Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea.

It is challenging to determine which patients with obstructive sleep apnea (OSA) have impaired driving ability. Vulnerability to this neurobehavioral impairment may be explained by lower brain metabolites levels involved in mitochondrial metabolism. This study compared markers of brain energy metabolism in OSA patients identified as vulnerable vs resistant to driving impairment following extended wakefulness. 44 patients with moderate-severe OSA underwent 28hr extended wakefulness with three 90min driving simulation assessments. Using a two-step cluster analysis, objective driving data (steering deviation and crashes) from the 2nd driving assessment (22.5 h awake) was used to categorise patients into vulnerable (poor driving, n = 21) or resistant groups (good driving, n = 23). 1 H magnetic resonance spectra were acquired at baseline using two scan sequences (short echo PRESS and longer echo-time asymmetric PRESS), focusing on key metabolites, creatine, glutamate, N-acetylaspartate (NAA) in the hippocampus, anterior cingulate cortex and left orbito-frontal cortex. Based on cluster analysis, the vulnerable group had impaired driving performance compared with the resistant group and had lower levels of creatine (PRESS p = ns, APRESS p = 0.039), glutamate, (PRESS p < 0.01, APRESS p < 0.01), NAA (PRESS p = 0.038, APRESS p = 0.035) exclusively in the left orbito-frontal cortex. Adjusted analysis, higher glutamate was associated with a 21% (PRESS) and 36% (APRESS) reduced risk of vulnerable classification. Brain mitochondrial bioenergetics in the frontal brain regions are impaired in OSA patients who are vulnerable to driving impairment following sleep loss. These findings provide a potential way to identify at risk OSA phenotype when assessing fitness to drive, but this requires confirmation in larger future studies.

Novel inhibitors of the high-affinity L-proline transporter as potential therapeutic agents for the treatment of cognitive disorders.

The incidence of cognitive disorders such as Alzheimer's disease continues to increase unabated. While cures for such diseases have eluded investigators, progress is being made on alleviating certain symptoms of these diseases. Mouse knockouts of the proline transporter (PROT), a high affinity Na(+)/Cl(-)-dependent transporter, indicated its potential as a novel therapeutic target for cognition improvement. Herein we report our investigation into a novel class of PROT inhibitors.

Quality Output Checklist and Content Assessment (QuOCCA): a new tool for assessing research quality and reproducibility.

Research must be well designed, properly conducted and clearly and transparently reported. Our independent medical research institute wanted a simple, generic tool to assess the quality of the research conducted by its researchers, with the goal of identifying areas that could be improved through targeted educational activities. Unfortunately, none was available, thus we devised our own. Here, we report development of the Quality Output Checklist and Content Assessment (QuOCCA), and its application to publications from our institute's scientists. Following consensus meetings and external review by statistical and methodological experts, 11 items were selected for the final version of the QuOCCA: research transparency (items 1-3), research design and analysis (items 4-6) and research reporting practices (items 7-11). Five pairs of raters assessed all 231 articles published in 2017 and 221 in 2018 by researchers at our institute. Overall, the results were similar between years and revealed limited engagement with several recommended practices highlighted in the QuOCCA. These results will be useful to guide educational initiatives and their effectiveness. The QuOCCA is brief and focuses on broadly applicable and relevant concepts to open, high-quality, reproducible and well-reported science. Thus, the QuOCCA could be used by other biomedical institutions and individual researchers to evaluate research publications, assess changes in research practice over time and guide the discussion about high-quality, open science. Given its generic nature, the QuOCCA may also be useful in other research disciplines.

The alpha-fetoprotein enhancer region activates the albumin and alpha-fetoprotein promoters during liver development.

The four members of the albumin gene family encode the serum transport proteins albumin, alpha-fetoprotein, alpha-albumin, and vitamin D-binding protein. These genes are transcribed primarily in the liver with each having a different pattern of developmental expression. The tight linkage of these genes, particularly that of albumin, alpha-fetoprotein and alpha-albumin, and their liver-specific expression, has led to the suggestion that these genes share common regulatory elements. To directly examine whether the alpha-fetoprotein enhancer region could regulate the albumin gene family, expression of these genes was monitored in mice in which this region was deleted by homologous recombination. Our data indicate that this enhancer region is required for alpha-fetoprotein and albumin activation early in liver development and alpha-fetoprotein reactivation during liver regeneration, but that albumin, alpha-albumin, and vitamin D-binding protein expression later in hepatic development is not affected by the absence of these enhancers. We also demonstrate that RNA polymerase II loading on the alpha-fetoprotein and albumin promoters is reduced in the absence of this enhancer region, indicating a direct role for these enhancers in the assembly of the RNA Polymerase II complex during liver development.

Step-Based Physical Activity Metrics and Cardiometabolic Risk: NHANES 2005-2006.

PURPOSE: This study aimed to catalog the relationships between step-based accelerometer metrics indicative of physical activity volume (steps per day, adjusted to a pedometer scale), intensity (mean steps per minute from the highest, not necessarily consecutive, minutes in a day; peak 30-min cadence), and sedentary behavior (percent time at zero cadence relative to wear time; %TZC) and cardiometabolic risk factors. METHODS: We analyzed data from 3388 participants, 20+ yr old, in the 2005-2006 National Health and Nutrition Examination Survey with ≥1 valid day of accelerometer data and at least some data on weight, body mass index, waist circumference, systolic and diastolic blood pressure, glucose, insulin, HDL cholesterol, triglycerides, and/or glycohemoglobin. Linear trends were evaluated for cardiometabolic variables, adjusted for age and race, across quintiles of steps per day, peak 30-min cadence, and %TZC. RESULTS: Median steps per day ranged from 2247 to 12,334 steps per day for men and from 1755 to 9824 steps per day for women, and median peak 30-min cadence ranged from 48.1 to 96.0 steps per minute for men and from 40.8 to 96.2 steps per minute for women for the first and fifth quintiles, respectively. Linear trends were statistically significant (all P < 0.001), with increasing quintiles of steps per day and peak 30-min cadence inversely associated with waist circumference, weight, body mass index, and insulin for both men and women. Median %TZC ranged from 17.6% to 51.0% for men and from 19.9% to 47.6% for women for the first and fifth quintiles, respectively. Linear trends were statistically significant (all P < 0.05), with increasing quintiles of %TZC associated with increased waist circumference, weight and insulin for men, and insulin for women. CONCLUSIONS: This analysis identified strong linear relationships between step-based movement/nonmovement dimensions and cardiometabolic risk factors. These data offer a set of quantified access points for studying the potential dose-response effects of each of these dimensions separately or collectively in longitudinal observational or intervention study designs.

An Objective Short Sleep Insomnia Disorder Subtype Is Associated With Reduced Brain Metabolite Concentrations In Vivo: A Preliminary Magnetic Resonance Spectroscopy Assessment.

Objectives: To evaluate brain metabolites in objective insomnia subtypes defined from polysomnography (PSG): insomnia with short sleep duration (I-SSD) and insomnia with normal sleep duration (I-NSD), relative to good sleeping controls (GSCs). Methods: PSG empirically grouped insomnia patients into I-SSD (n = 12: mean [SD] total sleep time [TST] = 294.7 minutes [30.5]) or I-NSD (n = 19: TST = 394.4 minutes [34.9]). 1H magnetic resonance spectroscopy (MRS) acquired in the left occipital cortex (LOCC), left prefrontal cortex, and anterior cingulate cortex was used to determine levels of creatine, aspartate, glutamate, and glutamine (referenced to water). Glutathione, glycerophosphocholine, lactate, myoinositol, and N-acetylaspartate measurements were also obtained. Sixteen GSCs were included for comparison. Multivariate analysis of variance was used to evaluate differences in creatine, aspartate, glutamate, and glutamine. Results: Aspartate and glutamine concentrations were reduced in the LOCC in I-SSD compared with I-NSD (both p < .05, d = .80-.99). Creatine displayed a nonsignificant mean reduction in I-SSD compared with I-NSD (p = .05, d = .58). Glutamine was reduced in I-SSD compared with controls (p < .05, d = .93). There were no differences in metabolites between all (I-SSD and I-NSD) insomnia patients and controls. In patients with insomnia, LOCC glutamine concentrations were found to be positively correlated with TST (r = .43, p < .05) and negatively correlated with wake-time after sleep onset (r = -.40, p < .05). Conclusions: Results indicate that I-SSD is associated with reduced brain metabolites in the LOCC compared with I-NSD and control concentrations of aspartate, glutamine, and creatine. Clinical Trial Registration: Insomnia MRS imaging sleep study: Australia New Zealand Clinical Trials Registry (ANZCTR): https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000050853. Trial Identification Number: 12612000050853.

Inhibitors of human histone deacetylase: synthesis and enzyme and cellular activity of straight chain hydroxamates.

Inhibitors of histone deacetylase (HDAC) have been shown to induce terminal differentiation of human tumor cell lines and to have antitumor effects in vivo. We have prepared analogues of suberoylanilide hydroxamic acid (SAHA) and trichostatin A and have evaluated them in a human HDAC enzyme inhibition assay, a p21(waf1) (p21) promoter assay, and in monolayer growth inhibition assays. One compound, 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide, was found to affect the growth of a panel of eight human tumor cell lines differentially.

N-hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824).

A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.

Viscoelastic properties of human cerebellum using magnetic resonance elastography.

BACKGROUND: The cerebellum has never been mechanically characterised, despite its physiological importance in the control of motion and the clinical prevalence of cerebellar pathologies. The aim of this study was to measure the linear viscoelastic properties of the cerebellum in human volunteers using Magnetic Resonance Elastography (MRE). METHODS: Coronal plane brain 3D MRE data was performed on eight healthy adult volunteers, at 80 Hz, to compare the properties of cerebral and cerebellar tissues. The linear viscoelastic storage (G') and loss moduli (G″) were estimated from the MRE wave images by solving the wave equation for propagation through an isotropic linear viscoelastic solid. Contributions of the compressional wave were removed via application of the curl-operator. RESULTS: The storage modulus for the cerebellum was found to be significantly lower than that for the cerebrum, for both white and grey matter. Cerebrum: white matter (mean±SD) G'=2.41±0.23 kPa, grey matter G'=2.34±0.22 kPa; cerebellum: white matter, G'=1.85±0.18 kPa, grey matter G'=1.77±0.24 kPa; cerebrum vs cerebellum, p<0.001. For the viscous behaviour, there were differences in between regions and also by tissue type, with the white matter being more viscous than grey matter and the cerebrum more viscous than the cerebellum. Cerebrum: white matter G″=1.21±0.21 kPa, grey matter G″=1.11±0.03 kPa; cerebellum: white matter G″=1.1±0.23 kPa, grey matter G″=0.94±0.17 kPa. DISCUSSION: These data represent the first available data on the viscoelastic properties of cerebellum, which suggest that the cerebellum is less physically stiff than the cerebrum, possibly leading to a different response to mechanical loading. These data will be useful for modelling of the cerebellum for a range of purposes.

Efficient activation of reconstructed rat embryos by cyclin-dependent kinase inhibitors.

BACKGROUND: Over the last decade a number of species, from farm animals to rodents, have been cloned using somatic cell nuclear transfer technology (SCNT). This technique has the potential to revolutionize the way that genetically modified animals are made. In its current state, the process of SCNT is very inefficient (<5% success rate), with several technical and biological hurdles hindering development. Yet, SCNT provides investigators with powerful advantages over other approaches, such as allowing for prescreening for the desired level of transgene expression and eliminating the excess production of undesirable wild-type animals. The rat plays a significant role in biomedical research, but SCNT has been problematic for this species. In this study, we address one aspect of the problem by evaluating methods of activation in artificially constructed rat embryos. PRINCIPAL FINDINGS: We demonstrate that treatment with a calcium ionophore (ionomycin) combined with a variety of cyclin-dependent kinase inhibitors is an effective way to activate rat embryos. This is in contrast to methods developed for the mouse embryo, which tolerates much less specific chemical treatments. Methods developed to activate mouse embryos do not translate well to rat embryos. CONCLUSIONS: Activation methods developed for one species will not necessarily translate to another species, even if it is closely related. Further, the parthenogenic response to chemical activators is not always a reliable indicator of how reconstructed embryos will react to the same activation method. A better understanding of rat oocyte physiology, although essential for developing better models of disease, may also provide insights that will be useful for making the SCNT process more efficient.

Lamotrigine-induced aseptic meningitis: a case report.

Aseptic meningitis could be a rare side effect of lamotrigine. Aseptic meningitis is a clinical condition where symptoms, signs and laboratory findings are consistent with meningeal inflammation but routine bacterial cultures are negative. Clinical presentation of aseptic meningitis is similar to bacterial meningitis with prominent symptoms of fever, headache and neck stiffness. Drug-induced aseptic meningitis is an uncommon adverse effect of several drugs. The most common ones are nonsteroidal anti-inflammatory drugs, intravenous immunoglobulins, intrathecal agents and vaccines. Disease manifestations vary with different drugs. A few cases of lamotrigine-induced aseptic meningitis have been published earlier. This is the fifth case reported of lamotrigine-induced aseptic meningitis. However, this is the first case which is associated with a second episode on rechallenge of lamotrigine.

In vivo brain viscoelastic properties measured by magnetic resonance elastography.

Magnetic resonance elastography (MRE) is a non-invasive imaging technique used to visualise and quantify mechanical properties of tissue, providing information beyond what can be currently achieved with standard MR sequences and could, for instance, provide new insight into pathological processes in the brain. This study uses the MRE technique at 3 T to extract the complex shear modulus for in vivo brain tissue utilizing a full three-dimensional approach to reconstruction, removing contributions of the dilatational wave by application of the curl operator. A calibrated phantom is used to benchmark the MRE measurements, and in vivo results are presented for healthy volunteers. The results provide data for in vivo brain storage modulus (G'), finding grey matter (3.1 kPa) to be significantly stiffer than white matter (2.7 kPa). The first in vivo loss modulus (G'') measurements show no significant difference between grey matter (2.5 kPa) and white matter (2.5 kPa).

The elk PRNP codon 132 polymorphism controls cervid and scrapie prion propagation.

The elk prion protein gene (PRNP) encodes either methionine (M) or leucine (L) at codon 132, the L132 allele apparently affording protection against chronic wasting disease (CWD). The corresponding human codon 129 polymorphism influences the host range of bovine spongiform encephalopathy (BSE) prions. To fully address the influence of this cervid polymorphism on CWD pathogenesis, we created transgenic (Tg) mice expressing cervid PrPC with L at residue 132, referred to as CerPrPC-L132, and compared the transmissibility of CWD prions from elk of defined PRNP genotypes, namely homozygous M/M or L/L or heterozygous M/L, in these Tg mice with previously described Tg mice expressing CerPrPC-M132, referred to as Tg(CerPrP) mice. While Tg(CerPrP) mice were consistently susceptible to CWD prions from elk of all three genotypes, Tg(CerPrP-L132) mice uniformly failed to develop disease following challenge with CWD prions. In contrast, SSBP/1 sheep scrapie prions transmitted efficiently to both Tg(CerPrP) and Tg(CerPrP-L132) mice. Our findings suggest that the elk 132 polymorphism controls prion susceptibility at the level of prion strain selection and that cervid PrP L132 severely restricts propagation of CWD prions. We speculate that the L132 polymorphism results in less efficient conversion of CerPrPC-L132 by CWD prions, an effect that is overcome by the SSBP/1 strain. Our studies show the accumulation of subclinical levels of CerPrPSc in aged asymptomatic CWD-inoculated Tg(CerPrP-L132) mice and also suggests the establishment of a latent infection state in apparently healthy elk expressing this seemingly protective allele.

19th-century pathology : The examination of 83 vault-interred bodies.

Eighty-three bodies that had been inhumed in airtight lead coffins for more than 150 years were subjected to postmortem examinations that included histological, dental, and microbiological studies. Preservation of internal structures was excellent in 29 cases, and moderate to good in 10. Skin and external features were well preserved in 10 other cases. The remaining bodies were reduced to skeletons. There was identifiable pathology in the majority of the well-preserved cases. In several bodies, more than one disease was present. It was possible to correlate the pathological findings with contemporary diagnoses in 10 cases.