RD Group Research Articles

CDX-301 prevents radiation-induced dysregulation of miRNA expression and biogenesis

Risks of radiation exposure necessitate the development ofradioprophylactic drugs. We have reported the efficacy of CDX-301, a recombinantly developed human protein form of Fms-related tyrosine kinase 3 ligand (Flt3L), as a radioprophylactic and radiomitigatory agent. Here, we performed global microRNA profiling to further understand the mechanism of action of CDX-301. We find that CDX-301 administration 24h prior to total body irradiation prevents radiation-induced dysregulation of microRNA biogenesis and expression in murine serum and spleen samples in a time- and tissue-dependent manner. Further analysis shows that activation of the HOTAIR regulatory pathway has a prominent function in radiation-induced injury responses, which is inhibited by pre-treatment with CDX-301. Moreover, CDX-301 attenuates radiation-induced dysregulation of several cellular functions such as inflammatory and immune responses. In corroboration, we also find that pre-treatment with CDX-301 restores the expression of bone marrow aplasia markers and inflammatory cytokines and growth factors, as well as the expression of genes associated with MAP kinase and TGF-β pathways that are altered by radiation. Our findings provide new insights into CDX-301-mediated molecular and cellular mechanisms and point to a possible novel radioprotective drug for the prevention of irradiation-induced injury and hematopoietic acute radiation syndrome.

Non-Small Cell Lung Cancer with Malignant Pleural Effusion May Require Primary Tumor Radiotherapy in Addition to Drug Treatment.

The impact of primary tumour radiotherapy on the prognosis for non-small-cell lung cancer (NSCLC) with controlled malignant pleural effusion (MPE-C) (MPE-C-NSCLC) is unclear. This study aimed to analyze the efficacy and safety of primary tumor radiotherapy in patients with MPE-C-NSCLC. A total of186 patients with MPE-C-NSCLC were enrolled and divided into two groups. The patients in the D group were treated with only drugs. Those in the RD group were treated with drugs plus primary tumour radiotherapy. The Kaplan-Meier method was used for survival analysis, and the Log rank test was used for between-group analysis and univariate prognostic analysis. The Cox proportional hazards model was used to perform multivariate analyses to assess the impacts of factors on survival. Propensity score matching (PSM) was matched based on clinical characteristics, systematic drug treatment and drug response to further adjust for confounding factors. The overall survival (OS) rates at 1, 2, and 3 years for the RD group and D group were 54.4%, 26.8%, and 13.3% and 31.1%, 11.5%, and 4.4%, respectively; the corresponding MSTs were 14 months and 8 months, respectively (χ 2=15.915, p<0.001). There was a significant difference in survival by PSM (p=0.027).Before PSM, multivariate analysis showed that metastasis status (organ≤3 and metastasis≤5), primary tumour radiotherapy, chemotherapy cycles≥4, and drug best response (CR+PR) were independent predictors of prolonged OS. After PSM, primary tumour radiotherapy and drug best response (CR+PR) were independent predictors of prolonged OS were still independent predictors of prolonged OS. There were no grade 4-5 radiation toxicities. For MPE-C-NSCLC, the response of systemic drug treatment plays a crucial role in survival outcomes, and we also should pay attention to primary tumour radiotherapy in addition to systematic drug treatment.

Ixazomib, Lenalidomide and Dexamethasone in Relapsed and Refractory Multiple Myeloma in Routine Clinical Practice: Extended Follow-Up Analysis and the Results of Subsequent Therapy.

Simple SummaryWe report the final outomes of the addition of ixazomib to the combination of lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma in the routine clinical practice. With prolonged follow-up, the overall response rate was similar in both cohorts, but the addition of ixazomib induced more deeper responses. Median progression free survival was significantly better in patients receiving ixazomib and translated into better overal survival. Inferior results were seen in patients who were pretreated with lenalidomide in previous regimens. We conclude that the treatment using IRD regimen in routine practice is easy, well tolerated, and with very good therapeutic outcomes, comparable to the outcomes of the clinical trial.Background: We confirmed the benefit of addition of ixazomib to lenalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma (RRMM) in unselected real-world population. We report the final analysis for overall survival (OS), second progression free survival (PFS-2), and the subanalysis of the outcomes in lenalidomide (LEN) pretreated and LEN refractory patients. Methods: We assessed 344 patients with RRMM, treated with IRD (N = 127) or RD (N = 217). The data were acquired from the Czech Registry of Monoclonal Gammopathies (RMG). With prolonged follow-up (median 28.5 months), we determined the new primary endpoints OS, PFS and PFS-2. Secondary endpoints included the next therapeutic approach and the survival measures in LEN pretreated and LEN refractory patients. Results: The final overall response rate (ORR) was 73.0% in the IRD cohort and 66.8% in the RD cohort. The difference in patients reaching ≥VGPR remained significant (38.1% vs. 26.3%, p = 0.028). Median PFS maintained significant improvement in the IRD cohort (17.5 vs. 12.5 months, p = 0.013) with better outcomes in patients with 1–3 prior relapses (22.3 vs. 12.7 months p = 0.003). In the whole cohort, median OS was for IRD vs. RD patients 40.9 vs. 27.1 months (p = 0.001), with further improvement within relapse 1-3 (51.7 vs. 27.8 months, p ˂ 0.001). The median PFS of LEN pretreated (N = 22) vs. LEN naive (N = 105) patients treated by IRD was 8.7 vs. 23.1 months (p = 0.001), and median OS was 13.2 vs. 51.7 months (p = 0.030). Most patients in both arms progressed and received further myeloma-specific therapy (63.0% in the IRD group and 53.9% in the RD group). Majority of patients received pomalidomide-based therapy or bortezomib based therapy. Significantly more patients with previous IRD vs. RD received subsequent monoclonal antibodies (daratumumab—16.3% vs. 4.3%, p = 0.0054; isatuximab 5.0% vs. 0.0%, p = 0.026) and carfilzomib (12.5 vs. 1.7%, p = 0.004). The median PFS-2 (progression free survival from the start of IRD/RD therapy until the second disease progression or death) was significantly longer in the IRD cohort (29.8 vs. 21.6 months, p = 0.016). There were no additional safety concerns in the extended follow-up. Conclusions: The IRD regimen is well tolerated, easy to administer, and with very good therapeutic outcomes. The survival measures in unsorted real-world population are comparable to the outcomes of the clinical trial. As expected, patients with LEN reatment have poorer outcomes than those who are LEN-naive. The PFS benefit of IRD vs. RD translated into significantly better PFS-2 and OS, but the outcomes must be accounted for imbalances in pretreatment group characteristics (especially younger age and stem cell transplant pretreatment), and in subsequent therapies.

Comparison of dexmedetomidine and clonidine with ropivacaine in epidural anaesthesia in vaginal hysterectomies

Background The present randomized double blind prospective study was carried out for Comparison of Dexmedetomidine and Clonidine along with Ropivacaine in epidural anaesthesia for vaginal hysterectomy. Methods: 60 female patients of ASA grade I and II, between the age group of 45 - 60 years were randomly assigned to 2 groups. Group RD: received 17 ml of 0.75% Ropivacaine and 1.5μg/kg of Dexmedetomidine , Group RC: received 17 ml of 0.75% Ropivacaine and 2μg/kg of Clonidine in supine position via epidural catheter. Onset, quality, duration of sensory and motor block and hemodynamic parameters evaluated. Results: Patients from Group RD have fast sensory block onset (i.e. 9.96±0.61min), prolonged two seg. regression time (138.93±4.48) and prolonged Analgesia time ((i.e 353.9±4.03min) as compared to Group RC i.e. (12.4±0.77), (128.8±3.46),(308.06±5.47) respectively. The duration of motor blockade was prolonged in patients of group RD (242.23±5.72min) as compared to the patients in group RC (230.66±5.20min). Patients in group RD were more sedated as compared to the patients in group RC. Initial fall in heart rate was more in patients of RD group as compared to the patients of group RC but later on both the groups showed stable heart rate.

Diabetes risk status and meeting the US physical activity recommendations in reproductive-aged women: 2011, 2013, 2015 and 2017 Behavioral Risk Factor Surveillance System.

Women at increased risk for type 2 diabetes, due to recognized prediabetes (PD) or previous gestational diabetes (GD), stand to benefit from meeting U.S. physical activity (PA) recommendations. This study examined the association of diabetes risk status with meeting aerobic activity (AA), muscle strengthening activity (MSA) and both recommendations. Non-pregnant women, 18-44, free of recognized diabetes, who participated in the 2011, 2013, 2015, or 2017 U.S. Behavioral Risk Factor Surveillance System survey (N=211,114) were categorized as no diabetes (ND; n=202,766, referent) versus at-risk for diabetes (RD; n=8348). Logistic regression models generated odds ratios (ORs) and 95% confidence intervals (95% CIs), adjusted for demographics and BMI. Tests for multiplicative interactions were performed for BMI category and race and ethnicity. There were lower odds of meeting AA, MSA and both recommendations in the RD group (referent=ND; OR 0.95 [5% CI 0.78, 0.97], 0.83 [95% CI 0.91, 0.98] and 0.87 [95% CI 0.78, 0.97], respectively). Effect modification by BMI category was detected for models assessing MSA (p=0.10), both (p=0.07) and neither recommendation (p=0.005), but not for AA. Among those with a BMI in the healthy and overweight groups, RD had decreased odds of meeting MSA recommendations (referent=ND; 0.69 [95% CI 0.58, 0.81] and 0.78 [95% CI 0.65, 0.93], respectively); among the healthy BMI, RD had 24% decreased odds of meeting both recommendations (referent=ND; 95% CI 0.63, 0.91). There was no difference in meeting PA recommendations among groups in the obese category, but the increased odds of meeting the AA recommendation among the RD group were approaching significance (referent=ND; [95% CI 1.00, 1.29], p=0.06]. Reproductive-aged women with previous GD or recognized PD stand to benefit from increasing PA, especially MSA, the least often met recommendation.

Prevalence of post-COVID-19 in patients with fibromyalgia: a comparative study with other inflammatory and autoimmune rheumatic diseases

ObjectivesTo determine the prevalence and characteristics of post-COVID-19 (PC) in fibromyalgia (FM) patients.MethodsRetrospective, multi-centric, observational study, comparing a group of FM patients (FM group) with another group of patients with other rheumatic diseases (RD group). COVID-19 diagnosis was established by positive polymerase chain reaction or antigen during acute infection or by positive antibodies thereafter. We considered PC diagnosis when symptoms remain after COVID-19. We collected the principal characteristics of COVID-19, the severity of fatigue, waking unrefreshed and cognitive impairment, and persistent symptoms. The American College of Rheumatology (ACR) criteria and the Combined Index of Severity in Fibromyalgia (ICAF) were collected in the FM group.ResultsRD group (n = 56) had more pneumonia (p = 0.001) and hospital admissions (p = 0.002), but the FM group (n = 78) had a higher number of symptoms (p = 0.002). The percentage of patients with PC was similar between groups (FM group 79.5%; RD group 66.1%, p = 0.081). FM group had more PC symptoms (p = 0.001), more impairment after COVID-19 (p = 0.002) and higher severity of fatigue, waking unrefreshed and cognitive impairment (p < 0.0001). Only loss of smell was more frequent in the FM group (p = 0.005). The FM group with PC (n = 29) showed more severity of the Combined Index of Severity in Fibromyalgia (ICAF) total score and physical factor after COVID-19, while emotional, coping factors and the ACR criteria did not change.ConclusionsThe prevalence of PC in FM patients is similar to RD patients. In FM patients, the presence of PC does not appear to impact the severity of FM.

Writing motivation in Chinese children with developmental dyslexia

BackgroundRecent models of writing acknowledge the influential role of motivation in writing development. There has been a paucity of research on writing motivation in children. This study investigated writing motivation among Chinese children with developmental dyslexia.MethodsForty‐one Chinese children with developmental dyslexia (RD) in Grades 3 to 5 and their typically developing counterparts matched on age (CA controls) (n = 41) were administered tasks assessing their writing motivation (perceived value of writing and writing apprehension), cognitive‐linguistic skills (word dictation, syntactic skills and working memory), and writing abilities (quality and productivity).ResultsThe results showed that the RD group performed significantly less well than the CA group in all cognitive‐linguistic skills and writing abilities measures. No significant between‐group differences were found in writing motivation measures. Multiple regression analysis results showed that perceived value of writing significantly predicted writing productivity in the RD group and writing quality in the CA group. Word dictation was the only significant predictor of writing quality in both the RD and the CA group.ConclusionsThese findings suggest that writing motivation influences writing performance in Chinese children with developmental dyslexia in elementary grades. Specifically, perceived value of writing predicts writing quality in typically developing Chinese children but predicts only writing productivity, not writing quality, in Chinese children with developmental dyslexia. The impact of writing motivation on writing performance becomes stronger with advances in component skills acquisition.

State-independent and -dependent behavioral and neuroelectrophysiological characteristics during dynamic decision-making in patients with current and remitted depression

BackgroundIt is unclear whether the altered decision-making (DM) observed in patients with major depressive disorder (MDD) is neurophysiological and whether it improves with remission of depressive symptoms. The aim of this study was to identify developmental patterns of DM behavior, related cognitive characteristics, and electrophysiological abnormalities in patients with MDD across clinical stages. MethodsA sample of 48 first-episode MDD patients (FD group), 41 remitted MDD patients (RD group), and 43 healthy controls (HCs) completed psychometric assessments and performed the balloon analogue risk task (BART) while event-related potentials (ERPs) were recorded. ResultsThe RD group had lower depressiveness, self-blame, rumination, and catastrophizing tendencies, and higher mental resilience scores than the FD group, but retained significant differences from HCs. MDD patients showed a more conservative DM strategy than HCs, with no significant difference between the FD and RD groups. Compared to the FD group, the RD group had a smaller FRN for negative feedback and a trend toward a smaller P3 for positive feedback. Compared with HCs, the RD group had a smaller P3 during the positive feedback phase. FRN amplitude correlated positively with depression level and negatively with mental resilience. LimitationsBecause a comparative cross-section design was employed, longitudinal studies are needed to make causal inferences. ConclusionMDD patients presented a stable risk-avoidance bias in actively depressed and remission periods, consistent with a state-independent impairment pattern. Significantly reduced FRN amplitudes during remission indicated a state-dependent impairment pattern, and FRN amplitudes correlated with depression level. An abnormal feedback P3 component may be a state-independent characteristic that may become more pronounced with MDD progression.

Effect of Krüppel-Like Factor 7 (KLF7) on High Sugar Induced Retinal Ganglion Cell Biological Activity and Oxidative Stress

This study investigated KLF7’s effect on sugar induced retinal ganglion cells (RGCs) biological activity. The RGCs cells divided into blank group (RA), high sugar group (RB), high sugar+NC group (RC) and high sugar+KLF7 group (RD) (transfected with KLF7 mimic) followed by analysis cell proliferation by MTT, cell apoptosis by flow cytometry and protein expression by western blot and ROS level. RB and RC group showed significantly reduced KLF7 mRNA and protein level compared to RA group (P &lt; 0.05) without different between RB and RC group (P &gt; 0.05). RD group had significantly increased LKF7 and Sirt1 protein expression (F = 113.3, P &lt; 0.0, 01), reduced cell proliferation (P &lt; 0.05) and increased RGCs apoptosis rate (P &lt; 0.05) compared with RB and RC group. After 24 h, RB and RC group presented significantly higher ROS level (P &lt; 0.05) which was reduced in RD group (P &lt; 0.05). In conclusion, KLF7 can change sugar induced retinal ganglion cell biological activity and reduce the oxidative stress level.

PROSPECTIVE INTERVENTIONAL STUDY OF COMPARISON BETWEEN EPIDURALANAESTHESIA PLAIN 0.75% ROPIVACAINE AND 0.75% ROPIVACAINE WITH DEXMEDITOMIDINE IN LOWER ABDOMINAL AND LOWER LIMB SURGERIES

1.1 AIMS: The aim of the study is to identify the benets of adding Dexmedetomidine 0.6mcg/kg to Ropivacaine 0.75% for epidural analgesia for surgeries involving lower abdomen and lower limb, and to observe the onset of sensory and motor blockade, duration of analgesia, and sedation score. 1.2 BACKGROUND: Studies indicate that regional anesthesia has numerous advantages for lower abdominal and lower limb surgeries when compares to general anesthesia. Hence distinct varieties of regional anesthetics are being used for epidural anesthesia. When looking into regional anesthesia it was learned that ropivacaine was the preferred regional anesthesia for its long-acting effect and lower the cardiotoxic action in comparison to Dexmedetomidine. Whereas in comparison to ropivacaine, Dexmedetomidine has an additional effect, along with prolonging the action and sedative effect its neuroprotective effect is mediated by activation of alpha 2 adrenergic receptor subtype [2]. After looking at the individual benets of Ropivacaine, and Dexmedetomidine, this study aims to see the potential benets of the combined effects of these two drugs. 1.3 OBJECTIVE: To study the onset of action, duration of sensory and motor blockade, and any hemodynamic variations, level of sensory and motor blockade. 1.4 METHODS: The Patients were randomly allocated to two groups and each group consisted of 50 patients 1) Group R -15ml of 0.75% Ropivacaine 2) Group RD- 15ml of 0.75% Ropivacaine + 0.6µg/kg of dexmedetomidine. 1.5 RESULTS:The study concluded that adding dexmedetomidine as an adjuvant to Ropivacaine for epidural anesthesia reduced the time to onset of action, and increased the duration of sensory blockade. Patients were calm, with sedation scores of 3 and 4 in RD Group, and did not require extra sedation. Patients were hemodynamically stable in both groups.

Distinct Features of Cerebral Blood Flow and Spontaneous Neural Activity as Integrated Predictors of Early Response to Antidepressants.

AimsThe purpose of this study is to explore whether pre-treatment features of brain function can discriminate non-responders to antidepressant medication in the early phase.MethodsForty-four treatment-responsive depressed (RD) patients, 36 non-responsive depressed (NRD) patients, and 42 healthy controls (HCs) were recruited. Regional cerebral blood flow (CBF) and amplitude of low-frequency fluctuation (ALFF) values were calculated for all subjects. Correlation analyses were used to explore the relationship between symptom improvement and CBF/ALFF. Receiver operating characteristics (ROC) and the 10-fold cross-validation support vector machine (SVM) classifier were applied for the discrimination of treatment response.ResultsCompared with the HCs, the RD and NRD groups exhibited lower CBF and ALFF in the right posterior lobe of the cerebellum. Compared with the NRD group, the RD group showed distinct CBF patterns in the left frontal striatal regions and right frontal cerebellar regions, as well as distinct ALFF features in the left frontoparietal striatum and right frontotemporal striatal cerebellar regions. The ROC and SVM classifier revealed the optimal power to distinguish the RD and NRD groups based on the combined measures (i.e., CBF and ALFF).ConclusionDistinct features of CBF and ALFF in the frontal striatal network may serve as promising neuroimaging predictors for identifying patients with blunted responsiveness, which may facilitate personalized antidepressant treatment.

DIA Comparative Proteomic Analysis of Retro-oil Fluid and Vitreous Fluid From Retinal Detachment Patients.

Objectives: There have been reports of unexplained visual loss following intra-ocular silicone oil (SiO) tamponade in retinal detachment patients, yet the underlying mechanism is unknown. The aim of this study was to investigate the mechanisms behind retinal toxicity following intra-ocular SiO tamponade in retinal detachment patients. Methods and Results: Vitreous fluid samples were acquired from 27 patients (27 eyes). Twelve eyes for data-independent acquisition (DIA) were divided into four groups: pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RD group), SiO removal after successful retinal reattachment (SO group), cataract surgery after successful retinal reattachment with sterilized air tamponade (FA group), and PPV for epiretinal membrane (ERM group). The remaining 15 eyes were used for enzyme-linked immunosorbent assay analysis. DIA was combined with two-dimensional liquid chromatography–tandem mass spectrometry to find expression changes in the proteome of vitreous. Mean number mass spectra, statistically differentially expressed proteins, gene ontology (GO), pathway representations, and protein interactions were analyzed. GO analysis showed that the protein categories of synapse organization, cell adhesion, and regulation of cell migration in the SO group were differentially expressed compared to the control or FA groups (p < 0.05). Through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, lysosome and cell adhesion were found to be significantly enriched in the SO group compared to the FA and control groups (p < 0.05). Cadherin 2, transferrin, and lysosome function may partially contribute to silicone oil-related vision loss. Conclusion: Vision loss-inducing novel molecular signatures and pathways that may be associated with SiO toxicity were identified. Transferrin may be a potential visual outcome biomarker for SiO tamponade.

Comparison of Intercostal Nerve Block with Ropivacaine and Ropivacaine-Dexmedetomidine for Postoperative Pain Control in Patients Undergoing Thoracotomy: A Randomized Clinical Trial.

BackgroundThoracotomy is one of the most painful surgeries, and failure to alleviate patients' pain can have dangerous consequences. ObjectivesThis study aimed to evaluate the addition of dexmedetomidine to ropivacaine in the intercostal block for postoperative pain control in patients undergoing thoracotomy.MethodsIn this randomized clinical trial, 74 patients aged 18 to 60 years with ASA class I or II, BMI less than 40, and no severe systemic problems referred to a teaching hospital in Ahvaz to undergo thoracotomy were included in the study and randomly divided into two groups. After surgery, an ultrasound-guided intercostal block was done with ropivacaine (5 cc of 0.25% solution; group R) or ropivacaine (5 cc of 0.25% solution) plus dexmedetomidine (0.5 µg/kg; group RD) per dermatome. Two dermatomes above and two dermatomes below the level of surgical incision were used. Pain, total opioid consumption, length of ICU stays, time to first rescue analgesic, and time to get out of bed were compared between the two groups.ResultsThe intercostal block significantly reduced pain in both groups (P < 0.0001). The pain was lower in the RD group than in the R group from six hours after the intervention up to 24 hours after (P < 0.001). The number of patients who needed rescue analgesia at 12 hours was significantly lower in the RD group (P < 0.05). The RD group also had lower total opioid consumption and a longer time to receive the first rescue analgesia (P < 0.01). There was no significant difference between the two groups in the length of hospitalization and the time to get out of bed.ConclusionsDexmedetomidine is an effective and safe choice to be used as an adjunct to ropivacaine in ICB, and it extends the duration of analgesia in combination with ropivacaine after thoracotomy.

RD Vs. VRD: What Is the First-Line, Real-Life Management of Multiple Myeloma Patients Ineligible for Stem Cell Auto Transplantation in the Emmy Cohort?

RD Vs. VRD: What Is the First-Line, Real-Life Management of Multiple Myeloma Patients Ineligible for Stem Cell Auto Transplantation in the Emmy Cohort?

Examining Distinctive Working Memory Profiles in Chinese Children With Predominantly Inattentive Subtype of Attention-Deficit/Hyperactivity Disorder and/or Reading Difficulties

Although evidence has shown that both RD and ADHD-I children suffer from working memory problems, inconsistencies in impaired modalities have been reported. This study aimed to (1) compare the three WM domains (i.e., verbal WM, visual-spatial WM, and behavioral WM) among pure ADHD-I, pure RD, comorbid ADHD-I+RD, and typical control groups and (2) examine the impact of comorbidity on the three WM domains. A Chinese sample of participants from Hong Kong included 29 children in the ADHD-I group, 78 children in the RD group, 31 children in the comorbid group (ADHD-I+RD), and 64 children in the TD control group. All participants completed the assessments individually. The findings showed that the children with ADHD-I and/or RD exhibited diverse cognitive profiles. In particular, RD was associated with verbal and visual-spatial working memory deficits, while ADHD-I was associated with behavioral working memory deficits. Interestingly, the comorbid condition demonstrated additive deficits of the two disorders but with greater deficits in behavioral working memory. These findings support the cognitive subtype hypothesis and provide a clearer picture of the distinctive working memory profiles of different groups, allowing for the development of intervention programs in the future.

Cognitive and Emotional Appraisal of Motivational Interviewing Statements: An Event-Related Potential Study.

The counseling process involves attention, emotional perception, cognitive appraisal, and decision-making. This study aimed to investigate cognitive appraisal and the associated emotional processes when reading short therapists' statements of motivational interviewing (MI). Thirty participants with work injuries were classified into the pre-contemplation (PC, n = 15) or readiness stage of the change group (RD, n = 15). The participants viewed MI congruent (MI-C), MI incongruent (MI-INC), or control phrases during which their electroencephalograms were captured. The results indicated significant Group × Condition effects in the frontally oriented late positive complex (P600/LPC). The P600/LPC's amplitudes were more positive-going in the PC than in the RD group for the MI congruent statements. Within the PC group, the amplitudes of the N400 were significantly correlated (r = 0.607–0.649) with the participants' level of negative affect. Our findings suggest that the brief contents of MI statements alone can elicit late cognitive and emotional appraisal processes beyond semantic processing.

Pro-Platelet Formation Is Impaired in Megakaryocytes of MYH9 -Related Disease Patients

IntroductionThe MYH9 gene encodes myosin-IIA, a nonmuscle myosin heavy chain that facilitates shape changes in diverse cell types. The mutation of MYH9 may lead to the MYH9 -related disease (MYH9 -RD), an autosomal dominant disorder with macrothrombocytopenia and leukocyte inclusion bodies at birth and the risk of developing nephropathy, deafness and cataracts during infancy or adult life. Currently, at least 44 different MYH9 mutations in all 40 exons have been reported. Mutated MYH9 protein expression is reduced in megakaryocytes and is clumped in a few aggregates together with the wild-type protein in neutrophils, where they form the inclusion bodies. In a mouse model, myosin-IIA protein inhibits pro-platelet formation and is regulated by Rho-associated kinase (ROCK). However, how the mutated myosin-IIA influences the pro-platelet formation (PPF) of megakaryocytes in patients has not been explored. The aim of this study is to determine the function and regulation of mutated myosin-IIA in MYH9 -RD patients' megakaryocytes.MethodsOne kindred with inherited macrothrombocytopenia was identified and 5 healthy donors were enrolled as controls. Peripheral blood smear review, slit lamp examination, pure-tone audiometry, renal ultrasonography and examination of blood (urea, creatinine, electrolytes) and urine were performed for each family member to diagnose and evaluate the disease. Bidirectional polymerase chain reaction (PCR) amplification and DNA sequence analysis were performed on all 40 MYH9 exons for each patient. Platelets from peripheral blood and megakaryocytes from bone marrow were fractionated for electron microscopy. Bone marrow tissues from patients were stained with fluorescein-labeled antibodies against CD41 and CD144 to observe the distribution of mature megakaryocytes in the vascular niche by confocal fluorescence microscopy. CD34+ cells were isolated from bone marrow samples by cell sorting for in vitro culture with TPO. On day 8, megakaryocytes were enriched using an albumin density gradient and seeded onto 96-well plates in serum-free medium with or without Y27632, the ROCK inhibitor. At the same time every day for 5 days, the percentage of proplatelet-displaying megakaryocytes was quantified by inverted microscopy.ResultsFive patients in the kindred were diagnosed with MYH9 -RD based upon peripheral blood smear review, one of whom had severe renal failure. None of the patients suffered from deafness or cataracts. A pathogenic heterozygous sequence variant in exon 39 (c.5521G>A, p.E1841K) was detected, which substitutes glutamate at codon 1841 to lysine. This mutation is one of the 44 reported pathogenic mutations. Electron microscopic results showed that platelets from patients had increased diameters and irregular shapes while megakaryocytes from patients had smaller diameters and a disorganized demarcation membrane system (DMS). Immunofluorescence results of bone marrow tissues showed that proplatelet-displaying mature megakaryocytes in MYH9 -RD patients located distally to the vascular niche, compared with the control group. CD34+ cells from bone marrow differentiated into megakaryocytes after in vitro culture with TPO. However, the PPF of megakaryocytes from MYH9 -RD patients appeared much earlier than that from controls. At the same time point, PPF megakaryocytes in MYH9 -RD patients were significantly increased compared to those of the control group. When cultured with Y27632, the PPF appearance time and proplatelet-displaying megakaryocyte percentage in the control group were advanced, while the MYH9 -RD group was not influenced.ConclusionThe mutation in exon 39 of the MYH9 gene may lead to morphological abnormalities of megakaryocytes and platelets. The regulation of myosin-IIA function by ROCK in patients may be decreased when the MYH9 gene is mutated. As a result, the timing of PPF of megakaryocytes with mutated myosin-IIA in the bone marrow niche of MYH9 -RD patients may be advanced, and their mis-location away from the vascular niche may lead to reduced platelet production and increased platelet destruction. DisclosuresNo relevant conflicts of interest to declare.

Does Past Experience Effect Balance in Older Women: a Cross-Sectional Study Comparing Retired Dancers and Age- Matched Controls?

Falls are increasing prevalent in the elderly but little data has been reported on the effect of previous life experience on balance ability. The aim of the present cross-sectional study was to determine whether participants with historically highly developed postural control (retired dancers) provided protection after activity had stopped by comparing their balance abilities with age-matched sedentary counterparts. Ten retired dancers [RD] 65 ± 7.36yrs and 10 sedentary controls[C] 66 ± 5.66yrs carried out a series of balance tests in a laboratory setting in a set order: Romberg, Functional Reach, Timed Up and Go, Berg and Tinetti. The RD group performed significantly better solely in the static balance tests (Romberg and Berg Balance) (p < 0.05). Therefore, past exercise history of the individual possibly needs to be considered when selecting a balance test battery with a need to use tests that have multiple constructs of balance. The RD group performed significantly better at static balance tests suggesting a possible skill retention from their dance careers.

Cats with calcium oxalate stones have increased urinary inosine, xanthosine and hypoxanthine when compared to cats with healthy renal function or chronic kidney disease

Objective Evaluate urinary metabolites in cats that formed oxalate stones during life as compared to cats with healthy kidneys or cats with chronic kidney disease. Methods The development and end of life effects of renal disease and calcium oxalate stone formation was evaluated with 42 cats evaluated from one year of age to end of life (21 spayed females and 21 neutered males). Each cat was assigned to one of three groups: calcium oxalate stone forming cats (CaOx, n=12, confirmed by stone analysis), cats with renal disease (RD, n=11) and healthy kidney cats (H, n=19). Their condition was defined during life or at the time of death. Urinary samples were collected throughout life in annual physical exams and at the end of life. Urine was stored at -80 oC until analyzed. Metabolomic analysis was completed by Metabolon (Durham, NC). Statistical analysis was completed on natural log transformed data using group as an independent variable, animal age as a continuous variable, and each cat as a random variable. A statistical cutoff of p<0.05 was used. Results There were 635 analytes measured. There were 297 with different metabolite concentrations when the RD group was compared to the H group (six increased, 291 decreased). There were 202 metabolites with different concentrations when the CaOx group was compared to the H group (10 increased, 192 decreased). There were 55 with different concentrations between the CaOx group and the RD group with all of them being elevated in the CaOx group. Of interest in this group was the elevation of oxalate and a number of the purine family of bases (inosine, hypoxanthine, xanthosine, and urate). Oxalate concentration in the CaOx group was similar to H while inosine and hypoxanthine were elevated as compared to both H and RD groups. Lactate was reduced in the RD cats and unchanged in the CaOx cats when compared to H, resulting in a comparative increase of lactate in the CaOx vs RD groups while pyruvate was unchanged between all groups. Given that oxalate concentration in CaOx group was similar to H, these results indicate that there may be other molecular pathways including those involving purine metabolism that are involved in CaOx stone formation. Multifactorial nutritional strategies may need to be assessed for anti-urolithiatic activity, in addition to lowering oxalate to prevent stone formation. Conclusions The aberrant metabolism and excretion of purines in cats may be a significant component in the formation of calcium oxalate stone formation.

Cats with calcium oxalate stones and renal disease have different plasma metabolome when compared to cats with healthy renal function

Objective Evaluate the effect of cats that formed oxalate stones during life on plasma metabolite concentration as compared to cats with healthy kidneys or cats with chronic kidney disease. Methods The development and end of life effects of renal disease and calcium oxalate stone formation was evaluated with 42 cats evaluated from one year of age to end of life (21 spayed females and 21 neutered males). Each cat was assigned to one of three groups: calcium oxalate stone forming cats (CaOx, n=12, confirmed by stone analysis), cats with renal disease (RD, n=11) and healthy kidney cats (H, n=19). Their condition was defined during life or at the time of death. Plasma samples were collected throughout life in annual physical exams and at the end of life. Plasma was stored at -80 oC until analyzed. Metabolomic analysis was completed by Metabolon (Durham, NC). Statistical analysis was completed on natural log transformed data using group as an independent variable, animal age as a continuous variable, and each cat as a random variable. A statistical cutoff of p<0.05 was used. Results There were 789 analytes measured. There were 144 metabolites with different concentrations when the RD group was compared to the H group (112 increased, 32 decreased). There were 130 with different concentrations when the CaOx group was compared to the H group (116 increased, 14 decreased). There were 69 with different concentrations between the CaOx group and the RD group (47 increased, 32 decreased. Both RD and CaOx had increased concentrations in circulating analytes known to increase with reduced renal function (creatinine, urea, pseduouridine). The CaOx cats had higher levels of 1-palmitoyl-GPI, 1-stearoyl-GPI, and mannitol/sorbitol when compared to the RD cats. The RD cats had higher levels of guanosine, guanine, inosine and hypoxanthine when compared to the CaOx cats. These higher levels was the result of increases in the RD cats and reduced concentrations in the CaOx cats (when compared to H). Conclusions The aberrant metabolism and clearance of purines in cats may be a significant component in the formation of calcium oxalate stone formation.