Analysis and applications of respiratory surface EMG: report of a round table meeting.

Surface electromyography (sEMG) can be used to measure the electrical activity of the respiratory muscles. The possible applications of sEMG span from patients suffering from acute respiratory failure to patients receiving chronic home mechanical ventilation, to evaluate muscle function, titrate ventilatory support and guide treatment. However, sEMG is mainly used as a monitoring tool for research and its use in clinical practice is still limited-in part due to a lack of standardization and transparent reporting. During this round table meeting, recommendations on data acquisition, processing, interpretation, and potential clinical applications of respiratory sEMG were discussed. This paper informs the clinical researcher interested in respiratory muscle monitoring about the current state of the art on sEMG, knowledge gaps and potential future applications for patients with respiratory failure.

Is loneliness associated with cancellation of medical appointments during the COVID-19 pandemic? Evidence from the Hamburg City Health Study (HCHS).

BACKGROUND: The COVID-19 pandemic engendered numerous societal and economic challenges in addition to health-related concerns. Maintenance of healthcare utilization assumed immense significance during this period. However, few studies have examined the association between loneliness and cancelled medical appointments during the COVID-19 pandemic. This study aimed to examine whether medical appointments are less likely to be cancelled with increased loneliness during a pandemic. We analyzed the association between loneliness and both patient- and provider-initiated appointment cancellations. METHODS: Cross-sectional data from the Hamburg City Health Study (HCHS) were collected during April 2020-November 2021. The analytical sample included 1,840 participants with an average age of 55.1 years (standard deviation: 6.5, range 45-76 years). Medical appointments cancelled by individuals-medical appointments in general, and GP, specialist, and dentist appointments-and appointments cancelled by healthcare providers served as outcome measures. Loneliness was quantified using a single item ranging from 0 to 10. Accordingly, we created empirical loneliness tertiles. Covariates were selected based on the Andersen model. Several penalized maximum likelihood logistic regressions were utilized to examine the association between loneliness and cancellation of medical appointments during the COVID-19 pandemic. RESULTS: The penalized maximum likelihood logistic regressions showed that, compared to individuals in the lowest loneliness tertiles, individuals in the other two tertiles reported a higher chance of medical appointments cancellation by individuals, particularly driven by cancelled GP appointments. Except for age and sex, none of the covariates were comparably associated with the outcomes. When appointments cancelled by healthcare providers served as outcomes, only a higher number of chronic conditions was significantly positively associated with it. CONCLUSIONS: Individuals scoring higher in loneliness had a greater chance of cancelling medical (particularly GP) appointments. This may contribute to a potential cascade of loneliness and skipped medical appointments in the future, resulting in adverse health outcomes over the medium-to-long term. Future research should examine whether lonely people are more likely to lack the social motivation to visit the doctor.

Sociocultural influences on dietary behavior and meal timing among Native Hawaiian and Pacific Islander women at risk of endometrial cancer: a qualitative investigation.

PURPOSE: Determine sociocultural influences on dietary behavior, body image, weight loss, and perceptions of the cultural appropriateness of a meal-timing intervention design and menu among Native Hawaiian and Pacific Islander (NHPI) women at risk of endometrial cancer. METHODS: Six 90-min videoconference focus groups among NHPI women (n = 35) recruited by a community champion in Utah. Eligible women were aged ≥ 18 years at risk of endometrial cancer (i.e., BMI ≥ 25 kg/m2, history of non-insulin-dependent diabetes or complex atypical endometrial hyperplasia) had a working cell phone capable of downloading a phone app, could use their cell phone during the day, and were not night-shift workers. Twelve semi-structured questions were posed during the focus groups. Using inductive qualitative methods based on Hatch's 9-step approach, de-identified transcript data were analyzed. RESULTS: Overarching themes included economic factors, cultural influences, meal choice and timing, and perceptions of health. Subthemes included affordability, waste avoidance, inundated schedules, and cultural influences. Perceptions of body size and weight loss were influenced by family, community, and social media, whose messages could be conflicting. Important intervention components included satisfying, convenient pre-made meals, while barriers included the need to cook for family members. CONCLUSIONS: Dietary interventions targeting metabolic health among NHPI women should consider the multitude of sociocultural and economic factors that influence food choices and meal timing in this population, including affordability, hectic schedules, and immigrant adjustment. Promoting the link between physical and mental well-being as opposed to weight loss is a key approach to reaching this population.

Studies on the mechanism of general anesthesia.

Inhaled anesthetics are a chemically diverse collection of hydrophobic molecules that robustly activate TWIK-related K+ channels (TREK-1) and reversibly induce loss of consciousness. For 100 y, anesthetics were speculated to target cellular membranes, yet no plausible mechanism emerged to explain a membrane effect on ion channels. Here we show that inhaled anesthetics (chloroform and isoflurane) activate TREK-1 through disruption of phospholipase D2 (PLD2) localization to lipid rafts and subsequent production of signaling lipid phosphatidic acid (PA). Catalytically dead PLD2 robustly blocks anesthetic TREK-1 currents in whole-cell patch-clamp recordings. Localization of PLD2 renders the TRAAK channel sensitive, a channel that is otherwise anesthetic insensitive. General anesthetics, such as chloroform, isoflurane, diethyl ether, xenon, and propofol, disrupt lipid rafts and activate PLD2. In the whole brain of flies, anesthesia disrupts rafts and PLDnull flies resist anesthesia. Our results establish a membrane-mediated target of inhaled anesthesia and suggest PA helps set thresholds of anesthetic sensitivity in vivo.

Patients with knee osteoarthritis can be divided into subgroups based on tibiofemoral joint kinematics of gait - an exploratory and dynamic radiostereometric study.

OBJECTIVE: Patients with advanced knee osteoarthritis (KOA) frequently alter their gait patterns in an attempt to alleviate symptoms. Understanding the underlying pathomechanics and identifying KOA phenotypes are essential to improve treatments. We investigated kinematics in patients with KOA to identify subgroups of homogeneous knee joint kinematics. METHOD: A total of 66 patients with symptomatic KOA scheduled for total knee arthroplasty and 15 age-matched healthy volunteers with asymptomatic, non-arthritic knees were included. We used k-means clustering to divide patients into subgroups based on dynamic radiostereometry-assessed tibiofemoral joint kinematics. Clinical characteristics such as knee ligament lesions and KOA scores were graded by magnetic resonance imaging and radiographs, respectively. RESULTS: We identified four clusters that were supported by clinical characteristics. The flexion group (n = 20) consisted primarily of patients with medial KOA. The abduction group (n = 17) consisted primarily of patients with lateral KOA. The anterior draw group (n = 10) was composed of patients with medial KOA, some degree of anterior cruciate ligament lesion and the highest KOA score. The external rotation group (n = 19) primarily included patients with medial collateral and posterior cruciate ligament lesions. CONCLUSION: Based on tibiofemoral gait patterns, patients with advanced KOA can be divided into four subgroups with specific clinical characteristics and different KOA-affected compartments. The findings add to our understanding of how knee kinematics may affect the patient's development of different types of KOA. This may inspire improved and more patient-specific treatment strategies in the future.

Correction to: BIOMEMBRANES 2018 : Evaluation of the possibility of simultaneous using membrane biosensors and vital dyes in determining the sensitivity of 2D and 2.5D systems based on cancer cell lines to oncotoxic drugs.

This research was supported by RSF grant (No. 18-15-00391).

Magnetometry based method for investigation of nanoparticle clearance from circulation in a liver perfusion model.

Nanoparticles (NPs) are among the most promising agents for advanced theranostics. However, their functioning in vivo is severely inhibited by the mononuclear phagocyte system (MPS), which rapidly removes all foreign entities from blood circulation. Little is known about the sequestration mechanisms and the ways to counteract them. New methods are highly demanded for investigation with high scrutiny of each aspect of NP clearance from blood. For example, while liver macrophages capture the majority of the administered particles, reliable investigation of this process in absence of other MPS components is hard to implement in vivo. Here, we demonstrate a novel method for real-time investigation hepatic uptake of NPs in an isolated perfused liver based on an extremely accurate magnetometric registration technique. The signal is obtained solely from the magnetic NPs without any 'background' from blood or tissues, which is a significant advantage over other techniques, e.g. optical ones. We illustrate the method capacity by investigation of behavior of different particles and show good correlation with in vivo studies. We also demonstrate notable suitability of the method for studying the NP clearance from the flow in the user-defined mediums, e.g. those containing specific serum components. Finally, the method was applied to reveal an interesting effect of short-term decrease of liver macrophage activity after the first interaction with small amounts of NPs. The developed perfusion model based on the high-performance magnetometry can be used for finding new mechanisms of NP sequestration and for development of novel 'stealth' nanoagents.

Polymodal Mechanism for TWIK-Related K+ Channel Inhibition by Local Anesthetic.

BACKGROUND: Local anesthetics cause reversible block of pain and robustly inhibit TWIK-related K channel (TREK-1) currents. Before local anesthesia onset, injection of local anesthetics can cause unwanted transient pain. TREK-1 is an anesthetic-sensitive potassium channel that when inhibited produces pain. A disordered C-terminal loop of TREK-1 is thought to contribute to anesthetic sensitivity, but the molecular basis for TREK-1 inhibition by local anesthetics is unknown. Phospholipase D2 (PLD2) is an enzyme that produces phosphatidic acid (PA) required for TREK-1 activation and also binds to the channel's C terminus. METHODS: Here, we use biophysical and cellular techniques to characterize direct and indirect lipid-mediated mechanism for TREK-1 inhibition (respectively). We characterized direct binding of local anesthetic to TREK-1 by reconstituting the purified channel into artificial membranes and measuring ion flux. We characterized indirect PA-mediated inhibition of TREK-1 by monitoring lipid production in live whole cells using a fluorescent PLD2 product release assay and ion channel current using live whole-cell patch-clamp electrophysiology. We monitored anesthetic-induced nanoscale translocation of PLD2 to TREK-1 channels with super-resolution direct stochastic reconstruction microscopy (dSTORM). RESULTS: We find local anesthetics tetracaine, lidocaine, and bupivacaine directly bind to and inhibit PLD2 enzymatic activity. The lack of PLD2 activity indirectly inhibited TREK-1 currents. Select local anesthetics also partially blocked the open pore of TREK-1 through direct binding. The amount of pore block was variable with tetracaine greater than bupivacaine and lidocaine exhibiting a minor effect. Local anesthetics also disrupt lipid rafts, a mechanism that would normally activate PLD2 were it not for their direct inhibition of enzyme catalysis. CONCLUSIONS: We propose a mechanism of TREK-1 inhibition comprised of (1) primarily indirect PLD2-dependent inhibition of lipid catalysis and (2) limited direct inhibition for select local anesthetics through partial open pore block. The inhibition through PLD2 explains how the C terminus can regulate the channel despite being devoid of structure and putative binding sites for local anesthetics.

The effect of the cutoff frequency on the sound production of a clarinet-like instrument.

The input impedance of woodwind instruments is characterized by at least two bands due to the lattice of open toneholes, a stop band at low frequencies, and a pass band at higher frequencies where the acoustic energy is able to propagate past the first open tonehole and into the lattice. The cutoff frequency that separates these two bands is an approximate value that is determined by the geometry of the lattice of open toneholes. It is expected that the frequency at which the stop band transitions to the pass band affects the sound produced by the instrument, but it is not known how this frequency affects the competition between self-sustained oscillation and radiation. A simplified model of a clarinet-like resonator is conceived such that the first input impedance peak and the cutoff frequency can be independently chosen. Experimental prototypes are built and the measured impedance of these prototypes is compared with the simulations. Resonators with very similar low frequency behavior but very different cutoff frequencies are then compared using digital synthesis to evaluate the influence of the cutoff frequency on sound production. The cutoff frequency impacts the synthesized pressure and acoustic volume velocity in the mouthpiece, particularly regarding the spectral content at high frequencies.

Inhibitors of the renin-angiotensin system ameliorates clinical and pathological aspects of experimentally induced nephrotoxic serum nephritis.

INTRODUCTION: Chronic kidney disease (CKD) is a global health concern, but the current treatments only slow down the progression. Thus an improved understanding of the pathogenesis and novel treatments of CKD are needed. The nephrotoxic nephritis (NTN) model has the potential to study the pathogenesis of CKD as it resembles human CKD. The classical treatments with angiotensin II receptor blocker (ARB) or the angiotensin-converting enzyme inhibitor (ACE I) have shown a clinical effect in CKD. METHODS: We characterized the disease development in the NTN model over 11 weeks by investigating functional and histopathological changes. We tested doses of 15 and 30 mg/kg/day enalapril and losartan in the NTN model in order to investigate the effect of inhibiting the renin-angiotensin-system (RAS). RESULTS: The NTN model displayed albuminuria peaking on days 6-7, mesangial expansion (ME), renal fibrosis, inflammation and iron accumulation peaking on day 42. However, albuminuria, ME, renal fibrosis and inflammation were still significantly present on day 77, suggesting that the NTN model is useful for studying both the acute and chronic disease phases. Enalapril and losartan significantly enhanced the glomerular filtration rate (GFR) and decreased albuminuria, ME, renal fibrosis and inflammation of NTN-induced kidney disease in mice. CONCLUSIONS: This is the first study showing a comprehensive pathological description of the chronic features of the murine NTN model and that inhibiting the RAS pathway show a significant effect on functional and morphological parameters.

Diffusion of multiwall carbon nanotubes (MWCNTs) through a high density polyethylene (HDPE) geomembrane.

The new applications for carbon nanotubes (CNTs) in various fields and consequently their greater production volume have increased their potential release to the environment. Landfills are one of the major locations where carbon nanotubes are expected to be disposed and it is important to ensure that they can limit the release of CNTs. Diffusion of multiwall carbon nanotubes (MWCNTs) dispersed in an aqueous media through a high-density polyethylene (HDPE) geomembrane (as a part of the landfill barrier system) was examined. Based on the laboratory tests, the permeation coefficient was estimated to be less than 5.1×10-15 m2/s. The potential performance of a HDPE geomembrane and geosynthetic clay liner (GCL) as parts of a composite liner in containing MWCNTs was modelled for six different scenarios. The results suggest that the low value of permeation coefficient of an HDPE geomembrane makes it an effective diffusive barrier for MWCNTs and by keeping the geomembrane defects to minimum during the construction (e.g., number of holes and length of wrinkles) a composite liner commonly used in municipal solid waste landfills will effectively contain MWCNTs.

Quantitative agreement between [(15)O]H2O PET and model free QUASAR MRI-derived cerebral blood flow and arterial blood volume.

The purpose of this study was to assess whether there was an agreement between quantitative cerebral blood flow (CBF) and arterial cerebral blood volume (CBVA) measurements by [(15)O]H2O positron emission tomography (PET) and model-free QUASAR MRI. Twelve healthy subjects were scanned within a week in separate MRI and PET imaging sessions, after which quantitative and qualitative agreement between both modalities was assessed for gray matter, white matter and whole brain region of interests (ROI). The correlation between CBF measurements obtained with both modalities was moderate to high (r(2): 0.28-0.60, P < 0.05), although QUASAR significantly underestimated CBF by 30% (P < 0.001). CBVA was moderately correlated (r(2): 0.28-0.43, P < 0.05), with QUASAR yielding values that were only 27% of the [(15)O]H2O-derived values (P < 0.001). Group-wise voxel statistics identified minor areas with significant contrast differences between [(15)O]H2O PET and QUASAR MRI, indicating similar qualitative CBVA and CBF information by both modalities. In conclusion, the results of this study demonstrate that QUASAR MRI and [(15)O]H2O PET provide similar CBF and CBVA information, but with systematic quantitative discrepancies.

Cerebrospinal fluid volumetric MRI mapping as a simple measurement for evaluating brain atrophy.

OBJECTIVES: To assess whether volumetric cerebrospinal fluid (CSF) MRI can be used as a surrogate for brain atrophy assessment and to evaluate how the T2 of the CSF relates to brain atrophy. METHODS: Twenty-eight subjects [mean age 64 (sd 2) years] were included; T1-weighted and CSF MRI were performed. The first echo data of the CSF MRI sequence was used to obtain intracranial volume, CSF partial volume was measured voxel-wise to obtain CSF volume (VCSF) and the T2 of CSF (T2,CSF) was calculated. The correlation between VCSF/T2,CSF and brain atrophy scores [global cortical atrophy (GCA) and medial temporal lobe atrophy (MTA)] was evaluated. RESULTS: Relative total, peripheral subarachnoidal, and ventricular VCSF increased significantly with increased scores on the GCA and MTA (R = 0.83, 0.78 and 0.78 and R = 0.72, 0.62 and 0.86). Total, peripheral subarachnoidal, and ventricular T2 of the CSF increased significantly with higher scores on the GCA and MTA (R = 0.72, 0.70 and 0.49 and R = 0.60, 0.57 and 0.41). CONCLUSION: A fast, fully automated CSF MRI volumetric sequence is an alternative for qualitative atrophy scales. The T2 of the CSF is related to brain atrophy and could thus be a marker of neurodegenerative disease. KEY POINTS: • A 1:11 min CSF MRI volumetric sequence can evaluate brain atrophy. • CSF MRI provides accurate atrophy assessment without partial volume effects. • CSF MRI data can be processed quickly without user interaction. • The measured T 2 of the CSF is related to brain atrophy.

Post-operative serious adverse events in a mixed surgical population - a retrospective register study.

BACKGROUND: The number of surgical procedures is increasing, and knowledge of surgical risk factors, post-operative mortality and serious adverse events (SAE) is essential. The aim with our study was to determine the risk of a composite outcome of post-operative: death; myocardial infarction; pulmonary embolism; stroke; gastrointestinal bleeding; dialysis or reoperation. METHODS: Data of surgical procedures in the period from January 1, 2012 to June 30, 2012 were retrieved from the Danish Anaesthesia Database (DAD). Follow-up of all patients undergoing hip or knee replacement, abdominal or gynaecological surgery was conducted retrieving data from The Danish Civil Registration System and the National Patient Register. Total observation time was from January 1, 2012 to June 6, 2013. RESULTS: A total7449 adult patients were included in the final analysis. The risk of the composite outcome during a follow-up until 342 days after inclusion of the last patient was estimated to 8.3%, 95% Confidence Intervals (CI) (7.8-9.0), with a median observation time of 437 days (IQR 387-485, range 0-522). The risk of the composite outcome within 90- and 180-day follow-up of each patient was 4.8% (4.4-5.3) and 5.9% (5.4-6.5), respectively. Mortality within longest follow-up as well as 90 and 180 days post-operatively was 3.6% (3.1-4.0), 1.7% (1.4-2.0), and 2.2% (1.9-2.6), respectively. CONCLUSION: We found a risk of one or more events in the composite outcome within 342 days after inclusion of the last patients of 8.3% (7.8-9.0). The results are applicable in estimations of adequate sample sizes in future clinical trials investigating effects of interventions on SAEs.

Nascent peptides that block protein synthesis in bacteria.

Although the ribosome is a very general catalyst, it cannot synthesize all protein sequences equally well. For example, ribosomes stall on the secretion monitor (SecM) leader peptide to regulate expression of a downstream gene. Using a genetic selection in Escherichia coli, we identified additional nascent peptide motifs that stall ribosomes. Kinetic studies show that some nascent peptides dramatically inhibit rates of peptide release by release factors. We find that residues upstream of the minimal stalling motif can either enhance or suppress this effect. In other stalling motifs, peptidyl transfer to certain aminoacyl-tRNAs is inhibited. In particular, three consecutive Pro codons pose a challenge for elongating ribosomes. The translation factor elongation factor P, which alleviates pausing at polyproline sequences, has little or no effect on other stalling peptides. The motifs that we identified are underrepresented in bacterial proteomes and show evidence of stalling on endogenous E. coli proteins.

[Arthroscopic treatment of chondral lesions of the ankle joint. Evidence-based therapy]. / Arthroskopische Behandlung von Knorpelverletzungen am Sprunggelenk. Evidenzbasierte Therapie.

Ankle sprains are the most relevant injuries of the lower extremities and can lead to damage to ligaments and osteochondral lesions. Up to 50 % of patients with a sprained ankle later develop a lesion of the cartilage in the ankle joint or an osteochondral lesion of the talus. This can lead to osteoarthritis of the injured ankle joint. Spontaneous healing is possible in all age groups in cases of a bone bruise in the subchondral bone but in isolated chondral injuries is only useful in pediatric patients. In many cases chondral and osteochondral injuries lead to increasing demarcation of the affected area and can result in progressive degeneration of the joint if not recognized in time. There also exist a certain number of osteochondral changes of the articular surface of the talus without any history of relevant trauma, which are collectively grouped under the term osteochondrosis dissecans. Perfusion disorders are discussed as one of many possible causes of these alterations. Nowadays, chondral and osteochondral defects can be treated earlier due to detection using very sensitive magnetic resonance imaging (MRI) and computed tomography (CT) techniques. The use of conservative treatment only has a chance of healing in pediatric patients. Conservative measures for adults should only be considered as adjuvant treatment to surgery.Based on a comprehensive analysis of the current literature, this article gives an overview and critical analysis of the current concepts for treatment of chondral and osteochondral injuries and lesions of the talus. With arthroscopic therapy curettage and microfracture of talar lesions are the predominant approaches or retrograde drilling of the defect is another option when the chondral coating is retained. Implantation of autologous chondral cells or homologous juvenile cartilage tissue is also possible with arthroscopic techniques. Osteochondral fractures (flake fracture) are usually performed as a mini-open procedure supported by arthroscopy. The use of the osteochondral autograft transfer system (OATS), implantation of membranes with or without autologous bone marrow transfer and possibly with growth factors or implantation of stem cells are carried out in combination with arthroscopic mini-open procedures. The results from the literature are discussed and compared with own results after arthroscopic treatment of chondral lesions of the talus.

Multi-vendor reliability of arterial spin labeling perfusion MRI using a near-identical sequence: implications for multi-center studies.

INTRODUCTION: A main obstacle that impedes standardized clinical and research applications of arterial spin labeling (ASL), is the substantial differences between the commercial implementations of ASL from major MRI vendors. In this study, we compare a single identical 2D gradient-echo EPI pseudo-continuous ASL (PCASL) sequence implemented on 3T scanners from three vendors (General Electric Healthcare, Philips Healthcare and Siemens Healthcare) within the same center and with the same subjects. MATERIAL AND METHODS: Fourteen healthy volunteers (50% male, age 26.4±4.7years) were scanned twice on each scanner in an interleaved manner within 3h. Because of differences in gradient and coil specifications, two separate studies were performed with slightly different sequence parameters, with one scanner used across both studies for comparison. Reproducibility was evaluated by means of quantitative cerebral blood flow (CBF) agreement and inter-session variation, both on a region-of-interest (ROI) and voxel level. In addition, a qualitative similarity comparison of the CBF maps was performed by three experienced neuro-radiologists. RESULTS: There were no CBF differences between vendors in study 1 (p>0.1), but there were CBF differences of 2-19% between vendors in study 2 (p<0.001 in most gray matter ROIs) and 10-22% difference in CBF values obtained with the same vendor between studies (p<0.001 in most gray matter ROIs). The inter-vendor inter-session variation was not significantly larger than the intra-vendor variation in all (p>0.1) but one of the ROIs (p<0.001). CONCLUSION: This study demonstrates the possibility to acquire comparable cerebral CBF maps on scanners of different vendors. Small differences in sequence parameters can have a larger effect on the reproducibility of ASL than hardware or software differences between vendors. These results suggest that researchers should strive to employ identical labeling and readout strategies in multi-center ASL studies.

Age-related changes in brain hemodynamics; A calibrated MRI study.

INTRODUCTION: Blood oxygenation-level dependent (BOLD) magnetic resonance imaging signal changes in response to stimuli have been used to evaluate age-related changes in neuronal activity. Contradictory results from these types of experiments have been attributed to differences in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2 ). To clarify the effects of these physiological parameters, we investigated the effect of age on baseline CBF and CMRO2 . MATERIALS AND METHODS: Twenty young (mean ± sd age, 28 ± 3 years), and 45 older subjects (66 ± 4 years) were investigated. A dual-echo pseudocontinuous arterial spin labeling (ASL) sequence was performed during normocapnic, hypercapnic, and hyperoxic breathing challenges. Whole brain and regional gray matter values of CBF, ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and CMRO2 were calculated. RESULTS: Whole brain CBF was 49 ± 14 and 40 ± 9 ml/100 g/min in young and older subjects respectively (P < 0.05). Age-related differences in CBF decreased to the point of nonsignificance (B=-4.1, SE=3.8) when EtCO2 was added as a confounder. BOLD CVR was lower in the whole brain, in the frontal, in the temporal, and in the occipital of the older subjects (P<0.05). Whole brain OEF was 43 ± 8% in the young and 39 ± 6% in the older subjects (P = 0.066). Whole brain CMRO2 was 181 ± 60 and 133 ± 43 µmol/100 g/min in young and older subjects, respectively (P<0.01). DISCUSSION: Age-related differences in CBF could potentially be explained by differences in EtCO2 . Regional CMRO2 was lower in older subjects. BOLD studies should take this into account when investigating age-related changes in neuronal activity.

A clinically realistic large animal model of intra-articular fracture that progresses to post-traumatic osteoarthritis.

OBJECTIVE: Translation of promising treatments for post-traumatic osteoarthritis (PTOA) to patients with intra-articular fracture (IAF) has been limited by the lack of a realistic large animal model. To address this issue we developed a large animal model of IAF in the distal tibia of Yucatan minipigs and documented the natural progression of this injury. DESIGN: Twenty-two fractures were treated using open reduction and internal fixation with either an anatomic reduction or an intentional 2-mm step-off. Pre-operatively, and 3 days, 1, 2, 4, 8, and 12 weeks post-operatively, animals were sedated for synovial fluid draws and radiographs. Limb loading was monitored at the same time points using a Tekscan Walkway. Animals were sacrificed at 12 weeks and the limbs were harvested for histological evaluation. RESULTS: All animals achieved bony union by 12 weeks, facilitating nearly complete recovery of the initial 60% decrease in limb loading. TNFα, IL1ß, IL6, and IL8 concentrations in the fractured limbs were elevated (P < 0.05) at specific times during the 2 weeks after fracture. Histological cartilage degeneration was more severe in the step-off group (0.0001 < P < 0.27 compared to normal) than in the anatomic reconstruction group (0.27 < P < 0.99 compared to normal). CONCLUSIONS: This model replicated key features of a human IAF, including surgical stabilization, inflammatory responses, and progression to osteoarthritic cartilage degeneration, thereby providing a potentially useful model for translating promising treatment options to clinical practice.