Studies In Healthy Individuals Research Articles

Modifiable Factors Associated with Knee Abduction During Weight-Bearing Activities: A Systematic Review and Meta-Analysis

Increased knee abduction angle during activity is suggested to be a risk factor for sustaining an anterior cruciate ligament (ACL) injury or developing patellofemoral pain syndrome (PFPS). Knowledge of the modifiable mechanisms that are associated with increased knee abduction will aid in the appropriate design of preventive and rehabilitative strategies for these injuries. Our objective was to systematically review modifiable mechanisms contributing to increased knee abduction in healthy people and in individuals with an ACL injury or PFPS. We performed a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the databases MEDLINE, CINAHL, and Embase until September 2015. Inclusion criteria were studies in healthy individuals and/or those with ACL injury or PFPS reporting (1) muscle strength, muscle activation, proprioception, and/or range of motion (ROM) and (2) knee abduction angle assessed with either motion analysis or visual observation during weight-bearing activity. In total, 33 articles were included. Reduced trunk strength, reduced gluteus maximus amplitude, decreased ankle ROM, and increased hip external rotation ROM were moderately associated with increased knee abduction angle (r -0.34 or higher, standardized difference in means (SDM) greater than -0.39, p<0.05, articles n=3, total sample size n=101-114) in healthy individuals. Decreased strength of hip abductors, external rotators, and extensors and knee flexors were at most weakly associated with increased knee abduction angle (r≤0.21, p=0.013-0.426, articles n=2-9, total sample size n=80-311). Too few articles included patients with knee injury to be included in any meta-analysis. The associations identified in this review indicate that investigation of strengthening of the trunk muscles, and improvement of gluteus maximus activation and ankle ROM to change knee kinematics is merited. Studies on modifiable factors associated with increased knee abduction angle in people with knee injury are needed.

Limited Association Between Aerobic Fitness and Pain in Healthy Individuals: A Cross-Sectional Study.

In healthy individuals and people with chronic pain, an inverse association between physical activity level and pain has been reported. Associations between objectively measured fitness and pain have also been found in people with chronic pain, but it is not clear whether the same relations are apparent in healthy individuals. The purpose of the present study was to examine the relation between aerobic capacity and pain in healthy individuals. Pressure pain threshold, ischemic pain tolerance, and pain ratings during ischemia were assessed and analyzed in relation to aerobic capacity in 35 healthy individuals. Correlation and multiple linear regression were used to analyze the data. Data from previous similar studies in healthy individuals and people with fibromyalgia were extracted and collated by literature review to support interpretation of the experimental data. No relation was found between aerobic capacity and any measure of pain, with the exception of a moderate inverse association between aerobic capacity and lower body pressure pain threshold in males (r = -0.58, P = 0.03) when data from male and female participants were analyzed separately. The limited association between aerobic capacity and quantitative sensory testing of pain was consistent with the data synthesis from previous studies of healthy individuals but differed from studies of people with fibromyalgia. Aerobic capacity is unrelated to pain in healthy young adults. For people with chronic pain, the negative relation between aerobic capacity and pain presumably arises from the underlying pathophysiology and/or associated behaviors of the disease process.

Hepcidina y parámetros del hierro en donantes de sangre

Introduction: The hepatic peptide hormone hepcidin is the principal regulator of iron absorption and tissue iron distribution. Recent studies have proposed hepcidin as a suitable biomarker to assess iron metabolism and its failures. Although the data were limited to information on the diagnostic properties of serum hepcidin, have not been well characterized and neither have enough studies in healthy individuals, and even in Colombia so far have not been any studies on the topic. Objective: quantify the concentrations of serum hepcidin, establish a normal range and determine the correlate with biochemical parameters associated with iron metabolism in a population of donors. Materials and methods: A cross-wise study was performed on total of 85 donors to whom an automatized blood panel was tested. Ferritin, iron and transferrin were measured through electrochimioluminiscence, inmmunoturbidimetry and colorimetry respectively. Seric hepcidin presence was evidenced by competitive ELISA. Data was statistically analized with a significance level of p< 0, 05. Results: Statistically significant differences were noticed in the hepcidin concentration when comparing women and men. Hepcidin concentrations in men were constant over age (median, 5.73nM). Only ferritin is strongly correlated with hepcidin. Normal values for women ranged between 1,67nM -11,3 nM while those for men did slightly higher 1,71 nM - 13,3 nM. Conclusions: Serum hepcidin levels are higher in men and demonstrates a strong in vivo correlation between seric hepcidin and iron either circulating or storage.

CD69 and CXCR6 Identify a Distinct Population of Human Bone Marrow and Spleen Resident NK Cells

In recent years, evidence has been provided that natural killer (NK) cells can function as anti-leukemic effector cells. In humans, two NK cell populations are usually distinguished: CD56dimCD16+ NK cells form the predominant population in blood while the CD56brightCD16- NK cell population is more prominent in tissues. However, little data regarding tissue specific characteristics of human NK cells are available, especially in bone marrow as an important localization of leukemic cells. Therefore, we evaluated the expression of chemokine receptors and adhesion molecules on NK cells in healthy donor blood, bone marrow and spleen by flow cytometry.Besides the two conventional NK cell subsets, a major third NK cell population was identified in bone marrow and spleen based on the combined expression of CD69 and CXCR6 (Figure 1). CD69+CXCR6+ NK cells represented 9-50% (mean 30%) of NK cells in marrow (n=15) and 26-57% (mean 43%) of NK cells in spleen (n=7). This CD69+CXCR6+ population was not detected in blood (n=15) nor in cord blood, neither mobilized into the blood stream after G-CSF treatment. The ratio and phenotype of the remaining conventional CD56bright and CD56dim NK cells in bone marrow and spleen were comparable to blood. Early after pediatric hematopoietic stem cell transplantation, CD69+CXCR6+ NK cells were absent in bone marrow, but gradually reached normal levels within the first year after transplantation.CD56 was expressed on marrow and spleen CD69+CXCR6+ NK cells at slightly lower levels than the conventional CD56bright NK cells and CD16 was expressed by 7-30% of CD69+CXCR6+ NK cells. CD69+CXCR6+ NK cells expressed high levels of the adhesion molecule CD54 (ICAM-1) as well as natural cytotoxicity triggering receptor NKp46 compared to the conventional CD56bright and CD56dim NK cell populations. CD69+CXCR6+ NK cells did not express the early differentiation markers CD117 (c-kit) and CD127 (IL7Rα), which are expressed by immature NK cells, type III innate lymphoid cells and, to some extent, by conventional CD56bright NK cells. The inhibitory receptor NKG2A, which is acquired early in maturation but lost during the differentiation of CD56dim NK cells, was expressed by 60% of CD69+CXCR6+ NK cells. Furthermore, CD69+CXCR6+ NK cells did not express markers acquired late in differentiation (KIRs, CD57, KLRG1, NKG2C).In functional experiments assessing cytokine producing capacity, CD69+CXCR6+ NK cells were comparable to the CD56dim subset, requiring the combined stimulation with IL12+IL15+IL18 to produce IFN-γ. However, with respect to cytotoxic potential, CD69+CXCR6+ NK cells more resembled the CD56bright NK cell subset; in resting state, CD69+CXCR6+ NK cells expressed perforin but not granzyme B, which was upregulated during overnight IL12+IL15 stimulation. Upon co-culture with K562 tumor cells, CD69+CXCR6+ NK cells degranulated (CD107a) at levels comparable to the conventional CD56bright and CD56dim NK cells.In summary, we identified a distinct NK cell population in human bone marrow and spleen. These cells were a) absent in blood, b) expressed tissue retention marker CD69, and c) were present alongside the conventional NK cell subsets in marrow and spleen. Together, these findings indicate that NK cells with the discriminative CD69+CXCR6+ phenotype constitute a tissue resident NK cell subset. Furthermore, CD69+CXCR6+ NK cells did not express CD49a+, distinguishing them from the recently described liver resident NK cells (Marquardt et al, 2015). Based on their surface receptor expression profile and functional characteristics, CD69+CXCR6+ NK cells have a mature signature that differs from both conventional NK cell subsets. Additional studies in healthy individuals and patients with immuno-hematological diseases are needed to investigate the immunological function of CD69+CXCR6+ NK cells. For example, these cells could have a local immunoregulatory or effector function. Alternatively, bone marrow and spleen may form a reservoir for effector cells waiting to be released into the blood stream. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Paradoxical Relationship Between Body Mass Index and Thyroid Hormone Levels: A Study Using Mendelian Randomization.

Free T3 (FT3) has been positively associated with body mass index (BMI) in cross-sectional studies in healthy individuals. This is difficult to reconcile with clinical findings in pathological thyroid dysfunction. We aimed to investigate whether childhood adiposity influences FT3 levels. Mendelian randomization using genetic variants robustly associated with BMI. Avon Longitudinal Study of Parents and Children, a population-based birth cohort. A total of 3014 children who had thyroid function measured at age 7, who also underwent dual x-ray absorptiometry scans at ages 9.9 and 15.5 years and have genetic data available. FT3. Observationally at age 7 years, BMI was positively associated with FT3: β-standardized (β-[std]) = 0.12 (95% confidence interval [CI]: 0.08, 0.16), P = 4.02 × 10(-10); whereas FT4 was negatively associated with BMI: β-(std) = -0.08 (95% CI: -0.12, -0.04), P = 3.00 × 10(-5). These differences persisted after adjustment for age, sex, and early life environment. Genetic analysis indicated 1 allele change in BMI allelic score was associated with a 0.04 (95% CI: 0.03, 0.04) SD increase in BMI (P = 6.41 × 10(-17)). At age 7, a genetically determined increase in BMI of 1.89 kg/m(2) was associated with a 0.22 pmol/L (95% CI: 0.07, 0.36) increase in FT3 (P = .004) but no substantial change in FT4 0.01 mmol/L, (95% CI: -0.37, 0.40), P = .96. Our analysis shows that children with a genetically higher BMI had higher FT3 but not FT4 levels, indicating that higher BMI/fat mass has a causal role in increasing FT3 levels. This may explain the paradoxical associations observed in observational analyses. Given rising childhood obesity levels, this relationship merits closer scrutiny.

Reprint of: Visual processing of words in a patient with visual form agnosia: A behavioural and fMRI study

Patient D.F. has a profound and enduring visual form agnosia due to a carbon monoxide poisoning episode suffered in 1988. Her inability to distinguish simple geometric shapes or single alphanumeric characters can be attributed to a bilateral loss of cortical area LO, a loss that has been well established through structural and functional fMRI. Yet despite this severe perceptual deficit, D.F. is able to “guess” remarkably well the identity of whole words. This paradoxical finding, which we were able to replicate more than 20 years following her initial testing, raises the question as to whether D.F. has retained specialized brain circuitry for word recognition that is able to function to some degree without the benefit of inputs from area LO. We used fMRI to investigate this, and found regions in the left fusiform gyrus, left inferior frontal gyrus, and left middle temporal cortex that responded selectively to words. A group of healthy control subjects showed similar activations. The left fusiform activations appear to coincide with the area commonly named the visual word form area (VWFA) in studies of healthy individuals, and appear to be quite separate from the fusiform face area (FFA). We hypothesize that there is a route to this area that lies outside area LO, and which remains relatively unscathed in D.F.

Computing an average when part of the population is not perceived.

The syndrome of unilateral spatial neglect (USN) after right-hemisphere damage is characterized by failure of salient left-sided stimuli to activate an orienting response, attract attention, and gain access to conscious awareness. The explicit failure processing left-sided visual information is not uniform, however, and patients seem to be more successful performing certain visual tasks than others. The source of this difference is still not clear. We focus on processing of visual scene statistical properties, asking whether, in computing the average size of an array of objects, USN patients give appropriate weight to objects on the left; disregard left-side objects entirely; or assign them an intermediate, lower weight, in accord with their tendency to neglect these objects. The interest in testing this question stems from a series of studies in healthy individuals that led Chong and Treisman [Chong, S. C., & Treisman, A. Statistical processing: Computing the average size in perceptual groups. Vision Research, 45, 891-900, 2005a; Chong, S. C., & Treisman, A. Attentional spread in the statistical processing of visual displays. Perception & Psychophysics, 67, 1-13, 2005b] to propose that processing of statistical properties (like the average size of visual scene elements) is carried out in parallel, with no need for serial allocation of focal attention to the different scene elements. Our results corroborate this suggestion, showing that objects in the left ("neglected") hemispace contribute to average size computation, despite a marked imbalance in spatial distribution of attention, which leads to a reduced weight of left-side elements in the averaging computation. This finding sheds light on the nature of the impairment in USN and on basic mechanisms underlying statistical processing in vision. We confirm that statistical processing depends mainly on spread-attention mechanisms, which are largely spared in USN.

Brain Functional Effects of Psychopharmacological Treatment in Major Depression: a Focus on Neural Circuitry of Affective Processing.

In the last two decades, neuroimaging research has reached a much deeper understanding of the neurobiological underpinnings of major depression (MD) and has converged on functional alterations in limbic and prefrontal neural networks, which are mainly linked to altered emotional processing observed in MD patients. To date, a considerable number of studies have sought to investigate how these neural networks change with pharmacological antidepressant treatment. In the current review, we therefore discuss results from a) pharmacological functional magnetic resonance imaging (fMRI) studies investigating the effects of selective serotonin or noradrenalin reuptake inhibitors on neural activation patterns in relation to emotional processing in healthy individuals, b) treatment studies in patients with unipolar depression assessing changes in neural activation patterns before and after antidepressant pharmacotherapy, and c) predictive neural biomarkers of clinical response in depression. Comparing results from pharmacological fMRI studies in healthy individuals and treatment studies in depressed patients nicely showed parallel findings, mainly for a reduction of limbic activation in response to negative stimuli. A thorough investigation of the empirical findings highlights the importance of the specific paradigm employed in every study which may account for some of the discrepant findings reported in treatment studies in depressed patients.

The Potential Utility of Eye Movements in the Detection and Characterization of Everyday Functional Difficulties in Mild Cognitive Impairment.

Mild cognitive impairment (MCI) refers to the intermediate period between the typical cognitive decline of normal aging and more severe decline associated with dementia, and it is associated with greater risk for progression to dementia. Research has suggested that functional abilities are compromised in MCI, but the degree of impairment and underlying mechanisms remain poorly understood. The development of sensitive measures to assess subtle functional decline poses a major challenge for characterizing functional limitations in MCI. Eye-tracking methodology has been used to describe visual processes in everyday, naturalistic action among healthy older adults as well as several case studies of severely impaired individuals, and it has successfully differentiated healthy older adults from those with MCI on specific visual tasks. These studies highlight the promise of eye-tracking technology as a method to characterize subtle functional decline in MCI. However, to date no studies have examined visual behaviors during completion of naturalistic tasks in MCI. This review describes the current understanding of functional ability in MCI, summarizes findings of eye-tracking studies in healthy individuals, severe impairment, and MCI, and presents future research directions to aid with early identification and prevention of functional decline in disorders of aging.

Effects of aripiprazole and haloperidol on neural activation during the n-back in healthy individuals: A functional MRI study

ObjectiveAntipsychotic drugs target neurotransmitter systems that play key roles in working memory. Therefore, they may be expected to modulate this cognitive function via their actions at receptors for these neurotransmitters. However, the precise effects of antipsychotic drugs on working memory function remain unclear. Most studies have been carried out in clinical populations, making it difficult to disentangle pharmacological effects from pathology-related brain activation. In this study, we aim to investigate the effects of two antipsychotic compounds on brain activation during working memory in healthy individuals. This would allow elucidation of the effects of current antipsychotic treatments on brain function, independently of either previous antipsychotic use or disease-related pathology. MethodsWe carried out a fully counterbalanced, randomised within-subject, double-blinded and placebo-controlled, cross-over study of the effects of two antipsychotic drugs on working memory function in 17 healthy individuals, using the n-back task. Participants completed the functional MRI task on three separate occasions (in randomised order): following placebo, haloperidol, and aripiprazole. For each condition, working memory ability was investigated, and maps of neural activation were entered into a random effects general linear regression model to investigate main working memory function and linear load. Voxel-wise and region of interest analyses were conducted to attain regions of altered brain activation for each intervention. ResultsAripiprazole did not lead to any changes in neural activation compared with placebo. However, reaction time to a correct response was significantly increased following aripiprazole compared to both placebo (p=0.046) and haloperidol (p=0.02). In contrast, compared to placebo, haloperidol dampened activation in parietal (BA 7/40; left: FWE-corr. p=0.005; FWE-corr. right: p=0.007) and frontal (including prefrontal; BA 9/44/46; left: FWE-corr. p=0.009; right: FWE-corr. p=0.014) cortices and the left putamen (FWE-corr. p=0.004). Compared with aripiprazole, haloperidol dampened activation in parietal cortex (BA7/40; left: FWE-corr. p=0.034; right: FWE-corr. p=0.045) and the left putamen (FWE-corr.p=0.015). Haloperidol had no effect on working memory performance compared with placebo. ConclusionCognitive functions are known to be impaired in schizophrenia and as such are an important target of treatments. Elucidating the mechanisms by which antipsychotic medications alter brain activation underlying cognition is essential to advance pharmacological treatment of this disorder. Studies in healthy individuals can help elucidate some of these mechanisms, whilst limiting the confounding effect of the underlying disease-related pathology. Our study provides evidence for immediate and differential effects of single-dose haloperidol and aripiprazole on brain activation during working memory in healthy individuals. We propose that these differences likely reflect their different receptor affinity profiles, although the precise mechanisms underlying these differences remain unclear.

King of the mountains: Tibetan and Sherpa physiological adaptations for life at high altitude.

Anecdotal evidence surrounding Tibetans' and Sherpas' exceptional tolerance to hypobaric hypoxia has been recorded since the beginning of high-altitude exploration. These populations have successfully lived and reproduced at high altitude for hundreds of generations with hypoxia as a constant evolutionary pressure. Consequently, they are likely to have undergone natural selection toward a genotype (and phenotype) tending to offer beneficial adaptation to sustained hypoxia. With the advent of translational human hypoxic research, in which genotype/phenotype studies of healthy individuals at high altitude may be of benefit to hypoxemic critically ill patients in a hospital setting, high-altitude natives may provide a valuable and intriguing model. The aim of this review is to provide a comprehensive summary of the scientific literature encompassing Tibetan and Sherpa physiological adaptations to a high-altitude residence. The review demonstrates the extent to which evolutionary pressure has refined the physiology of this high-altitude population. Furthermore, although many physiological differences between highlanders and lowlanders have been found, it also suggests many more potential avenues of investigation.

Visual processing of words in a patient with visual form agnosia: A behavioural and fMRI study

Patient D.F. has a profound and enduring visual form agnosia due to a carbon monoxide poisoning episode suffered in 1988. Her inability to distinguish simple geometric shapes or single alphanumeric characters can be attributed to a bilateral loss of cortical area LO, a loss that has been well established through structural and functional fMRI. Yet despite this severe perceptual deficit, D.F. is able to “guess” remarkably well the identity of whole words. This paradoxical finding, which we were able to replicate more than 20 years following her initial testing, raises the question as to whether D.F. has retained specialized brain circuitry for word recognition that is able to function to some degree without the benefit of inputs from area LO. We used fMRI to investigate this, and found regions in the left fusiform gyrus, left inferior frontal gyrus, and left middle temporal cortex that responded selectively to words. A group of healthy control subjects showed similar activations. The left fusiform activations appear to coincide with the area commonly named the visual word form area (VWFA) in studies of healthy individuals, and appear to be quite separate from the fusiform face area (FFA). We hypothesize that there is a route to this area that lies outside area LO, and which remains relatively unscathed in D.F.

Effect of advanced glycation end product intake on inflammation and aging: a systematic review.

Aging is associated with a chronic low-grade inflammatory status that contributes to chronic diseases such as age-related muscle wasting, kidney disease, and diabetes mellitus. Since advanced glycation end products (AGEs) are known to be proinflammatory, this systematic review examined the relation between the dietary intake of AGEs and inflammatory processes. The PubMed and Web of Science databases were screened systematically. Seventeen relevant studies in humans or animals were included. The intervention studies in humans showed mainly a decrease in inflammation in subjects on a low-AGE diet, while an increase in inflammation in subjects on a high-AGE diet was less apparent. About half of the observational studies found a relationship between inflammatory processes and AGEs in food. When the results are considered together, the dietary intake of AGEs appears to be related to inflammatory status and the level of circulating AGEs. Moreover, limiting AGE intake may lead to a decrease in inflammation and chronic diseases related to inflammatory status. Most of the trials were conducted in patients with chronic kidney disease or diabetes, and thus additional studies in healthy individuals are needed. Further investigation is needed to elucidate the effects of lifetime exposure of dietary AGEs on aging and health.

One left dorsolateral prefrontal cortical HF-rTMS session attenuates HPA-system sensitivity to critical feedback in healthy females

ObjectiveAlthough left dorsolateral prefrontal cortical (DLPFC) repetitive Transcranial Magnetic Stimulation (rTMS) is used to treat major depression, its underlying neurophysiological working mechanism remains to be determined. Prior research suggested that the clinical effects could be mediated by affecting the hypothalamic−pituitary−adrenal (HPA) system, but experimental studies in healthy individuals did not yield clear results. However, in healthy individuals, the influence of HF-rTMS on the HPA-system may only be detected when it is challenged. MethodsIn 30 rTMS naïve healthy females we evaluated the effect of one sham-controlled high frequency (HF)-rTMS session applied to the left DLPFC on the stress hormone cortisol by collecting salivary cortisol samples. In order to increase stress levels, 5min after stimulation, all participants performed the Critical Feedback Task (CFT), during which they were criticized on their performance. To take possible mood influences into account, all participants were also assessed with Visual Analogue Scales (VAS). ResultsThe experimental procedure did not affect mood differently in the real or sham stimulation. Area under the curve (AUCi) analysis showed that one real HF-rTMS session significantly influenced HPA-system sensitivity, as demonstrated by a decrease in cortisol concentrations. The sham procedure yielded no effects. ConclusionsIn line with former observations in major depression, one real left DLPFC HF-rTMS session significantly influenced HPA-system sensitivity in experimentally stressed females, resulting in decreases in cortisol levels.

Recognising neuroplasticity in musculoskeletal rehabilitation: A basis for greater collaboration between musculoskeletal and neurological physiotherapists

Evidence is emerging for central nervous system (CNS) changes in the presence of musculoskeletal dysfunction and pain. Motor control exercises, and potentially manual therapy, can induce changes in the CNS, yet the focus in musculoskeletal physiotherapy practice is conventionally on movement impairments with less consideration of intervention-induced neuroplastic changes. Studies in healthy individuals and those with neurological dysfunction provide examples of strategies that may also be used to enhance neuroplasticity during the rehabilitation of individuals with musculoskeletal dysfunction, improving the effectiveness of interventions. In this paper, the evidence for neuroplastic changes in patients with musculoskeletal conditions is discussed. The authors compare and contrast neurological and musculoskeletal physiotherapy clinical paradigms in the context of the motor learning principles of experience-dependent plasticity: part and whole practice, repetition, task-specificity and feedback that induces an external focus of attention in the learner. It is proposed that increased collaboration between neurological and musculoskeletal physiotherapists and researchers will facilitate new discoveries on the neurophysiological mechanisms underpinning sensorimotor changes in patients with musculoskeletal dysfunction. This may lead to greater integration of strategies to enhance neuroplasticity in patients treated in musculoskeletal physiotherapy practice.

A Review of the Clinical Consequences of Variation in Thyroid Function Within the Reference Range

Overt thyroid disease is associated with profound adverse health outcomes; however, data are conflicting for studies of borderline/subclinical thyroid dysfunction. Many studies of subclinical thyroid disease have had low power and were prone to selection bias. In contrast, large datasets are available from community studies in healthy individuals. Studies of the effects of variation of thyroid function across the reference range on health outcomes in these populations may provide useful information regarding thresholds for treatment of abnormal thyroid function. MEDLINE and the Cochrane Database of Systematic Reviews and Controlled Trials Register were searched for articles studying the effect of variation in thyroid hormone parameters within the reference range on cardiovascular, bone, metabolic, pregnancy, neurological, and psychological outcomes. Higher TSH/lower thyroid hormone levels are associated with more cardiovascular risk factors and cardiovascular events and worse metabolic parameters and pregnancy outcomes, whereas lower TSH/higher thyroid hormone levels are associated with reduced bone mineral density and increased fracture risk. The evidence base was good for cardiovascular, metabolic, bone, and pregnancy outcomes; however, high-quality data remained lacking for neurological and psychological outcomes. Common variation in persons with thyroid function in the normal range are associated with adverse health outcomes. These data suggest, by extrapolation, that carefully monitored treatment of even modest elevations of TSH may have substantial health benefits. Appropriately powered large-scale clinical trials analyzing the risks vs benefits of treating subclinical thyroid disease are required to determine whether these benefits can be achieved with levothyroxine therapy.

Cognitive reserve modulates neural responses in subjective and mild cognitive impairment

Cognitive reserve (CR) has been defined as a set of skills and repertoires, characterized by personal lifestyle and habits and is considered a protective factor against cognitive impairment (Scarmeas et al.,2003, Stern et al., 2009), particularly in the earlier stages. Indeed, a higher CR may be associated to a more efficient utilization of brain networks, as suggested by the more focused task-related neural responses found in functional magnetic resonance imaging (fMRI) studies in healthy individuals (Bernardi et al., 2011). Here we aim to determine the correlation between CR scores and patterns of brain response in both subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) subjects, while they perform a spatial attention task. Thirty-one MCI (14M, 74.0 yr ± 5.2) and 24 SCI (13M, 72.0 yr ± 5.8) patients underwent neuropsychological assessment and a fMRI experimental protocol (GE 1.5 T, GRE-EPI, TR 2.5s, TE 50ms, 33 Axial Slices, 3mm isotropic voxel, FA 90°, 180 volumes) during a visuo-spatial attention task (Bernardi et al., 2011). Cognitive Reserve Index (CRIq, Nucci et al., 2001) scores were correlated (Cox et al., 1996) to task-related brain responses, considering age as a confounding factor, after processing fMRI data at an individual and group level. CRIq scores negatively correlated with neural responses (p<0.05 cluster corrected) in the task-related bilateral parietal areas (R 2 =0.365) within the spatial dorsal stream, the superior, middle and inferior frontal cortex (R 2 =0.373), and the posterior cingulate cortex (R 2 =0.28).

In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: Application of the mechanistic absorption model GI-Sim

Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pKa, diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration–time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (Cmax and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development.

Abstract 1118: Circulating microRNA biomarkers for cancer exist in multiple biophysical states.

Abstract MicroRNAs (miRNAs) are small regulatory RNA molecules that function in a wide range of normal and pathologic cellular processes. Cell-free miRNAs circulate in blood (i.e. plasma, serum), are stable and can be diagnostic for cancer. Circulating microRNAs in cancer have been reported to exist in multiple biophysical states, including most famously as cargo of 50-100 nm extracellular vesicles known as exosomes. In prior studies of healthy individuals, we have found that a majority of plasma miRNAs are not vesicle-associated and are substantially present as part of a ribonucleoprotein complex containing Argonaute-2 (Ago2). In order to determine the state of miRNAs in the circulation of cancer patients, we quantitatively profiled the distribution of &amp;gt;300 miRNAs in progressive physical and biochemical fractions of plasma from individuals with metastatic prostate cancer and matched, healthy controls. Stepwise differential centrifugation was performed at 12,000g (to collect cell debris, etc.) and 120,000g (to collect exosomes), followed by Ago2-immunoprecipitation. Exosome fractions generally contained little miRNA, both in cases and in controls. Prostate cancer miRNA biomarkers (miR-141, miR-375) were predominantly soluble, partially associated with Ago2 (15-35% of total) and only marginally present in the exosome fraction (&amp;lt;1% of total). In order to quantify the amount of miRNA associated on average with an exosome, we used Nanoparticle Tracking Analysis (NTA) to quantify exosomes isolated from multiple in-vivo and in-vitro sources by differential ultracentrifugation, followed by miRNA extraction and quantification. We found that exosomes contain very few copies on average of their most abundant miRNAs (less than one copy per individual exosome). In contrast, a significant miR-141 biomarker signal was observed in the 12,000xg-pellet from plasma (approximately 30-45% of input), indicating some miRNA could be associated with larger and/or more dense particles (e.g., oncosomes). In summary, these results indicate that (i) prostate cancer-associated miRNAs are not predominantly contained within exosomes, (ii) the majority of exosomes do not carry significant amounts of miRNAs, and (iii) established biomarkers for prostate cancer are present in multiple physical states, including soluble (e.g., Ago2-associated) and large-particle associated (i.e. 12,000xg pellet) forms (possibly as cell debris or oncosomes). A more accurate understanding of the physical state of miRNA biomarkers will help guide their development to fully realize their diagnostic potential. Citation Format: John R. Chevillet, Emily N. Gallichotte, Heather H. Cheng, Lucia N. Vojtech, Jason D. Arroyo, Hilary Briggs, Robert L. Vessella, Celestia S. Higano, Evan Y. Yu, Era L. Pogosova-Agadjanyan, Derek L. Stirewalt, Florian Hladik, Muneesh Tewari. Circulating microRNA biomarkers for cancer exist in multiple biophysical states. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1118. doi:10.1158/1538-7445.AM2013-1118

Emotions and Neural Processing of Respiratory Sensations Investigated With Respiratory-Related Evoked Potentials

Patients with respiratory diseases such as asthma and chronic obstructive pulmonary disease frequently experience respiratory sensations, which are often perceived as unpleasant or threatening. However, the accurate perception of respiratory sensations is important for the management and treatment of these diseases. Emotions can substantially influence the perception of respiratory sensations and might affect the course of respiratory diseases, but the underlying neural mechanisms are poorly understood. The respiratory-related evoked potential (RREP) recorded from the electroencephalogram is a noninvasive technique that allowed first studies to examine the impact of emotions on the neural processing of respiratory sensations. In this review, we will briefly introduce the importance of the perception of respiratory sensations and the influence of emotions on respiratory perception. We then provide an overview on the technique of RREP and present a systematic review on recent findings using this technique in the context of emotions. The evidence currently available from studies in healthy individuals suggests that short-lasting emotional states and anxiety affect the later RREP components (N1, P2, P3) related to higher-order neural processing of respiratory sensations, but not the earlier RREP components (Nf, P1) related to first-order sensory processing. We conclude with a discussion of the implications of this work for future research that needs to focus on respiratory patient groups and the associated clinical outcomes.