A comparative multi-laboratory assessment of three factor VIII/von Willebrand factor concentrates

Five expert laboratories have participated in a cross-laboratory study to co-evaluate and compare three commercial Factor VIII/von Willebrand factor (VWF) concentrates. A total of nine factor concentrate lots were evaluated, comprising AHF (High Purity) (AHF HP; x3), Biostate (x3) and Humate/Haemate (x3). All laboratories blind tested for FVIII: C, VWF: Ag and VWF: CB, four tested for VWF: RCo, and one performed VWF: Multimers. The study yielded inter-laboratory CVs for VWF: Ag and FVIII:C around 10-15%, and for VWF:CB and VWF:RCo around 20%, significantly lower than those of previous multi-laboratory surveys. All three lots of AHF HP contained in the vicinity of 25 U/ml FVIII:C, around 60-75 U/ml of VWF:Ag, but only 30-45 U/ml of VWF:CB and 40-50 U/ml of VWF:RCo (thus, CB/Ag ratio around 0.5-0.6 and RCo/Ag ratio around 0.6-0.7). Study determined that FVIII: C and VWF: RCo levels were similar to manufacturer assigned levels. Some loss of the high molecular weight (HMW) multimers was observed, together with an intense low molecular weight (LMW) VWF band consistent with some reduction or proteolysis of HMW VWF. All three lots of Humate/Haemate contained in the vicinity of 23-32 U/ml of FVIII:C, 70-105 U/ml of VWF: Ag, 50-90 U/ml of VWF: CB and VWF: RCo (i.e. CB/Ag ratio around 0.6-0.9 and RCo/Ag ratio around 0.6-1.1). Study-determined FVIII: C and VWF: RCo levels were similar to manufacturer-assigned levels. The LMW multimer band seen with AHF HP was also observed with Humate/Haemate. All three lots of Biostate contained in the vicinity of 40-55 U/ml of FVIII:C, 105-170 U/ml of VWF:Ag, 90-150 U/ml of VWF:CB, and 90-135 U/ml of VWF:RCo (i.e. CB/Ag and RCo/Ag ratios around 0.7-1.0). Study-determined FVIII:C levels were similar to manufacturer-assigned levels. The LMW multimer band seen with AHF HP was not observed with Biostate. The defined pattern of increasing CB/ Ag from AHF HP to Humate/Haemate and Biostate was consistently observed in study data from each of the five laboratories. In conclusion, study findings indicate some differences in the retention of functional/ HMW VWF between factor concentrates, and this is expected to have significant implications in terms of clinical efficacy for therapy in VWD.     

Differential stimulatory effects of cannabinoids on VIP release and NO synthase activity in synaptosomal fractions from rat ileum

Cannabinoid-1 (CB1) and CB2 receptors are present on neurons of the enteric nervous system. Our aim was to study whether cannabinoid receptor activation is involved in the regulation of VIP release and NO synthesis in isolated fractions of nerve terminals from rat ileum. VIP was measured by RIA and NO synthesis was analyzed using a L-[3H]arginine assay. Anandamide stimulated VIP release (basal: 245.9+/-12.4pg/mg, 10(-6)M: 307.6+/-11.7pg/mg, [n=6, P<0.05], 10(-7)M: 367.0+/-26.1pg/mg, [n=6, P<0.01]). The cannabinoid receptor agonist WIN 55,212-2 had similar effects (basal: 250.5+/-37.4pg/mg, 10(-6)M: 320.9+/-34.7pg/mg; [n=4, P<0.05]). The stimulatory effect of anandamide was blocked by the selective CB2 receptor antagonist, SR144528 (10(-7)M) (anandamide 10(-6)M: 307.6+/-11.7pg/mg; +SR144528: 249.0+/-26.3pg/mg, [n=6, P<0.05]), whereas the selective CB1 receptor antagonist SR141716 A had no effect. NO synthesis was stimulated by anandamide ([fmol/mg/min] basal: 0.08+/-0.01, 10(-6)M: 0.16+/-0.03; 10(-7)M: 0.13+/-0.02, n=4, P<0.05) and WIN 55,212-2 ([fmol/mg/min] basal: 0.05+/-0.01, 10(-6)M: 0.1+/-0.02, n=4, P<0.05). The anandamide reuptake inhibitor, AM 404 increased basal NOS activity ([fmol/mg/min] control: 0.1+/-0.04, 10(-6)M: 0.28+/-0.08, n=7, P<0.05). The stimulatory effect of anandamide on NO synthase was not antagonized by antagonists at the CB1, CB2 or TRPV1 receptor, respectively. In conclusion, in enteric nerves anandamide stimulates VIP release by activation of a CB2 receptor specific pathway, while the stimulation of NO production suggests the existence of an additional type of cannabinoid receptor in the enteric nervous system.     

Cytokine gene variants and venous thrombotic risk in the BRATROS (BRAZILIAN THROMBOSIS STUDY)

INTRODUCTION: Venous thrombosis (VT) and inflammation are two closely related entities. In the present investigation we assessed whether there is a relation between genetic modifiers of the inflammatory response and the risk of VT. MATERIALS AND METHODS: 420 consecutive and unrelated patients with an objective diagnosis of deep VT and 420 matched controls were investigated. The frequencies of the following gene polymorphisms were determined in all subjects: TNF-alpha-308 G/A, LT-alpha+252 A/G, IL-6-174 G/C, IL1-ra 86 bp VNTR, IL-10-1082 A/G and CD-31 125 C/G. RESULTS: Overall odds ratio (OR) for VT related to TNF-alpha-308 G/A, LT-alpha+252 A/G, IL-6-174 G/C, A1 allele (4 bp repeat) of the IL1-ra 86 bp VNTR, IL-10-1082 A/G and CD-31 125 C/G were respectively: 1.0 (CI95: 0.8-1.5), 1.3 (CI95: 1.0-1.7), 1.1 (CI95: 0.9-1.5), 1.6 (CI95: 1-2.5), 1.2 (CI95: 0.8-1.7) and 0.8 (CI95: 0.6-1.1). A possible interaction between polymorphisms was observed only for the co-inheritance of the mutant alleles of the LT-alpha+252 A/G and IL-10-1082 G/A polymorphisms (OR=2; CI95: 1.1-3.8). The risk of VT conferred by factor V Leiden and FII G20210A was not substantially altered by co-inheritance with any of the cytokine gene polymorphisms. CONCLUSIONS: Cytokine gene polymorphisms here investigated did not significantly influence venous thrombotic risk.     

Decreased baroreflex sensitivity in isoproterenol-treated mice with cardiac hypertrophy

The baroreflex has been shown to be impaired in rat models of cardiac hypertrophy. In the present study, we investigated the effects of beta-adrenoceptor-induced cardiac hypertrophy on the baroreflex in mice. Male Swiss Webster mice weighing 20-25 g were treated with the beta-adrenoceptor agonist isoproterenol (IPM; 15 microg/g/day, s.c.) for 7 days or with vehicle (control, CM). After treatment, IPM (n=9) and CM (n=9) were anesthetized with ketamine + xylazine (91.0: 9.1 mg/kg, i.p.) and had their carotid artery and jugular vein cannulated to test the arterial baroreflex. The baroreflex was evaluated by measuring changes in heart rate (HR) in response to acute increases and decreases in mean arterial pressure (MAP) induced by bolus injections of phenylephrine and sodium nitroprusside (1.5-24.0 microg/kg, i.v.) in conscious animals. IPM showed an increased cardiac weight/body weight (1.18 +/- 0.03 mg/g) ratio compared to CM (0.95 +/- 0.03 mg/g, p<0.05), but similar values of resting MAP (108 +/- 4 vs. 111 +/- 2 mm Hg) and HR (606 +/- 25 vs. 629 +/- 26 bpm). Sigmoidal barocurve analysis showed that isoproterenol treatment significantly reduced the following parameters: baroreflex sensitivity (IPM: -4.26 +/- 0.19 vs. CM: -5.92 +/- 0.54 bpm/mm Hg, p<0.05), reflex bradycardia plateau (IPM: 387 +/- 26 vs. CM: 318 +/- 19 bpm, p<0.05) and HR range (IPM: 369 +/- 30 vs. CM: 442 +/- 20 bpm, p<0.05). Linear regression analysis of baroreflex function also showed a diminished reflex bradycardia (CM: -8.92 +/- 0.87 bpm/mm Hg vs. IPM: -4.94 +/- 0.52 bpm/mm Hg, p<0.05), but similar reflex tachycardia (CM: -3.88 +/- 0.45 bpm/mm Hg vs. IPM: -3.52 +/- 0.43 bpm/mm Hg). In conclusion, beta-adrenoceptor-induced cardiac hypertrophy in mice led to impaired sensitivity of the cardiac baroreflex, which could be due to a diminished vagal activity to the heart.     

Influence of moderate and profound hyperventilation on cerebral blood flow, oxygenation and metabolism

OBJECTIVE: The aim of the present study was to examine the impact of moderate and profound hyperventilation on regional cerebral blood flow (rCBF), oxygenation and metabolism. MATERIALS AND METHODS: Twelve anesthetized pigs were subjected to moderate (mHV) and profound (pHV) hyperventilation (target arterial pO(2): 30 and 20 mmHg, respectively) for 30 min each, after baseline normoventilation (BL) for 1 h. Local cerebral extracellular fluid (ECF) concentrations of glucose, lactate, pyruvate and glutamate as well as brain tissue oxygenation (p(ti)O(2)) were monitored using microdialysis and a Licox oxygen sensor, respectively. In nine pigs, regional cerebral blood flow (rCBF) was also continuously measured via a thermal diffusion system. RESULTS: Both moderate and profound hyperventilation resulted in a significant decrease in rCBF (BL: 37.9+/-4.3 ml/100 g/min; mHV: 29.4+/-3.6 ml/100 g/min; pHV: 23.6+/-4.7 ml/100 g/min; p<0.05) and p(ti)O(2) (BL: 22.7+/-4.1 mmHg; mHV: 18.9+/-4.9 mmHg; pHV: 13.0+/-2.2 mmHg; p<0.05). A p(ti)O(2) decrease below the critical threshold of 10 mmHg was induced in three animals by moderate hyperventilation and in five animals by profound hyperventilation. Furthermore, significant increases in lactate (BL: 1.06+/-0.18 mmol/l; mHV: 1.36+/-0.20 mmol/l; pHV: 1.67+/-0.17 mmol/l; p<0.005), pyruvate (BL: 46.4+/-7.8 micromol/l; mHV: 58.0+/-10.3 micromol/l; pHV: 66.1+/-12.7 micromol/l; p<0.05), and lactate/glucose ratio were observed during hyperventilation. (Data are presented as mean+/-S.E.M.) CONCLUSIONS: Both moderate and profound hyperventilation may result in insufficient regional oxygen supply and anaerobic metabolism, even in the uninjured brain. Therefore, the use of hyperventilation cannot be considered as a safe procedure and should either be avoided or used with extreme caution.     

Reliability of an fMRI paradigm for emotional processing in a multisite longitudinal study

Multisite neuroimaging studies can facilitate the investigation of brain‐related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala ( = 0.82), inferior frontal gyrus (IFG; = 0.83), anterior cingulate cortex (ACC; = 0.76), insula ( = 0.85), and fusiform gyrus ( = 0.91) for maximum activation and fair to excellent reliability in the amygdala ( = 0.44), IFG ( = 0.48), ACC ( = 0.55), insula ( = 0.42), and fusiform gyrus ( = 0.83) for mean activation across sites and test days. For the amygdala, habituation ( = 0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta‐analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single‐site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level‐dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms. Hum Brain Mapp 36:2558–2579, 2015. © 2015 Wiley Periodicals, Inc .     

Augmented cystine–glutamate exchange by pituitary adenylate cyclase‐activating polypeptide signaling via the VPAC1 receptor

In the central nervous system, cystine import in exchange for glutamate through system is critical for the production of the antioxidant glutathione by astrocytes, as well as the maintenance of extracellular glutamate. Therefore, regulation of system activity affects multiple aspects of cellular physiology and may contribute to disease states. Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a neuronally derived peptide that has already been demonstrated to modulate multiple aspects of glutamate signaling suggesting PACAP may also target activity of cystine–glutamate exchange via system . In this study, 24‐h treatment of primary cortical cultures containing neurons and glia with PACAP concentration‐dependently increased system function as measured by radiolabeled cystine uptake. Furthermore, the increase in cystine uptake was completely abolished by the system inhibitor, (S)‐4‐carboxyphenylglycine (CPG), attributing increases in cystine uptake specifically to system activity. Time course and quantitative PCR results indicate that PACAP signaling may increase cystine–glutamate exchange by increasing expression of xCT, the catalytic subunit of system . Furthermore, the potentiation of system activity by PACAP occurs via a PKA‐dependent pathway that is not mediated by the PAC1R, but rather the shared vasoactive intestinal polypeptide receptor VPAC1R. Finally, assessment of neuronal, astrocytic, and microglial‐enriched cultures demonstrated that only astrocyte‐enriched cultures exhibit enhanced cystine uptake following both PACAP and VIP treatment. These data introduce a novel mechanism by which both PACAP and VIP regulate system activity. Synapse 68:604–612, 2014 . © 2014 Wiley Periodicals, Inc.     

两种手术方式对Chiari畸形Ⅰ型合并脊髓空洞的系统评价及meta分析

目的 系统评价后颅窝减压（posterior fossa decompression,PFD）和后颅窝减压加硬膜成形术（posterior fossa decompression plus duraplasty,PFDD）在Chiari畸形Ⅰ型合并脊髓空洞患者中的有效性及安全性。方法 检索Embase、Cochrane、Pubmed、Ovid、Medline、ScienceDirect、谷歌学术、万方、知网等数据库自建库到2019年的文献,筛选文中对PFD与PFDD进行了比较的随机对照研究或非随机对照研究,统计术后临床症状和影像学改善情况、并发症等指标,运用Revman（5.3版本）进行数据分析。结果 最终纳入10篇文献,共3 188例,PFDD组1 383例,PFD组1 805例。在脊髓空洞改善率（OR：5.53;95%CI：2.86,10.69）、症状缓解率（OR：2.53;95%CI：1.30,4.91）、并发症发生率（OR：3.46;95%CI：1.40,8.59）、脑脊液漏发生率（OR：9.36;95%CI：2.63,33.34）、假性硬脑膜膨出率（OR：1.89;95%CI：1.28,2.79）方面PFDD组高于PFD组（P<0.05）。在切口感染发生率（OR：1.44;95%CI：0.57,3.59）、皮下积液发生率（OR：1.71;95%CI：0.50,5.80）方面两种术式无差异（P>0.05）。结论 针对Chiari畸形Ⅰ型合并脊髓空洞的患者,PFDD的有效性优于PFD。     

Creutzfeldt-Jakob病的临床分析（附4例报告）

目的 分析Creutzfeldt-Jakob病的临床特点.方法 回顾性分析4例散发性CJD病例.结果 主要临床症状和体征有进行性痴呆、精神症状、肌阵挛、视力下降、头晕等;4例均于2～23个月内死亡;MRI示：2例双侧皮质异常信号,1例右基底节区及皮质异常信号,1例两侧半卵圆中心、侧脑室周围白质区异常信号.4例脑电图均有异常,1例呈周期性同步放电.2例脑脊液14-3-3蛋白阳性.结论 CJD临床诊断以快速进行性痴呆和肌阵挛等临床症状为主,以MRI、脑电图、脑脊液14-3-3蛋白作为主要辅助检查方法.     

Prevalence of and Relationship Between Caregiver Adversity Scores and Child Client Eco-systemic Structural Family Therapy (ESFT) Outcome: Implications for Family Based Mental Health Services (FBMHS)

Adverse childhood experiences, especially with primary caregivers, impacts the mental, physical, and relational health of individuals (Felitti et al. in Am J Prev Med, 14(4):245–258. https://doi.org/10.1016/s0749-3797(98)00017-8, 1998). Therefore, caregiver adversity is important to consider when delivering therapeutic interventions to children (Gardner et al. in Clin Soc Work J 42(1):81–89. https://doi.org/10.1007/s10615-012-0428-8, 2014; Eslinger et al. in J Child Fam Stud 24(9):2757. https://doi.org/10.1007/s10826-014-0079-1, 2015; Hagan et al. in J Trauma Stress 30(6):690–697, 2017). This study analyzed archival data to understand the role of caregiver adversity in Eco-Systemic Structural Family Therapy (ESFT) outcomes, within Family Based Mental Health Services. Results indicate caregiver lifetime adversity score did not predict treatment outcome. However, caregiver current adversity and family length of stay were negatively correlated as were length of stay and client discharge level of care. These findings suggest that ESFT benefits families regardless of caregiver childhood adversity level and that clinician attention to caregiver current adversity is important to ensure families receive the full benefits of ESFT. Implications for optimizing ESFT and future directions for ESFT clinical research are discussed.

     

The impact of correction on MP2RAGE cortical T1 and apparent cortical thickness at 7T

Determination of cortical thickness using MRI has often been criticized due to the presence of various error sources. Specifically, anatomical MRI relying on T₁ contrast may be unreliable due to spatially variable image contrast between gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF). Especially at ultra‐high field (≥ 7T) MRI, transmit and receive B₁‐related image inhomogeneities can hamper correct classification of tissue types. In the current paper, we demonstrate that residual (transmit) inhomogeneities in the T₁‐weighted and quantitative T₁ images using the MP2RAGE sequence at 7T lead to biases in cortical thickness measurements. As expected, post‐hoc correction for the spatially varying profile reduced the apparent T₁ values across the cortex in regions with low , and slightly increased apparent T₁ in regions with high . As a result, improved contrast‐to‐noise ratio both at the GM‐CSF and GM‐WM boundaries can be observed leading to more accurate surface reconstructions and cortical thickness estimates. Overall, the changes in cortical thickness ranged between a 5% decrease to a 70% increase after correction, reducing the variance of cortical thickness values across the brain dramatically and increasing the comparability with normative data. More specifically, the cortical thickness estimates increased in regions characterized by a strong decrease of apparent T₁ after correction in regions with low due to improved detection of the pial surface_. The current results suggest that cortical thickness can be more accurately determined using MP2RAGE data at 7T if inhomogeneities are accounted for.     

Relapse prevention in major depressive disorder after successful ECT: a literature review and a naturalistic case series

OBJECTIVE: Medication-resistance in major depressive disorder (MDD) may be related to high relapse rates after successful ECT when continued medication (C-MED) is used to prevent relapse. An alternative could be to continue ECT (C-ECT). METHOD: Patients with medication-resistant MDD responding to ECT were offered C-ECT without medication. Follow-up was 6 months. Publications from a literature search were screened against prespecified criteria. RESULTS: With C-ECT the 6-month relapse-rate was 50% (6/12, 95% CI:21-79) in our medication-resistant group. In the review we found with C-ECT 29% (7/24,CI:13-51) in 'unknown' medication resistance and no data about medication-resistant depression. With C-MED at 6 months: no data were found concerning medication-resistant depression, 28% (35/124,CI:20-36) in 'unknown' resistance and 13% (2/15,CI:2-41) in non-resistance. With C-MED at 12 months, 73% (16/22,CI:50-90), 50% (16/32,CI:32-68) and 27% (8/30,CI:12-46) were found, respectively. CONCLUSION: The efficacy of C-MED is related negatively to medication resistance before ECT. This may also be the case for C-ECT. Further studies with C-ECT are urgently needed.     

Correction to: Identifying Subgroups of Toddlers with DSM‑5 Autism Spectrum Disorder Based on Core Symptoms

Journal of Autism and Developmental Disorders - A correction to this paper has been published: https://doi.org/10.1007/s10803-021-04954-5     

Correction to: Community Participation Comparison Between Adults on the Autism Spectrum and Adults in the General Population

Journal of Autism and Developmental Disorders - A correction to this paper has been published: https://doi.org/10.1007/s10803-021-05108-3     

Correction to: Effect of a Focused Social and Communication Intervention on Preterm Children with ASD: A Pilot Study

Journal of Autism and Developmental Disorders - A correction to this paper has been published: https://doi.org/10.1007/s10803-021-05109-2     

伴与不伴快速眼动睡眠行为障碍帕金森病患者临床差异的meta分析

目的 系统评价伴与不伴快速眼动睡眠行为障碍（RBD）帕金森病（PD）患者之间临床特征的差异。方法 检索PubMed、EMbase等外文数据库及中国生物医学数据库（CMB）、中国知识基础设施工程（CNKI）、维普中文科技期刊全文数据库（VIP）、万方数据库等中文数据库关于PD与RBD相关性分析的病例对照研究,检索时限从建库至2018年09月01日。对入选文献进行质量评价,并用Stata 12.0软件进行Meta分析。结果 共纳入了17项符合标准的病例对照研究,共计PD患者3006例,Meta分析结果显示：与不伴RBD的PD患者相比,伴RBD的PD患者年龄更大（SMD=0.26;95%CI 0.19~0.34;P<0.00 001）、病程更长（SMD=0.29;95%CI 0.21~0.37;P<0.00 001）、Hoehn-Yahr分级更高（SMD=0.22;95%CI 0.11~0.33;P<0.00 001）、UPDRS-Ⅲ评分更高（SMD=0.25;95%CI 0.15~0.36;P<0.00 001）、左旋多巴剂量更大（SMD=0.17;95%CI 0.08~0.26;P<0.00 001）,更易出现症状波动（OR=1.65;95%CI1.34~2.03;P<0.00 001）、异动症（OR=2.24;95%CI 1.74~2.88;P<0.00 001）,MMSE评分更低（SMD=-0.23;95%CI-0.40~-0.06;P=0.008）,幻觉（OR=3.15;95%CI 2.06~4.80;P<0.00 001）更多见,而性别（OR=1.15;95%CI 0.99~1.35;P=0.07）、发病年龄（SMD=0.09;95%CI-0.01~0.19;P=0.08）组间差异不明显。结论 PD患者中RBD的发生与患者年龄、病程有关,且伴RBD的PD患者需要更高的左旋多巴剂量、更易出现运动并发症,非运动症状更明显,提示伴RBD的PD患者中枢神经系统变性程度更严重、损害范围更广泛。     

Correction to: Implications of Applying “Clinically Significant Impairment” to Autism Assessment: Commentary on Six Problems Encountered in Clinical Practice

Journal of Autism and Developmental Disorders - A correction to this paper has been published: https://doi.org/10.1007/s10803-021-05069-7     

Correction to: Cortical activation abnormalities in bipolar and schizophrenia patients in a combined oddball–incongruence paradigm

European Archives of Psychiatry and Clinical Neuroscience - A correction to this paper has been published: https://doi.org/10.1007/s00406-021-01276-6