Characteristics of Pediatric Patients With Celiac Disease Identified Due to an Affected First-Degree Family Member.

The incidence of celiac disease in first-degree relatives of affected individuals is higher than in the general population, yet the clinical characteristics of this unique subset of patients has not been well described. Through a retrospective review of patients seen in a tertiary care pediatric celiac disease clinic, we identified 49 patients diagnosed with celiac disease following screening due to an affected first-degree relative. Although 51% of patients screened due to an affected first-degree relative were asymptomatic, their disease histology was as severe as those screened for symptoms suggestive of celiac disease. These findings support current recommendations to screen all first-degree relatives of patients with celiac disease regardless of clinical symptoms.

The solubility of calcium oxalates explains some aspects of their underrepresentation in the oral cavity.

OBJECTIVE: Clarifying the discrepancy between frequently high oxalate concentrations present in saliva, but negligible amounts of calcium oxalate deposits found on oral surfaces. METHODS: Studying the calcium oxalate concentration range that can lead to heterogeneous crystallization in the oral cavity. a) Minimum: calcium oxalate monohydrate (COM) seed crystals were pre-grown ([Ca2+] = [C2O42-] = 1 mM, 30 min, 37 °C), and then re-immersed for ≥6 h to find the solubility equilibrium concentration (no growth, no dissolution). The concentrations tested were [Ca2+]/[C2O42-] : 0.055/0.050, 0.060/0.055, 0.070/0.065 and 0.080/0.075 mM. Supersaturations were calculated via the Debye-Hückel-theory and COM morphologies examined by scanning electron microscopy (SEM). b) Maximum (at the heterogeneous/homogeneous crystallization equilibrium): hydroxyapatite (HA) seed crystals were used to heterogeneously crystallize COM (37 °C, 24 h), using oxalate concentrations between 0.2 and 0.5 mM and calcium concentrations of 0.5 mM. COM-forming oxalate consumption was spectroscopically examined; COM precipitates were investigated by SEM; and HA identity was confirmed by X-ray analysis. RESULTS: Within the concentration range of [Ca2+]/[C2O42-]:0.060/0.055 mM (minimum) and [Ca2+]/[C2O42-]:0.50/0.25 mM (maximum) COM precipitates heterogeneously. In terms of mass, this corresponds to a range of 8.04-36.53 mg/l (daily) or an average of 14.32 mg COM (mimicking e.g. plaque mineralization). Higher concentrations react homogeneously (mimicking precipitation within saliva). CONCLUSION: In vivo, only ∼0.05 % oxalate present in saliva reacts with oral surfaces daily, corresponding to ∼0.0665 µmol/l or ∼9.72 µg COM per day. Calcium-consuming calcium phosphate formation and phosphoproteins such as statherin obviously hinder intraoral COM formation.

Correction: Lifelong aerobic exercise protects against inflammaging and cancer.

[This corrects the article DOI: 10.1371/journal.pone.0210863.].

Health-care providers' perspectives on uncertainty generated by variant forms of newborn screening targets.

PURPOSE: Despite the public health successes of newborn bloodspot screening, uncertainty associated with variant forms of primary screening targets has led to discrepancies in medical management. This study explored health-care providers' approaches to managing atypical forms of inherited metabolic diseases (IMDs) in the absence of evidence-based guidelines. METHODS: Semistructured telephone interviews were conducted with metabolic specialists. 3-Methylcrotonyl CoA deficiency and variant forms of phenylketonuria, biotinidase deficiency, and fatty acid oxidation disorders were considered. Data were analyzed inductively and deductively using a novel taxonomy of uncertainty. RESULTS: Health-care providers (n = 12) navigate diagnostic, prognostic, and therapeutic challenges of uncertainty while interpreting patient and family attitudes, preferences, and ideas in the care of children with these result types. Participants explained the limits of classifying mild and atypical metabolic phenotypes. Participants also described the challenge of finding balance between cautious care and overmedicalization. Developing consistent care plans and honest communication with families were perceived as effective strategies when navigating uncertainty. CONCLUSION: Providers' experiences suggest a need for transparent and accessible guidelines that account for challenges associated with uncertainty generated by screening. Timely consideration of this challenge is warranted with increasing emergence of genotype-first approaches to screening.

Lifelong aerobic exercise protects against inflammaging and cancer.

Biological aging is associated with progressive damage accumulation, loss of organ reserves, and systemic inflammation ('inflammaging'), which predispose for a wide spectrum of chronic diseases, including several types of cancer. In contrast, aerobic exercise training (AET) reduces inflammation, lowers all-cause mortality, and enhances both health and lifespan. In this study, we examined the benefits of early-onset, lifelong AET on predictors of health, inflammation, and cancer incidence in a naturally aging mouse model (C57BL/J6). Lifelong, voluntary wheel-running (O-AET; 26-month-old) prevented age-related declines in aerobic fitness and motor coordination vs. age-matched, sedentary controls (O-SED). AET also provided partial protection against sarcopenia, dynapenia, testicular atrophy, and overall organ pathology, hence augmenting the 'physiologic reserve' of lifelong runners. Systemic inflammation, as evidenced by a chronic elevation in 17 of 18 pro- and anti-inflammatory cytokines and chemokines (P < 0.05 O-SED vs. 2-month-old Y-CON), was potently mitigated by lifelong AET (P < 0.05 O-AET vs. O-SED), including master regulators of the cytokine cascade and cancer progression (IL-1ß, TNF-α, and IL-6). In addition, circulating SPARC, previously known to be upregulated in metabolic disease, was elevated in old, sedentary mice, but was normalized to young control levels in lifelong runners. Remarkably, malignant tumours were also completely absent in the O-AET group, whereas they were present in the brain (pituitary), liver, spleen, and intestines of sedentary mice. Collectively, our results indicate that early-onset, lifelong running dampens inflammaging, protects against multiple cancer types, and extends healthspan of naturally-aged mice.

Thresholds for detection and awareness of masked facial stimuli.

It has been suggested that perception without awareness can be demonstrated by a dissociation between performance in objective (forced-choice) and subjective (yes-no) tasks, and such dissociations have been reported both for simple stimuli and more complex ones including faces. However, signal detection theory (SDT) indicates that the subjective measures used to assess awareness in such studies can be affected by response bias, which could account for the observed dissociation, and this was confirmed by Balsdon and Azzopardi (2015) using simple visual targets. However, this finding may not apply to all types of stimulus, as the detectability of complex targets such as faces is known to be affected by their configuration as well as by their stimulus energy. We tested this with a comparison of forced-choice and yes-no detection of facial stimuli depicting happy or angry or fearful expressions using a backward masking paradigm, and using SDT methods including correcting for unequal variances in the underlying signal distributions, to measure sensitivity independently of response criterion in 12 normal observers. In 47 out 48 comparisons there was no significant difference between sensitivity (da) in the two tasks: hence, across the range of expressions tested it appears that the configuration of complex stimuli does not enhance detectability independently of awareness. The results imply that, on the basis of psychophysical experiments in normal observers, there is no reason to postulate that performance and awareness are mediated by separate processes.

Absolute and relative blindsight.

The concept of relative blindsight, referring to a difference in conscious awareness between conditions otherwise matched for performance, was introduced by Lau and Passingham (2006) as a way of identifying the neural correlates of consciousness (NCC) in fMRI experiments. By analogy, absolute blindsight refers to a difference between performance and awareness regardless of whether it is possible to match performance across conditions. Here, we address the question of whether relative and absolute blindsight in normal observers can be accounted for by response bias. In our replication of Lau and Passingham's experiment, the relative blindsight effect was abolished when performance was assessed by means of a bias-free 2AFC task or when the criterion for awareness was varied. Furthermore, there was no evidence of either relative or absolute blindsight when both performance and awareness were assessed with bias-free measures derived from confidence ratings using signal detection theory. This suggests that both relative and absolute blindsight in normal observers amount to no more than variations in response bias in the assessment of performance and awareness. Consideration of the properties of psychometric functions reveals a number of ways in which relative and absolute blindsight could arise trivially and elucidates a basis for the distinction between Type 1 and Type 2 blindsight.

Illusory motion perception in blindsight.

Motion detection is typically spared in blindsight, which results from damage to the striate cortex (area V1) of the brain that is sufficient to eliminate conscious visual awareness and severely reduce sensitivity to luminance contrast, especially for high spatial and low temporal frequencies. Here we show that the discrimination of motion direction within cortically blind fields is not attributable to feature tracking (the detection of changes in position or shape), but is due instead to the detection of first-order motion energy (spatiotemporal changes in luminance). The key to this finding was a version of the line motion illusion entailing reverse-phi motion in which opposing motion directions are simultaneously cued by motion energy and changes in stimulus shape. In forced-choice tests, a blindsighted test subject selected the direction cued by shape change when the stimulus was presented in his intact field, but reliably selected the direction cued by motion energy when the same stimulus was presented in his blind field, where relevant position information was either inaccessible or invalid. Motion energy has been characterized as objectless, so reliance on motion energy detection is consistent with impaired access to shape information in blindsight. The dissociation of motion direction by visual field (cortically blind vs. intact) provides evidence that two pathways from the retina to MT/V5 (the cortical area specialized for motion perception) are functionally distinct: the retinogeniculate pathway through V1 is specialized for feature-based motion perception, whereas the retinocollicular pathway, which bypasses V1, is specialized for detecting motion energy.

Roles of electrostatics and conformation in protein-crystal interactions.

In vitro studies have shown that the phosphoprotein osteopontin (OPN) inhibits the nucleation and growth of hydroxyapatite (HA) and other biominerals. In vivo, OPN is believed to prevent the calcification of soft tissues. However, the nature of the interaction between OPN and HA is not understood. In the computational part of the present study, we used molecular dynamics simulations to predict the adsorption of 19 peptides, each 16 amino acids long and collectively covering the entire sequence of OPN, to the {100} face of HA. This analysis showed that there is an inverse relationship between predicted strength of adsorption and peptide isoelectric point (P<0.0001). Analysis of the OPN sequence by PONDR (Predictor of Naturally Disordered Regions) indicated that OPN sequences predicted to adsorb well to HA are highly disordered. In the experimental part of the study, we synthesized phosphorylated and non-phosphorylated peptides corresponding to OPN sequences 65-80 (pSHDHMDDDDDDDDDGD) and 220-235 (pSHEpSTEQSDAIDpSAEK). In agreement with the PONDR analysis, these were shown by circular dichroism spectroscopy to be largely disordered. A constant-composition/seeded growth assay was used to assess the HA-inhibiting potencies of the synthetic peptides. The phosphorylated versions of OPN65-80 (IC(50) = 1.93 microg/ml) and OPN220-235 (IC(50) = 1.48 microg/ml) are potent inhibitors of HA growth, as is the nonphosphorylated version of OPN65-80 (IC(50) = 2.97 microg/ml); the nonphosphorylated version of OPN220-235 has no measurable inhibitory activity. These findings suggest that the adsorption of acidic proteins to Ca2+-rich crystal faces of biominerals is governed by electrostatics and is facilitated by conformational flexibility of the polypeptide chain.

Evaluation of a 'bias-free' measure of awareness.

The derivation of a reliable, subjective measure of awareness that is not contaminated by observers' response bias is a problem that has long occupied researchers. Kunimoto et al. (2001) proposed a measure of awareness (a') which apparently meets this criterion: a' is derived from confidence ratings and is based on the intuition that confidence should reflect awareness. The aim of this paper is to explore the validity of this measure. Some calculations suggested that, contrary to Kunimoto et al.'s intention, a' can vary as a result of changes in response bias affecting the relative proportions of high- and low-confidence responses. This was not evident in the results of Kunimoto et al.'s original experiments because their method may have artificially 'clamped' observers' response bias close to zero. A predicted consequence of allowing response bias to vary freely is that it can result in a' varying from negative, through zero, to positive values, for a given value of discriminability (d'). We tested whether such variations are likely to occur in practice by employing Kunimoto et al.'s paradigm with various modifications, notably the removal of constraints upon the proportions of low- and high-confidence responses, in a visual discrimination task. As predicted, a' varied with response bias in all participants. Similar results were found when a' was calculated from pre-existing data obtained from a patient with blindsight: a' varied through a range of positive results without approaching zero, which is inconsistent with his well-documented lack of awareness. A second experiment showed how response bias could be manipulated to yield elevated values of a'. On the basis of these findings we conclude that Kunimoto's measure is not as impervious to response bias as was originally assumed.

Response latencies of neurons in visual areas MT and MST of monkeys with striate cortex lesions.

Cortical area, MT (middle temporal area) is specialized for the visual analysis of stimulus motion in the brain. It has been suggested [Brain 118 (1995) 1375] that motion signals reach area MT via two dissociable routes, namely a 'direct' route which bypasses primary visual cortex (area, striate cortex (V1)) and is specialized for processing 'fast' motion (defined as faster than 6 degrees/s) with a relatively short latency, and an 'indirect' route via area V1 for processing 'slow' motion (slower than 6 degrees/s) with a relatively long latency. We tested this proposal by measuring the effects of unilateral V1 lesions on the magnitudes and latencies of responses to fast- and slow-motion (depicted by random dot kinematograms (RDK) ) of single neurons in areas MT and medial superior temporal area (MST) of anaesthetized macaque monkeys. In the unlesioned hemisphere contralateral to a V1 lesion, response magnitudes and latencies of MT neurons were similar to those previously reported from MT neurons in normal monkeys, and there was no significant association between slow movement and long response latency (>100 ms), or between fast movement and short latency (< or =100 ms). V1 lesions led to diminished response magnitudes and increased latencies in area MT of the lesioned hemisphere, but did not selectively abolish MT responses to slow moving stimuli, or abolish long-latency responses to either slow- or fast-moving stimuli. Response magnitudes and latencies in area MST, which receives visual inputs directly from area MT and is also specialized for visual analysis of motion, were unaffected by V1 lesions (though we have shown elsewhere that directionally-selective responses in both areas were impaired by V1 lesions). Overall, the results are incompatible with the hypothesis that there are dissociable routes to MT specialized for processing separately fast and slow motion.