SLC6A8 creatine transporter deficiency can be detected by plasma creatine and creatinine concentrations.

Creatine transporter deficiency has been described with normal or uninformative levels of creatine and creatinine in plasma, while urine has been the preferred specimen type for biochemical diagnosis. We report a cohort of untreated patients with creatine transporter deficiency and abnormal plasma creatine panel results, characterized mainly by markedly decreased plasma creatinine. We conclude that plasma should be considered a viable specimen type for the biochemical diagnosis of this disorder, and abnormal results should be followed up with further confirmatory testing.

Prognostic Markers in Hospitalized COVID-19 Patients: The Role of IP-10 and C-Reactive Protein.

BACKGROUND: SARS-CoV-2 is responsible for COVID-19, a clinically heterogeneous disease, ranging from being completely asymptomatic to life-threating manifestations. An unmet clinical need is the identification at disease onset or during its course of reliable biomarkers allowing patients' stratification according to disease severity. In this observational prospective cohort study, patients' immunologic and laboratory signatures were analyzed to identify independent predictors of unfavorable (either death or intensive care unit admission need) or favorable (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. METHODS: Between January and May 2021 (third wave of the pandemic), we enrolled 139 consecutive SARS-CoV-2 positive patients hospitalized in Northern Italy to study their immunological and laboratory signatures. Multiplex cytokine, chemokine, and growth factor analysis, along with routine laboratory tests, were performed at baseline and after 7 days of hospital stay. RESULTS: According to their baseline characteristics, the majority of our patients experienced a moderate to severe illness. At multivariate analysis, the only independent predictors of disease evolution were the serum concentrations of IP-10 (at baseline) and of C-reactive protein (CRP) after 7 days of hospitalization. Receiver-operating characteristic (ROC) curve analysis confirmed that baseline IP - 10 > 4271 pg/mL and CRP > 2.3 mg/dL at 7 days predict a worsening in clinical conditions (87% sensitivity, 66% specificity, area under the curve (AUC) 0.772, p < 0.001 and 83% sensitivity, 73% specificity, AUC 0.826, p < 0.001, respectively). CONCLUSIONS: According to our results, baseline IP-10 and CRP after 7 days of hospitalization could be useful in driving clinical decisions tailored to the expected disease trajectory in hospitalized COVID-19 patients.

Expression and Clinical Correlation Analysis Between Repulsive Guidance Molecule a and Neuromyelitis Optica Spectrum Disorders.

Objectives: This study sought to explore the expression patterns of repulsive guidance molecules a (RGMa) in neuromyelitis optica spectrum disorders (NMOSD) and to explore the correlation between RGMa and the clinical features of NMOSD. Methods: A total of 83 NMOSD patients and 22 age-matched healthy controls (HCs) were enrolled in the study from October 2017 to November 2021. Clinical parameters, including Expanded Disability Status Scale (EDSS) score, degree of MRI enhancement, and AQP4 titer were collected. The expression of serum RGMa was measured by enzyme-linked immunosorbent assay (ELISA) and compared across the four patient groups. The correlation between serum RGMa levels and different clinical parameters was also assessed. Results: The average serum expression of RGMa in the NMOSD group was significantly higher than that in the HC group (p < 0.001). Among the patient groups, the acute phase group exhibited significantly higher serum RGMa levels than did the remission group (p < 0.001). A multivariate analysis revealed a significant positive correlation between RGMa expression and EDSS score at admission, degree of MRI enhancement, and segmental length of spinal cord lesions. There was a significant negative correlation between the expression of RGMa in NMOSD and the time from attack to sampling or delta EDSS. Conclusions: The current study suggests that RGMa may be considered a potential biomarker predicting the severity, disability, and clinical features of NMOSD.

Neuronal exosome proteins: novel biomarkers for predicting neonatal response to therapeutic hypothermia.

OBJECTIVE: Central nervous system (CNS) derived exosomes can be purified from peripheral blood and have been used widely in adult neurological disease. Application to neonatal neurological disease deserves investigation in the setting of hypoxic-ischaemic encephalopathy (HIE). DESIGN: Observational cohort. SETTING: Level III neonatal intensive care unit. PARTICIPANTS: Term/near-term neonates undergoing therapeutic hypothermia (TH) for HIE. INTERVENTIONS: Blood samples were collected at 0-6, 12, 24, 48 and 96 hours of life. MAIN OUTCOMES AND MEASURES: CNS exosomes were purified from serum using previously described methods. Biomarker protein levels were quantified using standard ELISA methods and normalised to exosome marker CD-81. The slope of change for biomarker levels was calculated for each time interval. Our primary outcome was MRI basal ganglia/watershed score of ≥3. RESULTS: 26 subjects were included (umbilical artery pH range 6.6-7.29; 35% seizures). An increasing MRI injury score was significantly associated with decreasing levels of synaptopodin between 0-6 and 12 hours (p=0.03) and increasing levels of lipocalin-2 (NGAL) between 12 and 48 hours (p<0.0001). Neuronal pentraxin was not significant. The negative predictive values for increasing synaptopodin and decreasing NGAL was 70.0% and 90.9%, respectively. CONCLUSIONS AND RELEVANCE: Our results indicate that CNS exosome cargo has the potential to act as biomarkers of the severity of brain injury and response to TH as well as quantify pharmacological response to neuroactive therapeutic/adjuvant agents. Rigorous prospective trials are critical to evaluate potential clinical use of exosome biomarkers.

Following the Clues: Usefulness of Biomarkers of Neuroinflammation and Neurodegeneration in the Investigation of HTLV-1-Associated Myelopathy Progression.

Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurodegenerative disease due to axonal damage of the corticospinal secondary to an inflammatory response against infected T-cells. In the present work, we aimed to evaluate biomarkers of neurodegeneration and neuroinflammation in the definition of HAM/TSP prognosis. Neurofilament light (NfL) and phosphorylated heavy (pNfH) chains, total Tau protein, cellular prion protein (PrPc), inflammatory chemokines, and neopterin were quantified in paired cerebrospinal fluid (CSF) and serum samples from HAM/TSP patients (n=21), HTLV-1 asymptomatic carriers (AC) (n=13), and HTLV-1 seronegative individuals with non-inflammatory non-degenerative neurological disease (normal-pressure hydrocephalus) (n=9) as a control group. HTLV-1 proviral load in peripheral blood mononuclear cells and the expression of chemokine receptors CCR4, CCR5, and CXCR3 in infected CD4+ T-cells (HTLV-1 Tax+ cells) were also assessed. CSF levels of Tau, NfL, and pNfH were similar between groups, but PrPc and neopterin were elevated in HAM/TSP patients. Most individuals in the control group and all HTLV-1 AC had CSF/serum neopterin ratio < 1.0, and two-thirds of HAM/TSP patients had ratio values > 1.0, which positively correlated with the speed of disease progression and pNfH levels, indicating active neuroinflammation. HAM/TSP patients showed high serum levels of CXCR3-binding chemokines (CXCL9, CXCL10, and CXCL11) and elevated CSF levels of CCL2, CCL3, CCL4, CCL17, CXCL5, CXCL10, and CXCL11. Indeed, CXCL10 concentration in CSF of HAM/TSP patients was 5.8-fold and 8.7-fold higher in than in HTLV-1 AC and controls, respectively, and correlated with CSF cell counts. HAM/TSP patients with typical/rapid disease progression had CSF/serum CXCL10 ratio > 1.0 and a higher frequency of CXCR3+Tax+CD4+ T-cells in blood, which indicated a positive gradient for the migration of infected cells and infiltration into the central nervous system. In conclusion, the slow progression of HAM/TSP abrogates the usefulness of biomarkers of neuronal injury for the disease prognosis. Thus, markers of inflammation provide stronger evidence for HAM/TSP progression, particularly the CSF/serum neopterin ratio, which may contribute to overcome differences between laboratory assays.

A paper-based ELISA for rapid sensitive determination of anaphylaxis-related MRGPRX2 in human peripheral blood.

Mas-related G-protein-coupled receptor X2 (MRGPRX2) has recently been reported to be associated with anaphylaxis. Detection of MRGPRX2 levels in human peripheral blood might serve as a powerful tool for predicting the predisposition of patients to anaphylactic reactions. For rapid measurement of MRGPRX2, we established a paper-based double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) using mouse monoclonal antibody and horseradish peroxidase (HRP)-labelled rabbit polyclonal antibody as capture antibody and detection antibody, respectively. We avoided chemical functionalization of the cellulose paper by introducing bovine serum albumin (BSA) to provide COOH and NH2 groups for covalent immobilization of the capture antibody. Through amide condensation, a two-layer immobilization strategy was applied with BSA-BSA and BSA-capture antibody networks as the first and second layers, respectively. This strategy improved the quantity, activity and stability of the immobilized antibody. We then established a paper-based ELISA to detect MRGPRX2 in human peripheral blood. Our method is less laborious, easier to implement, and more cost-effective than conventional ELISA, while offering similar sensitivity, specificity, and accuracy. Therefore, it could serve as an innovative clinical point-of-care diagnostic tool, especially in areas that lack advanced clinical equipment.

Investigation of C-reactive protein and AIM2 methylation as a marker for PTSD in Australian Vietnam veterans.

Chronic inflammation is a key factor in symptomology and comorbidities of post-traumatic stress disorder (PTSD). Levels of a proinflammatory marker, C-reactive protein (CRP) are increased in individuals with PTSD but it is not clear if this is due to trauma exposure or PTSD. Our study aimed to assess the relationship between serum CRP levels, CRP SNPs, methylation, mRNA expression and PTSD in a homogenous trauma exposed Australian Vietnam veteran cohort. We hypothesized that decreased DNA methylation would be associated with increased gene expression and increased peripheral CRP levels in PTSD patients and that this would be independent of trauma. Participants were 299 Vietnam veterans who had all been exposed to trauma and approximately half were diagnosed with PTSD. We observed higher levels of serum CRP in the PTSD group compared to the non-PTSD group but after controlling for BMI and triglycerides the association did not remain significant. No association was found between CRP SNPs and PTSD or CRP levels. Absent in Melanoma 2 (AIM2) which is a mediator of inflammatory response and a determinant of CRP levels was analysed for DNA methylation and mRNA expression. We observed a trend level association between PTSD and AIM2 methylation after controlling for age, smoking, triglycerides, BMI and cell types. There was no significant interaction between PTSD and CRP levels on AIM2 methylation after controlling for covariates. We observed that as AIM2 methylation levels decreased, AIM2 mRNA expression increased. Elevated CRP levels were associated with AIM2 mRNA in the trauma exposed cohort but there was no significant interaction effect with PTSD. Our results could not confirm that CRP is a marker of PTSD independent of trauma in this group of older veterans. CRP may be a broad marker of disease risk, or a marker of PTSD in younger cohorts than those in this study.

Endurance exercise improves avoidance learning and spatial memory, through changes in genes of GABA and relaxin-3, in rats.

Different exercise patterns, neurotransmitters, and some genes have numerous effects on learning and memory. This research aims to investigate the long-term effects of submaximal aerobic exercise on spatial memory (SM), passive avoidance learning (PAL), levels of serum relaxin-3, gamma-aminobutyric acid (GABA), RLN3 gene, and glutamic acid decarboxylase (GAD65/67 genes) in the brainstem of adult male Wistar rats. Fifty male Wistar rats were randomly divided into five groups: aerobic exercise groups, performed on a treadmill running (TR), for 5 weeks (Ex5, n = 10), 10 weeks (Ex10, n = 10), involuntary running wheel group for 5 weeks (IRW5, n = 10), sham (Sh, n = 10) and control (Co, n = 10). Consequently, SM, PAL, serum relaxin-3, GABA, and GAD65/67 and RLN3 genes were measured by ELISA and PCR. Ex5, Ex10 and IRW5 improved significantly SM (p ≤ 0.05), PAL (p ≤ 0.001) and decreased significantly relaxin-3 (p ≤ 0.001). RLN3 in the brain also decreased. However, it was not significant. GABA and GAD65/GAD67 increased significantly (p ≤ 0.05) in Ex5, Ex10 compared to Sh and Co. Aerobic exercise enhanced SM and PAL in Ex compared to Co and Sh. However, duration and type of exercise affected the level of enhancement. The serum relaxin-3 and RLN3 gene displayed reverse functions compared to GABA and GAD65/67 genes in Ex. Therefore, the changes of neurotransmitters in serum relaxin-3, GABA, and their genes: RLN3 and GAD65/67 respectively, influenced learning and memory meaningfully.

Meningioma preceding CASPR2 antibody limbic encephalitis with a stroke mimic: A case report.

RATIONALE: Todd paralysis (a stroke-like presentation in some patients with epilepsy) caused by limbic encephalitis (LE) is not easily distinguished from acute ischemic stroke by clinicians in the emergency room. PATIENT CONCERNS: We report a contactin-associated protein-like 2-antibody (CASPR2-Ab)-positive patient who presented with atypical LE. DIAGNOSES: CASPR2-Ab-positive LE was the presumed diagnosis. Re-evaluation of cerebrospinal fluid (CSF) samples revealed autoantibodies targeting CASPR2 at an immunoglobulin G titer of 1:1. The clinical presentation of subacute onset seizures, abnormal electroencephalography, hypermetabolism on positron emission tomography, good immunotherapy response, and the presence of specific antibodies in serum supports a diagnosis of autoimmune LE. INTERVENTION: The patient received glucocorticoids (1 g for 3 days and 500 mg for 3 days), immunoglobulin (25 g for 3 days), sodium valproate (1 g for 3 days), and clonazepam (1 mg for 3 days). OUTCOMES: Remission of temporal lobe epilepsy symptoms and cognitive dysfunction was observed. Follow-up analysis of CSF and serological examination were not approved by the patient. His Mini-Mental State Examination score improved to 21/30. Stable remission of symptoms was achieved throughout the follow-up period of 50 days. LESSONS: Autoimmune encephalitis (AE) should be considered in cases of late-onset epilepsy following meningioma peritumoral brain edema and resection. A diagnosis of AE should be considered in patients presenting with stroke-like symptoms if the magnetic resonance imaging abnormality does not match a known vascular territory. Early and correct diagnosis is crucial because immunotherapy is usually effective for this disease.

Basophil and mast cell activation tests by flow cytometry in immediate drug hypersensitivity: Diagnosis and beyond.

Immediate drug hypersensitivity reactions (IDHRs) constitute a significant health issue with serious consequences of diagnostic error. The primary diagnostics to document IDHRs usually consists of quantification of drug-specific IgE (sIgE) antibodies and skin tests. Unfortunately, the positive predictive value (PPV) and negative predictive value (NPV) of these tests are not absolutely, which leaves room for new tests. Over the last two decades, the basophil activation test (BAT), in which ex vivo activation of individual basophils is quantified by flow cytometry, has emerged as a reliable complementary diagnostic to document IDHRs, to explore allergenic recognition, to study cross-reactivity and to monitor therapy. However, the BAT is technically challenging requiring specialized personnel and equipment, fresh samples and the technique is lost as a diagnostic in patients showing a non-responder status of their cells. By consequence, the BAT has still not entered mainstream application. In contrast, mast cell activation tests (MATs) use serum samples that can be frozen, stored, and shipped to a recognized reference centre experienced in mast cell (MC) lines and/or cultures and capable of offering batch testing with necessary quality controls. This review does not only highlight the use of the BAT and MAT as diagnostics in IDHRs, but also outlines the potential of both techniques in further exploring and unveiling the mechanisms that govern drug-induced basophil and MC activation and degranulation.

Proteomic identification of biomarkers in maternal plasma that predict the outcome of rescue cerclage for cervical insufficiency.

OBJECTIVE: We sought to identify plasma protein biomarkers that are predictive of the outcome of rescue cerclage in patients with cervical insufficiency. METHODS: This retrospective cohort study included 39 singleton pregnant women undergoing rescue cerclage for cervical insufficiency (17-25 weeks) who gave plasma samples. Three sets of pooled plasma samples from controls (cerclage success, n = 10) and cases (cerclage failure, n = 10, defined as spontaneous preterm delivery at <33 weeks) were labeled with 6-plex tandem mass tag (TMT) reagents and analyzed by liquid chromatography-tandem mass spectrometry. Differentially expressed proteins between the two groups were selected from the TMT-based quantitative analysis. Multiple reaction monitoring-mass spectrometry (MRM-MS) analysis was further used to verify the candidate proteins of interest in patients with cervical insufficiency in the final cohort (n = 39). RESULTS: From MRM-MS analysis of the 40 proteins showing statistically significant changes (P < 0.05) from the TMT-based quantitative analysis, plasma IGFBP-2, PSG4, and PGLYRP2 levels were found to be significantly increased, whereas plasma MET and LXN levels were significantly decreased in women with cerclage failure. Of these, IGFBP-2, PSG4, and LXN levels in plasma were independent of cervical dilatation. A multiple-biomarker panel was developed for the prediction of cerclage failure, using a stepwise regression procedure, which included the plasma IGFBP-2, PSG4, and LXN (area under the curve [AUC] = 0.916). The AUC for this multiple-biomarker panel was significantly greater than the AUC for any single biomarker included in the multi-biomarker model. CONCLUSIONS: Proteomic analysis identified useful and independent plasma biomarkers (IGFBP-2, PSG4, and LXN; verified by MRM) that predict poor pregnancy outcome following rescue cerclage. Their combined analysis in a multi-biomarker panel significantly improved predictability.

Serum artemin is not correlated with sensitivity within dogs with naturally occurring osteoarthritis pain.

Osteoarthritis (OA) pain is associated with peripheral and central sensitization in humans and results in widespread increased sensitivity across the body. Sensitization contributes to the OA-associated pain (OAP) state. We recently identified increased levels of an endogenous neurotrophic factor, artemin (ARTN), in dogs with OAP compared to healthy pain-free controls. Circulating ARTN released from damaged tissues in OA, may play a central role in widespread sensitivity and pain. However, the relationship between ARTN and somatosensory sensitivity remains unknown. The study aimed to assess the relationship between serum ARTN concentrations and measures of sensitivity in dogs with OAP using quantitative sensory testing. We hypothesized that there would be a positive association between circulating ARTN and increased sensitivity to mechanical and thermal stimuli in dogs with OAP. We used linear and logistic regression models to assess the relationship between ARTN, sensitization, and pain within a cohort of 43 dogs with spontaneous OAP. Serum ARTN was not associated with the degree of sensitization within dogs with OAP. Further, across dogs with varying OAP severity, we did not find any association between ARTN, and clinical measures of joint pain and disability. Although a relationship between ARTN and joint pain was not ruled out.

Proteomic blood profiling in mild, severe and critical COVID-19 patients.

The recent SARS-CoV-2 pandemic manifests itself as a mild respiratory tract infection in most individuals, leading to COVID-19 disease. However, in some infected individuals, this can progress to severe pneumonia and acute respiratory distress syndrome (ARDS), leading to multi-organ failure and death. This study explores the proteomic differences between mild, severe, and critical COVID-19 positive patients to further understand the disease progression, identify proteins associated with disease severity, and identify potential therapeutic targets. Blood protein profiling was performed on 59 COVID-19 mild (n = 26), severe (n = 9) or critical (n = 24) cases and 28 controls using the OLINK inflammation, autoimmune, cardiovascular and neurology panels. Differential expression analysis was performed within and between disease groups to generate nine different analyses. From the 368 proteins measured per individual, more than 75% were observed to be significantly perturbed in COVID-19 cases. Six proteins (IL6, CKAP4, Gal-9, IL-1ra, LILRB4 and PD-L1) were identified to be associated with disease severity. The results have been made readily available through an interactive web-based application for instant data exploration and visualization, and can be accessed at https://phidatalab-shiny.rosalind.kcl.ac.uk/COVID19/ . Our results demonstrate that dynamic changes in blood proteins associated with disease severity can potentially be used as early biomarkers to monitor disease severity in COVID-19 and serve as potential therapeutic targets.

Involuntary movement in stiff-person syndrome with amphiphysin antibodies: A case report.

RATIONALE: Stiff-person syndrome (SPS) is a rare neurological immune disorder characterized by progressive axial and proximal limb muscle rigidity, stiffness, and painful muscle spasms. Amphiphysin antibodies are positive in approximately 5% of SPS patients. To date, there have been no relevant reports on involuntary movement in cases of SPS with amphiphysin antibodies. PATIENT CONCERNS: We describe the case of a 69-year-old man with a 2-year history of progressive stiffness in the neck, bilateral shoulders, and chest muscles, and a more-than-a-year history of dyspnea accompanied by mandibular involuntary movement. The patient was a vegetarian and had good health in the past. The family's medical history was unremarkable. DIAGNOSES: He was diagnosed with SPS based on the progressive muscle stiffness, the amphiphysin antibody seropositivity, the continuous motor activity on electromyography, and the effective treatment with benzodiazepines. INTERVENTIONS: The patient was orally administered clonazepam and baclofen, and corticosteroid IV followed by prednisone orally. OUTCOMES: In the hospital, after treatment with methylprednisolone, clonazepam, and baclofen, the patient's rigidity, stiffness, and dyspnea significantly improved. The involuntary movement of the mandible persisted throughout the treatment process. Currently, under oral treatment with baclofen and clonazepam, the patient's symptoms of muscle stiffness and dyspnea exist, and follow-up is continued. LESSONS: We report a rare and novel case of involuntary movement in SPS with amphiphysin antibodies. The present report explores the relationship between SPS and involuntary movement and expands the spectrum of clinical manifestations of SPS.

Blood reelin in the progression of chronic liver disease.

PURPOSE: Reelin is an extracellular matrix protein originally found to be associated with neuropsychiatric disorders. Recent findings indicate, that reelin may also play an important role in the process of liver fibrosis as well as in the development of hepatocellular carcinoma (HCC). Against this background, the aim of our study was to explore alterations in blood reelin levels in different stages of chronic liver diseases. PATIENTS AND METHODS: We analyzed blood samples of patients with chronic liver disease without liver fibrosis (n â€‹= â€‹25), with liver fibrosis (n â€‹= â€‹36), with liver cirrhosis (n â€‹= â€‹74), with HCC (n â€‹= â€‹26) as well as of healthy controls (n â€‹= â€‹15). Blood reelin concentrations were determined utilizing an enzyme-linked immunosorbent assay. RESULTS: Blood reelin levels were significantly elevated in patients who had liver fibrosis or cirrhosis compared to patients without liver fibrosis and healthy controls (13.9 (10.2-21.1) ng/ml vs. 11.2 (8.8-16.8) ng/ml, p â€‹= â€‹0.032). Importantly, patients with HCC displayed significantly higher reelin concentrations compared to patients with liver cirrhosis alone (27.0 (17.3-35.9) ng/ml vs. 16.6 (11.0-22.7) ng/ml, p â€‹< â€‹0.001). Blood reelin was not relevantly linked to liver function, inflammation and etiology of liver disease. CONCLUSIONS: Our results demonstrate, that blood reelin levels are altered in different stages of chronic liver disease, which makes reelin a potential biomarker in this setting. This may be especially relevant with regard to its use as an additional tumor marker of HCC.

Paraneoplastic Cerebellar Degeneration: The Importance of Including CDR2L as a Diagnostic Marker.

OBJECTIVE: Investigate the value of including cerebellar degeneration-related protein 2-like (CDR2L) as a marker in commercial diagnostic tests for anti-Yo-associated paraneoplastic cerebellar degeneration (PCD). METHODS: We included sera and CSF samples from 24 patients with suspected PCD (6 of whom had PCD with underlying gynecologic or breast cancer), who were positive for Yo antibodies using the commercially available, paraneoplastic neurologic syndromes (PNS) 14 Line Assay from Ravo Diagnostika. The samples were further evaluated using the EUROLINE PNS 12 Ag Line Assay and a cell-based assay (CBA) from Euroimmun. For confirmation of positive lineblot results, we used indirect immunofluorescence of rat cerebellar sections. We also tested all samples in 2 assays developed in-house: a CBA for CDR2L and a Western blot analysis using recombinant cerebellar degeneration-related protein 2 (CDR2) and CDR2L proteins. RESULTS: In PNS 14 and PNS 12 Ag Line Assays, anti-CDR2 reactivity was observed for 24 (100%) and 20 (83%) of the 24 samples, respectively. Thirteen of 24 subjects (54%) were also positive using the Euroimmun CBA. Rat cerebellar immunofluorescence was the best confirmatory test. In our in-house CBA for CDR2L and Western blot for CDR2 and CDR2L, only the 6 patients with confirmed PCD reacted with CDR2L. CONCLUSIONS: Commercially available tests for Yo antibody detection have low specificity for PCD because these assays use CDR2 as antigen. By adding a test for CDR2L, which is the major Yo antigen, the accuracy of PCD diagnosis greatly improved. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CBA for CDR2L accurately identifies patients with PCD.

LncRNA-SNHG16 promotes proliferation and migration of acute myeloid leukemia cells via PTEN/PI3K/AKT axis through suppressing CELF2 protein.

The silence of lncRNA small nucleolar RNA host gene 16 (SNHG16) suppressed acute lymphoblastic leukemia (ALL) cell proliferation and migration, whereas its role in acute myeloid leukemia (AML) still lacks clarity. This study showed that SNHG16 was upregulated in AML patients and cells. And SNHG16 overexpression remarkably enhanced the proliferation and migration capacities of HL60 and AML-193 cells, while SNHG16 knockdown acted the opposite way. Subsequently, we revealed that SNHG16 directly bound to CELF2 (CUGBP Elav-like family member 2) protein, and caused CELF2 mRNA unstably and proteins reducing. CELF2 was decreased both in AML patients and cells. CELF2 overexpression or interference weakened the effect of overexpressing or silencing SNHG16 on proliferation and migration. Moreover, the transfection of pcDNA-CELF2 elevated PTEN (phosphatase and tensin homolog) activity and hindered the phosphoinositide 3-kinase (PI3K)/AKT signaling. And SNHG16 reduced PTEN activity and promoted the PI3K/AKT pathway activation by restraining CELF2. Furthermore, GDC-0941 (a specific inhibitor of the PI3K/AKT pathway) impeded the effect of SNHG16 increase, and bpV(pic) (a specific PTEN inhibitor) declined the effect of SNHG16 decrease on cell proliferation and migration. Taken together, the present study indicated that SNHG16 promoted proliferation and migration of AML cells via PTEN/PI3K/AKT axis through suppressing CELF2 protein.

Pannexin 1 channels control the hemodynamic response to hypoxia by regulating O2-sensitive extracellular ATP in blood.

Pannexin 1 (Panx1) channels export ATP and may contribute to increased concentration of the vasodilator ATP in plasma during hypoxia in vivo. We hypothesized that Panx1 channels and associated ATP export contribute to hypoxic vasodilation, a mechanism that facilitates the matching of oxygen delivery to metabolic demand of tissue. Male and female mice devoid of Panx1 (Panx1-/-) and wild-type controls (WT) were anesthetized, mechanically ventilated, and instrumented with a carotid artery catheter or femoral artery flow transducer for hemodynamic and plasma ATP monitoring during inhalation of 21% (normoxia) or 10% oxygen (hypoxia). ATP export from WT vs. Panx1-/-erythrocytes (RBC) was determined ex vivo via tonometer experimentation across progressive deoxygenation. Mean arterial pressure (MAP) was similar in Panx1-/- (n = 6) and WT (n = 6) mice in normoxia, but the decrease in MAP in hypoxia seen in WT was attenuated in Panx1-/- mice (-16 ± 9% vs. -2 ± 8%; P < 0.05). Hindlimb blood flow (HBF) was significantly lower in Panx1-/- (n = 6) vs. WT (n = 6) basally, and increased in WT but not Panx1-/- mice during hypoxia (8 ± 6% vs. -10 ± 13%; P < 0.05). Estimation of hindlimb vascular conductance using data from the MAP and HBF experiments showed an average response of 28% for WT vs. -9% for Panx1-/- mice. Mean venous plasma ATP during hypoxia was 57% lower in Panx1-/- (n = 6) vs. WT mice (n = 6; P < 0.05). Mean hypoxia-induced ATP export from RBCs from Panx1-/- mice (n = 8) was 82% lower than that from WT (n = 8; P < 0.05). Panx1 channels participate in hemodynamic responses consistent with hypoxic vasodilation by regulating hypoxia-sensitive extracellular ATP levels in blood.NEW & NOTEWORTHY Export of vasodilator ATP from red blood cells requires pannexin 1. Blood plasma ATP elevations in response to hypoxia in mice require pannexin 1. Hemodynamic responses to hypoxia are accompanied by increased plasma ATP in mice in vivo and require pannexin 1.

Increased levels of pentraxins protein and cytokines bear good association in patients with severe dengue infection.

Dengue is an arboviral infection with high rates of morbidity and mortality throughout the tropics and sub-tropics. This work studied the status of pentraxin (CRP/SAP) protein, ferritin, TNF-α and IL-1ß levels in Dengue patients of different pathophysiological manifestations. Accordingly, clinically confirmed Dengue cases (n = 97) were enrolled and subsequently blood parameters were studied by Haematology cell counter and Biochemistry Autoanalyser. CRP, SAP, ferritin, TNF-α and IL-1ß ELISA were done in all the samples by using standard ELISA kits. Statistical Analysis was done in all the experiments. The levels of CRP (p < 0.0001), SAP (p < 0.0001), ferritin (p < 0.0001), TNF-α (p < 0.0001) and IL-1ß (p < 0.0001) were high in patients with Severe Dengue as compared to Dengue without warning signs. High levels of SGOT, SGPT and decreased platelet counts were found in severe patients as compared to Healthy donor. CRP/SAP as well as TNF-α/IL-1ß were independently associated with both dengue severity and overall disease manifestation. Statistically significant increased CRP, SAP, ferritin, TNF-α and IL-1ß titres were correlated in patients with severe clinical manifestations as compared to mild disease forms of dengue. Elevated levels of pentraxin, TNF-α/IL-1ß in blood during dengue infection could act as an early predictor in Severe Dengue infection.