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Background Autism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers, particularly in young children at the age when symptoms become fully established. Furthermore, such brain markers need to meet the requirements of precision medicine and be accurate in aiding diagnosis at an individual rather than only a group level. Objective This study aimed to identify and model brain-wide differences in structural connectivity using diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children. Methods A discovery cohort including 93 ASD and 26 TD children and two independent validation cohorts including 12 ASD and 9 TD children from three different cities in China were included. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) together with symptom severity and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed on the discovery dataset and the resulting model was tested on the two independent validation datasets. Results Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both autistic symptom severity and impaired general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification achieved very high accuracy of 96.77% in the discovery dataset, and 91.67% and 88.89% in the two independent validation datasets. Conclusions Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish novel individual ASD from TD children and may therefore represent a robust early brain biomarker which can address the requirements of precision medicine.

Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by μ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the μ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12264-022-00844-7.

October 2021,《自然》杂志于2021年10月刊登“电针驱动迷走-肾上腺轴的神经解剖学机制”一文，引起了针灸学术界的广泛关注和讨论。在前期工作的基础上，该研究证实PROKR2-Cre神经纤维在躯体不同部位和层次的差异性分布是电针低强度刺激“足三里”或“手三里”穴，通过“迷走-肾上腺轴”产生抗炎效应的关键。该研究成果是针灸基础科研领域的里程碑事件，是针灸学科与神经-免疫学科交叉相互碰撞融合的代表作，揭示了针刺起效的部分因素构成和穴位结构相对特异性的神经解剖学基础，对未来针灸科研模式的变革和针灸科研成果的转化具有一定指导意义，其研究思路、方法和结论值得针灸科研工作者学习和借鉴。.

Decreased attention to social information is considered an early emerging symptom of autism spectrum disorder (ASD), although the underlying causes remain controversial. Here we explored the impact of nonsocial object salience on reduced attention to social stimuli in male ASD compared with typically developing (TD) children. Correlations with blood concentrations of neuropeptides linked with social cognition were also investigated. Eye-tracking was performed in 102 preschool-aged boys (50 ASD, 52 TD) using a paradigm with social (faces) versus nonsocial (objects) stimuli presented in pairs in two conditions where nonsocial stimulus salience was varied. Basal oxytocin (OXT) and vasopressin concentrations were measured in blood. Compared with TD boys those with ASD viewed social stimuli less only when they were paired with low-salience nonsocial objects. Additionally, boys with ASD spent less time than TD ones viewing facial features, particularly the eyes. In TD boys, OXT concentrations and cognitive development scores were positively associated with time spent viewing the eye region, whereas for boys with ASD associations with time spent viewing faces were negative. Reduced gaze toward social stimuli in ASD relative to TD individuals may therefore be influenced by how salient the paired nonsocial objects are for the latter. On the other hand, reduced interest in the eyes of faces in boys with ASD is not influenced by how salient competing nonsocial stimuli are. Basal OXT concentrations and cognitive development scores are predictive of time spent viewing social stimuli in TD boys (eyes) and those with ASD (faces) but in the opposite direction. LAY SUMMARY: Children with autism exhibit reduced attention to social paired with nonsocial stimuli compared to typically developing children. Using eye-tracking we show this difference is due to typically developing rather than autistic boys being more influenced by how interesting competing nonsocial objects are. On the other hand, reduced time looking at the eyes in autistic relative to typically developing boys is unaffected by nonsocial object salience. Time spent viewing social stimuli is associated with cognitive development and blood levels of oxytocin.

ObjectiveAutism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers. This study aimed to identify and model brain-wide differences in structural connectivity using MRI diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children (3·5-6 years old).MethodsNinety-three ASD and 26 TD children were included in a discovery dataset and 12 ASD and 9 TD children from different sites included as independent validation datasets. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) under sedation together with symptom severity and behavioral and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed and the resulting model tested on two independent datasets.ResultsThirty-three structural connections showed increased FA in ASD compared to TD children and associated with both symptom severity and general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification accuracy is very high in the discovery dataset 96.77%, and 91·67% and 88·89% in the two independent validation datasets.ConclusionsIdentified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish individual ASD from TD children and may therefore represent a robust early brain biomarker.

Professor成都中医药大学梁繁荣教授团队于2019年7月29日在

Acupuncture has pain-relief effects, but no data were available on the use of transcutaneous electric acupoint stimulation (TEAS) in pain relief during oocyte retrieval. This study was designed to examine the effect of TEAS for pain relief in women undergoing transvaginal ultrasound-guided oocyte aspiration. This single-blinded, multicenter, randomized controlled trial was performed in China between May 2013 and May 2015. The subjects were randomized to mock TEAS and TEAS. TEAS or mock TEAS was administered 30 min before oocyte retrieval until the end of the operation. The primary and secondary endpoints were the pain measured using the visual analog scale (VAS) within 1 min and 1 hour after oocyte retrieval, respectively. Serum β-endorphin levels were tested in the first 50 patients/group. 390 women were undergoing oocyte retrieval. Pain levels evaluated using VAS within 1 min (18.6 ± 1.3 vs. 24.4 ± 1.7, P<0.01) and 1 h after oocyte aspiration (4.6 ± 0.7 vs. 6.8 ± 0.8, P<0.05) were lower in the TEAS group than in the mock TEAS group. Nausea assessment revealed a significantly lower VAS score in the TEAS group within 1 min (1.2 ± 0.4 vs. 2.9 ± 0.7, P<0.033). Serum β-endorphin levels were significantly higher in the TEAS group than in the mock TEAS group (11.4 ± 0.5 vs. 9.1 ± 0.4, P<0.001) after retrieval. Serum β-endorphin levels were higher in the TEAS group after the procedure than baseline (11.4 ± 0.5 vs. 9.1 ± 0.3, P<0.001). Oocyte retrieval causes pain and discomfort, but TEAS is effective and safe for suppressing the pain and alleviating nausea associated with the operation.

Autism spectrum disorder can be differentiated into three subtypes (aloof, passive, and active-but-odd) based on social behaviors according to the Wing Subgroups Questionnaire (WSQ). However, the correlations between the scores on some individual items and the total score are poor. In the present study, we translated the WSQ into Chinese, modified it, validated it in autistic and typically-developing Chinese children, and renamed it the Beijing Autism Subtyping Questionnaire (BASQ). Our results demonstrated that the BASQ had improved validity and reliability, and differentiated autistic children into these three subtypes more precisely. We noted that the autistic symptoms tended to be severe in the aloof, moderate in the passive, and mild in the active-but-odd subtypes. The modified questionnaire may facilitate etiological studies and the selection of therapeutic regimes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-018-0224-8) contains supplementary material, which is available to authorized users.

Several lines of evidence suggested that abnormal levels of certain chemical elements may contribute to the development of autism spectrum disorders (ASD). The present work aimed to investigate the multiple chemical elements profile in the erythrocytes of autistic versus typically developing children (TDC) of China. Analyses were carried out to explore the possible association between levels of elements and the risk as well as the severity of ASD. Erythrocyte levels of 11 elements (32%) among 34 detected elements in autistic group were significantly different from those in the TDC group. To our knowledge, this is the first study which compared the levels of rare earth elements in erythrocytes between children with or without ASD. Five elements including Pb, Na, Ca, Sb, and La are associated with the Childhood Autism Rating Scale (CARS) total score. Also, a series of tendencies were found in this research which was believed to affect auditory response, taste, smell, and touch, as well as fear or nervousness. It can be concluded that Chinese autistic children suffer from multi-chemical element imbalances which involves a complex combination of genetic and environmental factors. The results showed a significant correlation between abnormal levels of several chemical elements and the severity of the autistic syndrome. Lay SummaryIt is suggested that abnormal levels of some chemical elements may contribute to the development of autism spectrum disorders (ASD). In this work, the impact of element imbalances on the risk and severity of ASD was investigated, focusing on the analysis of abnormal levels of the multi-chemical elements profile in erythrocytes compared with typically developing children. Furthermore, the results showed a significant correlation between abnormal levels of several chemical elements and the severity of the autistic syndrome. Autism Res2018, 11: 834-845. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc.

With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture (EA) and transcutaneous electrical acupoint stimulation (TEAS), become more popular world-wide. Increasing evidence has demonstrated that EA and TEAS are effective in treating gynecological disorders, especially infertility. This present paper describes how to select acupoints for the treatment of infertility from the view of theories of traditional Chinese medicine and how to determine critical parameters of electric pulses of EA/TEAS based on results from animal and clinical studies. It summarizes the principles of clinical application of EA/TEAS in treating various kinds of reproductive disorders, such as polycystic ovary syndrome (PCOS), pain induced by oocyte retrieval, diminished ovarian reserve, embryo transfer, and oligospermia/ asthenospermia. The possible underlying mechanisms mediating the therapeutic effects of EA/TEAS in reproductive medicine are also examined.

A neurochemical hypothesis of acupuncture analgesia suggests that the pain relief effect of acupuncture is primarily due to activation of a central endorphin system. It has been shown that the primary afferent sensory fibers, a mesolymbic neural circuit, and a descending inhibitory pathway are critical in acupuncture analgesia. The therapeutic effects of electroacupuncture (EA) and related techniques, such as transcutaneous electroacupoint stimulation (TEAS), are frequency-dependent: different frequencies of EA activate different brain regions and release different neuropeptides. EA and TEAS have been used successfully to treat heroin addiction. Activation of endorphin gene expression and release by TEAS can explain the dramatic attenuation of withdrawal syndrome and prolongation of retention time during and after detoxification treatment in patients who are addicted to heroin. However, repeated EA at high intensity should be avoided because it can induce a gradual loss of the analgesic effect. Opioid-receptor desensitization occurs and is manifested as decreased ligand-binding affinity and second-messenger detachment. Repeated large doses of morphine induce morphine tolerance. Cross-tolerance between morphine and EA suggests similar underlying mechanisms. Recent studies have demonstrated that excessive activation of cholecystokinin (CCK), an antiopioid peptide, appears to be responsible. CCK-receptor subtype B (CCKBR) and opioid μ-receptor are co-expressed in the dorsal-horn neurons. Activation of CCKBR promotes formation of heteromerization of morphine-receptor and CCKBR. Interaction of the third transmembrane domain between the 2 receptors resulted in the reduced binding affinity of the opioid receptor.

Autism spectrum disorder (ASD) is a developmental disorder characterized by social behavior deficit in childhood without satisfactory medical intervention. Transcutaneous electrical acupoint stimulation (TEAS) is a noninvasive technique derived from acupuncture and has been shown to have similar therapeutic effects in many diseases. Valproic acid- (VPA-) induced ASD is a known model of ASD in rats. The therapeutic efficacy of TEAS was evaluated in the VPA model of ASD in the present study. The offspring of a VPA-treated rat received TEAS in the early life stage followed by a series of examinations conducted in their adolescence. The results show that following TEAS treatment in early life, the social and cognitive ability in adolescence of the offspring of a VPA rat were significantly improved. In addition, the abnormal pain threshold was significantly corrected. Additional studies demonstrated that the dendritic spine density of the primary sensory cortex was decreased with Golgi staining. Results of the transcriptomic study showed that expression of some transcription factors such as the neurotrophic factor were downregulated in the hypothalamus of the VPA model of ASD. The reduced gene expression was reversed following TEAS. These results suggest that TEAS in the early life stage may mitigate disorders of social and recognition ability and normalize the pain threshold of the ASD rat model. The mechanism involved may be related to improvement of synaptic plasticity.

The pain-relieving effect of acupuncture is known to involve primary afferent nerves (PANs) via their roles in signal transmission to the CNS. Using single-unit recording in rats, we characterized the generation and transmission of electrical signals in Aβ and Aδ fibers induced by acupuncture-like stimuli. Acupuncture-like signals were elicited in PANs using three techniques: manual acupuncture (MAc), emulated acupuncture (EAc), and electro-acupuncture (EA)-like peripheral electrical stimulation (PES). The discharges evoked by MAc and EAc were mostly in a burst pattern with average intra-burst and inter-burst firing rates of 90 Hz and 2 Hz, respectively. The frequency of discharges in PANs was correlated with the frequency of PES. The highest discharge frequency was 246 Hz in Aβ fibers and 180 Hz in Aδ fibers. Therefore, EA in a dense-disperse mode (at alternating frequency between 2 Hz and 15 Hz or between 2 Hz and 100 Hz) best mimics MAc. Frequencies of EA output >250 Hz appear to be obsolete for pain relief. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12264-020-00509-3) contains supplementary material, which is available to authorized users.

Studies have shown that arginine-vasopressin (AVP) is an important neuropeptide regulating social behaviors. The present work aimed to detect changes in the AVP numbers and level in a valproic acid (VPA)-induced rat model of autism and the underlying mechanism of its pathogenesis. Our results indicated that infants exposed to VPA showed obviously impaired communication and repetitive behaviors with reduced number of AVP-ir cells in paraventricular nucleus (PVN) and cerebrospinal fluid (CSF). The postnatal subcutaneous injection of AVP can alleviate social preference deficits and stereotyped behaviors, accompanied with the increase of the AVP concentrations in the CSF. We concluded that AVP system was involved in etiology of VPA-induced autism-like symptoms and postnatal AVP treatment rescued the behavioral deficits,which could be a promising treatment for autism.

Introduction A systematic review and meta-analysis was carried out to assess the clinical effectiveness of acupuncture in treating polycystic ovarian syndrome (PCOS). Methods RCTs that compared either acupuncture with no/sham (placebo) acupuncture or a certain therapy with acupuncture added in the treatment of PCOS were included in the review. Measures of treatment effectiveness were the pooled odds ratios (OR) for women with PCOS having acupuncture compared with women in the control group for the recovery of menstrual cycles, standardized mean difference (SMD) for body mass index (BMI), fasting insulin (FINS), fasting plasma glucose (FPG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and the ratio of LH/FSH. Results A total of nine RCTs (531 women) met criteria for inclusion into the systematic review. Using the random effects model, pooling of the effect estimates from all RCTs showed recovery of menstrual cycles (OR = 0.20, 95% CI: 0.09–0.41, P P = 0.04), and LH (SMD = −0.39, 95% CI: −0.65 to −0.12, P P > 0.05). Conclusions Acupuncture appears to significantly improve the recovery of the menstrual cycles and decrease the levels of BMI and LH in women with PCOS. However, the findings should be interpreted with caution due to the limited methodological quality of included RCTs.

Oxytocin (OXT) and arginine-vasopressin (AVP) are two closely related neuropeptides and implicated in the regulation of mammalian social behaviors. A prior clinical study in our laboratory suggested that electro-acupuncture (EA) alleviated social impairment in autistic children accompanied by changes of peripheral levels of OXT and AVP. However, it remains unclear whether EA stimulation had an impact on central OXT and AVP levels. In the present study, rats were subjected to a single session of EA (sEA) or repeated sessions of EA (rEA). Following the stimulation, mRNA levels and peptide levels of OXT/AVP systems were determined. The results showed that sEA led to region-specific up-regulation of OXT and AVP mRNA levels in the hypothalamus where the peptides were produced, without affecting the content of OXT and AVP in the hypothalamus and peripheral blood. The rEA of 5 sessions in 9 days was given to the low socially interacting (LSI) rats. LSI rats that underwent rEA showed significant improvement of social behavior characterized by spending more time investigating the strange rats in the three-chamber sociability test. The improved sociability was accompanied by an up-regulation of mRNA and the peptide levels of OXT or AVP in SON of the hypothalamus as well as a significant increase of the serum level of AVP. It is concluded that activation of OXT/AVP systems may be associated with the pro-social effect caused by EA stimulation.

To investigate the clinical efficacy of transcutaneous electrical acupoint stimulation (TEAS) in treating children with autism spectrum disorders.Forty-one autistic children receiving rehabilitation training were randomized into TEAS ((1) The TEAS group showed more significant improvement than the control group in ABC (TEAS intervention can significantly improve the autistic symptoms.

Several lines of evidence suggested that abnormal levels of certain chemical elements may contribute to the development of autism spectrum disorders (ASD). The present work aimed to investigate the multiple chemical elements profile in the erythrocytes of autistic versus typically developing children (TDC) of China. Analyses were carried out to explore the possible association between levels of elements and the risk as well as the severity of ASD. Erythrocyte levels of 11 elements (32%) among 34 detected elements in autistic group were significantly different from those in the TDC group. To our knowledge, this is the first study which compared the levels of rare earth elements in erythrocytes between children with or without ASD. Five elements including Pb, Na, Ca, Sb, and La are associated with the Childhood Autism Rating Scale (CARS) total score. Also, a series of tendencies were found in this research which was believed to affect auditory response, taste, smell, and touch, as well as fear or nervousness. It can be concluded that Chinese autistic children suffer from multi-chemical element imbalances which involves a complex combination of genetic and environmental factors. The results showed a significant correlation between abnormal levels of several chemical elements and the severity of the autistic syndrome.It is suggested that abnormal levels of some chemical elements may contribute to the development of autism spectrum disorders (ASD). In this work, the impact of element imbalances on the risk and severity of ASD was investigated, focusing on the analysis of abnormal levels of the multi-chemical elements profile in erythrocytes compared with typically developing children. Furthermore, the results showed a significant correlation between abnormal levels of several chemical elements and the severity of the autistic syndrome. Autism Res 2018, 11: 834-845. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.

The nonapeptides oxytocin (OXT) and arginine vasopressin (AVP) are two key mediators in regulating various aspects of mammalian social behaviours. There are several lines of evidence that genetic variants of the OXT/AVP system exist in autism spectrum disorder (ASD) and that this system is dysfunctional at least in some ASD entities. These findings have stimulated the interest to perform studies testing the potential therapeutic application of OXT/AVP in ASD. In this respect animal models are critical for investigating the pathophysiology and for compound screening leading to new therapeutic approaches. Based on findings in animal models that show alterations of the OXT/AVP system, it has been hypothesised that single- or multiple-dose administration or the stimulation of endogenous release can improve several social deficits. Here we comprehensively review the role of the OXT/AVP system in social recognition, social interaction and maternal behaviour in the light of different ASD animal models and patient studies. We further discuss implications for OXT/AVP-related pharmacological interventions to alleviate social deficits in ASD in the future.

The nonapeptides oxytocin (OXT) and arginine vasopressin (AVP) are two key mediators in regulating various aspects of mammalian social behaviours. There are several lines of evidence that genetic variants of the OXT/AVP system exist in autism spectrum disorder (ASD) and that this system is dysfunctional at least in some ASD entities. These findings have stimulated the interest to perform studies testing the potential therapeutic application of OXT/AVP in ASD. In this respect animal models are critical for investigating the pathophysiology and for compound screening leading to new therapeutic approaches. Based on findings in animal models that show alterations of the OXT/AVP system, it has been hypothesised that single- or multiple-dose administration or the stimulation of endogenous release can improve several social deficits. Here we comprehensively review the role of the OXT/AVP system in social recognition, social interaction and maternal behaviour in the light of different ASD animal models and patient studies. We further discuss implications for OXT/AVP-related pharmacological interventions to alleviate social deficits in ASD in the future.

Autism spectrum disorder (ASD) is defined by impairments of social interaction and the presence of obsessive behaviors. The "twin" nonapeptides oxytocin (OXT) and arginine-vasopressin (AVP) are known to play regulatory roles in social behaviors. However, the plasma levels and behavioral relevance of OXT and AVP in children with ASD have seldom been investigated. It is also unknown whether their mothers have abnormal plasma peptide levels. Here, using well-established methods of neuropeptide measurement and a relatively large sample size, we determined the plasma levels of the two neuropeptides in 85 normal children, 84 children with ASD, and 31 mothers from each group of children. As expected, children with ASD had lower plasma OXT levels than gender-matched controls (P = 0.028). No such difference was found for plasma AVP concentrations. Correlation analysis showed that ASD children with higher plasma OXT concentrations tended to have less impairment of verbal communication (Rho = -0.22, P = 0.076), while those with higher plasma AVP levels tended to have lower levels of repetitive use of objects (Rho = -0.231, P = 0.079). Unlike the findings in children, maternal plasma OXT levels showed no group difference. However, plasma AVP levels in the mothers of ASD children tended to be lower than in the mothers of normal children (P = 0.072). In conclusion, our results suggest that the OXT system is dysregulated in children with ASD, and that OXT and AVP levels in plasma seem to be associated with specific autistic symptoms. The plasma levels of OXT or AVP in mothers and their ASD children did not seem to change in the same direction.

Oxytocin (OXT) and vasopressin (AVP) are considered to be related to mammalian social behavior and the regulation of stress responses. The present study investigated the effects of chronic homotypic restraint stress (CHRS) on social behaviors and anxiety, as well as its repercussions on OXT- and AVP-positive neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) nuclei in rat. Male Sprague-Dawley rats receiving CHRS were exposed to repeated restraint stress of 30min per day for 10days. Changes in social approach behaviors were evaluated with the three-chambered social approach task. Changes in anxiety-like behaviors were evaluated in the light-dark box test. The number of neurons expressing oxytocin and/or vasopressin in PVN and SON were examined by immunohistochemistry techniques. The results demonstrated that social approach was increased and anxiety was decreased following 10-day exposure to CHRS. Furthermore, the number of OXT-immunoreactive cells in PVN was increased significantly, whereas no change in SON was seen. The number of AVP immunoreactive cells either in PVN or SON was unaffected. The results of this study suggest that certain types of stress could be effective in the treatment of social dysfunction in persons with mental disorders such as autism, social anxiety disorder. The therapeutic effects may be mediated by changes in the function of OXT neurons in PVN.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent impairment in social communication and social interaction. Recent studies revealed that environmental factors, especially the intrauterine developmental environment, played important roles in the development of ASD. It is hypothesized that maternal hyperandrogenism during pregnancy may increase the susceptibility of the fetus to ASD. In the present study, pregnant rats were treated with a low dose of letrozole (1μg/kg/day) in an attempt to produce a hyperandrogenic intrauterine environment for the developing fetus. Results showed that rat pups prenatally exposed to hyperandrogenic intrauterine environment emitted less number of ultrasonic vocalizations when isolated from their dams and littermates. Additionally, the female rats in the treatment group spent less time in social interaction in adolescence and exhibited impaired heterosexual interaction in adult. Moreover, the duration of social interaction and heterosexual interaction of the female offspring were negatively correlated with maternal serum testosterone levels during pregnancy. These results suggest that prenatal exposure to hyperandrogenic intrauterine environment could induce autistic-like behavior in female rats and maternal hyperandrogenism during pregnancy should be considered as a potential risk factor for the etiology of ASD.

Structures of Bi 2 Sr 2 CaCu 2 O y single crystals, as grown, annealed in O 2 and Ar at 400°C for 48 h, respectively, have been examined by X-ray diffraction. It is found that the crystal after annealing in O 2 structurally has good quality, while after annealing in Ar it has bad quality. Most important, multi-layer structure is found from the high resolution rocking curve of the crystal annealed in Ar. Considering the change of the T c value of the crystals after annealing in different atmospheres, we suggest besides oxygen content, structural modification may play an important role in the superconductivity of Bi 2 Sr 2 CaCu 2 O y .

An anomalously big jump of thermal expansion in the c direction of the Bi 1.7 Pb 0.3 Sr 2 Ca 2 Cu 3 O 10+ y has been observed at a temperature slightly above the superconductivity transition temperature, T c . The jump is one order of magnitude bigger than the estimated value with the classical theory of superconductivity. This anomalously big jump vanishes after the samples were annealed in O 2 for a long time and became nonsuperconducting. The correlation between the anomaly and the T c support the view that electron–phonon interaction as well as superconductivity is enhanced by anharmonicity of phonons in high- T c cuprates.

Bi2Sr2CaCu2Oy single crystal was studied by means of high-resolution X-ray diffraction and the local work function measurement with scanning tunneling microscope (STM). The results show that the single crystal is natively inhomogeneous. The rocking curve of 0 0 l reflection indicates that the c-axis lattice constant of the crystal varies in a narrow range, clearly showing a multi-layer character. The reflectivity measurement supports this result. It shows an obvious multi-layer character too. The small angle scattering indicates that although the c-axis lattice constant is little different in the crystal, it shows a long period of about 340 A. The local work function measurement with STM demonstrates that the crystal is inhomogeneous. Some part in the crystal acts like thin film and some part like substrate, supporting the results of X-ray analyses.

In 1983, the Southern Medical Journal advised its readers that a scientific basis might underlie the popular practice of ancient Chinese acupuncture. Recent studies have proven this to be correct, and a 1997 National Institutes of Health consensus panel recommended acupuncture as a useful clinical procedure.Pertinent articles in the literature were reviewed, including our own research. Significantly, we had access to recent important studies from China.Most of the 10,000 acupuncturists in the country today practice metaphysically explained "meridian theory" acupuncture using needles to supposedly remove blockages of a hypothesized substance "Qi." Scientific research has shown that healing is not by manipulating Qi but rather by neuroelectric stimulation for the gene expression of neuropeptides. Needles are not necessary. Evidence-based neuroelectric acupuncture requires no metaphysical rituals. It is a simple, useful clinical tool for pain modulation and other conditions and can be easily taught to physicians.

Chronic cold stress (4 degrees C) produced a sustained increase in mean arterial pressure in both normotensive and borderline hypertensive rats (BHR). The high blood pressure in BHRs was significantly reversed by a neuropeptide Y (NPY) Y1 receptor antagonist suggesting that NPY is involved in mediating stress-induced hypertension. Corresponding increases in adrenal NPY messenger RNA and NPY immunoreactivity were found during the stress; furthermore, chronic cold stress also potentiated the pressor response of rats to a subsequent acute stress test in which NPY has been shown to play a role. These results suggest that chronic cold stress-induced hypertension is mediated by elevated NPY release and vascular tone as a result of increased NPY gene expression and storage.

Pheochromocytoma (PC)-12 cells express Y1, Y2, and Y3neuropeptide Y (NPY) receptors when differentiated with nerve growth factor (NGF). The present work evaluated NGF-differentiated PC-12 cells as a model system to study modulation of NPY release by NPY autoreceptors. We demonstrated that both K+and nicotine stimulated concomitant release of NPY and dopamine from differentiated PC-12 cells. We also showed in this study that NPY release from PC-12 cells was attenuated in a concentration-dependent manner by peptide YY (PYY)-(13—36), a selective agonist for the Y2type of NPY receptors. This result demonstrated that NPY release could be modulated by NPY autoreceptors of the Y2subtype. The inhibitory action of PYY-(13—36) may be mediated at least in part by inhibition of N-type Ca2+channels, because PYY-(13—36) could not produce further inhibitory effects in the presence of a maximum effective concentration of ω-conotoxin, an N-type Ca2+-channel blocker. The inhibition by PYY-(13—36) could be blocked by pretreatment of cells with pertussis toxin, suggesting that an inhibitory GTP-binding protein was involved. Furthermore, the function of NPY autoreceptors could be modulated by other receptors such as β-adrenergic and ATP receptors. The evoked release of NPY was also attenuated by ATP and adenosine, which have been shown to be colocalized and coreleased with NPY from sympathetic nerve terminals. These results suggest that PC-12 cells differentiated with NGF may be an ideal model to study regulatory mechanisms of NPY release and that autoreceptor-mediated regulation of NPY release appears to act through the Y2subtype of the NPY receptor.

Acupuncture increases brain levels of arginine-vasopressin (AVP) and oxytocin (OXT), which are known to be involved in the modulation of mammalian social behavior. Transcutaneous electrical acupoint stimulation (TEAS) is often used clinically to produce a similar stimulation to that of acupuncture on the acupoints. In the present study, TEAS was applied to children with autism to assess its therapeutic efficacy. Seventy-six autistic children receiving rehabilitation training were divided into 2 groups: a treatment group receiving TEAS 30min per day, 5 days per week for 12 weeks (n=37) and a control group without TEAS treatment (n=39). A series of rating scales was used in outcome assessment. Plasma levels of AVP and OXT were determined by enzyme immunoassay (EIA) before and after treatment. The TEAS group showed a significant improvement over the control in their emotional response, fear or anxiety, level/consistency of intellective relations and general impressions on the Childhood Autism Rating Scale (CARS) as well as improvements in the sensory and related factors in the Autism Behavior Checklist (ABC). In addition, the varieties of accepted food increased after TEAS treatment. It appears that TEAS was effective in autistic children who showed passive and aloof behavior, but not in those who were active but odd. The plasma level of AVP was significantly higher in the TEAS group than in the control group after the intervention. In addition, the change in the plasma AVP level paralleled the improvement of some of the behavior factors in CARS, including adaptation to environmental change, listening response, perceptive response and fear or anxiety. It is concluded that TEAS is effective for the treatment of autistic children with a passive and aloof social interaction style. Changes in plasma levels of AVP and possibly OXT may be involved in mediating the therapeutic effect of TEAS.

Based on a block model, mainly considering the interaction between the perovskite, and the rock salt blocks in the unit cell of superconductors (marked by combinative energy), we calculated the influence of charge distribution on the combinative energy, which has a close relationship with the value of Tc. The holes in the Cu(2)–O plane, Cu(1)–O plane, and Ba–O plane were calculated, respectively. The holes in each plane were calculated in two different positions, in the corners and center. The results show that the hole in different sites influences the combinative energy obviously. When the hole is in the Cu(1)–O plane and Ba–O planes, the combinative energy is over 10 eV larger than that in the Cu(2)–O plane.

We provide the first functional evidence that calcitonin gene-related peptide (8-37) induces a direct vasoconstriction and reversibly antagonizes vasodilation of the mesenteric arterial bed induced by calcitonin gene-related peptide (CGRP) suggesting that CGRP (8-37) is a competitive antagonist of vascular CGRP receptors. Vasodilation induced by periarterial nerve stimulation was inhibited both by CGRP (8-37) and by desensitization of CGRP receptors. These results further support the evidence that the periarterial nerve stimulation-induced nonadrenergic noncholinergic vasodilation of the mesenteric vasculature is mediated by endogenous CGRP and its receptors.

1 The effect of neuropeptide Y (NPY) on cardiovascular function at three levels of the noradrenergic axis where the peptide is known to co-exist with noradrenaline (NA) and or adrenaline (A) was studied in normotensive Sprague-Dawley (SD), Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). 2 In the perfused mesenteric arterial bed, NPY and the structurally similar peptide intestinal polypeptide (PYY) decreased the periarterial nerve stimulation induced release of NA and potentiated the increase in perfusion pressure to nerve stimulation or exogenously applied agonists (e.g. angiotensin, vasopressin, phenylephrine). In contrast to NPY and PYY, C-terminal NPY fragments inhibited NA release and produced a parallel decrease in perfusion pressure thus supporting the concept of Y1 (post) and Y2 (pre) NPY receptors. 3 In the mesenteric artery of SHR the prejunctional inhibitory effect of NPY was attenuated while the postjunctional response was enhanced. 4 Following intrathecal (Int) injection of NPY, there was a decrease in blood pressure, total peripheral resistance (predominantly by a decrease in mesenteric vascular resistance) and renal nerve activity. The depressor effect of Int NPY was attenuated in the SHR. 5 Unilateral injections of NPY into the posterior hypothalamic nucleus increased blood pressure, hindquarter and renal vascular resistance and renal nerve activity. The pressor effect was enhanced in the SHR. 6 Periarterial nerve stimulation of the perfused mesenteric artery produced a frequency dependent vasodilation in beds pretreated with guanethidine and precontracted with methoxamine. The vasodilation was unaffected by propranolol or atropine but blocked by capsaicin or calcitonin gene related peptide (CGRP) antisera. CGRP decreased the vasoconstriction produced by nerve stimulation or exogenous NA. NA release was unaltered. 7 In SHR, the inhibitory effect of exogenous CGRP on the nerve stimulation induced increase in perfusion pressure was reduced as well as the duration of the vasodilation observed in the presence of guanethidine and methoxamine. 8 These results implicate NPY in the development or maintenance of hypertension in the SHR since the effects of NPY which decrease noradrenergic transmission or responsiveness are attenuated in the SHR, while those functions increasing noradrenergic responsiveness are increased in the SHR. Our results are consistent with CGRP serving as a noradrenergic-noncholinergic vasodilator neurotransmitter in the mesenteric arterial bed. A dysfunction of the CGRP system may also contribute to the pathogenesis of hypertension in the SHR.

Snake venom-derived sarafotoxin S6B (SRT) and porcine endothelium-derived endothelin-1 (ET) have striking structural similarities. In conscious, freely-moving rats, ET (0.67 nmol/kg) produced a transient tachycardia and fall in arterial blood pressure which was followed by a long-lasting increase in arterial pressure, bradycardia, decrease in cardiac output (CO) and marked increase in total peripheral resistance. In contrast, SRT (0.67 nmol/kg) produced only the sustained cardiovascular responses. The sustained cardiovascular effects of SRT or ET were similarly attenuated by nifedipine. SRT and ET (30 nM) produced vasoconstriction in the isolated perfused mesenteric vascular bed without initial vasodilation. SRT and ET had potent positive inotropic and negative chronotropic effects on isolated perfused hearts and induced toxic reactions including coronary vasospasm, arrhythmias, A-V block and ventricular fibrillation. In addition to SRT lacking the initial depressor response in vivo, several differences in the activities of the peptides were also observed. ET produced greater and longer-lasting actions than SRT in producing pressor and vasoconstrictor responses in all 3 preparations, and in its ability to induce toxic effects on the heart.

Summary 1 Chronic cold exposure of rats (7 days in a cold room at 4 °C) attenuated the sympathetic nerve stimulation (NS)-induced overflow of noradrenaline (NE) (measured by high-performance liquid chromatography, coupled to electrochemical detection) appearing in the perfusate/superfusate of the perfused mesenteric arterial bed as well as the increase in the perfusion pressure. 2 The same type of cold exposure resulted in an increase in tyrosine hydroxylase (TH) gene expression measured in the superior cervical ganglion and NE content measured in the mesenteric artery obtained from cold-exposed rats. 3 Addition of sodium nitroprusside, a nitric oxide (NO) donor, to the buffer perfusing the mesenteric arterial bed obtained from rats maintained at room temperature also resulted in an attenuation of the NS-induced overflow of NE and increase in perfusion pressure. 4 Nc-nitro-l-arginine methyl ester (l-NAME), an NO synthase inhibitor, placed in the drinking water prevented the attenuation of the pre- and post-junctional responses to NS of the mesenteric arterial bed obtained from cold-exposed rats. 5 l-NAME treatment also increased the cold-induced elevation of blood pressure seen in whole animals. 6 The present results are consistent with the idea that cold exposure leads to a concomitant increase in sympathetic nerve activity and production of NO. We hypothesize that the increase in production and release of NO results in a decrease in the biologically active form of NE despite increased synthesis and release of the catecholamine. 7 It is concluded that the above-mentioned interactions serve as a protective mechanism offsetting the increased release and action of NE from sympathetic nerves and thus preventing the development of hypertension.

Chronic cold stress of rats (4 °C; 1–3 weeks) induced a marked increase in gene expression (adrenal medulla; superior cervical ganglia), tissue content (mesenteric arterial bed) and nerve stimulation-induced overflow of NPY-immunoreactivity (NPYir) from the perfused mesenteric arterial bed. In contrast increased NPY neurotransmission was offset by an apparent decrease in the evoked overflow of norepinephrine (NE) due to a presumed deactivation of NE by nitric oxide (NO), despite increased sympathetic nerve activity. The net effect of these offsetting system was no change in basal or the evoked increase in perfusion pressure (sympathetic tone). It is concluded that differences in NPY and NE transmission act as an important compensatory mechanism preventing dramatic changes in arterial pressure when sympathetic nerve activity is high during cold stress.

Acupuncture is an ancient Chinese method to treat diseases and relieve pain. We have conducted a series of studies to examine the mechanisms of this ancient method for pain relief. This article reviews some of our major findings. Our studies showed that acupuncture produces analgesic effect and that electroacupuncture (EA) is more effective than manual acupuncture. Furthermore, electrical stimulation via skin patch electrodes is as effective as EA. The induction and recovering profiles of acupuncture analgesia suggest the involvement of humoral factors. This notion was supported by cross-perfusion experiments in which acupuncture-induced analgesic effect was transferred from the donor rabbit to the recipient rabbit when the cerebrospinal fluid (CSF) was transferred. The prevention of EA-induced analgesia by naloxone and by antiserum against endorphins suggests that endorphins are involved. More recent work demonstrated the release of endorphins into CSF following EA. In addition, low frequency (2 Hz) and high frequency (100 Hz) of EA selectively induces the release of enkephalins and dynorphins in both experimental animals and humans. Clinical studies suggesting its effectiveness for the treatment of various types of pain, depression, anxiety, spinally induced muscle spasm, stroke, gastrointestinal disorders, and drug addiction were also discussed.

Publisher Summary Evidence for the existence of these three cotransmitters—norepinephrine(NE), neuropeptide Y (NPY), and adenosine triphosphate (ATP)—has come from studies showing that they are located in sympathetic nerves and that they can be released under appropriate conditions. In addition, the application of each transmitter mimics a phase of sympathetic nerve stimulation and each phase can be blocked with appropriate antagonists. Earliere studies included the perfused mesenteric arterial bed of the rat and the nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cell. Both preparations were set up and utilized as previously described. The release of mediators was induced by periarterial nerve stimulation of the mesenteric arterial bed or depolarization with high K + (50 mM) of the PC12 cell. Nerve stimulation of the perfused mesenteric arterial bed resulted in the release of NE, ATP, and NPY. The release of NE was inhibited by NPY and NPY analogues. The ability of NPY to inhibit the evoked release of NE from the perfused mesenteric arterial bed of 8- to 10-week-old spontaneous hypertensive rat (SHRs) was attenuated compared with WKY rats while the postjunctional potentiation of the contractile effect induced by nerve stimulation or the exogenous administration of NE or ATP was enhanced. These results are consistent with alterations in the normal function of NPY playing a role in the development of hypertension in the SHR.

Han, S. P., X. Chen, Y. M. Wu, L. Naes and T. C. Westfall. Elevated neuropeptide Y gene expression and release during hypoglycemic stress. Peptides 18(9) 1335–1340, 1997.—Our previous studies show that neuropeptide Y (NPY) is involved in mediating sympathetic nerve stimulation-induced vasoconstriction. Insulin hypoglycemia is known to produce increased sympathetic output and elevated arterial pressure. The present study examined the role of NPY in the hypertensive response to insulin by examining the effects of insulin on NPY gene expression, tissue content and release. Subcutaneous injection of insulin produced an immediate increase in plasma NPY immunoreactivity (NPYir) and delayed increases in adrenal and neuronal NPY mRNA and adrenal NPYir in rats. These results suggest that NPY may play a role in insulin-induced hypertension.

Intrathecal administration of 1–100 pmol endothelin-1 in urethan-anesthetized rats elicited a dose-dependent decrease in arterial pressure and a modest bradycardia. The depressor response was associated with a sustained hindquarters vasodilation and a modest transient mesenteric vasoconstriction, indicating disparate effects on regional vascular resistance. In contrast, renal sympathetic nerve activity was unaffected except at the highest dose of endothelin-1 (100 pmol). The depressor effect of intrathecal endothelin is unlikely to be due to spinal ischemia produced by vasoconstriction, since a much greater dose of endothelin was needed to produce an increase in spinal vascular resistance compared with the dose necessary to produce hindquarters vasodilation and the depressor effect. Unlike intravenous administration, intrathecal endothelin-1 and endothelin-3 produced indistinguishable effects on arterial pressure, heart rate, renal sympathetic nerve activity, spinal blood flow, and spinal vascular resistance, suggesting that the spinal neuronal endothelin receptors may be less selective than those in the blood vessels. The centrally mediated depressor effect and the selective regional hemodynamic actions of intrathecal endothelin suggest a role of spinal endothelin in regulating cardiovascular function.

In the isolated perfused mesenteric vascular bed, porcine endothelin (ET) and sarafotoxin S6b produced direct vasoconstriction and potentiated nerve stimulation-induced vasoconstriction. ET also enhanced the vasoconstrictor response to exogenous norepinephrine (NE). Basal or stimulated endogenous NE release was not affected either by ET or sarafotoxin S6b. Qualitatively similar responses to ET and sarafotoxin S6b were always observed, although, in many cases, the response to ET was greater and longer lasting than to sarafotoxin S6b. These results indicate that vasoconstrictor responses to ET or sarafotoxin S6b are mediated primarily by postsynaptic mechanisms. No initial vasodilator response to ET or sarafotoxin S6b was observed in this mesenteric vascular preparation.

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorders characterized by impaired social interactions, communication deficits, and repetitive behavior. Although the mechanisms underlying its etiology and manifestations are poorly understood, several lines of evidence from rodent and human studies suggest involvement of the evolutionarily highly-conserved oxytocin (OXT) and arginine-vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behavior. As far as we know, there is no comprehensive review of the roles of the OXT and AVP systems in the development of ASD from the genetic aspect. In this review, we summarize the current knowledge regarding associations between ASD and single-nucleotide variants of the human OXT-AVP pathway genes OXT, AVP, AVP receptor 1a (AVPR1a), OXT receptor (OXTR), the oxytocinase/vasopressinase (LNPEP), and ADP-ribosyl cyclase (CD38).

Endothelin is a potent vasoactive peptide in anesthezed rats and isolated vascular smooth muscle. This study was performed to describe the hemodynamic effects of endothelin in conscious, freely moving rats. Endothelin (0.067-2 nmol/kg i.v.) produced long-lasting, dose-dependent increases in arterial pressure, mesenteric and, to a lesser degree, hindquarters vascular resistances and decreases in heart rate. We suggest that endothelin may play an important role in regulation of arterial pressure by modulating peripheral vasomotor tone.

Cholecystokinin (CCK) was originally isolated from the intestine and was later discovered to be widely distributed in gut endocrine tissue and the central and peripheral nervous systems. Numerous studies have concluded that CCK displays many properties of a neurotransmitter or neuromodulator [1]. CCK is very abundant in the caudato-putamen (cp) of the rat, where it appears to be mainly extrinsic. In the rat, some dopamine neurons in the substantia nigra also contain CCK [2], These neurons are known to be, at best, a minor source of CCK for the cp [3, 4]. The precise CCK cell groups projecting to the cp have not been conclusively identified, but it appears that the claustrumpiriform cortex area or the amygdala are likely sites for these CCK perikarya [3, 4].