Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial.

BACKGROUND: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. METHODS: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. FINDINGS: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. INTERPRETATION: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. FUNDING: Kura Oncology.

The Association of the Glymphatic Function with Parkinson's Disease Symptoms: Neuroimaging Evidence from Longitudinal and Cross-Sectional Studies.

OBJECTIVE: Emerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking. METHODS: In this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function. RESULTS: Overall, 289 patients with PD were enrolled in the cross-sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5-year follow-up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid-high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS-UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aß1-42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5. INTERPRETATION: The ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023;94:672-683.

C3a/C3aR synergies with TGF-ß to promote epithelial-mesenchymal transition of renal tubular epithelial cells via the activation of the NLRP3 inflammasome.

BACKGROUND: Complement component 3a and its receptor (C3a/C3aR) and the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome contribute to epithelial-mesenchymal transition (EMT). However, the relationship between C3a/C3aR and the NLRP3 inflammasome in EMT remains unclear. This study aimed to elucidate the roles of C3a/C3aR and the NLRP3 inflammasome involved in TGF-ß-induced EMT. METHOD: Mouse renal tubular epithelial cells (TCMK-1) were exposed to C3a and TGF-ß for 48 h. C3aR antagonist, MCC950, an inhibitor of the NLRP3 inflammasome and PD98059, an inhibitor of ERK signaling, were respectively applied to pretreat the cells at 30 min before C3a and TGF-ß administration.The cells were collected for western blot, immunofluorescence staining and ELISA. Unilateral ureteral obstruction (UUO) models were established using male C57BL/6 wild-type (WT) mice and age-matched C3aR-deficient mice. MCC950 was intraperitoneally injected in UUO mice. Kidney samples were collected for immunohistochemistry staining. RESULTS: In vitro, C3a synergized with TGF-ß to promote EMT and the activation of the NLRP3 inflammasome. Inhibition of C3aR attenuated EMT and the activation of the NLRP3 inflammasome. Inhibition of the NLRP3 inflammasome alleviated EMT but didn't affect the expression of C3aR. Inhibition of ERK signaling inhibited the activation of the NLRP3 inflammasome. In vivo, the expression of IL-1ß was significantly higher in UUO mice compared to the sham-operated mice. C3aR deficiency and inhibition of the NLRP3 Inflammasome contributed to decreased IL-1ß in UUO mice. CONCLUSION: Our data revealed that C3a/C3aR synergies with TGF-ß to activate the NLRP3 inflammasome to promote epithelial-mesenchymal transition of renal tubular epithelial cells through ERK signaling, and the way in which C3aR activates the inflammasome is to promote the assembly of the NLRP3 inflammasome.

Repetitive transcranial magnetic stimulation (rTMS) fails to improve cognition in patients with parkinson's disease: a Meta-analysis of randomized controlled trials.

BACKGROUND: Cognitive decline is one of the greatest concerns for patients with Parkinson's disease (PD) and their care partners. Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological treatment option used to improve cognitive function in PD, but its efficacy is unclear. We performed a meta-analysis to determine whether rTMS improves cognition in PD patients. METHODS: Eligibility criteria (PICOS) were as follows: (1) 'P': The patients participating were diagnosed with idiopathic PD; (2) 'I': Intervention using rTMS; (3) 'C': Sham stimulation as control; (4) 'O': The outcome of the study included cognitive evaluations; (5) 'S': The study adopted randomized controlled design. The standardized mean difference (SMD) of change of score was applied to measure efficacy, and we used Version 2 of the Cochrane tool to assess risk of bias. RESULTS: Twelve studies met the inclusion criteria. Compared with sham-controlled group, the pooled result showed a non-significant short-term effect of rTMS on global cognition (SMD: -0.15, 95% CI: -0.59 to 0.29, I2 = 36.7%), executive function (SMD: 0.03, 95% CI: -0.21 to 0.26, I2 = 0.0%), and attention and working memory (SMD: 0.05, 95% CI: -0.25 to 0.35, I2 = 0.0%). Long-term outcomes were either shown to be statistically nonsignificant. CONCLUSIONS: Based on a limited number of studies, rTMS fails to improve cognition in PD. We call for additional high-quality randomized controlled trials with adequate sample sizes to determine the efficacy of rTMS.

Identifying Parkinson's disease with mild cognitive impairment by using combined MR imaging and electroencephalogram.

OBJECTIVES: To analyse the changes of quantitative electroencephalogram (qEEG) and cortex structural magnetic resonance (MR) imaging in Parkinson's disease with mild cognitive impairment (PD-MCI) and to explore the "composite marker"-based machine learning model in identifying PD-MCI. METHODS: Retrospective analysis of patients with PD identified 36 PD-MCI and 35 PD with normal cognition (PD-NC). QEEG features of power spectrum and structural MR features of cortex based on surface-based morphometry (SBM) were extracted. Support vector machine (SVM) was established using combined features of structural MR and qEEG to identify PD-MCI. Feature importance evaluation algorithm of mean impact value (MIV) was established to sort the vital characteristics of qEEG and structural MR. RESULTS: Compared with PD-NC, PD-MCI showed a statistically significant difference in 5 leads and waves of qEEG and 7 cortical region features of structural MR. The SVM model based on these qEEG and structural MR features yielded an accuracy of 0.80 in the training set and had a high prediction accuracy of 0.80 in the test set (sensitivity was 0.78, specificity was 0.83, area under the receiver operating characteristic curve was 0.77), which was higher than the model built by the feature separately. QEEG features of theta wave in C3 had a marked impact on the model for classification according to the MIV algorithm. CONCLUSIONS: PD-MCI is characterized by widespread structural and EEG abnormality. "Composite markers" could be valuable for the individualized diagnosis of PD-MCI by machine learning. KEY POINTS: • Explore the brain abnormalities in Parkinson's disease with mild cognitive impairment by using the quantitative electroencephalogram and cortex structural MR simultaneously. • Multimodal features based support vector machine for identifying Parkinson's disease with mild cognitive impairment has an acceptable performance. • Theta wave in C3 is the most influential feature of qEEG and cortex structure MR imaging in identifying Parkinson's disease with mild cognitive impairment using support vector machine.

Non-pharmacological treatment for Parkinson disease patients with depression: a meta-analysis of repetitive transcranial magnetic stimulation and cognitive-behavioral treatment.

Background: Nowadays, antidepressants still are the mainstay of treatment for depression in Parkinson's disease (PD) but some recent studies report that medication might aggravate motor symptoms in PD patients. This meta-analysis aims to assess the effect of non-pharmacological treatments for depression in patients with PD.Materials and Methods: Only randomized controlled trials (RCTs) were included. The participants were PD patients with comorbid depression (dPD). The interventions had the equivalent effect of non-pharmacological treatments alone compared with control(s). Scores of depression scale were selected as the primary outcome, while scores of Unified Parkinson's Disease Rating Scale part III and the incidence of side effects were the secondary outcome. The statistics were pooled and presented as weighted mean differences (WMDs), standardized mean differences (SMDs), or risk ratios (RRs) with their 95% confidence intervals (CIs).Results: Fifteen articles were eventually included; twelve studies reported on repetitive transcranial magnetic stimulation (rTMS) and three used cognitive behavioral therapy (CBT). Other interventions failed to have qualified studies. Our data indicated that both rTMS and CBT could significantly improve depression scores in a short term (SMD = -0.621, 95% CI [-0.964, -0.278]; SMD = -1.148, 95% CI [-1.498, -0.798], respectively). In addition, rTMS could alleviate motor symptom (WMD = -2.617, 95% CI [-4.183, -1.051]) and was relatively safe (RR = 1.054, 95% CI [0.698, 1.592]).Conclusion: Our data suggest that rTMS can safely alleviate depression and motor symptoms in dPD at least for a short period. Moreover, compared with clinical monitoring, CBT can improve depressive symptoms.

Evaluating the Clinical Impact of Rapid Response Electroencephalography: The DECIDE Multicenter Prospective Observational Clinical Study.

OBJECTIVES: To measure the diagnostic accuracy, timeliness, and ease of use of Ceribell rapid response electroencephalography. We assessed physicians' diagnostic assessments and treatment plans before and after rapid response electroencephalography assessment. Primary outcomes were changes in physicians' diagnostic and therapeutic decision making and their confidence in these decisions based on the use of the rapid response electroencephalography system. Secondary outcomes were time to electroencephalography, setup time, ease of use, and quality of electroencephalography data. DESIGN: Prospective multicenter nonrandomized observational study. SETTING: ICUs in five academic hospitals in the United States. SUBJECTS: Patients with encephalopathy suspected of having nonconvulsive seizures and physicians evaluating these patients. INTERVENTIONS: Physician bedside assessment of sonified electroencephalography (30 s from each hemisphere) and visual electroencephalography (60 s) using rapid response electroencephalography. MEASUREMENTS AND MAIN RESULTS: Physicians (29 fellows or residents, eight attending neurologists) evaluated 181 ICU patients; complete clinical and electroencephalography data were available in 164 patients (average 58.6 ± 18.7 yr old, 45% females). Relying on rapid response electroencephalography information at the bedside improved the sensitivity (95% CI) of physicians' seizure diagnosis from 77.8% (40.0%, 97.2%) to 100% (66.4%, 100%) and the specificity (95% CI) of their diagnosis from 63.9% (55.8%, 71.4%) to 89% (83.0%, 93.5%). Physicians' confidence in their own diagnosis and treatment plan were also improved. Time to electroencephalography (median [interquartile range]) was 5 minutes (4-10 min) with rapid response electroencephalography while the conventional electroencephalography was delayed by several hours (median [interquartile range] delay = 239 minutes [134-471 min] [p < 0.0001 using Wilcoxon signed rank test]). The device was rated as easy to use (mean ± SD: 4.7 ± 0.6 [1 = difficult, 5 = easy]) and was without serious adverse effects. CONCLUSIONS: Rapid response electroencephalography enabled timely and more accurate assessment of patients in the critical care setting. The use of rapid response electroencephalography may be clinically beneficial in the assessment of patients with high suspicion for nonconvulsive seizures and status epilepticus.

Ultra-low-dose multiphase CT angiography derived from CT perfusion data in patients with middle cerebral artery stenosis.

PURPOSE: Computed tomography (CT) perfusion (CTP) source images contain both brain perfusion and cerebrovascular information, and may allow a dynamic assessment of collaterals. The purpose of the study was to compare the image quality and the collaterals identified on multiphase CT angiography (CTA) derived from CTP datasets (hereafter called CTPA) reconstructed with iterative model reconstruction (IMR) algorithm in patients with middle cerebral artery (MCA) steno-occlusion with those of routine CTA. METHODS: Consecutive patients with a unilateral MCA steno-occlusion underwent non-contrast CT (NCCT), CTP, and CTA. CTPA images were reconstructed from CTP datasets. The vascular attenuation, image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of routine CTA and CTPA were measured and analyzed by Student's t test. Subjective image quality and collaterals were scored and compared using the Wilcoxon signed-rank test. RESULTS: Fifty-eight patients (mean age 61.7 years, 78% males, median National Institutes of Health Stroke Scale score = 12) were included. The effective radiation dose of CTP was 1.28 mSv. The vascular attenuation, SNR, CNR, and the image quality of CTPA were considerably higher than that of CTA (all, p < 0.001). Collaterals were rated higher on CTPA compared with CTA (1.79 ± 0.64 vs. 1.22 ± 0.84, p < 0.001). Fifty-three percent of patients with poor collaterals assessed on single-phase CTA had good collaterals on CTPA. CONCLUSION: CTPA derived from CTP datasets reconstructed with IMR algorithm offers image quality comparable to routine CTA and provides time-resolved evaluation of collaterals in patients with MCA ischemic disease.

Cortical hypoperfusion in patients with idiopathic rapid eye movement sleep behavior disorder detected with arterial spin-labeled perfusion MRI.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is an important risk factor for α-synucleinopathy. OBJECTIVE: We investigated alterations in the cerebral blood flow (CBF) based on arterial spin-labeled (ASL) imaging in patients with iRBD to determine brain perfusion changes associated with the disorder. METHODS: Fifteen patients with iRBD and twenty age-gender-matched healthy controls were enrolled. Cortical perfusions were compared between the two groups after the ASL data was co-registered to the high-resolution T1-weighted images. RESULTS: No significant differences were detected between the groups in regard to age, gender, education, or UPDRS-III score. The iRBD group showed a lower MMSE score than the healthy controls (27.07 ± 2.25 vs. 28.55 ± 1.23, p < 0.05). Compared with the healthy controls, the iRBD group showed significantly decreased CBF values in the right inferior frontal gyrus, right middle frontal gyrus, and right insula (p < 0.05 corrected). CONCLUSION: The cortical hypoperfusion areas in patients with iRBD were similar to the patterns in patients with α -synucleinopathies. ASL perfusion MRI is a potential approach to find biomarkers in preclinical stages of α -synucleinopathies.

A Follow-up Study of Cerebral Microbleeds in Patients Who Received Stents for Symptomatic Cerebral Artery Stenosis.

BACKGROUND: The aims of this study were to explore (i) the dynamic changes in cerebral microbleeds (CMBs) in patients with symptomatic cerebral artery stenosis who received endovascular stent-assisted angioplasty and (ii) the risk factors associated with the new incidence of CMBs as well as whether CMBs increased the risk of vascular events in these patients. METHODS: Clinical information and magnetic resonance images were collected on admission and 3 months after endovascular stent-assisted angioplasty. Based on susceptibility-weighted imaging, the patients were divided into groups with or without newly developed CMBs, and between-group differences in risk factors were compared. We also compared whether CMBs increased the risk of vascular events among those patients. RESULTS: Seventy-three patients completed the relevant follow-up examinations. After an average follow-up period of 109 days, 7 (9.6%) patients showed new CMBs. A univariate analysis showed that the number of lacunar infarcts and the increase in systolic blood pressure were higher in patients with new CMBs than in those without new CMBs, and these differences were significant (P = 0.034, P = 0.001). Increased systolic blood pressure was an independent risk factor for developing new CMBs (P = 0.017). CONCLUSIONS: CMBs may be a continuously progressing cerebral small-vessel disease. The newly developed CMBs in patients with intracranial and/or extracranial stents were associated with increased systolic blood pressure but not with the number of baseline CMBs.

TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease.

Neuroinflammation and overactivated microglia underlies the pathogenesis of Parkinson's disease (PD). Furthermore, microglia could polarize into classic inflammatory M1 and immunosuppressive M2 phenotype. Thus, inhibiting the overactivated inflammatory M1 microglia by promoting the transformation of microglia to the protective M2 phenotype provides potential therapy for PD, but the mechanism that modulates microglia polarization remains unknown. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified immune receptor expressed by the microglia in the brain. Emerging evidence indicates that TREM2 enhances the phagocytosis function of microglia and suppress inflammation. Based on these evidence, we hypothesized that TREM2 might play a protective role through regulating microglia polarization. Here, we employ a lentiviral strategy to overexpress or suppress TREM2 on microglia and found that TREM2 was essential for M2 microglia polarization. Knockdown of TREM2 in BV2 microglia inhibited M2 polarization and lead to exaggeration of M1 microglial inflammatory responses, whereas overexpression of TREM2 promoted M2 polarization and alleviated microglial inflammation. We also observed that the TREM2 level was higher in the midbrain of PD mice, which was accompanied by an elevated level of Arginase-1 and increased proinflammatory cytokines, suggesting that TREM2 is an important factor in switching the microglia phenotypes. Taken together, these findings indicate that TREM2 plays a crucial role in altering the proinflammatory M1 microglia to M2 phenotype and has beneficial effects in the immune pathogenesis of PD.

A high-throughput pipeline for the production of synthetic antibodies for analysis of ribonucleoprotein complexes.

Post-transcriptional regulation of mRNAs plays an essential role in the control of gene expression. mRNAs are regulated in ribonucleoprotein (RNP) complexes by RNA-binding proteins (RBPs) along with associated protein and noncoding RNA (ncRNA) cofactors. A global understanding of post-transcriptional control in any cell type requires identification of the components of all of its RNP complexes. We have previously shown that these complexes can be purified by immunoprecipitation using anti-RBP synthetic antibodies produced by phage display. To develop the large number of synthetic antibodies required for a global analysis of RNP complex composition, we have established a pipeline that combines (i) a computationally aided strategy for design of antigens located outside of annotated domains, (ii) high-throughput antigen expression and purification in Escherichia coli, and (iii) high-throughput antibody selection and screening. Using this pipeline, we have produced 279 antibodies against 61 different protein components of Drosophila melanogaster RNPs. Together with those produced in our low-throughput efforts, we have a panel of 311 antibodies for 67 RNP complex proteins. Tests of a subset of our antibodies demonstrated that 89% immunoprecipitate their endogenous target from embryo lysate. This panel of antibodies will serve as a resource for global studies of RNP complexes in Drosophila. Furthermore, our high-throughput pipeline permits efficient production of synthetic antibodies against any large set of proteins.

Hypotension and bradycardia, a serious adverse effect of piribedil, a case report and literature review.

BACKGROUND: Dopamine agonists (DAs) are efficacious for the treatment of motor and nonmotor symptoms in patients with Parkinson's disease (PD). The treatment of PD with DAs is often complicated by adverse drug reactions (ADRs) of dopaminergic and non-dopaminergic origins. The DA piribedil is widely used in Asian, European, and Latin American countries; therefore, its ADRs are pertinent to clinicians. Here we present a rare case of hypotension and bradycardia that is significantly related to the dosage of piribedil. CASE PRESENTATION: A middle-aged male, diagnosed with PD, received dopamine replacement with piribedil. When taking 50 mg piribedil daily dose, the patient didn't feel any discomfort. Two hours after taking 100 mg piribedil he presented with serious concomitant hypotension and bradycardia with a blood pressure (BP) reading of 85/48 mmHg and a heart rate (HR) of 45 beats/min when sitting. After taking 75 mg piribedil, the patient showed the same symptoms with BP reading at 70/45 mmHg and HR of 47 beats/min in the same position. Upon replacing treatment with pramipexole 0.125 mg, 0.25 mg, and 0.375 mg three times a day, no further cardiovascular effects persisted. CONCLUSIONS: No studies have previously reported the simultaneous observation of position-unrelated hypotension and bradycardia after taking small doses of piribedil. More studies are needed to explore the effects of DAs on BP and HR, especially piribedil. Piribedil is efficacious for the treatment of PD, but it is important to weigh the potential risk of hypotension and bradycardia against the clinical benefits of this drug.

Synthesis and Characterization of Dinuclear Salan Rare-Earth Metal Complexes and Their Application in the Homo- and Copolymerization of Cyclic Esters.

Four rare-earth-metal aryloxo complexes stabilized by a tetradentate Salan ligand were prepared, and their catalytic properties for the (co)polymerization of lactides and ε-caprolactone were elucidated. The proton-exchange reactions of (C5H5)3Ln(THF) with the Salan ligand N, N'-(CH2Ph)2- N, N'-[CH2(2-OH-C6H2-Me2-3,5)]2 (LH2) in a 1:1 molar ratio, and subsequently with 1 equiv of p-methylphenol, gave the rare-earth-metal aryloxides [LLn(OC6H4-4-CH3)(THF) n]2 [ n = 0 and Ln = Y (1), Sm (2), and Nd (3); n = 1 and Ln = La (4)] in good isolated yields. These complexes were fully characterized by elemental analysis, IR, and NMR spectroscopy (for complexes 1 and 4). Solid-state structures of complexes 1-4 were confirmed by single-crystal X-ray diffraction analysis. Complexes 1-4 have dinuclear solid-state structures, with a Ln2O2 core bridging the Salan ligands. The coordination geometry around each of the metals is a slightly distorted octahedron in complexes 1-3, whereas it is a capped trigonal prism in complex 4. It was found that complexes 1-4 can initiate efficiently the homopolymerization of l-lactide (l-LA) and rac-lactide ( rac-LA) at 30 °C in tetrahydrofuran. The increasing activity of these complexes is in agreement with increasing ionic radii. A kinetic study revealed that seven-coordinated lanthanum complex 4 is more active for rac-LA polymerization compared with l-LA. A further study revealed that complex 4 was also an efficient initiator for the random copolymerization of l-LA and ε-caprolactone with the simultaneous addition of these two monomers, and the Tg values of the copolymers obtained increase linearly from -30.2 to +38.3 °C with an increase of the percentage of LA units. A mechanism study revealed that transesterification plays a crucial role in the formation of a random copolymer.

Romiplostim in children with immune thrombocytopenia: a phase 3, randomised, double-blind, placebo-controlled study.

BACKGROUND: The thrombopoietin receptor agonist romiplostim could be an effective treatment in symptomatic children with persistent or chronic immune thrombocytopenia. We aimed to assess whether romiplostim is safe and effective in children with immune thrombocytopenia of more than 6 months' duration. METHODS: In this phase 3 double-blind study, eligible participants were children with immune thrombocytopenia aged 1 year to 17 years and mean platelet counts 30 × 10(9)/L or less (mean of two measurements during the screening period) with no single count greater than 35 × 10(9)/L, and were recruited from 27 sites in the USA, Canada, and Australia. Participants were randomly assigned (2:1) through the interactive voice response system to receive weekly romiplostim or placebo for 24 weeks stratified by age (1 year to <6 years, 6 years to <12 years, 12 years to <18 years), adjusting the dose weekly from 1 µg/kg to 10 µg/kg to target platelet counts of 50-200 × 10(9)/L. Patients and investigators were blinded to the treatment assignment. The primary analysis included all randomised patients and the safety analysis included all randomised patients who received at least one dose of investigational product. The primary endpoint, durable platelet response, was defined as achievement of weekly platelet responses (platelet counts ≥50 × 10(9)/L without rescue drug use in the preceding 4 weeks) in 6 or more of the final 8 weeks (weeks 18-25). This study is registered with ClinicalTrials.gov, NCT 01444417. FINDINGS: Between Jan 24, 2012, and Sept 3, 2014, 62 patients were randomly assigned; 42 to romiplostim and 20 to placebo. Durable platelet response was seen in 22 (52%) patients in the romiplostim group and two (10%) in the placebo group (p=0·002, odds ratio 9·1 [95% CI 1·9-43·2]). Durable platelet response rates with romiplostim by age were 38% (3/8) for 1 year to younger than 6 years, 56% (10/18) for 6 years to younger than 12 years, and 56% (9/16) for 12 years to younger than 18 years. One (5%) of 19 patients in the placebo group had serious adverse events compared with 10 (24%) of 42 patients in the romiplostim group. Of these serious adverse events, headache and thrombocytosis, in one (2%) of 42 patients in the romiplostim group, were considered treatment related. No patients withdrew due to adverse events. INTERPRETATION: In children with chronic immune thrombocytopenia, romiplostim induced a high rate of platelet response with no new safety signals. Ongoing romiplostim studies will provide further information as to long-term efficacy, safety, and remission in children with immune thrombocytopenia. FUNDING: Amgen Inc.

Acupuncture for patients with mild to moderate Alzheimer's disease: a randomized controlled trial.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. However, none of medical treatment can stop or reverse the underlying neurodegenerative of AD at present. Acupuncture has attracted more and more attention in recent years due to its efficacy and very few side effects. Lately, a systematic review has thought that the evidence on the effectiveness of acupuncture in improving the cognitive function of AD patients was not powerful enough. Therefore, the aim of this study is to explore the efficacy and safety of acupuncture in patients with mild to moderate AD. METHODS: This was a randomized, controlled, parallel-group, exploratory study with 4-week baseline (T0), 12-week treatment phase (T1) and 12-week follow-up period (T2). Patients with mild to moderate AD meeting the included criteria were randomly allocated into either acupuncture or donepezil hydrochloride groups. The acupuncture group(AG) was given acupuncture treatment three times per week and the donepezil hydrochloride group(DG) group was administered donepezil hydrochloride once daily (5 mg/day for the first 4 weeks and 10 mg/day thereafter). Primary efficacy was measured using Alzheimer's disease Assessment Scale-Cognitive (ADAS-cog) and Clinician's Interview-Based Impression of Change-Plus (CIBIC-Plus). The second outcomes were measured with 23-Item Alzheimer's disease Cooperative Study Activities of Daily Living Scales (ADAS-ADL23) and Neuropsychiatric Index (NPI). RESULTS: Of 87 participants enrolled in the study, 79 patients finished their treatment and follow-up processes. The ADAS-cog scores for AG group showed obvious decreases at T2 and ∆(T2-T0)when compared with DG group, and significant between-group differences were detected (all p < 0.05). The mean CIBIC-Plus values for the AG group at T1 and T2 were much lower than that for the DG group, and there were significant differences between the two groups (푃<0.05). There were no significant between-group differences in the scores of ADAS-ADL23 and NPI during the study period. Treatment discontinuations due to adverse events were 0 (0%) and 4 (9.09%) for the AG and DG groups, respectively. CONCLUSIONS: Acupuncture is safe, well tolerated and effective in improving the cognitive function, global clinical status of AD. TRIAL REGISTRATION: ChiCTR-IOR-17010465 (Retroactively registered on 18 JAN 2017).

The patterns of EEG changes in early-onset Parkinson's disease patients.

The aim of this study was to investigate the patterns of brain activity changes in early-onset Parkinson's disease (EOPD) patients and its relationship with the severity of disease and motor deterioration. Electroencephalography (EEG) was performed in a sample of 52 nondemented EOPD patients and 20 healthy controls with similar age. All patients underwent a battery to assess PD severity and motor deterioration. The EEG data were rated by visual and quantitative analyses with the grant total EEG (GTE) score and NicoletOne Software. The parameters of relative band power and coherences for various frequency bands were calculated. In addition, all parameters were compared between groups and examined for correlations with the severity of disease and motor deterioration. The GTE score and two subscores including "Diffuse Slow Waves" and "Frequency of Rhythmic Background Activity" of EOPD increased comparing to control group. The relative beta band powers in seven regions (O1,O2,T5,T6,P3,P4 and C3) indicated significant decreases in EOPD patients and obvious increases in interhemispheric beta coherences were observed in the midtemporal area and frontal area (T3T4 and F3F4). Furthermore, correlation analyses revealed that longer duration was associated with the subscore of "background wave frequency". The beta frequency bands in the right posterior temporal (T6) showed negative relationship with the modified Hoehn-Yahr grading scores. This study is the first to depict the patterns of EEG changes in EOPD patients without dementia and offer a better understanding of the pathophysiological mechanisms underlying and prognostic purposes in EOPD. Some of these changes could serve as useful biomarkers in the study of EOPD.

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease.

AIM: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. METHODS: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale - Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale - Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. RESULTS: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. CONCLUSIONS: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.

[Acupuncture Regulated the Expressions of Hsp84 and Hsp86 and Postponed Brain Aging in SAMP8].

Objective To observe the correlations between heat shock protein 84 ( Hsp84)/ Hsp86 and brain aging in senescence accelerated mouse prone 8 (SAMP8) and the regulation effects of acupuncture. Methods Ten senescence accelerated mouse resistant 1 (SAMR1) were recruited as a normal control group. Another 30 SAMP8 mice were divided into the blank control group, the acupuncture group, and the non-acupoint group by random digit table, 10 in each group. Mice in the acupuncture group received treatment with "Sanjiao" acupuncture method. Mice in the non-acupoint group were needled at two fixed non-acupoints located at bilateral hypochondrium of the body. Catching stimulus at equal volume was given to mice in the rest two groups. All intervention was performed once per day for 15 successive days. Neuromuscular coordination of mice was evaluated. Levels of oxidative stress and protein carbonyl were determined. mRNA and protein expression levels of Hsp84 and Hsp86 in the hippocampus of mice and Neuro-2a cells were detected using Real-time PCR and Western blot. Results Compared with the normal control group, the success rate of tight rope experiment was lowered (P <0. 01) , levels of super- oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the hippocampus were reduced (P < 0. 01) , the levels of superoxide anion and protein carbonyl increased (P <0. 01, P <0. 05), mRNA and protein expression levels of Hsp84 and Hsp86 in the hippocampus decreased (P <0. 01) in the blank con- trol group. Compared with the blank control group and the non-acupoint group, the success rate of tight rope experiment was elevated (P <0. 05) , levels of SOD and GSH-Px were increased (P <0. 05, P < 0. 01) , the levels of superoxide anion and protein carbonyl decreased (P <0. 01 , P <0. 05), and expres- sion levels of Hsp84 and Hsp86 in the hippocampus increased (P <0. 01) in the acupuncture group. mR- NA expression levels of Hsp84 and Hsp86 were decreased in Neuro-2a cells after treated with AP21-35 (P <0. 01). Conclusions Increased oxidative damage of protein and decreased expression levels of Hsp84 and Hsp86 might be partial reasons for resulting in accumulation of denatured protein and brain aging in SAMP8. Acupuncture could delay brain aging by regulating the expressions of Hsp84 and Hsp86.