Immune modulation has been recognized as an effective anti-osteoporosis strategy since the pivotal role of the RANK/RANKL/OPG signaling in bone metabolism and remodeling was discovered. To investigate the potential preventive and/or therapeutic effects of immune modulator protein Ling Zhi-8(LZ-8) on osteoporosis, the osteoporosis animal model was established in Wistar rats by intramuscular injection of dexamethasone (DEX), namely glucocorticoids induced osteoporosis (GIOP) rats model. To investigate the potential preventive effect of rLZ-8 on GIOP, we co-treated the rats with DEX and rLZ-8 intraperitoneally during the GIOP modeling stage and analyze the bone mass measured by bone mineral content (BMC) and bone mineral density (BMD), as well as levels of phosphorus (Pi), calcium (Ca2+) and hydroxyproline (HOP) in femur of GIOP rats. Consistently, all results suggested that rLZ-8 could prevent bone loss in the femurs of GIOP rats. Through analyzing the trabeculae morphology and the trabeculae amount by H&E staining, we found rLZ-8 could also improve the structural deterioration in femurs of GIOP rats. In order to further verify the results and its mechanism obtained from bone analysis, multiple biomarkers, including minerals metabolism (Pi and Ca2+), bone formation markers (osteocalcin, ALP and IGF-1), bone resorption markers (TRACP5b, CTX-1 and HOP), cytokines (IL-1β, IL-6 and TNF-ɑ), oxidative stress indicators (GSH-px, SOD and MDA) and hormone molecules (testosterone, estradiol, calcitonin and parathyroid hormone) have been detected in serum or urine of rats. Results of these biomarkers in serum or urine confirmed rLZ-8's protective effect in GIOP. Through analyzing the relative expression level of OPG and RANKL in femurs via western blot, we foundrLZ-8 could increase OPG/RANKL ratio which could imped osteoclastogenesis process. To test the potential therapeutic effect of rLZ-8 on successfully generated GIOP rats, we administrated rLZ-8 to rats for three weeks starting from the ending day of 7 weeks treatment of DEX. We found rLZ-8 could also reverse the bone loss in GIOP rats. Through the BWs and organ coefficient analysis, we found rLZ-8 has little toxicity to the rats Our results suggested that rLZ-8 may be developed into promising anti-osteoporosis drug with both preventive and therapeutic properties.
Abstract Background The virulent class I Newcastle disease virus (NDV) variant 9a5b was generated from a nonvirulent NDV isolate Goose/Alaska/415/91 via nine consecutive passages in the chicken air sac, followed by five passages in the chick brain. The evolutionary mechanism of virulence in the class I NDV isolate is not fully understood. To elucidate this evolutionary mechanism, a reverse genetics manipulation specific for class I NDV is indispensable. Results A full-length cDNA clone of 9a5b and the helper plasmids pCI-NP, pCI-P, and pCI-L were constructed from segments of cDNA. After these plasmids were co-transfected into BSR T7/5 cells, infectious viral particles were obtained. The rescued viruses were genetically and biologically identical to the parental strain and showed similar pathogenicity in chickens. Conclusion A stable recovery method for class I NDV was established. Reverse genetics of the class I NDV variant 9a5b allowed for the generation of genetically altered and virulent NDV, and can be used as a foundation for research on the evolution of virulence in class I NDV isolates.
Objective
To evaluate the effectiveness of quantitative midbrain measurements in differentiating progressive supranuclear palsy (PSP) from multiple system atrophy (MSA) and Parkinson′s disease (PD).
Methods
Quantitative midbrain measurements, including midbrain width (MW), midbrain to pons ratio (M/P) and magnetic resonance parkinsonism index (MRPI), were performed in patients with parkinsonism who were diagnosed in the Movement Disorder Clinic of Peking Union Medical College Hospital during the period of January to September 2017. A cross-sectional study was conducted in the series to evaluate the effectiveness of these quantitative measurements.
Results
Ten PSP-RS, 15 MSA-P and 49 PD patients were included in this study. The values of MW, M/P and MRPI in PSP-RS patients were (8.21±1.30) mm, 0.49±0.06 and 15.26±4.53, respectively, with statistically significant difference compared to MSA-P ((10.24±0.77) mm, 0.65±0.09, 7.75±2.71) and PD patients ((10.53±0.93) mm, 0.62±0.06, 9.86±2.46; F=24.27, 18.37, 21.47, all P 10.77 showed ideal sensitivity and specificity (90.0% and 92.1%, 80.0% and 93.7%, 100.0% and 82.5%) in differentiating PSP-RS from MSA-P and PD.
Conclusion
Quantitative measurement of midbrain atrophy is useful in differentiating PSP-RS from MSA-P and PD.
Key words:
Supranuclear palsy, progressive; Magnetic resonance imaging; Mesencephalon; Diagnosis, differential
Introduction: Deep brain stimulation (DBS) is an effective therapy for resting tremor in Parkinson's disease (PD). However, quick and objective biomarkers for quantifying the efficacy of DBS intraoperatively are lacking. Therefore, we aimed to study how DBS modulates the intraoperative neuromuscular pattern of resting tremor in PD patients and to find predictive surface electromyography (sEMG) biomarkers for quantifying the intraoperative efficacy of DBS. Methods: Intraoperative sEMG of 39 PD patients with resting tremor was measured with the DBS on and off, respectively, during the intraoperative DBS testing stage. Twelve signal features (time and frequency domains) were extracted from the intraoperative sEMG data. These sEMG features were associated with the clinical outcome to evaluate the efficacy of intraoperative DBS. Also, an sEMG-based prediction model was established to predict the clinical improvement rate (IR) of resting tremor with DBS therapy. Results: A typical resting tremor with a peak frequency of 4.93 ± 0.98 Hz (mean ± SD) was measured. Compared to the baseline, DBS modulated significant neuromuscular pattern changes in most features except for the peak frequency, by decreasing the motor unit firing rate, amplitude, or power and by changing the regularity pattern. Three sEMG features were detected with significant associations with the clinical improvement rate (IR) of the tremor scale: peak frequency power (R = 0.37, p = 0.03), weighted root mean square (R = 0.42, p = 0.01), and modified mean amplitude power (R = 0.48, p = 0.003). These were adopted to train a Gaussian process regression model with a leave-one-out cross-validation procedure. The prediction values from the trained sEMG prediction model (1,000 permutations, p = 0.003) showed a good correlation (r = 0.47, p = 0.0043) with the true IR of the tremor scale. Conclusion: DBS acutely modulated the intraoperative resting tremor, mainly by suppressing the amplitude and motor unit firing rate and by changing the regularity pattern, but not by modifying the frequency pattern. Three features showed strong robustness and could be used as quick intraoperative biomarkers to quantify and predict the efficacy of DBS in PD patients with resting tremor.
Oculopharyngodistal myopathy (OPDM) is an autosomal dominant adult-onset degenerative muscle disorder characterized by ptosis, ophthalmoplegia and weakness of the facial, pharyngeal and limb muscles. Trinucleotide repeat expansions in non-coding regions of LRP12, G1PC1, NOTCH2NLC and RILPL1 were reported to be the etiologies for OPDM.In this study, we performed long-read whole-genome sequencing in a large five-generation family of 156 individuals, including 21 patients diagnosed with typical OPDM. We identified CGG repeat expansions in 5'UTR of RILPL1 gene in all patients we tested while no CGG expansion in unaffected family members. Repeat-primed PCR and fluorescence amplicon length analysis PCR were further confirmed the segregation of CGG expansions in other family members and 1000 normal Chinese controls. Methylation analysis indicated that methylation levels of the RILPL1 gene were unaltered in OPDM patients, which was consistent with previous studies. Our findings provide evidence that RILPL1 is associated OPDM in this large pedigree.Our results identified RILPL1 is the associated the disease in this large pedigree.
Corticospinal tract impairment is no longer an absolute exclusion in the updated Movement Disorder Society Parkinson's disease criteria. Triple stimulation technique (TST) is an accurate method to quantitatively assess the integrity and impairment of corticospinal pathway in a variety of neurological diseases. This study aims to evaluate the corticospinal tract impairment in Parkinson's disease (PD) patients using TST.Ten PD patients, 19 multiple-system atrophy parkinsonian variant (MSA-P) patients, and 12 healthy controls (HC) were sequentially recruited in this study. Information of age, disease duration, pyramidal signs, and Hoehn and Yahr (H&Y) stage was obtained from all patients. The TST was assessed at right abductor digiti minimi for HCs and both sides for patients. The Chi-square test was used for categorical variables, and variance analysis was performed for continuous variables in comparing the difference among PD, MSA-P, and HC, plus the post hoc tests for pairwise comparisons.All subjects were age and gender matched. There was no significant difference in disease duration (p = 0.855), H-Y stage (p = 0.067), and the percentage of pyramidal signs present (p = 0.581) between MSA-P and PD patients. The mean TST ratio was 55.5 ± 32.2%, 81.7 ± 19.8%, and 96.8 ± 3.0% for PD, MSA-P, and HCs, correspondingly. PD patients had a significant lower TST amplitude ratio than MSA-P and HCs. The TST ratio of MSA-P was lower than HCs, but there was no significant difference (p = 0.160). Additionally, it was significantly higher in percentage of abnormal TST ratio between PD patients and MSA-P (p = 0.010).Corticospinal tract impairment is not a rare manifestation in PD and can be quantitatively evaluated with TST. The result needs to be verified in amplified sample.
Cell division regulators play a vital role in neural progenitor cell (NPC) proliferation and differentiation. Cell division cycle 25C (CDC25C) is a member of the CDC25 family of phosphatases which positively regulate cell division by activating cyclin-dependent protein kinases (CDKs). However, mice with the Cdc25c gene knocked out were shown to be viable and lacked the apparent phenotype due to genetic compensation by Cdc25a and/or Cdc25b. Here, we investigate the function of Cdc25c in developing rat brains by knocking down Cdc25c in NPCs using in utero electroporation. Our results indicate that Cdc25c plays an essential role in maintaining the proliferative state of NPCs during cortical development. The knockdown of Cdc25c causes early cell cycle exit and the premature differentiation of NPCs. Our study uncovers a novel role of CDC25C in NPC division and cell fate determination. In addition, our study presents a functional approach to studying the role of genes, which elicit genetic compensation with knockout, in cortical neurogenesis by knocking down in vivo.
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