Impact of repeated blast exposure on active-duty United States Special Operations Forces.

United States (US) Special Operations Forces (SOF) are frequently exposed to explosive blasts in training and combat, but the effects of repeated blast exposure (RBE) on SOF brain health are incompletely understood. Furthermore, there is no diagnostic test to detect brain injury from RBE. As a result, SOF personnel may experience cognitive, physical, and psychological symptoms for which the cause is never identified, and they may return to training or combat during a period of brain vulnerability. In 30 active-duty US SOF, we assessed the relationship between cumulative blast exposure and cognitive performance, psychological health, physical symptoms, blood proteomics, and neuroimaging measures (Connectome structural and diffusion MRI, 7 Tesla functional MRI, [11C]PBR28 translocator protein [TSPO] positron emission tomography [PET]-MRI, and [18F]MK6240 tau PET-MRI), adjusting for age, combat exposure, and blunt head trauma. Higher blast exposure was associated with increased cortical thickness in the left rostral anterior cingulate cortex (rACC), a finding that remained significant after multiple comparison correction. In uncorrected analyses, higher blast exposure was associated with worse health-related quality of life, decreased functional connectivity in the executive control network, decreased TSPO signal in the right rACC, and increased cortical thickness in the right rACC, right insula, and right medial orbitofrontal cortex-nodes of the executive control, salience, and default mode networks. These observations suggest that the rACC may be susceptible to blast overpressure and that a multimodal, network-based diagnostic approach has the potential to detect brain injury associated with RBE in active-duty SOF.

Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation.

BACKGROUND: Catheter-based pulmonary vein isolation is an effective treatment for paroxysmal atrial fibrillation. Pulsed field ablation, which delivers microsecond high-voltage electrical fields, may limit damage to tissues outside the myocardium. The efficacy and safety of pulsed field ablation as compared with conventional thermal ablation are not known. METHODS: In this randomized, single-blind, noninferiority trial, we assigned patients with drug-refractory paroxysmal atrial fibrillation in a 1:1 ratio to undergo pulsed field ablation or conventional radiofrequency or cryoballoon ablation. The primary efficacy end point was freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation. The primary safety end point included acute and chronic device- and procedure-related serious adverse events. RESULTS: A total of 305 patients were assigned to undergo pulsed field ablation, and 302 were assigned to undergo thermal ablation. At 1 year, the primary efficacy end point was met (i.e., no events occurred) in 204 patients (estimated probability, 73.3%) who underwent pulsed field ablation and 194 patients (estimated probability, 71.3%) who underwent thermal ablation (between-group difference, 2.0 percentage points; 95% Bayesian credible interval, -5.2 to 9.2; posterior probability of noninferiority, >0.999). Primary safety end-point events occurred in 6 patients (estimated incidence, 2.1%) who underwent pulsed field ablation and 4 patients (estimated incidence, 1.5%) who underwent thermal ablation (between-group difference, 0.6 percentage points; 95% Bayesian credible interval, -1.5 to 2.8; posterior probability of noninferiority, >0.999). CONCLUSIONS: Among patients with paroxysmal atrial fibrillation receiving a catheter-based therapy, pulsed field ablation was noninferior to conventional thermal ablation with respect to freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation and with respect to device- and procedure-related serious adverse events at 1 year. (Funded by Farapulse-Boston Scientific; ADVENT ClinicalTrials.gov number, NCT04612244.).

Cefadroxil and cephalexin pharmacokinetics and pharmacodynamics in children with musculoskeletal infections.

Cephalexin, a first-generation cephalosporin, is the first-line oral therapy for children with musculoskeletal infections due to methicillin-susceptible Staphylococcus aureus (MSSA). Cefadroxil, a similar first-generation cephalosporin, is an attractive alternative to cephalexin given its longer half-life. In this study, we describe the comparative pharmacokinetics (PK) and pharmacodynamics (PD) of cephalexin and cefadroxil in children with musculoskeletal infections. Children aged 6 months to 18 years with a musculoskeletal infection were enrolled in a prospective, open-label, crossover PK study and given single oral doses of cefadroxil (50-75 mg/kg up to 2,000 mg) and cephalexin (50 mg/kg up to 1,375 mg). Population PK models were developed and used for dosing simulations. Our primary PD target was the achievement of free antibiotic concentrations above the minimum inhibitory concentration (fT >MIC) for 40% of the day for MICs ≤ 4 mg/L. PK of cephalexin (n = 15) and cefadroxil (n = 14) were best described using a one-compartment, first-order absorption model, with a lag time component for cefadroxil. PK parameters were notable for cefadroxil's longer half-life (1.61 h) than cephalexin's (1.10 h). For pediatric weight bands, our primary PD target was achieved by cephalexin 25 mg/kg/dose, maximum 750 mg/dose, administered three times daily and cefadroxil 40 mg/kg/dose, maximum 1,500 mg/dose, administered twice daily. More aggressive dosing was required to achieve higher PD targets. Among children with musculoskeletal infections, oral cephalexin and cefadroxil achieved PD targets for efficacy against MSSA. Given less frequent dosing, twice-daily cefadroxil should be further considered as an alternative to cephalexin for oral step-down therapy for serious infections due to MSSA.

Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus.

Membrane protein efflux pumps confer antibiotic resistance by extruding structurally distinct compounds and lowering their intracellular concentration. Yet, there are no clinically approved drugs to inhibit efflux pumps, which would potentiate the efficacy of existing antibiotics rendered ineffective by drug efflux. Here we identified synthetic antigen-binding fragments (Fabs) that inhibit the quinolone transporter NorA from methicillin-resistant Staphylococcus aureus (MRSA). Structures of two NorA-Fab complexes determined using cryo-electron microscopy reveal a Fab loop deeply inserted in the substrate-binding pocket of NorA. An arginine residue on this loop interacts with two neighboring aspartate and glutamate residues essential for NorA-mediated antibiotic resistance in MRSA. Peptide mimics of the Fab loop inhibit NorA with submicromolar potency and ablate MRSA growth in combination with the antibiotic norfloxacin. These findings establish a class of peptide inhibitors that block antibiotic efflux in MRSA by targeting indispensable residues in NorA without the need for membrane permeability.

Frontal cortex neurometabolites and mobility in older adults: a preliminary study.

BACKGROUND: The frontal cortex, relevant to global cognition and motor function, is recruited to compensate for mobility dysfunction in older adults. However, the in vivo neurophysiological (e.g., neurometabolites) underpinnings of the frontal cortex compensation for mobility dysfunction remain poorly understood. The purpose of this study was to investigate the relationships among frontal cortex neurophysiology, mobility, and cognition in healthy older adults. METHODS: Magnetic Resonance Spectroscopy (MRS) quantified N-acetylasparate (tNAA) and total choline (tCho) concentrations and ratios in the frontal cortex in 21 older adults. Four inertial sensors recorded the Timed Up & Go (TUG) test. Cognition was assessed using the Flanker Inhibitory Control and Attention Test which requires conflict resolution because of response interference from flanking distractors during incongruent trials. Congruent trials require no conflict resolution. RESULTS: tNAA concentration significantly related to the standing (p = 0.04) and sitting (p = 0.03) lean angles. tCho concentration (p = 0.04) and tCho ratio (p = 0.02) significantly related to TUG duration. tCho concentration significantly related to incongruent response time (p = 0.01). tCho ratio significantly related to both congruent (p = 0.009) and incongruent (p < 0.001) response times. Congruent (p = 0.02) and incongruent (p = 0.02) Flanker response times significantly related to TUG duration. CONCLUSIONS: Altered levels of frontal cortex neurometabolites are associated with both mobility and cognitive abilities in healthy older adults. Identifying neurometabolites associated with frontal cortex compensation of mobility dysfunction could improve targeted therapies aimed at improving mobility in older adults.

Pulmonary vein narrowing after pulsed field versus thermal ablation.

AIMS: When it occurs, pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is associated with significant morbidity. Even mild-to-moderate PV narrowing may have long-term implications. Unlike thermal ablation energies, such as radiofrequency (RF) or cryothermy, pulsed field ablation (PFA) is a non-thermal modality associated with less fibrotic proliferation. Herein, we compared the effects of PFA vs. thermal ablation on PV narrowing after AF ablation. METHODS AND RESULTS: ADVENT was a multi-centre, randomized, single-blind study comparing PFA (pentaspline catheter) with thermal ablation-force-sensing RF or cryoballoon (CB)-to treat drug-refractory paroxysmal AF. Pulmonary vein diameter and aggregate cross-sectional area were obtained by baseline and 3-month imaging. The pre-specified, formally tested, secondary safety endpoint compared a measure of PV narrowing between PFA vs. thermal groups, with superiority defined by posterior probability > 0.975. Among subjects randomized to PFA (n = 305) or thermal ablation (n = 302), 259 PFA and 255 thermal ablation (137 RF and 118 CB) subjects had complete baseline and 3-month PV imaging. No subject had significant (≥70%) PV stenosis. Change in aggregate PV cross-sectional area was less with PFA (-0.9%) than thermal ablation (-12%, posterior probability > 0.999)-primarily driven by the RF sub-cohort (-19.5%) vs. CB sub-cohort (-3.3%). Almost half of all PFA PV diameters did not decrease, but the majority (80%) of RF PVs decreased, regardless of PV anatomic location. CONCLUSION: In this first randomized comparison of PFA vs. thermal ablation, PFA resulted in less PV narrowing-thereby underscoring the qualitatively differential and favourable impact of PFA on PV tissue.

Oritavancin as sequential therapy for Gram-positive bloodstream infections.

BACKGROUND: Oritavancin, a long-acting lipoglycopeptide approved for use in acute bacterial skin and skin structure infections, has limited data evaluating use in serious infections due to Gram-positive organisms. We aimed to assess the effectiveness and safety of oritavancin for consolidative treatment of Gram-positive bloodstream infections (BSI), including infective endocarditis (IE). METHODS: We conducted a retrospective cohort study evaluating adult patients admitted to University of Colorado Hospital from March 2016 to January 2022 who received ≥ 1 oritavancin dose for treatment of Gram-positive BSI. Patients were excluded if the index culture was drawn at an outside facility or were > 89 years of age. The primary outcome was a 90-day composite failure (clinical or microbiological failure) in those with 90-day follow-up. Secondary outcomes included individual components of the primary outcome, acute kidney injury (AKI), infusion-related reactions (IRR), and institutional cost avoidance. RESULTS: Overall, 72 patients were included. Mean ± SD age was 54 ± 16 years, 61% were male, and 10% had IE. Organisms most commonly causing BSI were Staphylococcus aureus (68%, 17% methicillin-resistant), followed by Streptococcus spp. (26%), and Enterococcus spp. (10%). Patients received standard-of-care antibiotics before oritavancin for a median (IQR) of 11 (5-17) days. Composite failure in the clinically evaluable population (n = 64) at 90-days occurred in 14% and was composed of clinical and microbiological failure, which occurred in 14% and 5% of patients, respectively. Three patients (4%) experienced AKI after oritavancin, and two (3%) experienced an IRR. Oritavancin utilization resulted in earlier discharge for 94% of patients corresponding to an institutional cost-avoidance of $3,055,804 (mean $44,938/patient) from 1,102 hospital days saved (mean 16 days/patient). CONCLUSIONS: The use of oritavancin may be an effective sequential therapy for Gram-positive BSI to facilitate early discharge resulting in institutional cost avoidance.

Location of medial collateral ligament tears: introduction to a magnetic resonance imaging-based classification.

PURPOSE: Despite established tear grade classifications, there is currently no radiological classification for sMCL tear locations. This study aims to establish a magnetic resonance imaging (MRI) tear location classification system for sMCL tears, to enhance understanding and guide treatment decisions by categorizing tear types. METHODS: A retrospective search in a single institution's MRI database identified patients with acute, Grade III sMCL tears (< 30 days between injury and MRI) from January to December 2022. Non-acute and partial tears were excluded, and three observers assessed tear types based on the proposed sMCL MRI tear location system: type I (proximal 25%), Ib (proximal femoral bony avulsion), II (midsubstance, 25-75%), III (distal 25%), IIIb (distal tibial bony avulsion), IIIs (Stener-like lesion). The interclass correlation coefficient (ICC) was used to assess interrater and intrarater reliability for continuous data; Fleiss and Cohen's kappa assessed interrater and intrarater reliability for categorical data. RESULTS: MRI scans of thirty patients with diagnosed sMCL injuries (53% female, mean age 37 ± 13 years, range 16-68 years) were included based on inclusion/exclusion criteria. Interrater reliability was excellent (ICC: 0.968, 95% CI, 0.933-0.985), and intrarater reliability was excellent (ICC: 0.938, 95% CI: 0.874-0.970 & 0.900, 95% CI, 0.789-0.952). Type I injuries were most common (60%), followed by type III (33.3%), type II (3.3%), type Ib (3.3%), type IIIb (0.0%), and type IIIs (0.0%). CONCLUSION: The presented MRI-based sMCL tear location classification provides a reproducible system for grading high-grade sMCL injuries. We propose that this framework will significantly unify tear location understanding and support more informed treatment decisions.

Growth of long bones in European and Japanese quail from the 13th day of incubation to day 35 post-hatch.

This study described the growth, morphometric, biomechanical, and chemical properties of the femur, tibiotarsus, and tarsometatarsus of European and Japanese quail. Analyses were performed at 13 and 15 days of incubation, at hatch, and at 4, 7, 10, 14, 21, 28, and 35 days post-hatch (n=6/subspecies/period). Bone specimens were analyzed by cone-beam computed tomography, biomechanical assays, chemical analyses, and histomorphometry. Variables were fitted by the Gompertz function and its derivative or assessed using the analysis of variance. Analysis of the derivative of Gompertz curves showed that the growth behavior of the tarsometatarsal bone was similar between quail subspecies, and the femur and tibiotarsus of European quail increased first in width and then in length, whereas the opposite occurred in Japanese quail. There was an interaction between quail subspecies and days of growth on femoral, tarsometatarsal, and tibiotarsal bone densities. Femoral and tibiotarsal cross-sectional areas were influenced by the interaction of quail subspecies and day of growth. Interaction effects were significant for breaking strength and phosphorus percentage. European and Japanese quail have different femoral and tibiotarsal growth patterns, especially in the first few days after hatching, whereas tarsometatarsal growth is similar between subspecies.

Measurement of TT-TG can change with sequential MRIs due to variations in tibiofemoral rotation in patellofemoral instability patients.

PURPOSE: There are various anatomic risk factors for patellofemoral instability (PFI) that help guide surgical treatment, including the tibial tubercle to trochlear groove (TT-TG) distance. However, no study has analysed the temporal changes in TT-TG prior to surgical intervention. This study sought to understand the variations in TT-TG over time for pediatric patients suffering from PFI prior to surgical intervention. The authors hypothesised that the TT-TG would substantially change between time points. METHODS: Patients undergoing medial patellofemoral ligament (MPFL) reconstruction between 2014 and 2019 by one of two fellowship-trained orthopaedic surgeons were identified. Patients were included if they had two preoperative magnetic resonance imaging (MRI) performed on the same knee within 7.5 months of each other prior to any surgical intervention and had an initial TT-TG greater than 10 mm. RESULTS: After considering 251 patients for inclusion, 21 patients met the final inclusion criteria. The mean age was 14.5 ± 2.5 years and 61.9% were female. TT-TG was initially noted to be 15.1 ± 1.8 mm. At mean time after sequential MRIs of 5.0 ± 1.9 months, TT-TG was noted to be 16.7 ± 3.2 mm. The differences between initial and subsequent TT-TG ranged from a 21.2% decrease to a 61.1% increase, with a mean difference of an 11.3% increase. Comparison between initial and subsequent TT-TG values demonstrated a significant difference (p = 0.017). Change in tibiofemoral rotation ranged from -9.2° to 7.5°. When comparing the change in TT-TG to change in tibiofemoral rotation, a significant correlation was found (p = 0.019). CONCLUSION: Despite only a mean time between MRIs of 5 months, variations in TT-TG ranged from a decrease of 21.2% to an increase of 61.1%. The significant relationship between the changes in TT-TG and changes in tibiofemoral rotation between MRIs suggest that TT-TG measurements may vary due to variations in tibiofemoral rotation at the time of individual MRIs. LEVEL OF EVIDENCE: Level IV.

Interdigitated Columnar Representation of Personal Space and Visual Space in Human Parietal Cortex.

Personal space (PS) is the space around the body that people prefer to maintain between themselves and unfamiliar others. Intrusion into personal space evokes discomfort and an urge to move away. Physiologic studies in nonhuman primates suggest that defensive responses to intruding stimuli involve the parietal cortex. We hypothesized that the spatial encoding of interpersonal distance is initially transformed from purely sensory to more egocentric mapping within human parietal cortex. This hypothesis was tested using 7 Tesla (7T) fMRI at high spatial resolution (1.1 mm isotropic), in seven subjects (four females, three males). In response to visual stimuli presented at a range of virtual distances, we found two categories of distance encoding in two corresponding radially-extending columns of activity within parietal cortex. One set of columns (P columns) responded selectively to moving and stationary face images presented at virtual distances that were nearer (but not farther) than each subject's behaviorally-defined personal space boundary. In most P columns, BOLD response amplitudes increased monotonically and nonlinearly with increasing virtual face proximity. In the remaining P columns, BOLD responses decreased with increasing proximity. A second set of parietal columns (D columns) responded selectively to disparity-based distance cues (near or far) in random dot stimuli, similar to disparity-selective columns described previously in occipital cortex. Critically, in parietal cortex, P columns were topographically interdigitated (nonoverlapping) with D columns. These results suggest that visual spatial information is transformed from visual to body-centered (or person-centered) dimensions in multiple local sites within human parietal cortex.SIGNIFICANCE STATEMENT Recent COVID-related social distancing practices highlight the need to better understand brain mechanisms which regulate "personal space" (PS), which is defined by the closest interpersonal distance that is comfortable for an individual. Using high spatial resolution brain imaging, we tested whether a map of external space is transformed from purely visual (3D-based) information to a more egocentric map (related to personal space) in human parietal cortex. We confirmed this transformation and further showed that it was mediated by two mutually segregated sets of columns: one which encoded interpersonal distance and another that encoded visual distance. These results suggest that the cortical transformation of sensory-centered to person-centered encoding of space near the body involves short-range communication across interdigitated columns within parietal cortex.

Cardiovascular and metabolic health is associated with functional brain connectivity in middle-aged and older adults: Results from the Human Connectome Project-Aging study.

Several cardiovascular and metabolic indicators, such as cholesterol and blood pressure have been associated with altered neural and cognitive health as well as increased risk of dementia and Alzheimer's disease in later life. In this cross-sectional study, we examined how an aggregate index of cardiovascular and metabolic risk factor measures was associated with correlation-based estimates of resting-state functional connectivity (FC) across a broad adult age-span (36-90+ years) from 930 volunteers in the Human Connectome Project Aging (HCP-A). Increased (i.e., worse) aggregate cardiometabolic scores were associated with reduced FC globally, with especially strong effects in insular, medial frontal, medial parietal, and superior temporal regions. Additionally, at the network-level, FC between core brain networks, such as default-mode and cingulo-opercular, as well as dorsal attention networks, showed strong effects of cardiometabolic risk. These findings highlight the lifespan impact of cardiovascular and metabolic health on whole-brain functional integrity and how these conditions may disrupt higher-order network integrity.

Adenine nucleotide translocase regulates airway epithelial metabolism, surface hydration and ciliary function.

Airway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive pulmonary disease (COPD), which is impacted by cigarette smoking and has no therapeutic options. We utilized a high-copy cDNA library genetic selection approach in the amoeba Dictyostelium discoideum to identify genetic protectors to cigarette smoke. Members of the mitochondrial ADP/ATP transporter family adenine nucleotide translocase (ANT) are protective against cigarette smoke in Dictyostelium and human bronchial epithelial cells. Gene expression of ANT2 is reduced in lung tissue from COPD patients and in a mouse smoking model, and overexpression of ANT1 and ANT2 resulted in enhanced oxidative respiration and ATP flux. In addition to the presence of ANT proteins in the mitochondria, they reside at the plasma membrane in airway epithelial cells and regulate airway homeostasis. ANT2 overexpression stimulates airway surface hydration by ATP and maintains ciliary beating after exposure to cigarette smoke, both of which are key functions of the airway. Our study highlights a potential for upregulation of ANT proteins and/or of their agonists in the protection from dysfunctional mitochondrial metabolism, airway hydration and ciliary motility in COPD.This article has an associated First Person interview with the first author of the paper.

Logistical burden of offers and allocation inefficiency in circle-based liver allocation.

Recent changes to liver allocation replaced donor service areas with circles as the geographic unit of allocation. Circle-based allocation might increase the number of transplantation centers and candidates required to place a liver, thereby increasing the logistical burden of making and responding to offers on organ procurement organizations and transplantation centers. Circle-based allocation might also increase distribution time and cold ischemia time (CIT), particularly in densely populated areas of the country, thereby decreasing allocation efficiency. Using Scientific Registry of Transplant Recipient data from 2019 to 2021, we evaluated the number of transplantation centers and candidates required to place livers in the precircles and postcircles eras, nationally and by donor region. Compared with the precircles era, livers were offered to more candidates (5 vs. 9; p < 0.001) and centers (3 vs. 5; p < 0.001) before being accepted; more centers were involved in the match run by offer number 50 (9 vs. 14; p < 0.001); CIT increased by 0.2 h (5.9 h vs. 6.1 h; p < 0.001); and distribution time increased by 2.0 h (30.6 h vs. 32.6 h; p < 0.001). Increased burden varied geographically by donor region; livers recovered in Region 9 were offered to many more candidates (4 vs. 12; p < 0.001) and centers (3 vs. 8; p < 0.001) before being accepted, resulting in the largest increase in CIT (5.4 h vs. 6.0 h; p < 0.001). Circle-based allocation is associated with increased logistical burdens that are geographically heterogeneous. Continuous distribution systems will have to be carefully designed to avoid exacerbating this problem.

T1 relaxation time of ISMRM/NIST T1 phantom spheres at 7 T.

T1 relaxation times of the 14 T1 phantom spheres that make up the standard International Society for Magnetic Resonance in Medicine (ISMRM)/National Institute of Standards and Technology (NIST) system phantom are reported at 7 T. T1 values of six of the 14 T1 spheres at 7 T (with T1 > 270 ms) have been reported previously, but, to the best of our knowledge, not all of the T1s of the 14 T1 spheres at 7 T have been reported before. Given the increasing number of 7-T MRI systems in clinical settings and the increasing need for T1 phantoms that cover a wide range of T1 relaxation times to evaluate rapid T1 mapping techniques at 7 T, it is of high interest to obtain accurate T1 values for all the ISMRM/NIST T1 spheres at 7 T. In this work, T1 relaxation time was measured on a 7-T MRI scanner using an inversion-recovery spin-echo pulse sequence and derived by curve fitting to a signal equation that exhibits insensitivity to B 1 + inhomogeneity. Day-to-day reproducibility was within 0.4% and differences between two different RF coils within 1.5%. T1s of a subset of the 14 spheres were also measured by NMR at 7 T for comparison, and the T1 results were consistent between the MRI and NMR measurements. T1 measurements performed at 3 T on the same 14 spheres using the same sequence and fitting method yielded good agreement (mean percentage difference of -0.4%) with the reference T1 values available from the NIST, reflecting the accuracy of the reported technique despite being without the standard phantom housing. We found that the T1 values of all 14 NiCl2 spheres are consistently lower at 7 T than at 3 T. Although our results were well reproduced, this study represents initial work to quantify the 7-T T1 values of all 14 NIST T1 spheres outside of the standard housing and does not warrant reproducibility of the ISMRM/NIST system phantom as a whole. A future study to assess the T1 values of a version of the ISMRM/NIST system phantom that fits inside typical commercial coils at 7 T will be very helpful. Nonetheless, the details on our acquisition and curve-fitting methods reported here allow the T1 measurements to be reproduced elsewhere. The T1 values of all 14 spheres reported here will be valuable for the development of quantitative MR fingerprinting and rapid T1 mapping for a large variety of research projects, not only in neuroimaging but also in body MRI, musculoskeletal MRI, and gadolinium contrast-enhanced MRI, each of which is concerned with much shortened T1.

Pipecolate and Taurine are Rat Urinary Biomarkers for Lysine and Threonine Deficiencies.

BACKGROUND: The consumption of poor-quality protein increases the risk of essential amino acid (EAA) deficiency, particularly for lysine and threonine. Thus, it is necessary to be able to detect easily EAA deficiency. OBJECTIVES: The purpose of this study was to develop metabolomic approaches to identify specific biomarkers for an EAA deficiency, such as lysine and threonine. METHODS: Three experiments were performed on growing rats. In experiment 1, rats were fed for 3 weeks with lysine (L30), or threonine (T53)-deficient gluten diets, or nondeficient gluten diet (LT100) in comparison with the control diet (milk protein, PLT). In experiments 2a and 2b, rats were fed at different concentrations of lysine (L) or threonine (T) deficiency: L/T15, L/T25, L/T40, L/T60, L/T75, P20, L/T100 and L/T170. Twenty-four-hour urine and blood samples from portal vein and vena cava were analyzed using LC-MS. Data from experiment 1 were analyzed by untargeted metabolomic and Independent Component - Discriminant Analysis (ICDA) and data from experiments 2a and 2b by targeted metabolomic and a quantitative Partial Least- Squares (PLS) regression model. Each metabolite identified as significant by PLS or ICDA was then tested by 1-way ANOVA to evaluate the diet effect. A two-phase linear regression analysis was used to determine lysine and threonine requirements. RESULTS: ICDA and PLS found molecules that discriminated between the different diets. A common metabolite, the pipecolate, was identified in experiments 1 and 2a, confirming that it could be specific to lysine deficiency. Another metabolite, taurine, was found in experiments 1 and 2b, so probably specific to threonine deficiency. Pipecolate or taurine breakpoints obtained give a value closed to the values obtained by growth indicators. CONCLUSIONS: Our results showed that the EAA deficiencies influenced the metabolome. Specific urinary biomarkers identified could be easily applied to detect EAA deficiency and to determine which AA is deficient.

Chemical Exposure Highlighted without Any A Priori Information in an Epidemiological Study by Metabolomic FT-ICR-MS Fingerprinting at High Throughput and High Resolution.

Epidemiological studies aim to assess associations between diseases and risk factors. Such investigations involve a large sample size and require powerful analytical methods to measure the effects of risk factors, resulting in a long analysis time. In this study, chemical exposure markers were detected as the main variables strongly affecting two components coming from a principal component analysis (PCA) exploration of the metabolomic data generated from urinary samples collected on a cohort of about 500 individuals using direct introduction coupled with a Fourier-transform ion cyclotron resonance instrument. The assignment of their chemical identity was first achieved based on their isotopic fine structures detected at very high resolution (Rp > 900,000). Their identification as dimethylbiguanide and sotalol was obtained at level 1, thanks to the available authentic chemical standards, tandem mass spectrometry (MS/MS) experiments, and collision cross section measurements. Epidemiological data confirmed that the subjects discriminated by PCA had declared to be prescribed these drugs for either type II diabetes or cardiac arrhythmia. Concentrations of these drugs in urine samples of interest were also estimated by rapid quantification using an external standard calibration method, direct introduction, and MS/MS experiments. Regression analyses showed a good correlation between the estimated drug concentrations and the scores of individuals distributed on these specific PCs. The detection of these chemical exposure markers proved the potential of the proposed high-throughput approach without any prior drug exposure knowledge as a powerful emerging tool for rapid and large-scale phenotyping of subjects enrolled in epidemiological studies to rapidly characterize the chemical exposome and adherence to medical prescriptions.

Exploring the effects of dopamine on sensorimotor inhibition and mobility in older adults.

Dopaminergic activity decreases in older adults (OAs) with normal aging and is further reduced in Parkinson's disease (PD), affecting cortical motor and sensorimotor pathways. Levodopa is the prevailing therapy to counter dopamine loss in PD, though not all PD motor signs improve with levodopa. The purpose of this preliminary study was to explore the effects of levodopa on sensorimotor inhibition, gait and quiet standing in OAs and to investigate the relationships between sensorimotor inhibition and both gait and standing balance both OFF- and ON-levodopa. Fifteen OA males completed a gait, balance and sensorimotor assessments before and 1 h after they were given a 100 mg dose of levodopa. Short-latency afferent inhibition quantified sensorimotor inhibition. Wearable sensors characterized gait (two-minute walk) and standing balance (1-min stance). No sensorimotor inhibition, gait, or standing balance measures changed from OFF- to ON-levodopa. When OFF-levodopa, worse inhibition significantly related to increased double stance (r = 0.62; p = 0.01), increased jerkiness of sway (r = 0.57; p = 0.03) and sway area (r = 0.58; p = 0.02). While ON-levodopa, worse inhibition related to increased arm swing range of motion (r = 0.63; p = 0.01) and jerkiness of sway (r = 0.53; p = 0.04). The relationship between SAI and arm swing excursion significantly changed from OFF- to ON-levodopa (z = - 3.05; p = 0.002; 95% confidence interval = - 0.95, - 0.21). Sensorimotor inhibition relationships to both gait and balance may be affected by dopamine in OAs. Cortical restructuring due to the loss of dopamine may be responsible for the heterogeneity of levodopa effect in people with PD and OAs.

Effect of Multicomponent Home-Based Training on Gait and Muscle Strength in Older Adults After Hip Fracture Surgery: A Single Site Randomized Trial.

OBJECTIVE: To investigate the effect of 16-week home-based physical therapy interventions on gait and muscle strength. DESIGN: A single-blinded randomized controlled trial. SETTING: General community. PARTICIPANTS: Thirty-four older adults (N=34) post hip fracture were randomly assigned to either experimental group (a specific multi-component intervention group [PUSH], n=17, 10 women, age=78.6±7.3 years, 112.1±39.8 days post-fracture) or active control (a non-specific multi-component intervention group [PULSE], n=17, 11 women, age=77.8±7.8 years, 118.2±37.5 days post-fracture). INTERVENTION: PUSH and PULSE groups received 32-40 sessions of specific or non-specific multi-component home-based physical therapy, respectively. Training in the PUSH group focused on lower extremity strength, endurance, balance, and function for community ambulation, while the PULSE group received active movement and transcutaneous electrical nerve stimulation on extremities. MAIN OUTCOME MEASURES: Gait characteristics, and ankle and knee muscle strength were measured at baseline and 16 weeks. Cognitive testing of Trail Making Test (Part A: TMT-A; Part-B: TMT-B) was measured at baseline. RESULTS: At 16 weeks, both groups demonstrated significant increases in usual (P<.05) and fast (P<.05) walking speed, while there was no significant difference in increases between the groups. There was only 1 significant change in lower limb muscle strength over time (non-fractured side) between the groups, such that PUSH did better (mean: 4.33%, 95% confidence interval:1.43%-7.23%). The increase in usual and fast walking speed correlated with the baseline Trail-making Test-B score (r=-0.371, P=.037) and improved muscle strength in the fractured limb (r=0.446, P=.001), respectively. CONCLUSION: Gait speed improved in both home-based multicomponent physical therapy programs in older adults after hip fracture surgery. Muscle strength of the non-fractured limb improved in the group receiving specific physical therapy training. Specific interventions targeting modifiable factors such as muscle strength and cognitive performance may assist gait recovery after hip fracture surgery.

4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.

Metastases are the cause of the vast majority of cancer deaths. In the metastatic process, cells migrate to the vasculature, intravasate, extravasate, and establish metastatic colonies. This pattern of spread requires the cancer cells to change shape and to navigate tissue barriers. Approaches that block this mechanical program represent new therapeutic avenues. We show that 4-hydroxyacetophenone (4-HAP) inhibits colon cancer cell adhesion, invasion, and migration in vitro and reduces the metastatic burden in an in vivo model of colon cancer metastasis to the liver. Treatment with 4-HAP activates nonmuscle myosin-2C (NM2C) (MYH14) to alter actin organization, inhibiting the mechanical program of metastasis. We identify NM2C as a specific therapeutic target. Pharmacological control of myosin isoforms is a promising approach to address metastatic disease, one that may be readily combined with other therapeutic strategies.