Experimental neuroinflammation: a focus on mitochondria, oxygen and function

There is increasing evidence for "hypoxia-like" conditions in some inflammatory multiple sclerosis (MS) lesions raising the possibility that the tissue is deficient in energy. Accodingly, mitochondrial abnormalities have been described in some MS tissue, including reduced mitochondrial gene transcripts in MS motor cortex and decreased mitochondrial complex IV expression. To explore the role of mitochondrial defects in neuroinflammatory lesions, experimental inflammatory lesions were induced by the intraspinal injection of lipopolysaccharide in rats under general anaesthesia. The tissue was snap-frozen for histochemical assessment of mitochondrial complex II and/or IV activity at various intervals (1-28 days) post injection: the activity of the complexes was compared with porin expression or complex IV subunit I expression (presence of mitochondria or protein respectively). The oxygen concentration within the dorsal column was determined at 24 hours after lesion induction in vivo using an oxygen-sensitive optical probe. EMG potentials were also recorded at the foot dorsum in response to stimulation of the sciatic nerve. Presence of reactive oxygen and nitrogen species were examined by immunohistochemistry and by the fluorescent marker dihydroethidium (DHE) in vivo. Complex IV activity within the motor neurons was decreased 1 day after injection, further decreased by day 2, and returned to pre-injection baseline by day 5. Decreased complex IV activity exactly coincided with a temporary reduction in motor neuron excitability as measured by H reflex and F wave amplitude, which was maximal at day 2. The oxygen concentration within the dorsal columns at the site of the LPS lesion was significantly elevated when compared with the saline-injected and naïve control animals. DHE fluorescence revealed that superoxide production was increased at the lesion site and immmunohistochemistry revealed oxidative stress to DNA, lipids and protein. LPS-induced neuroinflammation results in a reversible and coincident decrease in both complex IV activity and motor neuron excitability, which was strengthened by the result that intraspinal LPS-injections causes hyperoxia, presumably from mitochondrial dysfunction. Nitric oxide has been implicated in neuronal dysfunction and although a causal relationship has not been established, observations support an interpretation that inflammation-mediated NO causes mitochondrial damage, increased oxygen concentration and formation of reactive oxygen species (ROS). These actions illustrate a vicious circle where ROS induce further damage, which results in energy deficiency displayed by reduced neuronal excitability and neurological deficits. The observations are consistent with energy deficiency and reduced function in neuroinflammatory lesions similar to those found in MS

Low Levels of Hemoglobin at Admission Are Associated With Increased 30-Day Mortality in Patients With Hip Fracture

INTRODUCTION: Previous smaller studies suggest that anemia is a risk factor for mortality in patients with hip fracture. The purpose of this investigation was to assess the correlation between hemoglobin at admission with 30-day mortality following a hip fracture in a large-scale study. PATIENTS AND METHODS: From January 1996 to December 2012, all patients with hip fracture (>60 years of age) admitted to Bispebjerg Hospital, Copenhagen, were identified from a local hip fracture database. We excluded conservatively treated patients and patients who died preoperatively. RESULTS: Seven thousand four hundred twenty-one consecutive patients with hip fracture were identified. Of those 7319 had a hemoglobin measurement on admission and were thus eligible for further analysis. Mean hemoglobin for patients alive at 30 days was 7.6 (standard deviation [SD]: 1.0) and for deceased patients 7.4 (SD: 1.1), P < .0001. Mean age was 82.6 years (SD: 8.5), and 76.5% of the population were female (N(females) = 5600). The 30-day mortality decreases for every increase in hemoglobin of 1.0 mmol/L in a univariate analysis (P < .0001). The hazard ratio (HR) with 95% confidence interval (CI) for 30-day mortality in patients with anemia (<7.3 mmol/L for females and <8.3 mmol/L for males; N(anemic) = 3235) was 1.66 (CI: 1.43-1.91, P < .0001). Adjusting for age, type of fracture, gender, and comorbidities (Charlson score) slightly attenuated the risk estimate (HR: 1.21, CI: 1.03-1.41, P = .02). CONCLUSION: This study demonstrates increased 30-day mortality in patients with low hemoglobin at admission, even after adjusting for comorbidities

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Risk scoring models for predicting peri-operative morbidity and mortality in people with fragility hip fractures: qualitative systematic review

Rationale: Accurate peri-operative risk prediction is an essential element of clinical practice. Various risk stratification tools for assessing patients’ risk of mortality or morbidity have been developed and applied in clinical practice over the years. This review aims to outline essential characteristics (predictive accuracy, objectivity, clinical utility) of currently available risk scoring tools for hip fracture patients. Methods: We searched eight databases; AMED, CINHAL, Clinical Trials.gov, Cochrane, DARE, EMBASE, MEDLINE and Web of Science for all relevant studies published until April 2015. We included published English language observational studies that considered the predictive accuracy of risk stratification tools for patients with fragility hip fracture. Results: After removal of duplicates, 15,620 studies were screened. Twenty-nine papers met the inclusion criteria, evaluating 25 risk stratification tools. Risk stratification tools considered in more than two studies were; ASA, CCI, E-PASS, NHFS and O-POSSUM. All tools were moderately accurate and validated in multiple studies; however there are some limitations to consider. The E-PASS and O-POSSUM are comprehensive but complex, and require intraoperative data making them a challenge for use on patient bedside. The ASA, CCI and NHFS are simple, easy and inexpensive using routinely available preoperative data. Contrary to the ASA and CCI which has subjective variables in addition to other limitations, the NHFS variables are all objective. Conclusion: In the search for a simple and inexpensive, easy to calculate, objective and accurate tool, the NHFS may be the most appropriate of the currently available scores for hip fracture patients. However more studies need to be undertaken before it becomes a national hip fracture risk stratification or audit tool of choice

A U-shaped relationship between haematocrit and mortality in a large prospective cohort study

Background: Only a limited number of studies have investigated the correlation between haematocrit (HCT) and mortality in the general population, and few of those studies have had data on a wide range of low and high levels of HCT. We investigated the association between baseline HCT and mortality in a prospective cohort study of 49 983 adult subjects in Iran with a broad spectrum of HCT values. Methods: Data on socio-demographic and life-style factors, past medical history, and levels of HCT were collected at enrollment. During a mean follow-up of 5 years (follow-up success rate ±99%), 2262 deaths were reported. Cox proportional hazards regression models were used to estimate hazard ratios and corresponding 95% confidence intervals. Results: There was a U-shaped relationship between categories of HCT and mortality in both sexes: both low and high levels of HCT were associated with increased overall mortality and mortality from cardiovascular disease. The U-shaped relationship persisted after several sensitivity analyses were done, including analyses restricted to non-smokers and non-users of opium; analyses excluding deaths from accidents and other external causes as well as deaths of persons with self-reported ischemic heart disease at the baseline interview for the study; and analyses excluding the first 2 years of follow-up. Self-reported past medical history and lack of data about lipids and other cellular blood components were the major limitations of the study. Conclusions: Low and high levels of HCT are associated with increased mortality in the general population. The findings in the present study can be of particular importance for low- and middle-income countries in which a substantial proportion of the population lives with suboptimal levels of HCT. © Published by Oxford University Press on behalf of the International Epidemiological Association 2013

The forgotten role of food cultures

Fermentation is one of if not the oldest food processing technique, yet it is still an emerging field when it comes to its numerous mechanisms of action and potential applications. The effect of microbial activity on the taste, bioavailability and preservation of the nutrients and the different food matrices has been deciphered by the insights of molecular microbiology. Among those roles of fermentation in the food chain, biopreservation remains the one most debated. Presumably because it has been underestimated for quite a while, and only considered - based on a food safety and technological approach - from the toxicological and chemical perspective. Biopreservation is not considered as a traditional use, where it has been by design - but forgotten - as the initial goal of fermentation. The 'modern' use of biopreservation is also slightly different from the traditional use, due mainly to changes in cooling of food and other ways of preservation, Extending shelf life is considered to be one of the properties of food additives, classifying - from our perspective - biopreservation wrongly and forgetting the role of fermentation and food cultures. The present review will summarize the current approaches of fermentation as a way to preserve and protect the food, considering the different way in which food cultures and this application could help tackle food waste as an additional control measure to ensure the safety of the food

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. Results: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum of CTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila.Peer reviewe

Association between adolescent idiopathic scoliosis prevalence and age at menarche in different geographic latitudes

BACKGROUND: Age at menarche is considered a reliable prognostic factor for idiopathic scoliosis and varies in different geographic latitudes. Adolescent idiopathic scoliosis prevalence has also been reported to be different in various latitudes and demonstrates higher values in northern countries. A study on epidemiological reports from the literature was conducted to investigate a possible association between prevalence of adolescent idiopathic scoliosis and age at menarche among normal girls in various geographic latitudes. An attempt is also made to implicate a possible role of melatonin in the above association. MATERIAL-METHODS: 20 peer-reviewed published papers reporting adolescent idiopathic scoliosis prevalence and 33 peer-reviewed papers reporting age at menarche in normal girls from most geographic areas of the northern hemisphere were retrieved from the literature. The geographic latitude of each centre where a particular study was originated was documented. The statistical analysis included regression of the adolescent idiopathic scoliosis prevalence and age at menarche by latitude. RESULTS: The regression of prevalence of adolescent idiopathic scoliosis and age at menarche by latitude is statistically significant (p < 0.001) and are following a parallel declining course of their regression curves, especially in latitudes northern than 25 degrees. CONCLUSION: Late age at menarche is parallel with higher prevalence of adolescent idiopathic scoliosis. Pubarche appears later in girls that live in northern latitudes and thus prolongs the period of spine vulnerability while other pre-existing or aetiological factors are contributing to the development of adolescent idiopathic scoliosis. A possible role of geography in the pathogenesis of idiopathic scoliosis is discussed, as it appears that latitude which differentiates the sunlight influences melatonin secretion and modifies age at menarche, which is associated to the prevalence of idiopathic scoliosis

SOSORT consensus paper: school screening for scoliosis. Where are we today?

This report is the SOSORT Consensus Paper on School Screening for Scoliosis discussed at the 4th International Conference on Conservative Management of Spinal Deformities, presented by SOSORT, on May 2007. The objectives were numerous, 1) the inclusion of the existing information on the issue, 2) the analysis and discussion of the responses by the meeting attendees to the twenty six questions of the questionnaire, 3) the impact of screening on frequency of surgical treatment and of its discontinuation, 4) the reasons why these programs must be continued, 5) the evolving aim of School Screening for Scoliosis and 6) recommendations for improvement of the procedure