Publications by authors named "Xiaoqiang Han"

35 Publications

Middle Cerebral Artery-to-Uterine Artery Pulsatility Index Ratio and Cerebroplacental Ratio Independently Predict Adverse Perinatal Outcomes in Pregnancies at Term.

Ultrasound Med Biol 2021 Jul 26. Epub 2021 Jul 26.

Department of Gynecology and Obstetrics, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, China. Electronic address:

This study aimed to investigate potential predictors, including the cerebroplacental ratio and the middle cerebral artery (MCA)-uterine artery pulsatility index (PI) ratio, for adverse perinatal outcomes in pregnancies at term. This was an observational, prospective study of recruited pregnancies at term. The data were extracted from the medical records in hospital. An adverse perinatal outcome was set as the primary observational endpoint. The receiver operating characteristic curve was plotted to investigate the predictive and cutoff values of risk factors for adverse perinatal outcomes. Univariate and multivariate logistic regression analyses evaluated independent risk factors (maternal, neonatal, prenatal ultrasound and Doppler variables) for adverse perinatal outcomes. There were 392 pregnancies at term included in the study, with 19.4% experiencing adverse perinatal outcomes. The MCA-uterine artery PI ratio was a good predictor of adverse perinatal outcomes by receiver operating characteristic curve analysis (area under the curve = 0.886, p < 0.001), and the cerebroplacental ratio (odds ratio, 0.42; 95% confidence interval, 0.20-0.93; p = 0.032) and MCA-uterine artery PI ratio (odds ratio, 0.25; 95% confidence interval, 0.16-0.42; p = 0.032) were two independent risk factors for adverse perinatal outcomes by univariate and multivariate logistic regression analyses. Notably, both MCA-uterine artery PI ratio and cerebroplacental ratio are significant predictors of adverse perinatal outcome in pregnancies at term.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2021.06.015DOI Listing
July 2021

New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Bone Marrow Transplant 2021 07 28;56(7):1509-1517. Epub 2021 Apr 28.

Department of Neurology, Uppsala University, Uppsala, Sweden.

Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.
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http://dx.doi.org/10.1038/s41409-021-01277-yDOI Listing
July 2021

The Cost Effectiveness of Immunoglobulin vs. Hematopoietic Stem Cell Transplantation for CIDP.

Front Neurol 2021 22;12:645263. Epub 2021 Mar 22.

Academic Department of Neuroscience and Sheffield, NIHR Translational Neuroscience BRC, Sheffield Teaching Hospitals NHS Foundation Trust, University of Sheffield, Sheffield, United Kingdom.

Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP. To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP. Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range $56,327-277,119, standard deviation $53,092). After HSCT, 80% of patients remain IVIG and immune treatment free for up to 5 years. In comparison, published cost of IVIG treatment in the USA for an average CIDP patient exceeds $136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins. Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted.
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http://dx.doi.org/10.3389/fneur.2021.645263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019941PMC
March 2021

Autologous Hematopoietic Stem Cell Transplantation for Stiff-Person Spectrum Disorder: A Clinical Trial.

Neurology 2021 02 14;96(6):e817-e830. Epub 2020 Dec 14.

From the Division of Immunotherapy (R.K.B., X.H., K.Q., I.A.), Department of Medicine, Department of Neurology (R.B., T.S.), Department of Preventive Medicine (I.H.), and Department of Pathology and Cell and Developmental Biology (T.S.), Northwestern University, Chicago, IL; and Department of Neurology (J.R.), University of Utah, Salt Lake City.

Objective: To test the hypothesis that autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) is safe and shows efficacy in the treatment of stiff-person spectrum disorder (SPSD).

Methods: Twenty-three participants were treated in a prospective open-label cohort study of safety and efficacy. After stem cell mobilization with cyclophosphamide (2 g/m) and filgrastim (5-10 µg/kg/d), participants were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day -5 to day -2; rabbit anti-thymocyte globulin (thymoglobulin) given intravenously at 0.5 mg/kg on day -5, 1 mg/kg on days -4 and -3, and 1.5 mg/kg on days -2, and -1 (total dose 5.5 mg/kg); and rituximab 500 mg IV on days -6 and +1. Unselected peripheral blood stem cells were infused on day 0. Safety was assessed by survival and National Cancer Institute common toxicity criteria for adverse events during HSCT. Outcome was assessed by ≥50% decrease or discontinuation of antispasmodic drugs and by quality of life instruments.

Results: There was no treatment-related mortality. One participant died 1 year after transplantation of disease progression. Of the 74% of participants who responded, 47% have stayed in remission for a mean of 3.5 years; 26% did not respond. Compared to nonresponders, responders were more likely to have pretransplantation intermittent muscle spasms (16 of 17 vs 0 of 6), normal reflexes (12 of 17 vs 0 of 6), and positive CSF anti-glutamic acid decarboxylase serology (12 of 14 vs 2 of 6). Compared to responders, nonresponders were more likely to have lead pipe rigidity (4 of 6 vs 0 of 17) and EMG-documented simultaneous contraction of agonist/antagonist limb muscles (4 of 6 vs 1 of 17). Pre-HSCT use of prescription serotonin selective receptor inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI) was more common in those who relapsed or never responded (9 of 12) compared to those responders who never relapsed (0 of 11).

Conclusion: In this cohort, HSCT was safe, but the beneficial effect of HSCT was variable and confined predominately to participants with episodic spasms and normal tendon reflexes without simultaneous cocontraction of limb agonist/antagonist muscles who were not taking SSRI or SNRI antidepressants.

Classification Of Evidence: This study provides Class IV evidence that, for a subset of people with SPSD, autologous nonmyeloablative HSCT improves outcomes.

Clinicaltrialsgov Identifier: NCT02282514.
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http://dx.doi.org/10.1212/WNL.0000000000011338DOI Listing
February 2021

Health economics and patient outcomes of hematopoietic stem cell transplantation versus disease-modifying therapies for relapsing remitting multiple sclerosis in the United States of America.

Mult Scler Relat Disord 2020 Oct 17;45:102404. Epub 2020 Jul 17.

College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, United States.

Objective: To estimate differences in treatment costs and health outcomes between non-myeloablative hematopoietic stem cell transplantation (HSCT) and disease-modifying therapies (DMTs) for the treatment of relapsing-remitting multiple sclerosis (RRMS).

Methods: We collected data on costs and reimbursements for patients who underwent HSCT for RRMS at Northwestern Memorial Hospital in Chicago (USA) between January 2017 and January 2019. The costs of HSCT were compared against those for DMTs in the United States, obtained from the literature. We also conducted a literature review to interpret the cost comparisons in terms of disease control and patients' wellbeing defined as no evidence of disease activity (NEDA), neurologic disability by the Expanded Disability Status Scale (EDSS), and quality of life by the short form SF-36, respectively.

Results: Outside of the data, herein, no other studies on cost of HSCT for RRMS were found in the literature. HSCT mean total costs, based on our own hospital, were $85,184 (range $70,635 to $120,260). Mean revenue collected was $95,268 (range $16,544 to $173,204). In comparison, according to the literature, 2019 DMT costs in the USA ranged from $80,000 to $100,000 per year per patient. Compared to DMTs, studies of HSCT reported greater improvement in no evidence of disease activity, disability, and quality of life.

Limitations: Costs of HSCT would be expected to vary by conditioning regimen utilized, patient selection, center experience, and regional variation. No cost data on other HSCT regimens or on the three most recently licensed DMTs, alemtuzumab, ocrelizumab, and cladribine, are available. Randomized trials for cost comparisons are missing and variations in HSCT designs, populations, and methodology preclude more precise cost estimates.

Conclusion: Costs of non-myeloablative HSCT after which DMTs are indefinitely discontinued, are approximately the same cost as those for one year of prescription DMTs. Since DMTs assessed in this analysis are given on an ongoing basis, whilst HSCT is not, HSCT is expected to produce long-term cost-savings. When considered alongside the available clinical evidence, which suggests that HSCT may generate more health gains than DMTs, HSCT is likely to represent a cost-effective use of resources. Model-based health economic analyses are required to substantiate this conclusion.
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http://dx.doi.org/10.1016/j.msard.2020.102404DOI Listing
October 2020

Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days.

Bone Marrow Transplant 2021 01 1;56(1):50-59. Epub 2020 Jul 1.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

We compared three fludarabine-based regimens for systemic sclerosis patients with a high-risk cardiac phenotype that according to EBMT criteria would be a contraindication for a high-dose cyclophosphamide (200 mg/kg) transplant regimen. All three regimens included fludarabine, ATG, and cyclophosphamide (60 mg/kg), while two regimens also included rituximab with or without IVIG. Treatment related mortality (TRM) was 2.4%. The mean number of days of neutropenia (ANC < 500) was 5.2, the mean number of platelet and red blood cell transfusions was 0.3 and 1.85, respectively. Skin score, forced vital capacity (FVC), and total lung capacity (TLC) improved with all three regimens. For patients whose regimen did not include rituximab versus those that included rituximab, 1-year overall relapse rate was higher 36% (5/14) versus 3.6% (1 of 28) (p = 0.01), secondary autoimmune diseases were higher 21% (3/14) versus 0% (0/28) (p = 0.03), and upper respiratory tract infections were higher 28% (4/14) versus 3.6% (1/28) (p = 0.04). In this safety study, a fludarabine-based regimen was relatively safe with a TRM of 2.4% and a neutropenic interval of only 5.2 days in systemic sclerosis patients with a high-risk cardiac phenotype. The addition of rituximab decreased 1-year relapse rate, risk of late secondary autoimmune diseases, and upper-respiratory tract infections.
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http://dx.doi.org/10.1038/s41409-020-0978-2DOI Listing
January 2021

Hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyradiculoneuropathy.

J Neurol 2020 Nov 27;267(11):3378-3391. Epub 2020 Jun 27.

Academic Department of Neuroscience and Sheffield, NIHR Translational Neuroscience BRC, Sheffield Teaching Hospitals, NHS Foundation Trust, University of Sheffield, Sheffield, UK.

Objective: Determine toxicity and efficacy of autologous hematopoietic stem cell transplantation (HSCT) for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are dependent on intravenous immunoglobulins or plasmapheresis.

Methods: Unselected peripheral blood stem cells were re-infused on day 0 after conditioning with cyclophosphamide 200 mg/kg/intravenously (IV), rATG (thymoglobulin) 5.5 mg/kg/IV, and rituximab 1000 mg/IV.

Results: Sixty-six patients underwent HSCT for CIDP. Data on sixty patients with a mean follow-up of 4.5 years (range 2-5 years) were available for analysis. There were no treatment-related deaths, and overall survival was 97%. Post-transplant immune medication-free remission was 80%, 78%, 76% 78%, and 83% at 1, 2, 3, 4, and 5 years. Ambulation without assistance improved from 33% pre-HSCT to 82% 82%, 81%, 86%, and 83% at 1, 2, 3, 4, and 5 years, respectively. Mean right/left hand grip strength (kg) improved significantly (all p values < 0.01) from 18.1/16.5 pre-HSCT to 26.3/25.4, 29.2/28.2, 28.8/28.6, 30.3/25.5, and 30.8/29.1 at 1, 2, 3, 4, and 5 years, respectively. Average nerve conduction velocity (NCV) (m/s) improved significantly (all p values ≤ 0.001) from a mean of 27.2 pre-HSCT to 33.5, 33.8, 37.7, 38.2, and 38.3 at 1, 2, 3, 4, and 5 years, respectively. Average compound motor action potential (CMAP) (mv) improved significantly (p values ≤ 0.001) from a mean of 3.6 pre-HSCT to 4.6, 4.6, 5.0, 5.1, and 4.1 at 1, 2, 3, 4, and 5 years, respectively.

Conclusion: A randomized trial is indicated to verify these results and confirm that HSCT reverses disability and offers long-term immune therapy independence.
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http://dx.doi.org/10.1007/s00415-020-10010-6DOI Listing
November 2020

Field evaluation of spray drift and environmental impact using an agricultural unmanned aerial vehicle (UAV) sprayer.

Sci Total Environ 2020 Oct 29;737:139793. Epub 2020 May 29.

Shandong Provincial Engineering Technology Research Center for Agricultural Aviation Intelligent Equipment, College of Agricultural Engineering and Food Science, Shandong University of Technology, Zibo 255022, China; National Center for International Collaboration Research on Precision Agricultural Aviation Pesticides Spraying Technology (NPAAC), College of Electronic Engineering, South China Agricultural University, Guangzhou 510642, China; Department of Biological and Agricultural Engineering, Texas A&M University, College Station, TX 77845, USA. Electronic address:

Unmanned Aerial Vehicle (UAV) applications at low-volume using fine and very fine size droplets have been adopted in several commercial spray scenarios allowing water-saving and high-efficiency operation in delivery of pesticides. However, spray drift associated with UAV applications, especially for fine droplets generated from spinning disk nozzles, has not been fully understood, raising environmental and regulatory concerns. The objectives of this study were to compare the drift potential of three different volume median diameter (VMD, or Dv) of 100, 150 and 200 μm from a commercial quadcopter equipped with centrifugal nozzles exposed to different wind speeds under field conditions. Prior to field test, the droplet size of the centrifugal nozzle was measured by a laser-diffraction particle-size analyzer. The results showed that the relationship between rotation speed and Dv agrees with the negative power function. Field tests found that the deposition at 12 m downwind direction decreased by an order of magnitude compared with the average deposition within the in-swath zone. The deposition of almost all the treatments at 50 m downwind is lower than the detection limits of 0.0002 μL/cm. Based on the results from this study, the drift distance of this specific very popular UAV model is much less than that of manned aerial applicators. Based on the predicted equation (R = 0.83), the detected drift amount increased with increasing wind speed and decreasing Dv. This work provides basic information to quantify the effect of wind speeds and droplet sizes on UAV spray drift potential which supports on-going regulatory guideline development for spray buffer zone and drift risk assessment protocols.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139793DOI Listing
October 2020

A pilot feasibility study of non-myeloablative allogeneic hematopoietic stem cell transplantation for refractory Crohn Disease.

Bone Marrow Transplant 2020 12 28;55(12):2343-2346. Epub 2020 May 28.

Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

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http://dx.doi.org/10.1038/s41409-020-0953-yDOI Listing
December 2020

Autologous nonmyeloablative hematopoietic stem cell transplantation for neuromyelitis optica.

Neurology 2019 10 2;93(18):e1732-e1741. Epub 2019 Oct 2.

From the Division of Immunotherapy, Department of Medicine (R.K.B., X.H., C.B.), and Departments of Neurology (R.B.), Radiology (J.G.), and Preventive Medicine (B.J., I.H.), Northwestern University Feinberg School of Medicine, Chicago, IL; and the Departments of Neurology (J.J., S.J.P.) and Laboratory Medicine and Pathology (J.J., J.P.F., S.J.P.) and Center for Multiple Sclerosis and Autoimmune Neurology (S.J.P.), Mayo Clinic College of Medicine, Rochester, MN.

Objective: To determine if autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) could be a salvage therapy for neuromyelitis optica spectrum disorder (NMOSD).

Methods: Thirteen patients were enrolled in a prospective open-label cohort study (11 NMOSD aquaporin-4-immunoglobulin G [AQP4-IgG]-positive, 1 NMOSD without AQP4, and 1 NMOSD AQP4-IgG-positive with neuropsychiatric systemic lupus erythematosus [SLE]). Following stem cell mobilization with cyclophosphamide (2 g/m) and filgrastim, patients were treated with cyclophosphamide (200 mg/kg) divided as 50 mg/kg IV on day -5 to day -2, rATG (thymoglobulin) given IV at 0.5 mg/kg on day -5, 1 mg/kg on day -4, and 1.5 mg/kg on days -3, -2, and -1 (total dose 6 mg/kg), and rituximab 500 mg IV on days -6 and +1. Unselected peripheral blood stem cells were infused on day 0. AQP4-IgG antibody status was determined by Clinical Laboratory Improvement Amendments-validated ELISA or flow cytometry assays. Cell-killing activity was measured using a flow cytometry-based complement assay.

Results: Median follow-up was 57 months. The patient with coexistent SLE died of complications of active lupus 10 months after HSCT. For the 12 patients with NMOSD without other active coexisting autoimmune diseases, 11 patients are more than 5 years post-transplant, and 80% are relapse-free off all immunosuppression ( < 0.001). At 1 and 5 years after HSCT, Expanded Disability Status Scale score improved from a baseline mean of 4.4 to 3.3 ( < 0.01) at 5 years. The Neurologic Rating Scale score improved after HSCT from a baseline mean of 69.5 to 85.7 at 5 years ( < 0.01). The Short Form-36 health survey for quality of life total score improved from mean 34.2 to 62.1 ( = 0.001) at 5 years. In the 11 patients whose baseline AQP4-IgG serostatus was positive, 9 patients became seronegative by the immunofluorescence or cell-binding assays available at the time; complement activating and cell-killing ability of patient serum was switched off in 6 of 7 patients with before and after HSCT testing. Two patients remained AQP4-IgG-seropositive (with persistent complement activating and cell-killing ability) and relapsed within 2 years of HSCT. No patient with seronegative conversion relapsed.

Conclusion: Prolonged drug-free remission with AQP4-IgG seroconversion to negative following nonmyeloablative autologous HSCT warrants further investigation.
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http://dx.doi.org/10.1212/WNL.0000000000008394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946475PMC
October 2019

Clinical recovery after 5 level of posterior decompression spine surgeries in patients with cervical spondylotic myelopathy: A retrospective cohort study.

Asian J Surg 2020 May 31;43(5):613-624. Epub 2019 Aug 31.

Department of Outpatient, Ankang Hospital of Traditional Chinese Medicine, Ankang, Shaanxi, 725000, China. Electronic address:

Background/objective: The selection of surgical technique in patients with cervical spondylotic myelopathy relies on the surgeon(s) and patients' conditions. The objectives of the study were to test the hypotheses that French-door laminoplasty recovers faster than laminectomy and has good outcome measures.

Methods: Data regarding surgical, radiological, and clinical outcome measures of 330 patients with cervical spondylotic myelopathy operated under French-door laminoplasty (fdLP group, n = 110), open-door laminoplasty (odLP group, n = 110), or laminectomy (LC group, n = 110) were collected from the records of institute and analyzed.

Results: Patients of fdLP group (p < 0.0001, q = 11.65) and odLP group (p < 0.0001, q = 11.27) both had significantly improved modified Rankin scale score than those of LC group. In addition, patients of fdLP group had minimum blood loss during operations and that was maximum for patients of the LC group. Unlike patients of fdLP group (p < 0.0001, q = 80) and LC group (p < 0.0001, q =122), those of odLP group had lost more amount of cervical lordotic after surgery. Open-door laminoplasty had significantly reduced cervical range of motion than laminectomy (p < 0.0001, q = 15.45) and French-door laminoplasty (p < 0.0001, q = 13.45). After 12-months, fdLP group had higher bone union rate than odLP group (p = 0.007, q = 3.395) and LC group (p = 0.007, q = 4.243). French door laminoplasty had a better postoperative quality of life.

Conclusions: Among the posterior decompression spine surgeries, French-door laminoplasty is superior surgical procedure than laminectomy and could be superior surgical technique than open-door laminoplasty.
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http://dx.doi.org/10.1016/j.asjsur.2019.08.003DOI Listing
May 2020

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

JAMA 2019 01;321(2):165-174

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Importance: Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).

Objective: To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.

Design, Setting, And Participants: Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.

Interventions: Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).

Main Outcomes And Measures: The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios.

Results: Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, -1.7; 95% CI, -2.03 to -1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).

Conclusions And Relevance: In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

Trial Registration: ClinicalTrials.gov Identifier: NCT00273364.
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http://dx.doi.org/10.1001/jama.2018.18743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439765PMC
January 2019

Compressive properties and constitutive modeling of different regions of 8-week-old pediatric porcine brain under large strain and wide strain rates.

J Mech Behav Biomed Mater 2019 01 10;89:122-131. Epub 2018 Sep 10.

School of Mechanical, Electronic and Control Engineering, Beijing Jiaotong University, Beijing 100044, China.

Porcine head is often used as a human surrogate in traumatic head injury research. Extensive research on mechanical properties of adult human/porcine brain tissues has been performed previously; however, very limited data is available for children, which is particular important for modeling the pediatric traumatic brain injury (TBI). In this study, uniaxial compression tests at strain rates of 0.01/s, 1/s and 50/s up to 50% strain were performed for the corona radiata, corpus callosum, thalamus, cortex, cerebellum and brainstem of 8-week-old piglets. No significant difference in tissue strength was found among the cerebrum regions of cortex, thalamus, corona radiata and corpus callosum. The average stress of cerebellum was approximate 21% and 15% higher than that of cerebrum at a strain of 0.25 and 0.5, respectively, but it did not reach statistical significant level than most of the cerebrum regions. Brainstem was the stiffest among these 6 regions, and it was significant stiffer than most regions of cerebrum, with average stress of about 28% and 40% higher at a strain of 0.25 and 0.5, respectively. The strengths of all these three regions showed significant strain-rate dependent characteristics, with the strain rate increasing from 0.01/s to 50/s, the average stress of cerebrum, cerebellum and brainstem increased to approximate 4.6, 6.3 and 6.3 times, respectively at a strain of 0.25; and increased to approximate 1.9, 2.6, and 2.5 times, respectively at a strain of 0.5. One-term Ogden model was used to fit the experimental data to obtain the material parameters and numerical simulation was performed on the compression of cerebrum specimen. Results show that the constitutive model and the calibrated parameters can well represent the compressive behavior of the brain tissue at different strain rates. The results of this study are useful for developing biofidelic pediatric brain FE models and further predict the brain injuries under impact conditions.
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http://dx.doi.org/10.1016/j.jmbbm.2018.09.010DOI Listing
January 2019

Construction of a Statistical Cervical Vertebrae Geometric Model for Children 3-10 Years Old.

Ann Biomed Eng 2018 Nov 19;46(11):1816-1829. Epub 2018 Jun 19.

HanDan Central Hospital, Handan, 056001, China.

Cervical spinal injuries of children in motor vehicle crashes have high morbidity and mortality rates. Cervical vertebrae change rapidly in both size and shape during growth. To accurately assess the risk of spinal injury for children of different ages, it is necessary to understand how the spatial geometric features of vertebrae change with the child's age and neck size. In this study, an innovative semi-automated method was developed that can extract and align geometric points from computed tomography scans to accurately represent complex three-dimensional vertebral geometry. Based on these spatial geometric points, a statistical cervical vertebrae geometry model for children aged 3-10 YO was established based on principal component analysis and multivariate regression. According to this model, the vertebra spatial geometries for children of different ages and neck circumferences were represented, and its variation with age were accounted for. Statistical results show that age has a significant effect on anterior-posterior length (APL), transverse process width (TPW), vertebral body circumference (VBC) and height (VBH), whereas the significance of location and its interaction with age effects on these four parameters are different. The VBC and VBH increase more rapidly with age than the APL and TPW. In addition, the APL of C6 and C7 increase significantly faster than that of C3. As for the shape changes with child growth, the inclination angle of the upper surface of the lateral mass for C1 and the tilt angle of the articular process of the articular facet joint for C3-7 increase; and the shape of odontoid process of C2 becomes higher and steeper. This study can provide geometric basis for developing multiple pediatric cervical finite element models and anthropomorphic test devices to further quantify child neck injury risk with different ages and neck geometries.
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http://dx.doi.org/10.1007/s10439-018-2071-1DOI Listing
November 2018

Synthesis, Insecticidal, Fungicidal Activities and Structure⁻Activity Relationships of Tschimganin Analogs.

Molecules 2018 06 18;23(6). Epub 2018 Jun 18.

State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Sinochem Agrochemicals R&D Co., Ltd., No. 8-1 Shenliao Dong Road, Tiexi District, Shenyang 110021, China.

For the first time, a novel series of tschimganin analogs were designed, synthesized, and evaluated for their insecticidal and fungicidal activities. Their structures were characterized by ¹H-NMR, C-NMR and HRMS. Some of these compounds displayed excellent insecticidal and fungicidal activities, suggesting that they have potential to be used as bifunctional agrochemicals. Compound and with electron donating groups showed better inhibitory activity and growth inhibition activity towards (Hübner). The properties and positions of the substituents on the benzene ring have an important influence on the acaricidal activity of tschimganin analogs. Topomer comparative molecular field analysis (CoMFA) was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds against Ugarov et Nikolski. It was indicated that higher electronegativity was beneficial for acaricidal activity. Moreover, compound having a 2-hydroxy-3,5- dinitrophenyl moiety displayed a fungicidal spectrum as broad as azoxystrobin against these phytopathogens.
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http://dx.doi.org/10.3390/molecules23061473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099738PMC
June 2018

Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome.

Bone Marrow Transplant 2018 06 31;53(6):692-700. Epub 2018 May 31.

Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.

Some patients with systemic lupus erythematosus (SLE) are refractory to traditional therapies, dependent on chronic corticosteroids, have organ damage, and are at high risk of mortality. In this group of patients, we report outcome at a median of five years after autologous hematopoietic stem cell transplant (HSCT) using two different non-myeloablative regimens. Four patients received a conditioning regimen of cyclophosphamide (200 mg/kg) and alemtuzumab (60 mg), while 26 patients underwent conditioning with cyclophosphamide (200 mg/kg), rATG (Thymoglobulin) (5.5 mg/kg), and rituximab 1000 mg. Unselected peripheral blood stem cells were infused on day 0. There were no treatment related deaths. Of the four patients treated with cyclophosphamide and alemtuzumab, none entered remission. For the 26 patients treated with cyclophosphamide, rATG, and rituximab, disease remission defined as no immune suppressive drugs except hydroxychloroquine and/or 10 mg or less of prednisone a day was 92% at 6 months, 92% at one year, 81% at 2 years, 71% at 3 years, and 62% at 4 and 5 years post-HSCT. Autologous HSCT outcome is dependent on the conditioning regimen but prior organ damage may cause lingering symptoms.
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http://dx.doi.org/10.1038/s41409-018-0173-xDOI Listing
June 2018

Synthesis and Biological Activity of 2',3'-iso-Aryl-abscisic Acid Analogs.

Molecules 2017 Dec 15;22(12). Epub 2017 Dec 15.

College of Science, China Agricultural University, Beijing 100193, China.

2',3'--Benzoabscisic acid (-PhABA), an excellent selective abscisic acid (ABA) analog, was developed in our previous work. In order to find its more structure-activity information, some structural modifications were completed in this paper, including the substitution of phenyl ring and replacing the ring with heterocycles. Thus, 16 novel analogs of -PhABA were synthesized and screened with three bioassays, Arabidopsis and lettuce seed germination and rice seedling elongation. Some of them, i.e., 2',3'--pyridoabscisic acid (-PyABA) and 2',3'--franoabscisic acid (-FrABA), displayed good bioactivities that closed to -PhABA and natural (+)-ABA. Some others, for instance, substituted--PhABA, exhibited certain selectivity to different physiological process when compared to -PhABA or (+)-ABA. These analogs not only provided new candidates of ABA-like synthetic plant growth regulators (PGRs) for practical application, but also new potential selective agonist/antagonist for probing the specific function of ABA receptors.
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http://dx.doi.org/10.3390/molecules22122229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149786PMC
December 2017

Recent Advances on Bioactive Constituents in Ferula.

Drug Dev Res 2017 11 8;78(7):321-331. Epub 2017 Aug 8.

Key Laboratory at Universities of Xinjiang Uygur Autonomous Region for Oasis Agricultural Pest Management and Plant Protection Resource Utilization, College of Agricultural, Shihezi University, Shihezi, 832002, China.

Preclinical Research The genus Ferula (Umbelliferea) is widely distributed across Central Asia and the Mediterranean. Some plants of the genus Ferula have been used as sources of pharmaceuticals for centuries. Ferula is a rich source of biologically active compounds, including coumarin derivatives, sesquiterpene-substituted compounds, daucane esters, humulane, and germacrane compounds, aromatic lactones and disulfide compounds. Therefore, utilizing these bioactive constituents with antimicrobial and insecticidal effects not only can provide a new strategy for developing drug and green pesticide, but also protect endangered plant resources. In the present review, research advances on the bioactive constituents of the genus Ferula the plant sources. Drug Dev Res 78 : 321-331, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ddr.21402DOI Listing
November 2017

Design and Functional Characterization of a Novel Abscisic Acid Analog.

Sci Rep 2017 03 8;7:43863. Epub 2017 Mar 8.

College of Science, China Agricultural University, Beijing, 100193, China.

The phytohormone abscisic acid (ABA) plays a crucial role in mediating plant growth and development by recruiting genetically redundant ABA receptors. To overcome its oxidation inactivation, we developed a novel ABA analog named 2',3'-benzo-iso-ABA (iso-PhABA) and studied its function and structural characterization with A. thaliana ABA receptors. The (+)-iso-PhABA form showed much higher ABA-like activities than (+)-ABA including inhibitory effects on the seed germination of lettuce and A. thaliana, wheat embryo germination and rice seedling elongation. The PP2C (protein phosphatases 2C) activity assay showed that (+)-iso-PhABA acted as a potent and selective ABA receptor agonist, which is preferred to PYL10. In some cases, (-)-iso-PhABA showed moderate to high activity for the PYL protein inhibiting PP2C activity, suggesting different mechanisms of action of iso-PhABA and ABA. The complex crystal structure of iso-PhABA with PYL10 was determined and elucidated successfully, revealing that (+)-iso-PhABA was better coordinated in the same binding pocket compared to (+)-ABA. Moreover, the detailed interaction network of iso-PhABA/PYL10 was disclosed and involves hydrogen bonds and multiple hydrophobic interactions that provide a robust framework for the design of novel ABA receptor agonists/antagonists.
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http://dx.doi.org/10.1038/srep43863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341028PMC
March 2017

Synthesis and fungicidal activity of 1,1-diaryl tertiary alcohols.

Bioorg Med Chem Lett 2016 12 1;26(24):5936-5942. Epub 2016 Nov 1.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. Electronic address:

A series of 1,1-diaryl tertiary alcohols and some of their dehydration derivatives were designed, synthesized and evaluated for their antifungal activities. Some compounds exhibited moderate inhibitory activities against seven plant pathogens at 50μg/mL in vitro, compounds 5g and 7c displayed nearly the same or higher fungicidal activities against some certain plant pathogens compared with the lead compound pyrimorph. A qualitative structure-activity relationship (SAR) analysis revealed that the Cl substituent and its position at the pyridine ring were crucial for the compounds' activities. Specially, several compounds displayed 100% protection effect against wheat powdery mildew or cucumber anthrax at 400mg/mL in vivo, which suggested that these compounds might be potential fungicidal candidates for certain plant diseases.
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http://dx.doi.org/10.1016/j.bmcl.2016.10.090DOI Listing
December 2016

A semi-automatic method of generating subject-specific pediatric head finite element models for impact dynamic responses to head injury.

J Mech Behav Biomed Mater 2016 07 25;60:557-567. Epub 2016 Mar 25.

State Key Laboratory of Automotive Safety and Energy, Tsinghua University, Beijing 100084, PR China.

To account for the effects of head realistic morphological feature variation on the impact dynamic responses to head injury, it is necessary to develop multiple subject-specific pediatric head finite element (FE) models based on computed tomography (CT) or magnetic resonance imaging (MRI) scans. However, traditional manual model development is very time-consuming. In this study, a new automatic method was developed to extract anatomical points from pediatric head CT scans to represent pediatric head morphological features (head size/shape, skull thickness, and suture/fontanel width). Subsequently, a geometry-adaptive mesh morphing method based on radial basis function was developed that can automatically morph a baseline pediatric head FE model into target FE models with geometries corresponding to the extracted head morphological features. In the end, five subject-specific head FE models of approximately 6-month-old (6MO) were automatically generated using the developed method. These validated models were employed to investigate differences in the head dynamic responses among subjects with different head morphologies. The results show that variations in head morphological features have a relatively large effect on pediatric head dynamic response. The results of this study indicate that pediatric head morphological variation had better be taken into account when reconstructing pediatric head injury due to traffic/fall accidents or child abuses using computational models as well as predicting head injury risk for children with obvious difference in head size and morphologies.
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http://dx.doi.org/10.1016/j.jmbbm.2016.03.021DOI Listing
July 2016

Preparative separation of gallocatechin gallate from Camellia ptilophylla using macroporous resins followed by sephadex LH-20 column chromatography.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Feb 24;1011:6-13. Epub 2015 Dec 24.

Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Hong Kong, China; CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. Electronic address:

Gallocatechin gallate (GCG) possesses multiple potential biological activities. However, the content of GCG in traditional green tea is too low which limits its in-depth pharmacological research and application. In the present study, a simple, efficient and environment-friendly chromatographic separation method was developed for preparative enrichment and separation of GCG from cocoa tea (Camellia ptilophylla) which contains high content of GCG. In the first step, the adsorption properties of selected resins were evaluated, and XAD-7HP resin was chosen by its adsorption and desorption properties for GCG. In order to maximize column efficiency for GCG collection, the operating parameters (e.g., flow rate, ethanol concentration, and bed height) were optimized. We found that the best combination was the feed concentration at 20mg/mL, flow rate at 0.75 BV/h and the ratio of diameter to bed heights as 1:12. Under these conditions, the purity of GCG was 45% with a recovery of 89%. In order to obtain pure target, a second step was established using column chromatography with sephadex LH-20 gel and 55% ethanol-water solution as eluent. After this step, the purity of the GCG was 91% with a recovery of 68% finally.
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http://dx.doi.org/10.1016/j.jchromb.2015.12.039DOI Listing
February 2016

Synthesis, resolution and biological evaluation of cyclopropyl analogs of abscisic acid.

Bioorg Med Chem 2015 Sep 26;23(18):6210-7. Epub 2015 Jul 26.

Department of Applied Chemistry, China Agricultural University, Beijing 100193, China. Electronic address:

cis-2,3-Cyclopropanated abscisic acid (cis-CpABA) has high photostability and good ABA-like activity. To further investigate its activity and action mechanism, 2S,3S-2,3-cyclopropanated ABA (3a) and 2R,3R-2,3-cyclopropanated ABA (3b) were synthesized. Bioassay showed that 3a displayed higher inhibitory activity in germination than that of 3b and ABA at the concentration of 3.0 μM, but 3a and 3b had much weaker inhibitory activity in inhibition seedling growth compared to ABA. The study of photostability revealed that 3a and 3b showed high stability under UV light exposure, which were 4 times and 3 times greater than (±)-ABA, respectively. Action mechanism study showed that 3a presented higher inhibition on phosphatase activity of HAB1 than 3b, although they all inferior to ABA. Molecular docking studies of 3a, 3b and ABA receptor PYL10 were agreement with the bioassay data and confirmed the importance of the configuration of the 2,3-cyclopropyl ABA analogs for their bioactivity in somewhat. This study provides a new approach for the design of ABA analogs, and the results validated structure-based design for this target class.
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http://dx.doi.org/10.1016/j.bmc.2015.07.042DOI Listing
September 2015

Synthesis and bioactivity of 2',3'-benzoabscisic acid analogs.

Bioorg Med Chem Lett 2015 Jun 31;25(11):2438-41. Epub 2015 Mar 31.

Department of Applied Chemistry, China Agricultural University, Beijing 100193,China. Electronic address:

2',3'-Benzoabscisic acid 4a is significantly more active than (±)-ABA and can be potentially used as a plant growth regulator for agriculture. In this study, six 4a analogs were designed and synthesized. Bioassay showed that 4a displayed greater activity than (±)-ABA and the six analogs produced less inhibition than 4a itself. Specially, some analogs displayed markedly different activities to different physiological and biochemical process, which were largely different from ABA and 4a. Compared to (±)-ABA, 4b and 4c were more effective germination inhibitors for lettuce, but less effective inhibitors for rice elongation. Five-membered analog 5 was higher or slightly weaker in inhibiting Arabidopsis seed germination and rice elongation, respectively, but at least 10 times less effective than (±)-ABA in lettuce seed germination. Dual acid 6 and alkyne acid 20 nearly produced no inhibitory activity for Arabidopsis seed germination, but displayed excellent activity in inhibiting rice seedling growth. The preference of the analogs to different physiology process indicated that they might provide a strategy to develop novel ABA agonists or antagonist and be used as probe to investigate the function of different ABA receptors.
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http://dx.doi.org/10.1016/j.bmcl.2015.03.071DOI Listing
June 2015

Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis.

JAMA 2015 Jan;313(3):275-84

Department of Neuroscience and Neurology, Uppsala University, Uppsala, Sweden.

Importance: No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability.

Objective: To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS.

Design, Setting, And Participants: Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014.

Interventions: Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells.

Main Outcomes And Measures: Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan.

Results: Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128).

Conclusions And Relevance: Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.
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http://dx.doi.org/10.1001/jama.2014.17986DOI Listing
January 2015

Synthesis, photostability and bioactivity of 2,3-cyclopropanated abscisic acid.

Phytochemistry 2013 Dec 5;96:72-80. Epub 2013 Nov 5.

College of Science, China Agricultural University, Beijing 100193, China.

The plant hormone abscisic acid (ABA) plays a central role in the regulation of plant development and adaptation to environmental stress. The isomerization of ABA to the biologically inactive 2E-isomer by light considerably limits its applications in agricultural fields. To overcome this shortcoming, an ABA analogue, cis-2,3-cyclopropanated ABA, was synthesized, and its photostability and biological activities were investigated. This compound showed high photostability under UV light exposure, which was 4-fold higher than that of (±)-ABA. cis-2,3-cyclopropanated ABA exhibited high ABA-like activity, including the ability to effectively inhibit seed germination, seedling growth and stomatal movements of Arabidopsis. In some cases, its bioactivity approaches that of (±)-ABA. trans-2,3-cyclopropanated abscisic acid was also prepared, an isomer that was more photostable but which showed weak ABA-like activity.
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http://dx.doi.org/10.1016/j.phytochem.2013.09.029DOI Listing
December 2013

A highly efficient regioselective addition of acetylides to enediones based on steric effects.

Molecules 2013 Sep 3;18(9):10776-88. Epub 2013 Sep 3.

Department of Applied Chemistry, China Agricultural University, 2 West Yuanmingyuan West Road, Beijing 100193, China.

A simple and efficient strategy for the synthesis of 1-ethynylcyclohex-2-enol derivatives was developed utilizing regioselective addition of acetylides to enediones based on steric effects. Further investigation of the substrate scope of enediones indicated that all the addition reactions ocurred in good yield.
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http://dx.doi.org/10.3390/molecules180910776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270633PMC
September 2013

Enhanced efferocytosis of apoptotic cardiomyocytes through myeloid-epithelial-reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction.

Circ Res 2013 Sep 8;113(8):1004-12. Epub 2013 Jul 8.

From the Department of Pathology, Microbiology and Immunology, Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Rationale: Efficient clearance of apoptotic cells (efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function.

Objective: We set out to identify mechanisms of dying cardiomyocyte engulfment by phagocytes and, for the first time, to assess the causal significance of disrupting efferocytosis during myocardial infarction.

Methods And Results: In contrast to other apoptotic cell receptors, macrophage myeloid-epithelial-reproductive tyrosine kinase was necessary and sufficient for efferocytosis of cardiomyocytes ex vivo. In mice, Mertk was specifically induced in Ly6c(LO) myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic cardiomyocytes, independently of changes in noncardiomyocytes, and a reduced index of in vivo efferocytosis. Importantly, suppressed efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk; reciprocal transplantation of Mertk(+/+) marrow into Mertk(-/-) mice corrected systolic dysfunction. Interestingly, an inactivated form of myeloid-epithelial-reproductive tyrosine kinase, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of myeloid-epithelial-reproductive tyrosine kinase inactivation after myocardial infarction.

Conclusions: These data collectively and directly link efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.
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http://dx.doi.org/10.1161/CIRCRESAHA.113.301198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840464PMC
September 2013

Cardiac involvement and treatment-related mortality after non-myeloablative haemopoietic stem-cell transplantation with unselected autologous peripheral blood for patients with systemic sclerosis: a retrospective analysis.

Lancet 2013 Mar 28;381(9872):1116-24. Epub 2013 Jan 28.

Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Background: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group.

Methods: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests.

Findings: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05).

Interpretation: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated.

Funding: None.
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http://dx.doi.org/10.1016/S0140-6736(12)62114-XDOI Listing
March 2013

Mitotically inactivated embryonic stem cells can be used as an in vivo feeder layer to nurse damaged myocardium after acute myocardial infarction: a preclinical study.

Circ Res 2012 Oct 22;111(10):1286-96. Epub 2012 Aug 22.

Division of Immunotherapy, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA.

Rationale: Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown.

Objective: To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences.

Methods And Results: After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 5-bromo-2'-deoxyuridine assays revealed de novo in vivo cardiomyocyte DNA synthesis. Microarray gene expression profiling demonstrated an early increase in metabolism, DNA proliferation, and chromatin remodeling pathways, and a decrease in fibrosis and inflammatory gene expression compared with media-treated controls.

Conclusions: As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.
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http://dx.doi.org/10.1161/CIRCRESAHA.111.262584DOI Listing
October 2012
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