However, there are reports of significant increases in blood viscosity and oxidative stress among smokers. The main objective of the study was to ascertain the association of toxicity from cigarette smoking on whole blood viscosity in our data. Methods: This study analysed the archived clinical data of 20 cigarette smokers and 20 apparently healthy individuals. Results: The data show that on average, oxidative stress levels are relatively the same between groups, while whole blood viscosity is statistically significantly lower in non-smokers compared to smokers. Conclusions: This report suggests that oxidative stress induced whole blood hyper-viscosity could be a valid biomarker for laboratory testing of smoking toxicity among cigarette smokers.

Suboptimal adherence remains a significant concern for adolescents with Type 1 diabetes, the treatment regimen for which is complex and includes numerous behaviors. Accurate assessment of adherence is critical for effective healthcare and to measure trial outcomes. Without a valid biomarker of adherence, assessment strategies must rely on measuring management behaviors. This paper provides an overview of approaches to measure adherence, with an emphasis on contemporary, validated measures that are appropriate for current diabetes care. Objective measures include electronic data from diabetes management devices. Subjective measures include self/parent-report questionnaires, structured interviews and diaries/logbooks. Practical strategies for selecting measurement approaches for clinical and research purposes are reviewed, and implications of adherence assessment for clinical care delivery and adherence-promotion are discussed.

The promising utility of multi-modality evoked potential batteries to objectively measure multi-tract dysfunction has been evaluated by several groups using different methods.To independently evaluate the use of multi-modality evoked potential batteries as surrogate biomarkers for both physical and cognitive status in a cohort of Primary Progressive Multiple Sclerosis patients and identify the most potentially useful scoring method of those described.28 Patients with Primary Progressive Multiple Sclerosis underwent clinical evaluation with Kurtzke's Modified EDSS and the Multiple Sclerosis Functional Composite (MSFC). 19 Participants also underwent the Minimal Assessment of Cognitive Function in Multiple Sclerosis. Visual, Brainstem Auditory, Somatosensory and Motor Evoked Potentials were recorded on all. Results were graded by variants of the Global Evoked Potential Score, Multiple Evoked Potential Score and Summation of Z transformed Evoked Potential Latencies for correlation against the clinical scores.Multi-modal evoked potential batteries generally show moderate and useful correlation with clinical status as measured by the regulatory standard of EDSS (r = .65 vs. mEPS p.005) and MSFC (r = .39 vs. mEPS p.05). The graded qualitative mEPS scoring system displayed the strongest relationship although the influence of scoring system applied appeared reassuringly minimal. Non-association with cognitive impairment is an important limitation however.

Recently fourteen systematic reviews applying the same selection and evaluation criteria analyzed the induction of micronuclei in lymphocytes as biomarker for DNA damage induced by human exposure to a given chemical or chemical mixture. The results obtained in the individual reviews were summarized to evaluate the validity of the Cytokinesis-Block-Micronucleus assay in lymphocytes (L-CBMN) and propose recommendations for its use in occupational and environmental exposure studies. All systematic reviews found consistent increases of MN frequencies in exposed subjects versus controls in all genotoxic compounds or group of chemicals investigated, in the following decreasing order: As/Cr/Ni, vinyl chloride, formaldehyde, Hg/Pb/Cd, "miscellaneous", pesticides, cytostatics/antineoplastics, anaesthetic gasses, dust/asbestos/other fibers, polycyclic aromatic hydrocarbons, ethylene oxide, butadiene, styrene and petroleum/derivatives. Two reviews compared the results with the recommended exposure limits. For styrene, MN was found not to be induced under the recommended threshold limit. For vinyl chloride the safe exposure limit based on the L-CBMN data is lower than the current one. The L-CBMN thus appears to be a valid biomarker to assess DNA damage in populations exposed to genotoxic chemicals. Many shortcomings have been reported in assessment of confounding factors, such as lifestyle patterns, in particular diet and the major one the exposure assessment. All these factors together with methodological variables may contribute to the large variability in MN frequencies, also in controls. Information on frequency and origin of MN in more than one tissue (e.g. lymphocytes and buccal cells) in parallel, may provide better understanding of the mechanisms involved. Use of automated MN scoring systems to increase numbers of cells scored and facilitate screening more individuals would increase data reliability and provide information on the link between mutagenicity and carcinogenicity, if the studies are done prospectively. Efforts should be made to unravel the genotoxic effects induced when chronic and/or mixed exposures are involved.

Major Depression is mainly related to structural and functional alterations in brain networks involving limbic and prefrontal regions. Reduced olfactory sensitivity in depression is associated with reduced olfactory bulb (OB) volume. We determined if the OB volume reduction is a specific biomarker for depression and whether its diagnostic accuracy allows its use as a valid biomarker to support its diagnosis.84 in-patients with mixed mental disorders and 51 age-matched healthy controls underwent structural MR imaging with a spin-echo T2-wheighted sequence. Individual OB volume was calculated manually (interrater-reliability = .81, p.001) and compared between groups. Multiple regression analysis with OB volume as dependent variable and Receiver Operator Characteristic analysis to obtain its diagnostic accuracy for depression were ruled out.Patients exhibited a 13.5% reduced OB volume. Multiple regression analysis showed that the OB volume variation was best explained by depression (β = -.19), sex (β = -.31) and age (β = -.29), but not by any other mental disorder. OB volume attained a diagnostic accuracy of 68.1% for depression.The patient group mainly contained highly comorbid patients with mostly internalizing disorders which limits the generalisability of the results of the regression analysis.The OB may serve as a marker for depression. We assume that reduced neural olfactory input to subsequent limbic and salience processing structures moderates this relation. However, the OB was in an inferior position compared to conventional questionnaires for diagnosis of depression. Combination with further structural or functional measurements is suggested.

Introduction: Biobehavioral research requires the ability to objectively measure the presence and/or severity of disease, symptoms and their burden, or to determine the effect of treatment on outcomes. Biomarker research has advanced care for patients across the lifespan. There have been significant advancements in biological marker use for nursing research in recent years. The purposes of this article are to define the characteristics of a valid biomarker; review common biological sources of genetic, hormonal, and proteomic biomarkers with attention to practical strengths, weaknesses, and challenges for specimen selection and quality; and discuss potential use of biomarkers in clinical and research settings. Methods: Authors draw on the literature and research experiences to address the issues relevant to incorporating biomarkers into nursing research. Results and Discussion: An overview of the practical aspects of incorporating biomarkers into nursing research, and the resultant actual and potential clinical applications, are discussed.

Rupture of abdominal aortic aneurysm (AAA) is unpredictable and lethal. A clinically valid biomarker to monitor the disease has not been available. Based on our recent discoveries that uncoupled endothelial nitric oxide synthase (eNOS)/tetrahydrobiopterin deficiency plays a causal role in various models of AAA, the present study examined the relationship between circulating and tissue levels of tetrahydrobiopterin (H4B) in angiotensin II-infused hyperphenylalaninemia (hph-1) and apoE null mice. For apoE null mice, tissue and plasma H4B levels decreased time dependently, to 2.69 ± 0.15 and 1.99 ± 0.06 pmol/mg, respectively (from 4.86 ± 0.32 and 3.31 ± 0.13 pmol/mg at baseline) by week 3, when aneurysms developed. For hph-1 mice, tissue and plasma H4B levels decreased significantly to 1.02 ± 0.10 and 0.98 ± 0.09 pmol/mg, respectively (from 1.84 ± 0.18 and 1.48 ± 0.12 pmol/mg at baseline), by week 1, when aneurysms developed. Oral folic acid administration, which has been shown to improve aortic H4B levels to completely prevent or markedly decrease the incidence of AAA, significantly increased tissue and plasma H4B levels in both animal models starting at week 1. The two H4B measurements at all conditions showed significant linear correlation, suggesting that plasma H4B accurately predicts its tissue levels when H4B is either reduced or enhanced. Together, these data demonstrate that H4B levels decrease with AAA development and increase with folic acid treatment in two different murine models of AAA and that plasma H4B levels accurately reflect H4B levels in the tissue, suggesting that circulating H4B levels may be used clinically as a novel and powerful biomarker for the development and response to treatment of AAA.

Background A valid biomarker is ‘an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention’. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS-diarrhea (IBS-D) patients, IBS-constipation (IBS-C) patients and healthy volunteers (HV). Methods In 30 HV, 30 IBS-C patients and 64 IBS-D patients, we characterized bowel symptoms and quantitated pathophysiological mechanisms: bile acid (BA) synthesis (serum C4 and FGF19), fecal BA and fat, colonic transit (CT), and intestinal permeability (IP). We used multiple logistic regression and receiver-operating characteristic (ROCAUC) to appraise three factors (fecal BA, CT, and IP) individually and in combination to identify discriminant targets for treatment in IBS. Key Results There were significant associations between the three subgroups and symptoms reflecting bowel function and the quantitative traits. There were significant associations between fecal BA and CT at 48 h (r = 0.43; p

Background: MicroRNAs have altered expression levels in various diseases and may play an important role in the diagnosis and prognosis of colorectal cancer (CRC). Methods: We systemically reviewed and quantitatively synthesized the scientific evidence pertaining to microRNA-20a (miR-20a) as a CRC biomarker. A keyword and reference search in PubMed yielded 32 studies, in which miR-20a was measured in feces, serum, or tumor tissue. Data were extracted from a total of 5014 cancer cases and 2863 controls. Results: Twenty out of 21 relevant studies found that miR-20a was upregulated in CRC patients compared to controls. Meta-analysis revealed a pooled miR-20a fold change of 2.45 (95% CI: 2.24−2.66) in CRC patients versus controls. To estimate sensitivity and specificity of miR-20a as a diagnostic biomarker of CRC, a pooled area under the receiver operating characteristic curve (AUROC) was calculated (0.70, 95% CI: 0.63−0.78). The prognostic capacity of miR-20a was assessed using hazard ratios (HRs) for the overall survival (OS). The meta-analysis estimated the pooled HR for OS to be 2.02 (95% CI: 0.90−3.14) in CRC patients with high miR-20a expression. Conclusions: miR-20a may be a valid biomarker for CRC detection but may not be a strong predictor of poor prognosis in CRC.

The corticomuscular coupling (CMC) characterization between the motor cortex and muscles during motion control is a valid biomarker of motor system function after stroke, which can improve clinical decision-making. However, traditional CMC analysis is mainly based on the coherence method that can’t determine the coupling direction, whereas Granger Causality (GC) is limited in identifying linear cause–effect relationship. In this paper, a time-frequency domain copula-based GC (copula-GC) method is proposed to assess CMC characteristic. The 32-channel electroencephalogram (EEG) signals over brain scalp and electromyography (EMG) signals from upper limb were recorded during controlling and maintaining steady-state force output for five stroke patients and five healthy controls. Then, the time-frequency copula-GC analysis was applied to evaluate the CMC strength in both directions. Experimental results show that the CMC strength of descending direction is greater than that of ascending direction in the time domain for healthy controls. With the increase of grip strength, the bi-directional CMC strength has an increasing trend. Meanwhile, the bi-directional CMC strength of right hand is larger than that of left hand. In addition, the bi-directional CMC strength of stroke patients is lower than that of healthy controls. In the frequency domain, the strongest CMC is observed at the beta frequency band. Additionally, the CMC strength of descending direction is slightly larger than that of ascending direction in healthy controls, while the CMC strength of descending direction is lower than that of ascending direction in stroke patients. We suggest that the proposed time-frequency domain analysis approach based on copula-GC can effectively detect complex functional coupling between cortical oscillations and muscle activities, and provide a potential quantitative analysis measure for motion control and rehabilitation evaluation.

This paper will review the current status of genomic-based therapy of gynecologic malignancies. The routine “standard-of-care” delivery of targeted therapeutics based on the presence of specific molecular biomarkers in the management of the gynecologic malignancies has been delayed compared to the substantial progress made in several other tumor types. However, relatively recently reported and rather robust phase 3 trial data have confirmed a potentially major role for PARP inhibitors as both active treatment and maintenance therapy of advanced ovarian cancer. Further, data demonstrating the presence of a specific molecular phenotype (micro-satellite instability high – MSI-H) is a valid biomarker for the potential clinical utility of checkpoint inhibitor immunotherapy has relevance for all gynecologic malignancies, and particularly in the setting of metastatic or recurrent endometrial cancer.Conclusions. The introduction of PARP inhibitors into the oncology armamentarium has substantially impacted standard-of-care strategies in the management of ovarian cancer. It is anticipated that the results of ongoing and future trials will further define the role of genomic-based therapy in ovarian cancer and other gynecologic malignancies.

At the end of each year, it is traditional to ask what we have learned in the past year and how we will we proceed. Although we may have slightly different answers, most of us will probably agree that the increasing availability of whole-genome resequencing has changed our view of genomic diversity and will significantly change research into, and probably the clinical application of, the field of pharmacogenomics. The utilization of individual phenotypes or genotypes to improve individual healthcare is the most immediate and convincing promise since the beginning of pharmacogenetics. To achieve this aim, the most convincing concept for therapy individualization is still that of single genotypes with a valid biomarker status. Single genotypes that are functionally well understood on the molecular and cellular level and that reproducibly modulate pharmacokinetics or pharmacodynamics, as well as the efficacy and side effects of drugs, can be used as valid biomarkers to individualize drug therapy. Out of thousands of pharmacogenomics research publications, only a few new valid biomarkers are emerging. Indeed, the US FDA lists only 18 pharmacogenetically valid pharmacogenetic biomarkers (inherited genetic polymorphisms) and 14 tumor genomic biomarkers [101]. Probably every human gene carries some polymorphisms, but the number of genes carrying loss-of-function or knockout polymorphisms is small. According to a recent deep-sequencing analysis, each Caucasian individual may carry nearly 200 heterozygous knockout genes and 50 homozygous functional knockouts [1]. Already decades before hundreds of human genomes were decoded by deep sequencing and other technologies, we realized a particular enrichment of functional knockouts in genes coding for drug-metabolizing enzymes. There are frequent knockouts of CYP2C19, CYP2D6, CYP3A5, GSTM1, GSTT1 and UGT2B17 and nearly knockouts (negligible

Circulating tumor cells (CTCs) are one of the most crucial topics in rare cell biology and have become the focus of a significant and emerging area of cancer research. While CTC enumeration is a valid biomarker in prostate cancer, the current FDA-approved CTC technology is unable to detect CTCs in a large portion of late stage prostate cancer patients. Here we introduce the NanoVelcro CTC Chip, a device composed of a patterned silicon nanowire substrate (SiNW) and an overlaid polydimethylsiloxane (PDMS) chaotic mixer. Validated by two institutions participating in the study, the NanoVelcro Chip assay exhibits very consistent efficiency in CTC-capture from patient samples. The utilized protocol can be easily replicated at different facilities. We demonstrate the clinical utility of the NanoVelcro Chip by performing serial enumerations of CTCs in prostate cancer patients after undergoing systemic therapy. Changes in CTC numbers after 4–10 weeks of therapy were compared with their clinical responses. We observed a statistically significant reduction in CTCs counts in the clinical responders. We performed long-term follow up with serial CTC collection and enumeration in one patient observing variations in counts correlating with treatment response. This study demonstrates the consistency of the NanoVelcro Chip assay over time for CTC enumeration and also shows that continuous monitoring of CTC numbers can be employed to follow responses to different treatments and monitor disease progression.

A high intake of fruit and vegetables (FV) is associated with reduced risk of chronic disease, although the evidence base is mostly observational. Blood biomarkers offer an objective indicator of FV intake, potentially improving estimates of intakes based on traditional methods. A valid biomarker of overall FV intake would be able to confirm population intakes, more precisely evaluate the association between intakes and health outcomes and confirm compliance in FV interventions. Several substances have been proposed as biomarkers of FV intake: vitamin C, the carotenoids and polyphenols. Certain biomarkers are strong predictors of single FV; however, the proposed single biomarkers of FV consumption are only modestly predictive of overall FV consumption. This is likely to be due to the complexity of the FV food group. While accurately measuring FV intake is important in nutrition research, another critical question is: how best can an increase in FV intake be achieved? Increased FV intake has been achieved in efficacy studies using intensive dietary advice. Alternative, less intensive methods for encouraging FV consumption need to be developed and tested for population level intervention. Systematic reviews suggest peer support to be an effective strategy to promote dietary change. This review will describe the evidence for a link between increased FV intake and good health, outline possible novel biomarkers of FV consumption, present the most recently available data on population intake of FV and examine the usefulness of different approaches to encourage increased consumption of FV.

PURPOSE: Head and Neck Squamous Cell Carcinomas (HNSCC) cause more than 300,000 deaths worldwide each year. Locoregional and distant recurrences represent worse prognostic events and accepted surrogate markers of patients’ overall survival. No valid biomarker and salvage therapy exist to identify and treat patients at high-risk of recurrence. We aimed to verify if selected microRNAs (miRs) could be used as biomarkers of recurrence in HNSCC. EXPERIMENTAL DESIGN: A Nanostring array was used to identify miRs associated with locoregional recurrence in 44 HNSCC patients. Bioinformatic approaches validated the signature and identified potential miR targets. Validation experiments were performed using an independent cohort of primary HNSCC samples and a panel of HNSCC cell lines. In vivo experiments validated the in vitro results. RESULTS: Our data identified a four-miR signature that classified HNSCC patients at high- or low-risk of recurrence. These miRs collectively impinge on the epithelial-mesenchymal transition process. In silico and wet lab approaches showed that miR-9, expressed at high levels in recurrent HNSCC, targets SASH1 and KRT13, while miR-1, miR-133 and miR-150, expressed at low levels in recurrent HNSCC, collectively target SP1 and TGFβ pathways. A six-genes signature comprising these targets identified patients at high risk of recurrences, as well. Combined pharmacological inhibition of SP1 and TGFβ pathways induced HNSCC cell death and, when timely administered, prevented recurrence formation in a preclinical model of HNSCC recurrence. CONCLUSIONS: By integrating different experimental approaches and competences, we identified critical mediators of recurrence formation in HNSCC that may merit to be considered for future clinical development. TRANSLATIONAL RELEVANCE. Most of HNSCC patients are diagnosed with a locally advanced disease and are treated with the combination of surgery, radiotherapy, and chemotherapy. This highly toxic approach is curative in about half of the cases but recurrent patients do not have effective salvage therapies. Therefore there is the urgency to identify and validate solid biomarkers able to classify patients at high risk that may benefit for specific targeted approaches. Our work tackled these two unmet clinical needs and identified a microRNA signature of locoregional recurrence in HNSCC patients. Starting from this signature, we identified two druggable pathways (i.e. SP1 and TGFβ) that when timely and concomitantly targeted efficiently prevented recurrence formation in a preclinical model. Both SP1 and TGFβ inhibitors have been already used to treat human patients, thus our work is of potential immediate translational relevance.

Induction of transplantation tolerance remains the ideal long-term clinical and logistic solution to the current challenges facing the management of renal allograft recipients. In this review, we describe the recent studies and advances made in identifying biomarkers of renal transplant tolerance, from study inceptions, to the lessons learned and their implications for current and future studies with the same goal. With the age of biomarker discovery entering a new dimension of high-throughput technologies, here we also review the current approaches, developments, and pitfalls faced in the subsequent statistical analysis required to identify valid biomarker candidates.

A soluble proteinuric substance has been postulated as a cause of primary focal segmental glomerulosclerosis (FSGS), and one candidate soluble urokinase receptor (suPAR). Evaluation of published results shows that serum suPAR determinations by current methodology do not reliably distinguish FSGS from other proteinuric glomerular diseases and serum suPAR cannot currently be considered a valid biomarker for primary or secondary FSGS. However, this should not discourage further research on potential roles of suPAR in proteinuric renal disease, including FSGS.

clinical NEUroPROteomics of neurodegenerative diseases (cNEUPRO) is a Specific Targeted Research Project (STREP) within the sixth framework program of the European Commission dedicated to the search for novel biomarker candidates for Alzheimer's disease and other neurodegenerative diseases. The ultimate goal of cNEUPRO is to identify one or more valid biomarker(s) in blood and CSF applicable to support the early and differential diagnosis of dementia disorders. The consortium covers all steps required for the discovery of novel biomarker candidates such as acquisition of high quality CSF and blood samples from relevant patient groups and controls, analysis of body fluids by various methods, and finally assay development and assay validation. Here we report the standardized procedures for diagnosis and preanalytical sample-handling within the project, as well as the status of the ongoing research activities and some first results. © 2010 Philipp Spitzer et al.

Background: The long-chain omega-3 (n–3) fatty acids derived from fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a reduced risk of cardiovascular disease and other chronic diseases. Study of the associations between EPA and DHA intake and disease requires a valid biomarker of dietary intake; however, the direct measurement of tissue fatty acid concentrations is expensive and time consuming. Objective: Because the nitrogen stable isotope ratio (15N/14N, expressed as δ15N) is elevated in fish, we investigated whether δ15N is a valid alternative biomarker of EPA and DHA intake. Design: We examined the relation between red blood cell (RBC) δ15N and RBC EPA and DHA in a community-based sample of 496 Yup'ik Eskimos with widely varying intake of n–3 fatty acids. We also assessed the correlation between δ15N and dietary EPA and DHA intake based on 24-h dietary recalls and 3-d food records completed by a subset of 221 participants. Results: RBC δ15N was strongly correlated with RBC EPA and DHA (r = 0.83 and 0.75, respectively). These correlations differed only modestly by sex and age class. RBC δ15N also correlated with dietary EPA and DHA intake (r = 0.47 and 0.46, respectively) and did not differ by sex and age. Conclusions: The results strongly support the validity of RBC δ15N as a biomarker of EPA and DHA intake. Because the analysis of RBC δ15N is rapid and inexpensive, this method could facilitate wide-scale assessment of EPA and DHA intake in clinical and epidemiologic studies.

Background and Purpose— Experimental stroke studies indicate that oxidative stress is a major contributing factor to ischemic cerebral injury. Oxidative stress is also implicated in activation of matrix metalloproteinases (MMPs) and blood-brain barrier injury after ischemia-reperfusion. Plasma biomarkers of oxidative stress may have utility as early indicators of efficacy in Phase 2 trials of antioxidant therapies in human stroke. To date, a valid biomarker has been unavailable. We measured F2-isoprostanes (F2IPs), free-radical induced products of neuronal arachadonic acid peroxidation, in acute ischemic stroke. We aimed to determine the change in plasma F2IP levels over time and relationship with plasma MMP-9 in tPA-treated and tPA-untreated stroke patients. Methods— We performed a case–control study of consecutive ischemic stroke patients (25 tPA-treated and 27 tPA-untreated) presenting within 8 hours of stroke onset. Controls were individuals without prior stroke from a primary care clinic network serving the source population from which cases were derived. Infarct volume was determined on acute diffusion-weighted MRI (DWI) performed within 48 hours using a semi-automated computerized segmentation algorithm. Phlebotomy was performed at Results— In 52 cases and 27 controls, early (median 6 hours postonset) F2IPs were elevated in stroke cases compared with controls (medians 0. 041 versus 0.0295pg/mL, P =0.012). No difference in F2IPSs was present at later time points. Early plasma F2IPs correlated with MMP-9 in all patients ( P =0.01) and the tPA-treated subgroup ( P =0.02). No correlation was found with NIHSS, DWI infarct volume, 90-day Rankin score, or C-reactive protein ( P >0.05 for all). Conclusions— In early human stroke we found evidence of increased oxidative stress and a relationship with MMP-9 expression, supporting findings from experimental studies.

Background Children’s exposure to manganese (Mn) is a public health concern and consistent policy guidelines for safe levels of Mn exposure is lacking. The complexity of establishing exposure thresholds for Mn partially relates to its dual role as an essential micronutrient with low levels required for good health, but also as a neurotoxin at high levels. Questions exist about the age-related susceptibility to excess Mn, particularly for children, and how best to measure chronic exposures. To address this concern we conducted a systematic review of studies examining children’s exposure to Mn and neurodevelopmental outcomes focused on selection of biomarker-based and environmental measurements of Mn exposure to identify the scientific advances and research gaps. Methods PubMed and EMBASE databases were searched through March 2016 for studies that were published in English, used a biomarker-based or environmental measurement of Mn exposure, and measured at least one neurological outcome for children aged 0–18 years. Ultimately, thirty-six papers from 13 countries were selected. Study designs were cross-sectional (24), prospective cohorts (9), and case control (3). Neurodevelopmental outcomes were first assessed for Mn exposure in infants (6 papers), toddlers or preschoolers (3 papers) and school-age children (27 papers). Results Studies of school-aged children most frequently measured Intelligence Quotient (IQ) scores using Mn biomarkers of hair or blood. Higher hair concentrations of Mn were consistently associated with lower IQ scores while studies of blood biomarkers and IQ scores had inconsistent findings. Studies of infants and toddlers most frequently measured mental and psychomotor development; findings were inconsistent across biomarkers of Mn (hair, cord blood, tooth enamel, maternal or child blood and dentin). Although few studies measured environmental sources of Mn, hair biomarkers were associated with Mn in drinking water and infant formula. Only one paper quantified the associations between environmental sources of Mn and blood concentrations. Conclusion Hair-Mn was the more consistent and valid biomarker of Mn exposure in school-aged children. Accurate measurement of children’s exposure to Mn is crucial for addressing these knowledge gaps in future studies. However, research on biomarkers feasible for fetuses and infants is urgently needed given their unique vulnerability to excessive Mn.

The AmpliChip CYP450 Test, which analyzes patient genotypes for cytochrome P450 (CYP) genes CYP2D6 and CYP2C19, is a major step toward introducing personalized prescribing into the clinical environment. Interest in adverse drug reactions (ADRs), the genetic revolution, and pharmacogenetics have converged with the introduction of this tool, which is anticipated to be the first of a new wave of such tools to follow over the next 5-10 years. The AmpliChip CYP450 Test is based on microarray technology, which combines hybridization in precise locations on a glass microarray and a fluorescent labeling system. It classifies individuals into two CYP2C19 phenotypes (extensive metabolizers [EMs] and poor metabolizers [PMs]) by testing three alleles, and into four CYP2D6 phenotypes (ultrarapid metabolizers [UMs], EMs, intermediate metabolizers [IMs], and PMs) by testing 27 alleles, including seven duplications. CYP2D6 is a metabolic enzyme with four activity levels (or phenotypes): UMs with unusually high activity; normal subjects, known as EMs; IMs with low activity; and PMs with no CYP2D6 activity (7% of Caucasians and 1-3% in other ethnic groups). Levels of evidence for the association between CYP2D6 PMs and ADRs are relatively reasonable and include systematic reviews of case-control studies of some typical antipsychotics and tricyclic antidepressants (TCAs). Evidence for other phenotypes is considerably more limited. The CYP2D6 PM phenotype may be associated with risperidone ADRs and discontinuation due to ADRs. Venlafaxine, aripiprazole, duloxetine, and atomoxetine are newer drugs metabolized by CYP2D6 but studies of the clinical relevance of CYP2D6 genotypes are needed. Non-psychiatric drugs metabolized by CYP2D6 include metoprolol, tamoxifen, and codeine-like drugs. CYP2C19 PMs (3-4% of Caucasians and African Americans, and 14-21% of Asians) may require dose adjustment for some TCAs, moclobemide, and citalopram. Other drugs metabolized by CYP2C19 are diazepam and omeprazole. The future of pharmacogenetics depends on the ability to overcome serious obstacles, including the difficulties of conducting and publishing studies in light of resistance from grant agencies, pharmaceutical companies, and some scientific reviewers. Assuming more studies are published, pharmacogenetic clinical applications may be compromised by economic factors and the lack of physician education. The combination of a US FDA-approved test, such as the AmpliChip CYP450 Test, and an FDA definition of CYP2D6 as a 'valid biomarker' makes CYP2D6 genotyping a prime candidate to be the first successful pharmacogenetic test in the clinical environment. One can use microarray technology to test for hundreds of single nucleotide polymorphisms (SNPs) but, taking into account the difficulties for single gene approaches such as CYP2D6, it is unlikely that very complex pharmacogenetic approaches will reach the clinical market in the next 5-10 years.

The integration of oxytocin (OT) into behavioral science seems to hold considerable promise for advancing our understanding of human health and development but methodological issues restrict the measurement of OT in large studies, in everyday social settings, or when repeated sampling is required. Measuring OT in saliva could overcome many of these limitations. In this paper, we rigorously evaluate the feasibility of doing so. A series of experiments leads to the conclusion that saliva does not contain oxytocin in measurable amounts, and that OT is not a valid salivary biomarker when measured by currently available immunological methods. Levels of immuno-reactive OT in saliva are primarily due to non-specific interference with antibody-antigen binding. We can state with a high degree of certainty that measurement of OT in saliva does not yield meaningful indices of individual differences or intra-individual change.