Whole Blood Transcriptome Analysis in Children with Sickle Cell Anemia

Whole transcriptome RNA-sequencing was performed to quantify RNA expression changes in whole blood samples collected from steady state sickle cell anemia (SCA) and control subjects. Pediatric SCA and control subjects were recruited from Atlanta (GA)—based hospital(s) systems and consented for RNA sequencing. RNA sequencing was performed on an Ion Torrent S5 sequencer, using the Ion Total RNA-seq v2 protocol. Data were aligned to the hg19 reference genome and analyzed in the Partek Genomics studio package (v7.0). 223 genes were differentially expressed between SCA and controls (± 1.5 fold change FDR p < 0.001) and 441 genes show differential transcript expression (± 1.5 fold FDR p < 0.001). Differentially expressed RNA are enriched for hemoglobin associated genes and ubiquitin-proteasome pathway genes. Further analysis shows higher gamma globin gene expression in SCA (33-fold HBG1 and 49-fold HBG2, both FDR p < 0.05), which did not correlate with hemoglobin F protein levels. eQTL analysis identified SNPs in novel non-coding RNA RYR2 gene as having a potential regulatory role in HBG1 and HBG2 expression levels. Gene expression correlation identified JHDM1D-AS1(KDM7A-DT), a non-coding RNA associated with angiogenesis, enhanced GATA1 and decreased JAK-STAT signaling to correlate with HBG1 and HBG2 mRNA levels. These data suggest novel regulatory mechanisms for fetal hemoglobin regulation, which may offer innovative therapeutic approaches for SCA.

Functional Deletion/Insertion Promoter Variants in SCARB1 Associated With Increased Susceptibility to Lipid Profile Abnormalities and Coronary Heart Disease

Background: Genetic variants in Scavenger receptor Class B Type 1 (SCARB1) influencing high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) risk were identified by recent genome-wide association studies. Further study of potential functional variants in SCARB1 may provide new ideas of the complicated relationship between HDL-C and CHD.Methods: 2000 bp in SCARB1 promoter region was re-sequenced in 168 participants with extremely high plasma HDL-C and 400 control subjects. Putative risk alleles were identified using bioinformatics analysis and reporter-gene assays. Two indel variants, rs144334493 and rs557348251, respectively, were genotyped in 5,002 CHD patients and 5,175 control subjects. The underlying mechanisms were investigated.Results: Through resequencing, 27 genetic variants were identified. Results of genotyping in 5,002 CHD patients and 5,175 control subjects revealed that rs144334493 and rs557348251 were significantly associated with increased risk of CHD [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09 to 1.52, p = 0.003; OR: 2.65, 95% CI: 1.66–4.24, p = 4.4 × 10−5). Subsequent mechanism experiments demonstrated that rs144334493 deletion allele attenuated forkhead box A1 (FOXA1) binding to the promoter region of SCARB1, while FOXA1 overexpression reversely increased SR-BI expression.Conclusion: Genetic variants in SCARB1 promoter region significantly associated with the plasma lipid levels by affecting SR-BI expression and contribute to the susceptibility of CHD.

Peripheral NF-κB dysregulation in people with schizophrenia drives inflammation: putative anti-inflammatory functions of NF-κB kinases

Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined ‘high inflammation’ individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying ‘high inflammation’ compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

Relationship Between Dietary Omega-3 and Omega-6 Polyunsaturated Fatty Acids Level and Sarcopenia. A Meta-Analysis of Observational Studies

Objective: This study investigates the relationship between dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) levels and sarcopenia.Methods: A comprehensive literature search in the databases of PubMed, Web of Science, and Embase (up to July 2021) were conducted to identify the observational studies on the relationship between dietary omega-3 and omega-6 PUFAs level and sarcopenia. The pooled odds ratio (OR) of sarcopenia for the highest vs. lowest dietary omega-3 and omega-6 PUFAs level and the standard mean difference (SMD) of dietary omega-3 and omega-6 PUFAs levels for sarcopenia vs. control subjects were calculated.Results: A total of six studies were identified in this meta-analysis. The overall multi-variable adjusted OR showed that dietary omega-3 PUFAs level was inversely associated with sarcopenia (OR = 0.41, 95% CI: 0.26–0.65; P = 0.0001). Moreover, the overall combined SMD showed that the dietary omega-3 PUFAs level in sarcopenia was lower than that in control subjects (SMD = −0.19, 95% CI: −0.32 to −0.07; P = 0.002). With regard to dietary omega-6 PUFAs level, the overall multi-variable adjusted OR suggested no significant relationship between dietary omega-6 PUFAs level and sarcopenia (OR = 0.64, 95% CI: 0.33–1.24; P = 0.19). However, the overall combined SMD showed that the dietary omega-6 PUFAs level in sarcopenia was slightly lower than that in control subjects (SMD = −0.15, 95% CI: −0.27 to −0.02; P = 0.02).Conclusion: Our results suggested that the dietary omega-3 PUFAs level was inversely associated with sarcopenia. However, current evidence is still insufficient to demonstrate the definite relationship between dietary omega-6 PUFAs levels and sarcopenia. More well-designed prospective cohort studies with the dietary omega-3/omega-6 PUFAs ratio are still needed.

Magnetic Resonance Spectroscopy of Hypoxic-Ischemic Encephalopathy After Cardiac Arrest

Objective:To correlate brain metabolites to clinical outcome using magnetic resonance spectroscopy (MRS) in patients undergoing targeted temperature management (TTM) after cardiac arrest, and assess their relationships to MRI and EEG variables.Methods:A prospective cohort of 50 patients was studied. The primary outcome was coma recovery to follow commands. Comparison of MRS measures in the posterior cingulate gyrus, parietal white matter, basal ganglia, and brainstem were also made to 25 normative control subjects.Results:Fourteen of 50 achieved coma recovery before hospital discharge. There was a significant decrease in total N-acetyl-aspartate (NAA/Cr) and an increase in lactate (Lac/Cr) in patients who did not recover, with changes most prominent in the posterior cingulate gyrus. Patients who recovered had decrease in NAA/Cr as compared to control subjects. NAA/Cr had a strong monotonic relationship with MRI cortical apparent diffusion coefficient (ADC); lactate level exponentially increased with decreasing ADC. EEG suppression/burst suppression was universally associated with lactate elevation.Conclusions:NAA and lactate changes are associated with clinical/MRI/EEG changes consistent with hypoxic-ischemic encephalopathy (HIE) and are most prominent in the posterior cingulate gyrus. NAA/Cr decrease observed in patients with good outcomes suggests mild HIE in patients asymptomatic at hospital discharge. The appearance of cortical lactate represents a deterioration of aerobic energy metabolism and is associated with EEG background suppression, synaptic transmission failure, and severe, potentially irreversible HIE.Classification of Evidence:This study provides Class IV evidence that in patients undergoing TTM after cardiac arrest, brain MRS-determined decrease in total NAA/Cr and an increase in Lac/Cr are associated with an increased risk of not recovering.

Clinical Evaluation of the Modified Faine Criteria in Patients Admitted with Suspected Leptospirosis to the Territorial Hospital, New Caledonia, 2018 to 2019

Leptospirosis is endemic in New Caledonia. Clinical diagnosis is often difficult and its evolution can be fatal. Leptospirosis requires specific management before biological confirmation. Modified Faine criteria (Faine Score) have been suggested to diagnose leptospirosis on epidemiological (parts A and B) and biological (part C) criteria. The main objective of our study was to assess the relevance of the epidemiological–clinical modified Faine score, parts A and B (MF A + B), in patients with suspected leptospirosis in New Caledonia. A monocentric case–control study was conducted in suspect patients for whom a Leptospira polymerase chain reaction (PCR) test was done within the first 7 days of signs onset at the tertiary hospital from January 1, 2018 to January 4, 2019. Cases and control subjects were matched 1:2 in the gender and age categories. Bivariate, and then multivariable, analyses studied the association between the MF A + B score and a positive Leptospira PCR test, adjusted on the variables retained. In all, 35 cases and 70 control subjects matched for age and gender were analyzed. Multivariable analysis by logistic regression found a significant association between an MF A + B score taken from the categories “possible leptospirosis” (score, 20–25) and “presumed leptospirosis” (score, > 26), and the case or control subject status (P < 0.0001). Model performance was high, with an area under the curve value of 99.27%, 93.55% sensitivity, and 96.36% specificity, which classified subjects correctly in 95.35% of cases. Our study suggests using the MF A + B score to identify possible cases of leptospirosis and initiate antibiotic therapy before biological confirmation in New Caledonia. This score should be evaluated in areas where more differential diagnoses exist and where PCR is not widely available.

Increased blood group 2 innate lymphoid cells are involved in blood eosinophilia and itching in Kimura disease

Background: Kimura disease (KD) is a rare, chronic inflammatory disorder characterized by blood eosinophilia, general itching, and subcutaneous head and neck mass lesions; however, the etiology of this disease is unknown. We hypothesized that group 2 innate lymphoid cells (ILC2s) in peripheral blood may play an essential role in the pathogenesis of KD. Methods: The prevalence of blood ILC2s and their ability to produce interleukin (IL) -4, IL-5, IL-13, and IL-31 in patients with KD were compared with those in control subjects and in patients with house dust mite (HDM) -induced allergic rhinitis (AR). Changes in blood ILC2 prevalence, blood eosinophilia, and clinical symptoms after surgery and steroid therapy were evaluated. Results: Blood ILC2 prevalence in patients with KD were eight times and six times higher than those in control subjects and in patients with AR, respectively. There was a strong positive correlation between ILC2 prevalence and blood eosinophilia. Patients with KD showed increased serum IL-13 and decreased IL-31 levels. KD patient-derived blood ILC2s produced large amounts of IL-5 and IL-13 in response to prostaglandin (PG) D and leukotriene (LT) D , compared to ILC2s derived from control subjects and patients with AR. Surgery and systemic steroid therapy ameliorated general itching with a concomitant decrease in blood ILC2s and blood eosinophilia. Upon disease recurrence, blood ILC2 prevalence and blood eosinophilia increased concurrently with general itching. Conclusion: Increased blood ILC2s may be involved in blood eosinophilia and general itching through the production of IL-5 and IL-13 in patients with KD.

Polygenic Prediction of Type 2 Diabetes in Africa

OBJECTIVE Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American–, European-, or multiethnic-derived PRSs would improve polygenic prediction in continental Africans. RESEARCH DESIGN AND METHODS Using the PRSice software, ethnic-specific PRSs were computed with weights from the T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects). RESULTS The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American–derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European- and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19–4.03; P = 2.79 × 10−17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile. CONCLUSIONS African American–derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D.

Ankle-Injury Patients Perform More Microadjustments during Walking: Evidence from Velocity Profiles in Gait Analysis

Introduction. We evaluated the velocity profiles of patients with lateral collateral ligament (LCL) injuries of the ankle with a goal of understanding the control mechanism involved in walking. Methods. We tracked motions of patients’ legs and feet in 30 gait cycles recorded from patients with LCL injuries of the ankle and compared them to 50 gait cycles taken from normal control subjects. Seventeen markers were placed on the foot following the Heidelberg foot measurement model. Velocity profiles and microadjustments of the knee, ankle, and foot were calculated during different gait phases and compared between the patient and control groups. Results. Patients had a smaller first rocker percentage and larger second rocker percentage in the gait cycle compared to controls. Patients also displayed shorter stride length and slower strides and performed more microadjustments in the second rocker phase than in other rocker/swing phases. Patients’ mean velocities of the knee, ankle, and foot in the second rocker phase were also significantly higher than that in control subjects. Discussion. Evidence from velocity profiles suggested that patients with ligament injury necessitated more musculoskeletal microadjustments to maintain body balance, but these may also be due to secondary injury. Precise descriptions of the spatiotemporal gait characteristics are therefore crucial for our understanding of movement control during locomotion.

Effect of malocclusion on jaw motor function and chewing in children: a systematic review

Objective To investigate the effects of dental/skeletal malocclusion and orthodontic treatment on four main objective parameters of chewing and jaw function (maximum occlusal bite force [MOBF], masticatory muscle electromyography [EMG], jaw kinematics, and chewing efficiency/performance) in healthy children. Materials and methods Systematic searches were conducted in MEDLINE (OVID), Embase, and the Web of Science Core Collection. Studies that examined the four parameters in healthy children with malocclusions were included. The quality of studies and overall evidence were assessed using the Joanna Briggs Institute and GRADE tools, respectively. Results The searches identified 8192 studies; 57 were finally included. The quality of included studies was high in nine studies, moderate in twenty-three studies, and low in twenty-five studies. During the primary dentition, children with malocclusions showed similar MOBF and lower chewing efficiency compared to control subjects. During mixed/permanent dentition, children with malocclusion showed lower MOBF and EMG activity and chewing efficiency compared to control subjects. The jaw kinematics of children with unilateral posterior crossbite showed a larger jaw opening angle and a higher frequency of reverse chewing cycles compared to crossbite-free children. There was a low to moderate level of evidence on the effects of orthodontic treatment in restoring normal jaw function. Conclusions Based on the limitations of the studies included, it is not entirely possible to either support or deny the influence of dental/skeletal malocclusion traits on MOBF, EMG, jaw kinematics, and masticatory performance in healthy children. Furthermore, well-designed longitudinal studies may be needed to determine whether orthodontic treatments can improve chewing function in general. Clinical relevance Comprehensive orthodontic treatment, which includes evaluation and restoration of function, may or may not mitigate the effects of malocclusion and restore normal chewing function.