Alterations in Cortical Activation Among Individuals With Chronic Ankle Instability During Single-Limb Postural Control

Context: Chronic ankle instability (CAI) is characterized by repetitive ankle sprains and perceived instability. Whereas the underlying cause of CAI is disputed, alterations in cortical motor functioning may contribute to the perceived dysfunction. Objective: To assess differences in cortical activity during single-limb stance among control, coper, and CAI groups. Design: Cross-sectional study. Setting: Biomechanics laboratory. Patients or Other Participants: A total of 31 individuals (10 men, 21 women; age = 22.3 ± 2.4 years, height = 169.6 ± 9.7 cm, mass = 70.6 ± 11.6 kg), who were classified into control (n = 13), coper (n = 7), and CAI (n = 11) groups participated in this study. Intervention(s): Participants performed single-limb stance on a force platform for 60 seconds while wearing a 24-channel functional near-infrared spectroscopy system. Oxyhemoglobin (HbO2) changes in the supplementary motor area (SMA), precentral gyrus, postcentral gyrus, and superior parietal lobe were measured. Main Outcome Measure(s): Differences in averages and standard deviations of HbO2 were assessed across groups. In the CAI group, correlations were analyzed between measures of cortical activation and Cumberland Ankle Instability Tool (CAIT) scores. Results: No differences in average HbO2 were present for any cortical areas. We observed differences in the standard deviation for the SMA across groups; specifically, the CAI group demonstrated greater variability than the control (r = 0.395, P = .02; 95% confidence interval = 0.34, 0.67) and coper (r = 0.38, P = .04; 95% confidence interval = −0.05, 0.69) groups. We demonstrated a strong correlation that was significant in the CAI group between the CAIT score and the average HbO2 of the precentral gyrus (ρ = 0.64, P = .02) and a strong correlation that was not significant between the CAIT score and the average HbO2 of the SMA (ρ = 0.52, P = .06). Conclusions: The CAI group displayed large differences in SMA cortical-activation variability. Greater variations in cortical activation may be necessary for similar static postural-control outcomes among individuals with CAI. Consequently, variations in cortical activation for these areas provide evidence for an altered neural mechanism of postural control among populations with CAI

Periplasmic Cleavage and Modification of the 1-Phosphate Group of Helicobacter Pylori Lipid A

Pathogenic bacteria modify the lipid A portion of their lipopolysaccharide to help evade the host innate immune response. Modification of the negatively charged phosphate groups of lipid A aids in resistance to cationic antimicrobial peptides targeting the bacterial cell surface. The lipid A of Helicobacter pylori contains a phosphoethanolamine (pEtN) unit directly linked to the 1-position of the disaccharide backbone. This is in contrast to the pEtN units found in other pathogenic Gram-negative bacteria, which are attached to the lipid A phosphate group to form a pyrophosphate linkage. This study describes two enzymes involved in the periplasmic modification of the 1-phosphate group of H. pylori lipid A. By using an in vitro assay system, we demonstrate the presence of lipid A 1-phosphatase activity in membranes of H. pylori. In an attempt to identify genes encoding possible lipid A phosphatases, we cloned four putative orthologs of Escherichia coli pgpB, the phosphatidylglycerol-phosphate phosphatase, from H. pylori 26695. One of these orthologs, Hp0021, is the structural gene for the lipid A 1-phosphatase and is required for removal of the 1-phosphate group from mature lipid A in an in vitro assay system. Heterologous expression of Hp0021 in E. coli resulted in the highly selective removal of the 1-phosphate group from E. coli lipid A, as demonstrated by mass spectrometry. We also identified the structural gene for the H. pylori lipid A pEtN transferase (Hp0022). Mass spectrometric analysis of the lipid A isolated from E. coli expressing Hp0021 and Hp0022 shows the addition of a single pEtN group at the 1-position, confirming that Hp0022 is responsible for the addition of a pEtN unit at the 1-position in H. pylori lipid A. In summary, we demonstrate that modification of the 1-phosphate group of H. pylori lipid A requires two enzymatic steps

Attention is associated with postural control in those with chronic ankle instability

Chronic ankle instability (CAI) is often debilitating and may be affected by a number of intrinsic and environmental factors. Alterations in neurocognitive function and attention may contribute to repetitive injury in those with CAI and influence postural control strategies. Thus, the purpose of this study was to determine if there was a difference in attentional functioning and static postural control among groups of Comparison, Coper and CAI participants and assess the relationship between them within each of the groups. Recruited participants performed single-limb balance trials and completed the CNS Vital Signs (CNSVS) computer-based assessment to assess their attentional function. Center of pressure (COP) velocity (COPv) and maximum range (COPr), in both the anteroposterior (AP) and mediolateral (ML) directions were calculated from force plate data. Simple attention (SA), which measures self-regulation and attention control was extracted from the CNSVS. Data from 45 participants (15 in each group, 27=female, 18=male) was analyzed for this study. No significant differences were observed between attention or COP variables among each of the groups. However, significant relationships were present between attention and COP variables within the CAI group. CAI participants displayed significant moderate to large correlations between SA and AP COPr (r=-0.59, p=0.010), AP COPv (r=-0.48, p=0.038) and ML COPr (r=-0.47, p=0.034). The results suggest a linear relationship of stability and attention in the CAI group. Attentional self-regulation may moderate how those with CAI control postural stability. Incorporating neurocognitive training focused on attentional control may improve outcomes in those with CAI

Resistance to the Antimicrobial Peptide Polymyxin Requires Myristoylation of Escherichia Coli and Salmonella Typhimurium Lipid A

Attachment of positively charged, amine-containing residues such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and phosphoethanolamine (pEtN) to Escherichia coli and Salmonella typhimurium lipid A is required for resistance to the cationic antimicrobial peptide, polymyxin. In an attempt to discover additional lipid A modifications important for polymyxin resistance, we generated polymyxin-sensitive mutants of an E. coli pmrAC strain, WD101. A subset of polymyxin-sensitive mutants produced a lipid A that lacked both the 3′-acyloxyacyl-linked myristate (C14) and L-Ara4N, even though the necessary enzymatic machinery required to synthesize L-Ara4N-modified lipid A was present. Inactivation of lpxM in both E. coli and S. typhimurium resulted in the loss of L-Ara4N addition, as well as, increased sensitivity to polymyxin. However, decoration of the lipid A phosphate groups with pEtN residues was not effected in lpxM mutants. In summary, we demonstrate that attachment of L-Ara4N to the phosphate groups of lipid A and the subsequent resistance to polymyxin is dependent upon the presence of the secondary linked myristoyl group

Lung Megakaryocytes are Immune Modulatory Cells that Present Antigen to CD4+ T cells.

Although platelets are the cellular mediators of thrombosis, they are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered bone marrow–resident (BM-resident) cells. However, platelet-producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared with BM Mks. We therefore sought to define the immune functions of lung Mks. Using single-cell RNA sequencing of BM and lung myeloid-enriched cells, we found that lung Mks, which we term MkL, had gene expression patterns that are similar to antigen-presenting cells. This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment, as evidenced by BM Mks having an MkL-like phenotype under the influence of pathogen receptor challenge and lung-associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in an MHC II–dependent manner both in vitro and in vivo. These data indicated that MkL had key immune regulatory roles dictated in part by the tissue environment.pre-print236 K

Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets

Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen's d = -0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD

Core Outcomes for Colorectal Cancer Surgery: A Consensus Study

Background: Colorectal cancer (CRC) is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well-designed randomized controlled trials (RCTs); however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard “core” set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery. Methods and Findings: The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals) from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods). Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78%) centers, including 90 professionals, and 97 out of 267 (35%) patients. Second round response rates were high for all stakeholders (>80%). Analysis of responses lead to 45 and 23 outcome domains being retained after the first and second surveys, respectively. Consensus meetings generated agreement on a 12 domain COS. This constituted five perioperative outcome domains (including anastomotic leak), four quality of life outcome domains (including fecal urgency and incontinence), and three oncological outcome domains (including long-term survival). Conclusion: This study used robust consensus methodology to develop a core outcome set for use in colorectal cancer surgical trials. It is now necessary to validate the use of this set in research practice

Extensive HIV-1 Intra-Host Recombination Is Common in Tissues with Abnormal Histopathology

There is evidence that immune-activated macrophages infected with the Human Immunodeficiency Virus (HIV) are associated with tissue damage and serve as a long-lived viral reservoir during therapy. In this study, we analyzed 780 HIV genetic sequences generated from 53 tissues displaying normal and abnormal histopathology. We found up to 50% of the sequences from abnormal lymphoid and macrophage rich non-lymphoid tissues were intra-host viral recombinants. The presence of extensive recombination, especially in non-lymphoid tissues, implies that HIV-1 infected macrophages may significantly contribute to the generation of elusive viral genotypes in vivo. Because recombination has been implicated in immune evasion, the acquisition of drug-resistance mutations, and alterations of viral co-receptor usage, any attempt towards the successful eradication of HIV-1 requires therapeutic approaches targeting tissue macrophages