Cortical thickness is associated with altered autonomic function in cognitively impaired and non-impaired older adults

Abstract

Background

Parasympathetic nervous system (PNS) is critical for adaptation to environment demands. PNS can reflect an individual's regulatory capacity of frontal brain regions and has been linked to cognitive capacity. Yet, the relationship of PNS function with cognitive decline and abnormal frontal function that characterize preclinical progression toward Alzheimer's disease (AD) is unclear. Here, we aimed to elucidate the relationship between PNS function and AD-associated neurodegeneration by testing two competing hypotheses involving frontal regions' activity (neurodegeneration vs. compensation).

Methods

In 38 older human adults with amnestic mild cognitive impairment (aMCI) or normative cognition, we measured AD-associated neurodegeneration (AD signature cortical thickness; ADSCT), resting-state fMRI of frontal regions' spontaneous activation, and an electrocardiography measure of PNS (high frequency heart rate variability; HF-HRV). HF-HRV was assessed at rest and during a cognitive task protocol designed to capture HF-HRV reactivity.

Results

Higher HF-HRV at rest was significantly related to both more severe AD-associated neurodegeneration (lower ADSCT scores) and worse cognitive ability. Cognitive impairments were also related to greater suppression of HF-HRV reactivity. High activities of the anterior cingulate cortex significantly mediated relationships between ADSCT and both HF-HRV at rest and HF-HRV reactivity. Notably, these relationships were not affected by the clinical phenotype.

Conclusions

We show that AD-associated neurodegeneration is associated with altered PNS regulation and that compensatory processes linked to frontal overactivation might be responsible for those alterations. This finding provides the first line of evidence in a new framework for understanding how early-stage AD-associated neurodegeneration affects autonomic regulation.

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Sensorimotor control of breathing in the mdx mouse model of Duchenne muscular dystrophy

Abstract

Patients with Duchenne muscular dystrophy (DMD) hypoventilate with consequential arterial blood gas derangement relevant to disease progression. Whereas deficits in DMD diaphragm are recognized, there is a paucity of knowledge in respect of the neural control of breathing in dystrophinopathies. We sought to perform an analysis of respiratory control in a model of DMD, the mdx mouse. In eight week old male wild-type and mdx mice, ventilation and metabolism, carotid body afferent activity, and diaphragm muscle force-generating capacity, and muscle fibre size, distribution and centronucleation were determined. Diaphragm EMG activity and responsiveness to chemostimulation was determined. During normoxia, mdx mice hypoventilated, owing to a reduction in tidal volume. Basal CO₂ production was not different between wild-type and mdx mice. Carotid sinus nerve responses to hyperoxia were blunted in mdx suggesting hypoactivity. However, carotid body, ventilatory and metabolic responses to hypoxia were equivalent in wild-type and mdx mice. Diaphragm force was severely depressed in mdx mice, with evidence of fibre remodelling and damage. Diaphragm EMG responses to chemoactivation were enhanced in mdx mice. We conclude that there is evidence of chronic hypoventilation in young mdx mice. Diaphragm dysfunction confers mechanical deficiency in mdx resulting in impaired capacity to generate normal tidal volume at rest and decreased absolute ventilation during chemoactivation. Enhanced mdx diaphragm EMG responsiveness suggests compensatory neuroplasticity facilitating respiratory motor output, which may extend to accessory muscles of breathing. Our results may have relevance to emerging treatments for human DMD aiming to preserve ventilatory capacity.

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From the international space station to the clinic: how prolonged unloading may disrupt lumbar spine stability

Background contextProlonged microgravity exposure is associated with localized low back pain and an elevated risk of post-flight disc herniation. Though the mechanisms by which microgravity impairs the spine are unclear, they should be foundational for developing in-flight countermeasures for maintaining astronaut spine health. Because human spine anatomy has adapted to upright posture on Earth, observations of how spaceflight affects the spine should also provide new and potentially important information on spine biomechanics that benefit the general population.

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Objective measurement of function following lumbar spinal stenosis decompression reveals improved functional capacity with stagnant real-life physical activity

Lumbar spinal stenosis (LSS) is a prevalent and costly condition associated with significant dysfunction. Alleviation of pain and improvement of function are the primary goals of surgical intervention. While prior studies have measured subjective improvements in function after surgery, few have examined objective markers of functional improvement.

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Analysis of cervical spine alignment in currently asymptomatic individuals: prevalence of kyphotic posture and its relationship with other spinopelvic parameters.

Many studies tend to characterize cervical kyphosis as a significant clinical condition that needs to be treated. Moreover, opinions vary on whether cervical kyphosis should be considered a pathologic status or a natural occurrence in asymptomatic people.

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A minimum of 5-year follow-up after lumbar transforaminal epidural steroid injections in patients with lumbar radicular pain due to intervertebral disc herniation

Patients with lumbosacral radiculopathy from a intervertebral disc herniation are frequently treated by transforaminal epidural steroid injections (TFESIs). The long-term outcomes of these patients are poorly described.

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Occipital and external acoustic meatus to axis angle as a predictor of the oropharyngeal space in healthy volunteers: a novel parameter for craniocervical junction alignment

The occipito-C2 angle (O-C2a) influences the oropharyngeal space. However, O-C2a has several limitations. There is no normal value of O-C2a due to wide individual variations, and O-C2a does not reflect translation of the cranium to the axis, another factor influencing the oropharyngeal space in patients with atlantoaxial subluxation.

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Should long segment cervical fusions be routinely carried into the thoracic spine? –multi-center analysis

While recommendations for caudal "end level" in posterior cervical reconstruction remain highly variable, the benefits of routine extension of posterior cervical fusions into the thoracic spine remain unclear.

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Phase I/II trial of combined kyphoplasty and intraoperative radiotherapy in spinal metastases

Spinal metastases occur in 30-50% of patients with systemic cancer. The primary goals of palliation are pain control and prevention of local recurrence.

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Effect of pre-injection opioid use on post-injection patient-reported outcomes following epidural steroid injections for radicular pain

Chronic opioid therapy is associated with worse patient-reported outcomes (PROs) following spine surgery. However, little literature exists on the relationship between opioid use and patient-reported outcomes following epidural steroid injections for radicular pain.

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Genomic disorders 20 years on - mechanisms for clinical manifestations

Genomic disorders result from copy number variants (CNVs) or submicroscopic rearrangements of the genome rather than from single nucleotide variants (SNVs). Diverse technologies, including array comparative genomic hybridization (aCGH) and, more recently, whole genome sequencing and whole exome sequencing, have enabled robust genome-wide unbiased detection of CNVs in affected individuals and in reportedly healthy controls. Sequencing of breakpoint junctions has allowed for elucidation of upstream mechanisms leading to genomic instability and resultant structural variation, whereas studies of the association between CNVs and specific diseases or susceptibility to morbid traits have enhanced our understanding of the downstream effects. In this review, we discuss the hallmarks of genomic disorders as they were defined during the first decade of the field, including genomic instability and the mechanism for rearrangement defined as nonallelic homologous recombination (NAHR); recurrent versus nonrecurrent rearrangements; and gene dosage sensitivity. Moreover, we highlight the exciting advances of the second decade of this field, including a deeper understanding of genomic instability and the mechanisms underlying complex rearrangements, mechanisms for constitutional and somatic chromosomal rearrangements, structural intra-species polymorphisms and susceptibility to NAHR, the role of CNVs in the context of genome-wide copy number and single nucleotide variation, and the contribution of non-coding CNVs to human disease.

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Event-related potential components as measures of aversive conditioning in humans

Abstract

For more than 60 years, the gold standard for assessing aversive conditioning in humans has been the skin conductance response (SCR), which arises from the activation of the peripheral nervous system. Although the SCR has been proven useful, it has some properties that impact the kinds of questions it can be used to answer. In particular, the SCR is slow, reaching a peak 4–5 s after stimulus onset, and it decreases in amplitude after a few trials (habituation). The present study asked whether the late positive potential (LPP) of the ERP waveform could be a useful complementary method for assessing aversive conditioning in humans. The SCR and LPP were measured in an aversive conditioning paradigm consisting of three blocks in which one color was paired with a loud noise (CS+) and other colors were not paired with the noise (CS−). Participants also reported the perceived likelihood of being exposed to the noise for each color. Both SCR and LPP were significantly larger on CS+ trials than on CS− trials. However, SCR decreased steeply after the first conditioning block, whereas LPP and self-reports were stable over blocks. These results indicate that the LPP can be used to assess aversive conditioning and has several useful properties: (a) it is a direct response of the central nervous system, (b) it is fast, with an onset latency of 300 ms, (c) it does not habituate over time.

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Flashing a smile: Startle eyeblink modulation by masked affective faces

Abstract

Affective faces are important stimuli with relevance to healthy and abnormal social and affective information processing. The aim of this study was to investigate the effect of brief presentations of affective faces on attention and emotional state across the time course of stimulus processing, as indexed by startle eyeblink response modulation. Healthy adults were presented with happy, neutral, and disgusted male and female faces that were backward masked by neutral faces. Startle responses were elicited at 300, 800, and 3,500 ms following stimulus presentation to probe early and late startle eyeblink modulation, indicative of attention allocation and emotional state, respectively. Results revealed that, at 300 ms, both face expression and face gender modulated startle eyeblink response, suggesting that more attention was allocated to masked happy compared to disgusted female faces, and masked disgusted compared to neutral male faces. There were no effects of either face expression or face gender on startle modulation at 800 ms. At 3,500 ms, target face expression did not modulate startle, but male faces elicited larger startle responses than female faces, indicative of a more negative emotional state. These findings provide a systematic investigation of attention and emotion modulation by brief affective faces across the time course of stimulus processing.

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Preadmission statin use improves the outcome of less severe sepsis patients - a population-based propensity score matched cohort study

Abstract

Background.

Randomized controlled trials on the post-admission use of statins in sepsis patients have not shown a survival benefit. Whether preadmission use of statins would confer any beneficial effects in sepsis patients has not been well studied.

Methods.

We conducted a population-based cohort study on a national health insurance claims database between 1999 and 2011. Sepsis patients were identified by ICD-9 codes compatible with the third International consensus definitions for sepsis. Use of statin was defined as the cumulative use of any statin for more than 30 days before the indexed sepsis admission. We determined the association between statin use and sepsis outcome by multivariate-adjusted Cox proportional hazard models and propensity score matched analysis. To minimize baseline imbalance between statin users and non-statin users, we matched/adjusted for social economic status, comorbidities, proxies for healthy lifestyle, health care facility utilization, and use of medications.

Results.

We identified 52 737 sepsis patients, of which 3599 received statin treatment. Statins use was associated with a reduced 30-day mortality after multivariable adjustment (HR 0.86, 95% CI, 0.78–0.94) and propensity score matching (HR, 0.88; 95% CI, 0.78–0.99). On subgroup analysis, the beneficial effects of statins were not significant in patients receiving ventilator support or requiring ICU admission.

Conclusions.

In this national cohort study, preadmission statin therapy before sepsis development was associated with a 12% reduction in mortality when compared with patients who never received a statin. There were no consistent beneficial effects of statins in all patient subgroups.

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Vitamin D deficiency accelerates ageing and age-related diseases- a novel hypothesis

Abstract

Ageing can occur at different rates, but what controls this variable rate is unknown. Here I have developed a hypothesis that Vitamin D may act to control the rate of ageing. The basis of this hypothesis emerged from studyng the various cellular processes that control ageing. These processes such as autophagy, mitochondrial dysfunction, inflammation, oxidative stress, epigenetic changes, DNA disorders and alterations in Ca²⁺ and reactive oxygen species (ROS) signalling are all known to be regulated by Vitamin D. The activity of these processes will be enhanced in individuals that are deficient in Vitamin D. Not only will this increase the rate of ageing, but it will also increase the probability of developing age-related diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis and cardiovascular disease. In individual with normal Vitamin D levels, these ageing related processes will occur at lower rates resulting in a reduced rate of ageing and enhanced protection against these age-related diseases.

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Can low-load blood-flow restriction training elicit muscle hypertrophy with modest inflammation and cellular stress, but minimal muscle damage?

Abstract

Blood flow restriction (BFR) training is characterised by the application of a pneumatic cuff to the working limb during resistance or aerobic exercise.

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Calcium influx through TRPV4 channels modulates the adherens contacts between retinal microvascular endothelial cells

Abstract

The identity of microvascular endothelial (MVE) mechanosensors that sense blood flow in response to mechanical and chemical stimuli and regulate vascular permeability in the retina is unknown. Taking advantage of immunohistochemistry, calcium imaging, electrophysiology, impedance measurements and vascular permeability assays, we show that the transient receptor potential isoform 4 (TRPV4) plays a major role in Ca²⁺/cation signalling, cytoskeletal remodelling and barrier function in retinal microvasculature in vitro and in vivo. Human retinal MVECs (HrMVECs) predominantly expressed Trpv1 and Trpv4 transcripts, and TRPV4 was broadly localized to the plasma membrane of cultured cells and intact blood vessels in the inner retina. Treatment with the selective TRPV4 agonist GSK1016790A (GSK101) activated a nonselective cation current, robustly elevated [Ca²⁺]_i and reversibly increased the permeability of MVEC monolayers. This was associated with disrupted organization of endothelial F-actin, downregulated expression of occludin and remodelling of adherens contacts consisting of vascular endothelial cadherin (VE-cadherin) and β−catenin. In vivo, GSK101 increased the permeability of retinal blood vessels in wild type, but not in TRPV4 knockout mice. Agonist-evoked effects on barrier permeability and cytoskeletal reorganization were antagonized by the selective TRPV4 blocker HC 067047. Human choroidal endothelial cells (CECs) showed lower TRPV4 mRNA/protein levels and less pronounced agonist-evoked calcium signals compared to MVECs. These findings demonstrate a major role for TRPV4 in Ca²⁺ homeostasis and barrier function in the human retinal microvascular endothelial barrier and suggest TRPV4 may differentially contribute to the inner vis à vis outer blood-retinal barrier function.

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Prenatal diagnosis of femoral facial syndrome: Three case reports and literature review

Facial femoral syndrome (FFS) is a rare congenital abnormality, also known as femoral hypoplasia-unusual facies syndrome, characterized by variable degrees of femoral hypoplasia, associated with specific facial features. Other organ malformations are sometimes present. Most cases are sporadic, but rare family observations suggest genetic origin. However, no chromosomal or genetic abnormalities have ever been incriminated. We conducted a comprehensive literature review and added three new unreported observations. Through these 92 cases, authors aimed to determine sonographic signs that should direct towards diagnosis, and discuss potential genetic etiology. Diagnosis was suspected prenatally in 27.2% of cases, and maternal diabetes was found in 42.4% of patients. When fetal karyotype was available, it was normal in 97.1% of cases, but genomic variations of unknown significance were discovered in all three cases in which array comparative genomic hybridization (CGH) techniques were applied. Femoral affection defining FFS was hypoplasia in 78.3% of cases, agenesis in 12%, and both in 9.8%. Affection was bilateral in 84.8% of cases. Retrognathia was present in 65.2% of cases, cleft lip and/or palate in 63%, and other organ malformations in 53.3%. Intellectual development was normal in 79.2% of cases. Better prenatal recognition of this pathology, notably frequently associated malformations, should lead to a more precise estimation of functional prognosis. It seems likely that today's tendency to systematically employ array-CGH and exome/genome sequencing methods to investigate malformative sequences will allow the identification of a causal genetic abnormality in the near future.

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Mutations in folate transporter genes and risk for human myelomeningocele

The molecular mechanisms linking folate deficiency and neural tube defect (NTD) risk in offspring remain unclear. Folate transporters (SLC19A1, SLC46A1, SLC25A32, and FOLH1) and folate receptors (FOLR1, FOLR2, and FOLR3) are suggested to play essential roles in transporting folate from maternal intestinal lumen to the developing embryo. Loss of function variants in these genes may affect folate availability and contribute to NTD risk. This study examines whether variants within the folate transporter and receptor genes are associated with an increased risk for myelomeningocele (MM). Exons and their flanking intron sequences of 348 MM subjects were sequenced using the Sanger sequencing method and/or next generation sequencing to identify variants. Frequencies of alleles of single nucleotide polymorphisms (SNPs) in MM subjects were compared to those from ethnically matched reference populations to evaluate alleles' associated risk for MM. We identified eight novel variants in SLC19A1 and twelve novel variants in FOLR1, FOLR2, and FOLR3. Pathogenic variants include c.1265delG in SLC19A1 resulting in an early stop codon, four large insertion deletion variants in FOLR3, and a stop_gain variant in FOLR3. No new variants were identified in SLC46A1, SLC25A32, or FOLH1. In SLC19A1, c.80A>G (rs1051266) was not associated with our MM cohort; we did observe a variant allele G frequency of 61.7%, higher than previously reported in other NTD populations. In conclusion, we discovered novel loss of function variants in genes involved in folate transport in MM subjects. Our results support the growing evidence of associations between genes involved in folate transport and susceptibility to NTDs.

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