The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

TSH RECEPTOR GENETIC ALTERATIONS IN THE AUTONOMOUSLY FUNCTIONING THYROID ADENOMAS

Objective To determine the relationship between TSH receptor gene mutations and autonomously functioning thyroid adenomas (AFTAs). Methods The thyroid samples from 14 cases of diagnosed AFTAs were analyzed, with normal thyroid specimens adjacent to the tumors as controls. The 155 base pairs DNA fragments which encompassed the third cytoplasmic loop and the sixth transmembrane segments in the TSH receptor gene exon 10 were amplified by Polymerase chain reaction (PCR) and analyzed by the single-strand conformation polymorphism (SSCP). Direct sequencing of the PCR products was performed with Prism Dye Terminator Cycle Sequencing Core Kit. Results 6 of 14 AFTA specimens displayed abnormal migration in SSCP analysis. In sequence analysis of 3 abnormally migrated samples, one base substitution at nucleotide 1957 (A to C) and two same insertion mutations of one adenosine nucleotide between nucleotide 1972 and 1973 were identified. No mutations were found in controls. Conclusion This study confirmed the presence of TSH receptor gene mutations in AFTAs; both one-point substitution mutation and one-base insertion mutation were found to be responsible for the pathogenesis of AFTAs.

Short-term exposure to ambient ozone associated with cardiac arrhythmias in healthy adults

Objective The exact biological mechanism whereby exposure to ambient ozone(O3)may contribute to clinical onset of cardiovascular events remains unclear.In this study,we aim to examine the impacts of O3 exposure on cardiac arrhythmias and potential pathways involved through autonomic dysfunction and myocardial injury.Methods Seventy-three non-smoking healthy adults were followed with 4 repeated measurements of 24-hour ambulatory arrhythmias,heart rate variability,ST-segment deviation,and blood pressure(BP)in Beijing,China,2014‒2016.Generalized additive mixed models coupled with distributed lag nonlinear models were constructed to evaluate the associations and potential interlinks between O3 exposure and outcome measurements.Results During the study period,24-hour average concentrations of ambient O3 were 47.4µg/m3(ranging from 1.0 to 165.9µg/m3).Increased risks of premature ventricular contraction and ventricular tachycardia were associated with interquartile range increases in O3 exposure during the last 5 days before each participant's clinic visit,with relative risks of 2.14(95%confidence interval[CI]:1.95 to 2.32)and 5.47(95%CI:3.51 to 7.43),respectively.Mediation analyses further showed that sympathetic activation,parasympathetic inhibition,and elevated BP levels,as well as heightened risks of ST-segment depression could mediate up to 47.74%of the risks of arrhythmias attributable to O3 exposure.Conclusion Our results suggest that short-term exposure to ambient O3 could prompt the genesis of arrhythmias partially through worsening autonomic function and myocardial burden.

Sympathetic skin response in patients with myasthenia gravis: A comparative analysis

BACKGROUND： The examination of sympathetic skin response is an important index for assessing the autonomic nerve function, and patients with myasthenia gravis are always accompanied by dysautonomia. Therefore, it will be important to know whether sympathetic skin response can be used as the index for the clinical evaluation of myasthenia gravis. OBJECTIVE： To investigate the diagnostic value of sympathetic skin response in the damage of autonomic nerve function of patients with myasthenia gravis. DESIGN： A case-controlled comparative observation. SETTING： Department of Neurology and Room of Nerve Electromyogram, the Affiliated Hospital of North Sichuan Medical College. PARTICIPANTS： Thirty outpatients or inpatients with myasthenia gravis were selected from the Department of Neurology, the Affiliated Hospital of North Sichuan Medical College from May 2006 to May 2007, including 9 males and 21 females, aged 8 - 72 years with a mean age of （28 ± 5） years old. They were all accorded with the diagnostic standards of myasthenia gravis, accompanied by different severity of autonomic nerve symptoms, including poor skin nutrition, sweating of hands and feet, pyknocardia, persistent hypotension, abdominal pain, constipation, etc. They all had not taken any drug affecting the autonomic nerve function before the examination. Informed consents were obtained from all the patients. Meanwhile, 30 healthy physical examinees were enrolled as the normal control group, including 10 males and 20 females, aged 10 - 75 years with a mean age of （31 ±5） years old. Approval was obtained from the hospital ethic committee. METHODS： After admission, the patients were examined with sympathetic skin response using DANTEC keypoint 2.0 electromyography evoked potential apparatus （Danmark）. The changes of the latency and wave amplitude of sympathetic skin response were observed. The subjects in the normal control group were examined with the same methods at physical examination. Abnormality was judged by the disappearance of wave form, latency longer than that in the normal control group by Mean＋2.5SD, or wave amplitude lower than the average value in the normal control group by 50%. MAIN OUTCOME MEASURES： The results of the latency and wave amplitude of sympathetic skin response were compared between the patients with myasthenia gravis and normal controls. RESULTS： All the 30 patients with myasthenia gravis and 30 healthy physical examinees were involved in the final analysis of results. There were no significant differences between the left and right upper and lower limbs in both the myasthenia gravis group and normal control group （P 〉 0.05）. In the myasthenia gravis group, the abnormal rate of sympathetic skin response was 37% （11/30）, the latency was prolonged and the wave amplitude was decreased as compared with those in the normal control group, and there were significant differences （P 〈 0.01）. CONCLUSION： Sympathetic skin response can be used as an electrophysiological index for judging the damages of autonomic nerve function in patients with myasthenia gravis.

Clinical Study on Evaluation of Autonomic Nervous Dysfunction Based on Imaging Urodynamic Examination with Slow Filling and Synchronous Blood Pressure Monitoring in the Patients with Cervicothoracic Spinal Cord Injury

Objective: Explore the rule of autonomic nervous dysfunction in the patients with urination disorder after high level spinal cord injury, and seek a safe, objective and accurate method to evaluate autonomic nervous function. Patients and Method: 48 patients with dysuria after cervicothoracic SCI were selected. Before, during and after imaging urodynamic examination with slow filling in supine position, blood pressure and ECG were monitored simultaneously. The symptoms of sweating, shivering, headache, flushing and chills were observed and recorded. The study of the relationship among the changes of blood pressure, heart rate and urodynamic indexes and the above symptoms was analyzed. Results: They were divided into three groups: group A (no obvious abnormality), group B (hyperactivity) and group C (hypoactivity) according to their BP, HR and existing the symptoms or not. Conclusion: The incidence of autonomic dysfunction in the high level SCI patients with dysuria was very high (79.17%), most of them were hyperactivity, and a few were low function. The changes of SBP and DBP in the hypoactivity group all appeared an increasing and then declining trend, while the change of HR in the low function one was lower than normal and decreased continuously. The main inducements of AD are neurogenic detrusor overactivity, detrusor sphincter dyssynergia, elevated abdominal pressure and abnormal bladder sensitivity. The asymptomatic patients had a higher occurrence rate (43.75%). Only by imaging urodynamic examination with slow filling and synchronous blood pressure monitoring, can autonomic nervous function of the patients be evaluated safely, objectively, early and accurately.

What Information Gap Activities can Teach Us in TESOL

Starting from presenting and analyzing some information gap activities during the previous teaching experience, this article has inferred the major roles of information gap activities. Some strategies to implement the information gap activities are also recommended together with the functions of the instructors via these activities. What information gap activities can teach us in TESOL （teaching English for speakers of other languages） is that information gap activities contribute to setting up a climate of a mutual autonomous learning style both for the learners and the instructors, and these activities activate a diversity in the learning atmosphere.

Heart rate variability and its response to thyroxine replacement therapy in patients with hypothyroidism

Objective To analyze heart rate variability (HRV)and its changes with thyroxine treatment in patients with hypothyroidism. Methods HRV was analyzed using 24-hour electrocardiographic recording in 38 patients with hypothyroidism and 21 normal controls. The changes in HRV were evaluated for the 18 hypothyroid patients after 3 months of thyroxine therapy.Results The time domain measurements of HRV in hypothyroid patients were much lower than those in the control group. As to HRV frequency domain, the high frequency power was significantly higher, but the ratio of low frequency power to frequency power for hypothyroid patients was lower than in the controls. These abnormal changes of HRV measurements in hypothyroid patients were improved after treatment with thyroxine and were associated with recovery of serum concentrations of FT3 and FT4. Conclusions Patients with hypothyroidism often have autonomic neuropathies with a higher level of vagal tone. These abnormalities could be partly improved by thyoxine therapy.

Heart Rate Variability in Patients with Acute Ischemic Stroke at Different Stages of Renal Dysfunction： A Cross-sectional Observational Study

Background： Renal function is associated with mortality and functional disabilities in stroke patients, and impaired autonomic function is common in stroke, but little is known regarding its effects on stroke patients with renal dysfunction. This study sought to evaluate the association between autonomic function and stroke in patients with renal dysfunction. Methods： This study comprised 232 patients with acute ischemic stroke consecutively enrolled from February 2013 to November 2014 at Guangdong Provincial Hospital of Chinese Medicine in China. All patients recruited underwent laboratory evaluation and 24 h Holter electrocardiography （ECG）. Autonomic function was measured based on the heart rate variability （HRV） using 24 h Holter ECG. Renal damage was assessed through the estimated glomerular filtration rate （eGFR）, and stroke severity was rated according to the National Institutes of Health Stroke Scale （NIHSS）. The Barthel index and modifed Rankin score were also determined following admission. All the clinical covariates that could potentially affect autonomic outcome variables were adjusted with linear regression. Results： In the patients with a mild or moderate decreased eGFR, the values for the standard deviation of the averaged normal-to-normal RR interval （SDANN） index （P = 0.022L very low frequency （VLF） （P = 0.043）, low frequency （LF） （P= 0.023）, and ratio of low-to-high frequency power （LF/HF） （P = 0.001 ） were significantly lower than those in the patients with a normal eGFR. A lnultinomial linear regression indicated that eGFR （t - 2.47, P - 0.014）, gender （t - -3.60, P 〈0.001）, and a history of hypertension （t = -2.65, P = 0.008） were the risk factors of LF/HF; the NIHSS score （SDANN index： t = -3.83, P 〈 0.001 ; VLF： t = -3.07, P = 0.002： LF： t = -2.79, P = 0.006） and a history of diabetes （SDANN index： t = -3.58, P 〈 0.001; VLF： t = -2.54, P = 0.012; LF： t = -2.87, P = 0.004） were independent factors Ibr the SDANN index, VLF, and LF; the Oxfordshire Community Stroke Project （t = -2.38, P = 0.018） was related to the SDANN index. Conclusions： Autonomic dysfunction is aggravated with the progression ofeGFR stage in patients with acute ischemic stroke; the eGFR is an independent factor of LF/HF in the adjusted models. Stroke severity and a history of diabetes are more significantly associated with HRV in patients with acute ischemic stroke at different stages of renal dysfnnction.

Evaluation of the Health Status of Six Volunteers from the Mars 500 Project Using Pulse Analysis

Objective：To comprehensively evaluate the health status of 6 volunteers from the Mars 500Project through analyzing their pulse graphs and determining the changes in cardiovascular function,degree of fatigue and autonomic nervous function.Methods：Six volunteers were recruited;all were male aged 26–38years（average 31.83±4.96 years）.Characteristic parameters reflecting the status of cardiovascular functions were extracted,which included left ventricular contraction,vascular elasticity and peripheral resistance.The degree of fatigue was determined depending on the difference between the calendar age and biological age,which was calculated through the analysis of blood pressure value and characteristic parameters.Based on the values of pulse height variation and pulse time variation on a 30-s pulse graph,autonomic nervous function was evaluated.All parameters examined were marked on an equilateral polygon to form an irregular polygon of the actual figure,then health status was evaluated based on the coverage area of the actual figure.Results：The results demonstrated：（1）volunteers developed weakened pulse power,increased vascular tension and peripheral resistance,and slight decreased ventricular systolic function;（2）the degree of fatigue was basically mild or moderate;and（3）autonomic nervous function was excited but generally balanced.Conclusions：These volunteers were in the state of sub-health.According to Chinese medicine theories,such symptoms are mainly caused by the weakening of healthy qi,Gan（Liver）failing in free coursing,and disharmony between Gan and Wei（Stomach）,which manifests as a weak and string-like pulse.

Cardiac autonomic function in patients with myasthenia gravis:analysis of the heart-rate variability in the time-domain

Aim:Myasthenia gravis(MG)is a neuromuscular transmission disorder caused by acetylcholine receptor autoantibodies.Cardiac autonomic dysfunctions were rarely reported in patients with MG.Functional cardiac abnormalities were variable and reported in patients at severe stages of the disease and with thymoma.We investigated cardiac functions in patients with MG using Ambulatory 24‑h electrocardiographic Holter‑Monitoring.Methods:This study included 20 patients with MG with a mean age of 28.45±8.89 years and duration of illness of 3.52±1.15 years.The standard Holter reports include data for heart‑rate,ventricular ectopies(VEs),supraventricular ectopies(SVEs),heart-rate variability(HRV),ST,QT,atrial fibrillation and T‑wave alternans.Results:VEs,SVEs and ST‑T changes were reported in 55%,40%and 20%of patients respectively.Compared with healthy subjects(n=20),HRV components including SDNN,SDANN,SDNN Index,RMS‑SD and pNN50(P=0.001 for all)were reduced in patients indicating sympathetic and parasympathetic autonomic dysfunctions.HRV abnormalities were reported in 30-60%of patients.No significant correlations were identified between SDNN,RMS‑SD,pNN50,and duration of illness.Conclusion:Depressed HRV may be an early manifestation of autonomic neuropathy in patients with MG even in milder stages of the disease.This information is useful in rating disease progression and the efficacy of therapeutic interventions.