Exendin-4 increases the firing activity of hippocampal CA1 neurons through TRPC4/5 channels.

The central neuropeptide GLP-1 is synthesized by preproglucagon (PPG) neurons in the brain. GLP-1 receptors are widely distributed in central nervous system. Hippocampus is a key component of the limbic system which is involved in learning, memory, and cognition. Previous studies have shown that overexpression of GLP-1 receptors in the hippocampus could improve the process of learning and memory. However, up to now, the direct electrophysiological effects and possible molecular mechanisms of GLP-1 in hippocampal CAl neurons remain unexplored. The present study aims to evaluate the effects and mechanisms of GLP-1 on the spontaneous firing activity of hippocampal CAl neurons. Employing multibarrel single-unit extracellular recordings, the present study showed that micro-pressure administration of GLP-1 receptor agonist, exendin-4, significantly increased the spontaneous firing rate of hippocampal CA1 neurons in rats. Furthermore, application of the specific GLP-1 receptor antagonist, exendin(9-39), alone significantly decreased the firing rate of CA1 neurons, suggesting that endogenous GLP-1 modulates the firing activity of CA1 neurons. Co-application of exendin(9-39) completely blocked exendin-4-induced excitation of hippocampal CA1 neurons. Finally, the present study demonstrated for the first time that the transient receptor potential canonical 4 (TRPC4)/TRPC5 channels may be involved in exendin-4-induced excitation. The present studies may provide a rationale for further investigation of the modulation of GLP-1 on learning and memory as well as its possible involvement in Alzheimer's disease.

Epidemiology of autism spectrum disorders: Global burden of disease 2019 and bibliometric analysis of risk factors.

Background: To explore the geographical pattern and temporal trend of autism spectrum disorders (ASD) epidemiology from 1990 to 2019, and perform a bibliometric analysis of risk factors for ASD. Methods: In this study, ASD epidemiology was estimated with prevalence, incidence, and disability-adjusted life-years (DALYs) of 204 countries and territories by sex, location, and sociodemographic index (SDI). Age-standardized rate (ASR) and estimated annual percentage change (EAPC) were used to quantify ASD temporal trends. Besides, the study performed a bibliometric analysis of ASD risk factors since 1990. Publications published were downloaded from the Web of Science Core Collection database, and were analyzed using CiteSpace. Results: Globally, there were estimated 28.3 million ASD prevalent cases (ASR, 369.4 per 100,000 populations), 603,790 incident cases (ASR, 9.3 per 100,000 populations) and 4.3 million DALYs (ASR, 56.3 per 100,000 populations) in 2019. Increases of autism spectrum disorders were noted in prevalent cases (39.3%), incidence (0.1%), and DALYs (38.7%) from 1990 to 2019. Age-standardized rates and EAPC showed stable trend worldwide over time. A total of 3,991 articles were retrieved from Web of Science, of which 3,590 were obtained for analysis after removing duplicate literatures. "Rehabilitation", "Genetics & Heredity", "Nanoscience & Nanotechnology", "Biochemistry & Molecular biology", "Psychology", "Neurosciences", and "Environmental Sciences" were the hotspots and frontier disciplines of ASD risk factors. Conclusions: Disease burden and risk factors of autism spectrum disorders remain global public health challenge since 1990 according to the GBD epidemiological estimates and bibliometric analysis. The findings help policy makers formulate public health policies concerning prevention targeted for risk factors, early diagnosis and life-long healthcare service of ASD. Increasing knowledge concerning the public awareness of risk factors is also warranted to address global ASD problem.

[Value of fractional exhaled nitric oxide combined with impulse oscillometry in the diagnosis of asthma in preschool children]. / å‘¼å‡ºæ°”ä¸€æ°§åŒ–æ°®è”åˆè„‰å†²æŒ¯è¡æ£€æŸ¥åœ¨å­¦é¾„å‰å„¿ç«¥å“®å–˜ä¸­çš„è¯Šæ–­ä»·å€¼ç ”ç©¶.

OBJECTIVES: To evaluate the value of fractional exhaled nitric oxide (FeNO) combined with impulse oscillometry (IOS) in the diagnosis of asthma in preschool children, and to establish the optimal predictive model. METHODS: A retrospective analysis was performed on 156 children with wheezing, aged 3-5 years, who were admitted from September 2019 to December 2020. These children were divided into an asthma group with 52 children and a non-asthma group with 104 children. The two groups were compared in terms of IOS parameters, FeNO, and clinical data. The multivariate logistic regression analysis was used to establish the optimal predictive model. RESULTS: Compared with the non-asthma group, the asthma group had significantly higher total respiratory system impedance at 5 Hz (Z5), resistance of respiratory system at 5 Hz and 20 Hz (R5 and R20, respectively), resonance frequency, reactance area (AX), and FeNO and a significantly lower reactance difference at 5 Hz (P<0.05). The receiver operating characteristic (ROC) curve analysis showed that Z5, R5, R20, and FeNO had a certain value in the diagnosis of asthma (P<0.05). The multivariate logistic regression analysis established the optimal predictive model of R20+AX+FeNO, with an area under the ROC curve of 0.858 (P<0.05), a sensitivity of 78.8%, and a specificity of 76.9%. CONCLUSIONS: FeNO combined with IOS is helpful for the diagnosis of asthma in preschool children, and the model of R20+AX+FeNO has a certain value in the diagnosis of asthma in these children.

Epidemiological characteristics, clinical characteristics, and prognostic factors of children with atopy hospitalised with adenovirus pneumonia.

BACKGROUND: Atopy may be associated with disease severity and a poor prognosis of human adenovirus (HAdV) pneumonia in children. Our aim was to observe the clinical characteristics and pulmonary radiological changes in children with atopy and HAdV pneumonia in China. METHODS: Children hospitalised with HAdV pneumonia from June 2018 to December 2019 were analysed. All children were divided into atopic with HAdV, non-atopic with HAdV, and atopic without HAdV infection group. Each group was further divided into the mild and severe pneumonia groups according to disease severity. Standard treatment was initiated after admission, and regular follow-up evaluations were conducted at 1 month after discharge. Baseline and clinical characteristics and pulmonary radiological changes in children with and without atopy were evaluated. Risk factors associated with small airway lesions in patients with HAdV pneumonia were analysed. RESULTS: The eosinophil count in the atopic group was significantly higher than that in the non-atopic group (P < 0.05). Severe coughing, wheezing, and small airway lesions on chest high-resolution computed tomography (HRCT) upon admission, after discharge and 1 month after discharge were significantly higher in the atopic group (with or without HAdV infection) than in the non-atopic group (P < 0.05). There were significant differences in the number of patients with wheezing and small airway lesions during hospitalisation and after discharge among the three groups (P < 0.05). The risks of small airway lesions in children with a family or personal history of asthma, severe infection, atopy, and HAdV infection were 2.1-, 2.7-, 1.9-, 2.1-, and 1.4-times higher than those in children without these characteristics, respectively. CONCLUSIONS: Children with atopy and HAdV pneumonia may experience severe coughing in mild cases and wheezing in mild and severe cases. Children with atopy are more susceptible to the development of small airway lesions, recurrent wheezing after discharge and slower recovery of small airway lesions as observed on pulmonary imaging than non-atopic children after HAdV infection. A family or personal history of asthma, atopy, severe infection, and HAdV infection are independent risk factors associated with the development of small airway lesion as observed on chest HRCT.

Repetitive transcranial magnetic stimulation promotes functional recovery and differentiation of human neural stem cells in rats after ischemic stroke.

Stem cells hold great promise as a regenerative therapy for ischemic stroke by improving functional outcomes in animal models. However, there are some limitations regarding the cell transplantation, including low rate of survival and differentiation. Repetitive transcranial magnetic stimulation (rTMS) has been widely used in clinical trials as post-stroke rehabilitation in ischemic stroke and has shown to alleviate functional deficits following stroke. The present study was designed to evaluate the therapeutic effects and mechanisms of combined human neural stem cells (hNSCs) with rTMS in a middle cerebral artery occlusion (MCAO) rat model. The results showed that human embryonic stem cells (hESCs) were successfully differentiated into forebrain hNSCs for transplantation and hNSCs transplantation combined with rTMS could accelerate the functional recovery after ischemic stroke in rats. Furthermore, this combination not only significantly enhanced neurogenesis and the protein levels of brain-derived neurotrophic factor (BDNF), but also rTMS promoted the neural differentiation of hNSCs. Our findings are presented for the first time to evaluate therapeutic benefits of combined hNSCs and rTMS for functional recovery after ischemic stroke, and indicated that the combination of hNSCs with rTMS might be a potential novel therapeutic target for the treatment of stroke.

Adenosine A2A Receptor Modulates the Activity of Globus Pallidus Neurons in Rats.

The globus pallidus is a central nucleus in the basal ganglia motor control circuit. Morphological studies have revealed the expression of adenosine A2A receptors in the globus pallidus. To determine the modulation of adenosine A2A receptors on the activity of pallidal neurons in both normal and parkinsonian rats, in vivo electrophysiological and behavioral tests were performed in the present study. The extracellular single unit recordings showed that micro-pressure administration of adenosine A2A receptor agonist, CGS21680, regulated the pallidal firing activity. GABAergic neurotransmission was involved in CGS21680-induced modulation of pallidal neurons via a PKA pathway. Furthermore, application of two adenosine A2A receptor antagonists, KW6002 or SCH442416, mainly increased the spontaneous firing of pallidal neurons, suggesting that endogenous adenosine system modulates the activity of pallidal neurons through adenosine A2A receptors. Finally, elevated body swing test (EBST) showed that intrapallidal microinjection of adenosine A2A receptor agonist/antagonist induced ipsilateral/contralateral-biased swing, respectively. In addition, the electrophysiological and behavioral findings also revealed that activation of dopamine D2 receptors by quinpirole strengthened KW6002/SCH442416-induced excitation of pallidal activity. Co-application of quinpirole with KW6002 or SCH442416 alleviated biased swing in hemi-parkinsonian rats. Based on the present findings, we concluded that pallidal adenosine A2A receptors may be potentially useful in the treatment of Parkinson's disease.

Effects of methylprednisolone or immunoglobulin when added to standard treatment with intravenous azithromycin for refractory Mycoplasma pneumoniae pneumonia in children.

BACKGROUND: The prevalence of Mycoplasma pneumoniae pneumonia has increased considerably in recent years. To evaluate the efficacy of combined treatment of azithromycin with intravenous immunoglo-bulin (IVIG) or methylprednisolone in children with refractory Mycoplasma pneumoniae pneumonia (RMPP). METHODS: Children with RMPP were randomly allocated to group A [intravenous azithromycin (IA)+ methylprednisolone], group B (IA+IVIG) or group C (IA alone). Following a 7-day treatment, group C patients were randomly separated into two sub-groups: group C1 (IA+methylprednisolone) and group C2 (IA+IVIG). Temperature, respiratory symptoms and signs were examined. The average febrile period after treatment (F2), average total febrile period (F3), infiltration absorption, atelectasis resolution, pleural effusion disappearance were determined. The levels of C-reactive protein (CRP), D-dimer, and lactate dehydrogenase (LDH) were measured. RESULTS: Seven days after enrollment, the average F2 after treatment of group A was the shortest. Compared with the control group C, the combined treatment group A and B showed higher rates of infiltration absorption, atelectasis resolution and pleural effusion disappearance, while lower levels of serum CRP, D-dimer and LDH. Fourteen days after enrollment, all children with combined therapy clinically improved, and presented better laboratory results. Group C1 showed shorter F3 and lower levels of CRP and LDH than those of group C2. Overall, group A showed the shortest F3, also has the lowest CRP and LDH. CONCLUSIONS: Azithromycin with IVIG or methylprednisolone was better treatment for children with RMPP than azithromycin alone. IVIG treatment may be beneficial, especially when the efficacy of corticosteroids is insecure, thus could be considered as an alternative of primary therapeutic approaches.

Indicating value of lower extremity atherosclerotic disease ultrasound screening for cardiovascular diseases in type 2 diabetes patients / 上海交通大学学报（医学版）

Objective·To verify the indicating value of the simple screening of lower extremity atherosclerosis artery disease (LEAD) by lower extremity arterial ultrasound examination for coronary atherosclerotic heart disease (CAD) in patients with type 2 diabetes. Methods·A total of 606 type 2 diabetes patients were enrolled. Their clinical data and biochemical parameters (hepatorenal function, glycometabolism, tumor markers) were collected. All patients were undertaken lower extremity vascular ultrasound and CT angiography (CTA) scan for coronary artery disease. According to the results of lower extremity ultrasound, patients were divided into two groups, patients with LEAD group (n=318) and patients without LEAD group (n=288). According to the history of coronary CTA or percutaneous coronary intervention (PCI) or percutaneous transluminal coronary angioplasty (PTCA), the patients were divided into CAD group (n=280) and non-combined CAD group (n=326). The prevalence of CAD in different LEAD groups was compared and their relationship was analyzed. Results·The degree of LEAD was proportional to the prevalence of CAD. Both of the prevalences of CAD in group with arterial stenosis >50% (81%) and group with plaque and stenosis<50% (63%) were significantly higher than that in group without plaque (29%) (P=0.021,P=0.015, respectively). Spearman analysis found that age, sex, duration of diabetes, systolic blood pressure, total cholesterol, LEAD, femoral artery intima-media thickness were positively correlated with CAD. However, high density lipoprotein cholesterol and glomerular filtration rate were negatively associated with CAD. Logistic regression analysis revealed that duration of diabetes, existence of LEAD were independent associated factors of CAD. After adjusting the confounding factors, odds ratio risk analysis showed the risk increased 4.818 times in patients with LEAD (OR=5.818, 95% CI 2.627-12.888, P=0.000). Conclusion·The evaluation of LEAD by ultrasound has an indicating value for CAD in type 2 diabetes patients.

Indicating value of lower extremity atherosclerotic disease ultrasound screening for cardiovascular diseases in type 2 diabetes patients / 上海交通大学学报（医学版）

Objective·To verify the indicating value of the simple screening of lower extremity atherosclerosis artery disease (LEAD) by lower extremity arterial ultrasound examination for coronary atherosclerotic heart disease (CAD) in patients with type 2 diabetes. Methods·A total of 606 type 2 diabetes patients were enrolled. Their clinical data and biochemical parameters (hepatorenal function, glycometabolism, tumor markers) were collected. All patients were undertaken lower extremity vascular ultrasound and CT angiography (CTA) scan for coronary artery disease. According to the results of lower extremity ultrasound, patients were divided into two groups, patients with LEAD group (n=318) and patients without LEAD group (n=288). According to the history of coronary CTA or percutaneous coronary intervention (PCI) or percutaneous transluminal coronary angioplasty (PTCA), the patients were divided into CAD group (n=280) and non-combined CAD group (n=326). The prevalence of CAD in different LEAD groups was compared and their relationship was analyzed. Results·The degree of LEAD was proportional to the prevalence of CAD. Both of the prevalences of CAD in group with arterial stenosis >50% (81%) and group with plaque and stenosis<50% (63%) were significantly higher than that in group without plaque (29%) (P=0.021,P=0.015, respectively). Spearman analysis found that age, sex, duration of diabetes, systolic blood pressure, total cholesterol, LEAD, femoral artery intima-media thickness were positively correlated with CAD. However, high density lipoprotein cholesterol and glomerular filtration rate were negatively associated with CAD. Logistic regression analysis revealed that duration of diabetes, existence of LEAD were independent associated factors of CAD. After adjusting the confounding factors, odds ratio risk analysis showed the risk increased 4.818 times in patients with LEAD (OR=5.818, 95% CI 2.627-12.888, P=0.000). Conclusion·The evaluation of LEAD by ultrasound has an indicating value for CAD in type 2 diabetes patients.

Electroacupuncture Ameliorates Learning and Memory and Improves Synaptic Plasticity via Activation of the PKA/CREB Signaling Pathway in Cerebral Hypoperfusion.

Electroacupuncture (EA) has shown protective effects on cognitive decline. However, the underlying molecular mechanisms are ill-understood. The present study was undertaken to determine whether the cognitive function was ameliorated in cerebral hypoperfusion rats following EA and to investigate the role of PKA/CREB pathway. We used a rat 2-vessel occlusion (2VO) model and delivered EA at Baihui (GV20) and Dazhui (GV14) acupoints. Morris water maze (MWM) task, electrophysiological recording, Golgi silver stain, Nissl stain, Western blot, and real-time PCR were employed. EA significantly (1) ameliorated the spatial learning and memory deficits, (2) alleviated long-term potentiation (LTP) impairment and the reduction of dendritic spine density, (3) suppressed the decline of phospho-CREB (pCREB) protein, brain-derived neurotrophic factor (BDNF) protein, and microRNA132 (miR132), and (4) reduced the increase of p250GAP protein of 2VO rats. These changes were partially blocked by a selective protein kinase A (PKA) inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89), suggesting that the PKA/CREB pathway is potentially involved in the effects of EA. Moreover, any significant damage to the pyramidal cell layer of CA1 subregion was absent. These results demonstrated that EA could ameliorate learning and memory deficits and alleviate hippocampal synaptic plasticity impairment of cerebral hypoperfusion rats, potentially mediated by PKA/CREB signaling pathway.

Direct modulation of firing activity by dopamine D2 like receptors in the globus pallidus of both normal and parkinsonian rats.

The globus pallidus occupies a critical position in the indirect pathway of the basal ganglia circuit, which regulates movement under both normal and pathological conditions. Previous studies have shown that the globus pallidus receives dopaminergic innervation from the axonal collaterals of nigrostriatal fibers. Both dopamine D1 and D2 like receptors are expressed in the globus pallidus. The present study was aimed to investigate the direct in vivo electrophysiological effects of dopamine D2 like receptors in the globus pallidus of both normal and parkinsonian rats. Extracellular recordings of multi-barreled microelectrode were used in the present study. In normal rats, micro-pressure ejection of dopamine D2 like receptor agonist quinpirole induced different effects on the firing rate of globus pallidus neurons. In 24 out of the 61 pallidal neurons, quinpirole significantly increased the firing rate by (62.7 ± 11.2)%. In another 16 neurons, quinpirole decreased the spontaneous firing rate by (37.5 ± 2.9)%. Furthermore, co-application of dopamine D2 like receptor antagonist, sulpride, blocked quinpirole-induced modulation of the firing rate of pallidal neurons. On the 6-hydroxydopamine (6-OHDA) lesioned side of parkinsonian rats, quinpirole increased the firing rate in 25 out of the 47 pallidal neurons by (64.2 ± 10.1)%, while decreased the firing rate in 11 neurons by (51.9 ± 6.2)%. Our findings suggest that activation of pallidal dopamine D2 like receptors may bidirectionally modulate the spontaneous firing of globus pallidus neurons in both normal and parkinsonian rats.

Repetitive magnetic stimulation promotes neural stem cells proliferation by upregulating MiR-106b in vitro.

Neural stem cells (NSCs) proliferation can be influenced by repetitive transcranial magnetic stimulation (rTMS) in vivo via microRNA-106b-25 cluster, but the underlying mechanisms are poorly understood. This study investigated the involvement of microRNA-106b-25 cluster in the proliferation of NSCs after repetitive magnetic stimulation (rMS) in vitro. NSCs were stimulated by rMS (200/400/600/800/1000 pulses per day, with 10 Hz frequency and 50% maximum machine output) over a 3-day period. NSCs proliferation was detected by using ki-67 and EdU staining. Ki-67, p21, p57, cyclinD1, cyclinE, cyclinA, cdk2, cdk4 proteins and miR-106b, miR-93, miR-25 mRNAs were detected by Western blotting and qRT-PCR, respectively. The results showed that rMS could promote NSCs proliferation in a dose-dependent manner. The proportions of ki-67+ and Edu+ cells in 1000 pulses group were 20.65% and 4.00%, respectively, significantly higher than those in control group (9.25%, 2.05%). The expression levels of miR-106b and miR-93 were significantly upregulated in 600-1000 pulses groups compared with control group (P<0.05 or 0.01 for all). The expression levels of p21 protein were decreased significantly in 800/1000 pulses groups, and those of cyclinD1, cyclinA, cyclinE, cdk2 and cdk4 were obviously increased after rMS as compared with control group (P<0.05 or 0.01 for all). In conclusion, our findings suggested that rMS enhances the NSCs proliferation in vitro in a dose-dependent manner and miR-106b/p21/cdks/cyclins pathway was involved in the process.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate firing of globus pallidus neurons in vivo.

The globus pallidus plays a significant role in motor control under both health and pathological states. Recent studies have revealed that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels occupy a critical position in globus pallidus pacemaking activity. Morphological studies have shown the expression of HCN channels in the globus pallidus. To investigate the in vivo effects of HCN channels in the globus pallidus, extracellular recordings and behavioral tests were performed in the present study. In normal rats, micro-pressure ejection of 0.05mM ZD7288, the selective HCN channel blocker, decreased the frequency of spontaneous firing in 21 out of the 40 pallidal neurons. The average decrease was 50.4±5.4%. Interestingly, in another 18 out of the 40 pallidal neurons, ZD7288 increased the firing rate by 137.1±27.6%. Similar bidirectional modulation on the firing rate was observed by a higher concentration of ZD7288 (0.5mM) as well as another HCN channel blocker, CsCl. Furthermore, activation of HCN channels by 8-Br-cAMP increased the firing rate by 63.0±9.3% in 15 out of the 25 pallidal neurons and decreased the firing rate by 46.9±9.4% in another 8 out of the 25 pallidal neurons. Further experiments revealed that modulation of glutamatergic but not GABAergic transmission may be involved in ZD7288-induced increase in firing rate. Consistent with electrophysiological results, further studies revealed that modulation of HCN channels also had bidirectional effects on behavior. Taken together, the present studies suggest that HCN channels may modulate the activity of pallidal neurons by different pathways in vivo.

Effects of secretin on neuronal activity and feeding behavior in central amygdala of rats.

Previous studies have shown that secretin and secretin receptors are expressed in central amygdala neurons. By using both in vivo extracellular recording as well as behavioral test, we investigated the direct electrophysiological effects of secretin in the central amygdala and its involvement in feeding behavior. Micro-pressure ejection of secretin increased the spontaneous firing rate by 104.22±26.18% in 13 out of the 27 central amygdala neurons. In other 6 out of the 27 neurons, secretin decreased the firing rate by 68.80±12.10%. Firing patter analysis showed that secretin did not change the firing pattern significantly. Further electrophysiological recordings revealed that secretin decreased the firing rate of glucose-sensitive neurons. In behavioral test, microinjection of secretin into the central amygdala significantly reduced cumulative food intake through cAMP-activated protein kinase activation. Based on the present electrophysiological and behavioral findings, we hypothesized that secretin may suppress food intake by its modulation of spontaneous firing of central amygdala neurons.

Phylogenetic and recombination analysis of rice black-streaked dwarf virus segment 9 in China.

Rice black-streaked dwarf virus (RBSDV) is an economically important virus that causes maize rough dwarf disease and rice black-streaked dwarf disease in East Asia. To study RBSDV variation and recombination, we examined the segment 9 (S9) sequences of 49 RBSDV isolates from maize and rice in China. Three S9 recombinants were detected in Baoding, Jinan, and Jining, China. Phylogenetic analysis showed that Chinese RBSDV isolates could be classified into two groups based on their S9 sequences, regardless of host or geographical origin. Further analysis suggested that S9 has undergone negative and purifying selection.

HCN channels modulate the activity of the subthalamic nucleus in vivo.

The subthalamic nucleus is a key component in the indirect pathway of the basal ganglia, which mediates a variety of motor functions. The subthalamic nucleus neurons have intrinsic pacemaking properties. Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are expressed in the central nervous system, including the subthalamic nucleus. However, the in vivo modulation of HCN channels in the subthalamic nucleus remains relatively obscure. To investigate the direct effects of HCN channels in the subthalamic nucleus, multi-barrel extracellular recordings and behavioral tests were performed in the present study. In 42 out of the 89 subthalamic nucleus neurons, micropressure ejection of HCN channel inhibitor, ZD7288 (0.05 mM), decreased the spontaneous firing rate from 11.6 ± 1.8 to 5.7 ± 1.3 Hz (P < 0.001). The average decrease was 56.7 ± 5.3 %. In another 47 out of the 89 subthalamic nucleus neurons, micropressure ejection of ZD7288 increased the spontaneous firing rate from 9.5 ± 1.6 to 16.3 ± 2.4 Hz (P < 0.001), with the average increase of 142.2 ± 29.8 %. Activation of HCN channels by 8-Br-cAMP also produced bidirectional modulation on the firing rate of the subthalamic nucleus neurons. Furthermore, unilateral microinjection of ZD7288 or 8-Br-cAMP produced postural behavior in awake rats. The present electrophysiological and behavioral findings demonstrated that the pharmacological blockade or activation of HCN channels produces bidirectional modulation on the excitability of the subthalamic nucleus.

7,8-dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cell death through modulating PI3K/Akt and JNK pathways.

We have recently shown that 7,8-dihydroxyflavone (7,8-DHF) protects PC12 cells against 6-OHDA-induced cytotoxicity through its antioxidant activity. In the present study, we investigated the molecular mechanisms underlying the neuronal protective activity of 7,8-DHF. Western blot analysis showed that 6-OHDA (100µM, 24h) enhanced the phosphorylation of JNK and ERK1/2, but it markedly suppressed the expression of p-Akt, implying that 6-OHDA induces PC12 cell death through activating the pro-apoptotic MAPKs pathway but suppressing the survival PI3K/Akt pathway. More importantly, addition of 7,8-DHF fully prevented the activation of JNK and suppression of Akt induced by 6-OHDA. Interestingly, pretreatment with the PI3K-specific inhibitor LY294002 largely blocked 7,8-DHF function in protecting PC12 cells from 6-OHDA-induced cell death. In contrast, the MEK inhibitor PD98059 showed little effect on the protective activity of 7,8-DHF. These results suggest that 7,8-DHF might protect PC12 cells from 6-OHDA-induced cell death through activating PI3K/Akt pathway and inhibiting JNK pathway.

Clinical characteristics and genetic profiles of 44 patients with severe combined immunodeficiency (SCID): report from Shanghai, China (2004-2011).

Severe combined immunodeficiency (SCID), a rare type of genetic associated immune disorder, is poorly characterized in mainland China. We retrospectively reviewed 44 patients with SCID who received treatment from 2004 to 2011 in Shanghai, China, and herein summarize their clinical manifestations and immunological and preliminary genetic features. The male-to-female ratio was 10:1. Twenty five patients presented with X-SCID symptoms. Only one patient was diagnosed before the onset of symptoms due to positive family history. The mean time of delay in the diagnosis of X-SCID was 2.69 months (range, 0.5-8.67). Thirty-seven of the 44 patients died by the end of 2011 with the mean age of death being 7.87 months (range, 1.33-31). Six patients received hematopoietic stem cell transplantation (HSCT); only one of them survived, who was transplanted twice. The time between onset and death was shorter in the HSCT-treated group compared with the untreated group (2.87 ± 1.28 and 3.34 ± 0.59 months, respectively), probably due to active infections during transplantation. Bacillus Calmette-Guérin (BCG) complications occurred in 14 of the 34 patients who received BCG vaccination. Transfusion-induced graft-versus-host disease occurred in 5 patients. Total 20 mutations in interleukin-2 receptor subunit gamma (IL2RG) were identified in 22 patients, including 11 novel mutations. Most patients were misdiagnosed before referred to our SCID Center. Therefore, establishing more diagnostic centers dedicated to the care of PID and accessible by primary immunodeficiency patients will facilitate early, correct diagnosis and better care of SCID in China.

[Protective effect of melatonin on myocardial injury in severely- burned rats].

OBJECTIVE: To investigate the protective effect of melatonin (MLT) on myocardial injury in severely-burned rats and its mechanism. METHODS: A total of 30 Sprague-Dawley (SD) rats were randomly assigned to three groups: sham group, burn group and MLT group, each n=10. The dorsal skin of animal was immersed into boiling water for 15 seconds to induce 30% total body surface area (TBSA) full-thickness burn, or immersed into 37 centigrade water for sham operation. Immediately after burn, the animals in burn group and MLT group were given intraperitoneally vehicle (1% alcohol in normal saline) or MLT (10 mg/kg) respectively. Six hours postburn, the blood from tail vessel was collected for serum preparation. After sacrificed, the myocardial tissues of rats were collected for the determination of malondialdehyde (MDA) and reduced glutathione (GSH) as well as glutathione peroxidase (GSH-Px) and myeloperoxidase (MPO) activities. Serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) were also estimated. RESULTS: Compared with the sham control, burn injury increased MDA by 66.7% (1.55±0.17 nmol/mg vs. 0.93±0.05 nmol/mg) and decreased GSH by 27.8% (13.58±0.33 nmol/mg vs. 18.82±0.55 nmol/mg, both P<0.01) in myocardial tissues, GSH-Px activity was also slightly inhibited (74.04±3.42 nmol×min(-1)×mg(-1) vs. 93.79±3.76 nmol×min(-1)×mg(-1), P<0.05), but MPO level was found to increase to 2.8 folds (9.43±1.15 U/g vs. 3.41±0.27 U/g, P<0.01). These changes indicated the occurrence of oxidative stress in myocardial tissues after severe burn. MLT treatment relieved most of the abnormality with significant statistical significances (MDA: 0.89±0.08 nmol/mg vs. 1.55±0.17 nmol/mg, GSH: 17.23±0.54 nmol/mg vs. 13.58±0.33 nmol/mg, MPO: 6.91±0.51 U/g vs. 9.43±1.15 U/g, P<0.05 or P<0.01). In addition, the serum levels of CK and LDH in burn group increased to 37.8 folds and 7.4 folds respectively (both P<0.01). MLT treatment reduced CK by 32.9% and reduced LDH by 21.2% (P<0.05 and P<0.01). CONCLUSION: MLT treatment exerts the protective effect on myocardial injury in severely-burned rats, which is attributed predominantly to its inhibition on burn-induced oxidative stress injury.