Implication of locus coeruleus dysfunction in Prader-Willi syndrome: Insights from a mouse model.

Prader-Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/-p) animals. Compared to WT mice, Ndn + m/-p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/-p and WT mice, but Ndn + m/-p mice were less anxious. After acute restraint, Ndn + m/-p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/-p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/-p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.

Auto-setting multi-soliton temporal spacing in a fiber laser by a hybrid GA-PSO algorithm.

Multi-soliton operation in fiber lasers is a promising platform for the investigation of soliton interaction dynamics and high repetition-rate pulse. However, owing to the complex interaction process, precisely manipulating the temporal spacing of multiple solitons in a fiber laser is still challenging. Herein, we propose an automatic way to control the temporal spacing of multi-soliton operation in an ultrafast fiber laser by a hybrid genetic algorithm-particle swarm optimization (GA-PSO) algorithm. Relying on the intelligent adjustment of the electronic polarization controller (EPC), the on-demand temporal spacing of the double solitons can be effectively achieved. In particular, the harmonic mode locking with equal temporal spacing of double solitons is also obtained. Our approach provides a promising way to explore nonlinear soliton dynamics in optical systems and optimize the performance of ultrafast fiber lasers.

Prevalence of Hepatitis E Virus and Its Associated Outcomes among Pregnant Women in China.

Hepatitis E virus (HEV) is a significant public health concern worldwide. Pregnant women are at high risk of severe HEV infection. Various adverse outcomes in pregnant women related to HEV infection have been well documented in low-income and middle-income countries with poor sanitation. However, previous studies have provided inconsistent conclusions regarding the effects of HEV infection on the health of pregnant women and their infants in developed countries and contemporary China. In China, previous studies on HEV in pregnant women mainly focused on anti-HEV IgM and/or anti-HEV IgG. In this study, 4244 pregnant women were retrospectively analyzed for HEV-related markers. The positive rates of HEV antigen, HEV RNA, anti-HEV IgM, and anti-HEV IgG were 0.28%, 0.54%, 0.35%, and 10.49%, respectively. Among the 467 pregnant women who tested positive for at least one HEV-related marker, 92.93% (434) were positive for anti-HEV IgG only and 0.21% (1) were positive for HEV antigen, anti-HEV IgM, and anti-HEV IgG. Although the prevalence of anti-HEV IgG significantly increased with age, the prevalence of anti-HEV IgM, HEV RNA, and HEV antigen did not differ among pregnant women of different ages. Thirty-three pregnant women were positive for at least one of anti-HEV IgM, HEV antigen, and HEV RNA, and these individuals were recently or currently infected with HEV. None of the 33 pregnant women exhibited obvious clinical symptoms. Of the 33 pregnant women, 39.39% (13) experienced adverse fetal outcomes, including preterm birth, fetal distress, and low birth weight, the incidence of which was significantly higher than in pregnant women who were not recently or currently infected with HEV. These findings suggest that maternal HEV infection may impact the health of fetuses; thus, these results may contribute to the development of appropriate public health interventions for this population.

Probing the Effect of Acidosis on Tether-Mode Mechanotransduction of Proprioceptors.

Proprioceptors are low-threshold mechanoreceptors involved in perceiving body position and strain bearing. However, the physiological response of proprioceptors to fatigue- and muscle-acidosis-related disturbances remains unknown. Here, we employed whole-cell patch-clamp recordings to probe the effect of mild acidosis on the mechanosensitivity of the proprioceptive neurons of dorsal root ganglia (DRG) in mice. We cultured neurite-bearing parvalbumin-positive (Pv+) DRG neurons on a laminin-coated elastic substrate and examined mechanically activated currents induced through substrate deformation-driven neurite stretch (SDNS). The SDNS-induced inward currents (ISDNS) were indentation depth-dependent and significantly inhibited by mild acidification (pH 7.2~6.8). The acid-inhibiting effect occurred in neurons with an ISDNS sensitive to APETx2 (an ASIC3-selective antagonist) inhibition, but not in those with an ISNDS resistant to APETx2. Detailed subgroup analyses revealed ISDNS was expressed in 59% (25/42) of Parvalbumin-positive (Pv+) DRG neurons, 90% of which were inhibited by APETx2. In contrast, an acid (pH 6.8)-induced current (IAcid) was expressed in 76% (32/42) of Pv+ DRG neurons, 59% (21/32) of which were inhibited by APETx2. Together, ASIC3-containing channels are highly heterogenous and differentially contribute to the ISNDS and IAcid among Pv+ proprioceptors. In conclusion, our findings highlight the importance of ASIC3-containing ion channels in the physiological response of proprioceptors to acidic environments.

Determinants affecting the blood mercury levels of preschool children in Shanghai, China: A cross-sectional study.

Infants and children are vulnerable to mercury (Hg)-induced toxicity, which has detrimental effects on their neurological development. This study measured blood Hg levels (BMLs) and identified potential factors influencing BMLs, including demographic and socioeconomic factors, lifestyle, and daily dietary habits, among 0 to 7-year-old children in Shanghai. Our study recruited 1474 participants, comprising 784 boys and 690 girls. Basic demographic and lifestyle information were obtained and blood Hg were analyzed using the Direct Mercury Analyzer 80. The blood Hg concentrations of children in Shanghai ranged from 0.01 to 17.20 µg/L, with a median concentration of 1.34 µg/L. Older age, higher familial socioeconomic status, higher residential floors, and a higher frequency of consuming aquatic products, rice, vegetables, and formula milk were identified as risk factors. Other potential influencing factors including the mother's reproductive history (gravidity and parity), smoking (passive smoking), supplementation of fish oil and calcium need to be further investigated. These findings can be useful in establishing appropriate interventions to prevent children's high blood Hg concentrations in Shanghai and other similar metropolitan cities.

Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviates atherosclerosis through the modulation of M1 polarization.

BACKGROUND: Inflammation and immune dysfunction with classically activated macrophages(M1) infiltration are important mechanisms in the progression of atherosclerosis (AS). Dynamin-related protein 1 (DRP1)-dependent mitochondrial fission is a novel target for alleviating inflammatory diseases. This study aimed to investigate the effects of DRP1 inhibitor Mdivi-1 on AS. METHODS: ApoE-/- mice were fed with a high-fat diet supplemented with or without Mdivi-1. RAW264.7 cells were stimulated by ox-LDL, pretreated with or without MCC950, Mito-TEMPO, or Mdivi-1. The burden of plaques and foam cell formation were determined using ORO staining. The blood lipid profles and inflammatory cytokines in serum were detected by commercial kits and ELISA, respectively. The mRNA expression of macrophage polarization markers, activation of NLRP3 and the phosphorylation state of DRP1 were detected. Mitochondrial reactive oxygen species (mito-ROS), mitochondrial staining, ATP level and mitochondrial membrane potential were detected by mito-SOX, MitoTracker, ATP determination kit and JC-1 staining, respectively. RESULTS: In vivo, Mdivi-1 reduced the plaque areas, M1 polarization, NLRP3 activation and DRP1 phosphorylation at Ser616. In vitro, oxidized low-density lipoprotein (ox-LDL) triggered M1 polarization, NLRP3 activation and abnormal accumulation of mito-ROS. MCC950 and Mito-TEMPO suppressed M1 polarization mediated foam cell formation. Mito-TEMPO significantly inhibited NLRP3 activation. In addition, Mdivi-1 reduced foam cells by inhibiting M1 polarization. The possible mechanisms responsible for the anti-atherosclerotic effects of Mdivi-1 on reducing M1 polarization were associated with suppressing mito-ROS/NLRP3 pathway by inhibiting DRP1 mediated mitochondrial fission. In vitro, similar results were observed by DRP1 knockdown. CONCLUSION: Inhibition of DRP1-dependent mitochondrial fission by Mdivi-1 alleviated atherogenesis via suppressing mito-ROS/NLRP3-mediated M1 polarization, indicating DRP1-dependent mitochondrial fission as a potential therapeutic target for AS.

Carbachol increases locus coeruleus activation by targeting noradrenergic neurons, inhibitory interneurons and inhibitory synaptic transmission.

The locus coeruleus (LC) consists of noradrenergic (NA) neurons and plays an important role in controlling behaviours. Although much of the knowledge regarding LC functions comes from studying behavioural outcomes upon administration of muscarinic acetylcholine receptor (mAChR) agonists into the nucleus, the exact mechanisms remain unclear. Here, we report that the application of carbachol (CCh), an mAChR agonist, increased the spontaneous action potentials (sAPs) of both LC-NA neurons and local inhibitory interneurons (LC I-INs) in acute brain slices by activating M1/M3 mAChRs (m1/3 AChRs). Optogenetic activation of LC I-INs evoked inhibitory postsynaptic currents (IPSCs) in LC-NA neurons that were mediated by γ-aminobutyric acid type A (GABAA ) and glycine receptors, and CCh application decreased the IPSC amplitude through a presynaptic mechanism by activating M4 mAChRs (m4 AChRs). LC-NA neurons also exhibited spontaneous phasic-like activity (sPLA); CCh application increased the incidence of this activity. This effect of CCh application was not observed with blockade of GABAA and glycine receptors, suggesting that the sPLA enhancement occurred likely because of the decreased synaptic transmission of LC I-INs onto LC-NA neurons by the m4 AChR activation and/or increased spiking rate of LC I-INs by the m1/3 AChR activation, which could lead to fatigue of the synaptic transmission. In conclusion, we report that CCh application, while inhibiting their synaptic transmission, increases sAP rates of LC-NA neurons and LC I-INs. Collectively, these effects provide insight into the cellular mechanisms underlying the behaviour modulations following the administration of muscarinic receptor agonists into the LC reported by the previous studies.

Nintedanib Induces the Autophagy-Dependent Death of Gastric Cancer Cells by Inhibiting the STAT3/Beclin1 Pathway.

BACKGROUND: Tyrosine kinase inhibitors are currently the most widely studied targeted therapies for gastric cancer. As a triple tyrosine inhibitor, nintedanib can alleviate the progression of a variety of cancers, but it is poorly studied in gastric cancer. AIMS: To investigate the effect of nintedanib on gastric cancer. METHODS: This study investigated nintedanib's effect on gastric cancer autophagy in vivo and in vitro, and the activity and morphological changes of gastric cancer cells were detected by MTT and HE staining. Proliferation, migration, invasion, and EMT-related marker proteins of AGS and MKN-28 cells were detected. The effects of nintedanib on autophagy in gastric cancer cells were detected by acridine orange, immunofluorescence, and Western blotting assays. The regulation of nintedanib on STAT3 and Beclin1 was detected by qPCR and Western blotting assays. Subsequently, the effects of nintedanib on the tumor STAT3/Beclin1 pathway were verified by stably overexpressing STAT3 in gastric cancer cell lines and tumor-bearing experiments in nude mice. RESULTS: The results showed that nintedanib could inhibit gastric cancer cells' proliferation and EMT process. Meanwhile, autophagy was induced in AGS and MKN-28 cells, and the expression of autophagy-related protein Beclin1 was upregulated, and the phosphorylation level of STAT3 was downregulated. Nintedanib inhibited STAT3 phosphorylation and upregulated Beclin1 to inhibit tumor growth in gastric cancer cell lines with stable STAT3 overexpression and tumor-bearing experiments in nude mice. CONCLUSIONS: By inhibiting STAT3, nintedanib upregulated Beclin1 and caused autophagic death in gastric cancer cells.

Effects of APOE ε2 allele on basal forebrain functional connectivity in mild cognitive impairment.

BACKGROUND: Basal forebrain cholinergic system (BFCS) dysfunction is associated with cognitive decline in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Apolipoprotein E (APOE) ε2 is a protective genetic factor in AD and MCI, and cholinergic sprouting depends on APOE. OBJECTIVE: We investigated the effect of the APOE ε2 allele on BFCS functional connectivity (FC) in cognitively normal (CN) subjects and MCI patients. METHOD: We included 60 MCI patients with APOE ε3/ε3, 18 MCI patients with APOE ε2/ε3, 73 CN subjects with APOE ε3/ε3, and 36 CN subjects with APOE ε2/ε3 genotypes who had resting-state functional magnetic resonance imaging data from the Alzheimer's disease Neuroimaging Initiative. We used BFCS subregions (Ch1-3 and Ch4) as seeds and calculated the FC with other brain areas. Using a mixed-effect analysis, we explored the interaction effects of APOE ε2 allele × cognitive status on BFCS-FC. Furthermore, we examined the relationships between imaging metrics, cognitive abilities, and AD pathology markers, controlling for sex, age, and education as covariates. RESULTS: An interaction effect on functional connectivity was found between the right Ch4 (RCh4) and left insula (p < 0.05, corrected), and between the RCh4 and left Rolandic operculum (p < 0.05, corrected). Among all subjects and APOE ε2 carriers, RCh4-left Insula FC was associated with early tau deposition. Furthermore, no correlation was found between imaging metrics and amyloid burden. Among all subjects and APOE ε2 carriers, FC metrics were associated with cognitive performance. CONCLUSION: The APOE ε2 genotype may play a protective role during BFCS degeneration in MCI.

An attention base U-net for parotid tumor autosegmentation.

A parotid neoplasm is an uncommon condition that only accounts for less than 3% of all head and neck cancers, and they make up less than 0.3% of all new cancers diagnosed annually. Due to their nonspecific imaging features and heterogeneous nature, accurate preoperative diagnosis remains a challenge. Automatic parotid tumor segmentation may help physicians evaluate these tumors. Two hundred eighty-five patients diagnosed with benign or malignant parotid tumors were enrolled in this study. Parotid and tumor tissues were segmented by 3 radiologists on T1-weighted (T1w), T2-weighted (T2w) and T1-weighted contrast-enhanced (T1wC) MR images. These images were randomly divided into two datasets, including a training dataset (90%) and an validation dataset (10%). A 10-fold cross-validation was performed to assess the performance. An attention base U-net for parotid tumor autosegmentation was created on the MRI T1w, T2 and T1wC images. The results were evaluated in a separate dataset, and the mean Dice similarity coefficient (DICE) for both parotids was 0.88. The mean DICE for left and right tumors was 0.85 and 0.86, respectively. These results indicate that the performance of this model corresponds with the radiologist's manual segmentation. In conclusion, an attention base U-net for parotid tumor autosegmentation may assist physicians to evaluate parotid gland tumors.

Different patterns of exosomal α-synuclein between Parkinson's disease and probable rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α-synuclein (α-Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α-Syn (t-exo α-Syn), neural-derived exosomal α-Syn (n-exo α-Syn) and exosomal apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD. METHODS: In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α-Syn concentrations were measured using a one-step paramagnetic particle-based chemiluminescence immunoassay, and ASC levels were measured using the Ella system. RESULTS: It was found that t-exo α-Syn was significantly increased in the PD group compared to the pRBD and HC groups (p < 0.0001), whilst n-exo α-Syn levels were significantly increased in both the PD and pRBD groups compared to HCs (p < 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α-Syn in exosomes. CONCLUSIONS: Our results suggest that both t-exo α-Syn and n-exo α-Syn were elevated in the PD group, whilst only n-exo α-Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α-Syn and may facilitate synucleinopathy.

Dhh signaling pathway regulates reconstruction of seminiferous tubule-like structure.

The reconstruction of a tubule-like structure in vitro has provided a promising system to analyze factors that drive morphogenesis and the underlying mechanisms. In this study, we took advantage of the inhibitor cyclopamine and a smoothened agonist to detect the role of the Dhh signaling pathway in the reconstructed tubule-like structure. Sertoli cells did not show polarity, rounded peritubular myoid cells and scattered Leydig cells were observed, combined with less laminin and lower proliferation of Leydig, peritubular myoid, germ, and Sertoli cells. However, in the presence of SAG, elongated peritubular myoid cells gathered at the bottom of polarized Sertoli cells, and most of the Leydig cells gathered at the outer part of the elongated peritubular myoid cells. Moreover, SAG promoted the secretion of laminin, assisting in the formation of the basal membrane and promoting the proliferation of Leydig, peritubular myoid, and germ cells. The level of Gli1 was significantly downregulated when treated with cyclopamine, whereas it was significantly upregulated when treated with SAG. These results indicate that the Dhh signaling pathway regulates the reconstruction of tubule-like structures by regulating the expression of Gli1.

A multiple-tissue-specific magnetic resonance imaging model for diagnosing Parkinson's disease: a brain radiomics study.

Brain radiomics can reflect the characteristics of brain pathophysiology. However, the value of T1-weighted images, quantitative susceptibility mapping, and R2* mapping in the diagnosis of Parkinson's disease (PD) was underestimated in previous studies. In this prospective study to establish a model for PD diagnosis based on brain imaging information, we collected high-resolution T1-weighted images, R2* mapping, and quantitative susceptibility imaging data from 171 patients with PD and 179 healthy controls recruited from August 2014 to August 2019. According to the inclusion time, 123 PD patients and 121 healthy controls were assigned to train the diagnostic model, while the remaining 106 subjects were assigned to the external validation dataset. We extracted 1408 radiomics features, and then used data-driven feature selection to identify informative features that were significant for discriminating patients with PD from normal controls on the training dataset. The informative features so identified were then used to construct a diagnostic model for PD. The constructed model contained 36 informative radiomics features, mainly representing abnormal subcortical iron distribution (especially in the substantia nigra), structural disorganization (e.g., in the inferior temporal, paracentral, precuneus, insula, and precentral gyri), and texture misalignment in the subcortical nuclei (e.g., caudate, globus pallidus, and thalamus). The predictive accuracy of the established model was 81.1 ± 8.0% in the training dataset. On the external validation dataset, the established model showed predictive accuracy of 78.5 ± 2.1%. In the tests of identifying early and drug-naïve PD patients from healthy controls, the accuracies of the model constructed on the same 36 informative features were 80.3 ± 7.1% and 79.1 ± 6.5%, respectively, while the accuracies were 80.4 ± 6.3% and 82.9 ± 5.8% for diagnosing middle-to-late PD and those receiving drug management, respectively. The accuracies for predicting tremor-dominant and non-tremor-dominant PD were 79.8 ± 6.9% and 79.1 ± 6.5%, respectively. In conclusion, the multiple-tissue-specific brain radiomics model constructed from magnetic resonance imaging has the ability to discriminate PD and exhibits the advantages for improving PD diagnosis.

Experiences of living with juvenile idiopathic arthritis: a qualitative systematic review.

OBJECTIVE: The objective of this review was to investigate the available qualitative evidence to enhance understanding of the experiences of children and young adults living with juvenile idiopathic arthritis, and their carers, in any setting. INTRODUCTION: Juvenile idiopathic arthritis is the most common chronic rheumatic disease in childhood. Despite the availability of effective treatments, persistent pain, growth retardation, physical disability, and psychological problems can occur. This may reduce the quality of life for patients with juvenile idiopathic arthritis by negatively affecting their family, educational, and social well-being. Patient-centered management and care for patients with juvenile idiopathic arthritis requires increasing attention to their self-reported quality of life and experiences, in addition to clinically measured disease activity. Furthermore, caring for children with juvenile idiopathic arthritis may have negative impacts on the lives of their carers and families. The experiences of carers have been poorly understood and studied. This review describes experiences and perspectives from patients and carers in order to inform the needs of families throughout their juvenile idiopathic arthritis journey. INCLUSION CRITERIA: Studies describing the experiences of patients aged <21 years who have been diagnosed with juvenile idiopathic arthritis according to the International League of Associations for Rheumatology criteria, as well as the experiences of their carers, have been considered. METHODS: A comprehensive search using PubMed, CINAHL, Embase, PsycINFO, Web of Science, and Google Scholar, as well as relevant conference proceedings of the American College of Rheumatology (2018-2019), the European Pediatric Rheumatology Congress 2018, the European League Against Rheumatism (2018-2019), and the Asia Pacific League of Associations for Rheumatology (2018-2019), was undertaken in December 2020 to identify pertinent published and unpublished studies. Studies published in English from 2001 to 2020 were included. The JBI approach to study selection, critical appraisal, data extraction, and data synthesis was used. RESULTS: Ten studies were included in this review. A total of 61 findings were extracted and aggregated to form 12 categories. From the 12 categories, five synthesized findings were developed: i) Self-management of juvenile idiopathic arthritis requires pain management, medication management, and the acquisition of knowledge and professional support; ii) A promising relationship with health care professionals but unbalanced access to services; iii) Parental financial burden and their adjustment to maintain family happiness; iv) Patients and parents support the web-based approach to communicate and develop self-management skills and acknowledge the importance of clinical trials; v) Desire to live a normal life without prejudice from school, social settings, and the workplace. CONCLUSIONS: This review has provided a comprehensive overview of experiences and perceptions of patients juvenile idiopathic arthritis and their parents. It is important to understand what they need to know about the disease. This review also highlights the importance of appropriate web-based programs, career counseling, infrastructures, and school facilities. Findings in this review can guide future policy and practice in order to improve care for families and children with juvenile idiopathic arthritis. Further research is required to develop management strategies for medication intolerance and to evaluate the longitudinal benefits of relevant juvenile idiopathic arthritis programs. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42019133165.

Characterizing mild cognitive impairment in prodromal Parkinson's disease: A community-based study in China.

OBJECTIVE: The International Parkinson and Movement Disorder Society (MDS) has published research criteria for prodromal Parkinson's disease (pPD), which includes cognitive impairment as a prodromal marker. However, the clinical features of mild cognitive impairment (MCI) in pPD remain unknown. Our study aimed to evaluate the frequency and clinical features of mild cognitive impairment of pPD in the elderly in China. METHODS: The cross-sectional community-based study recruited 2688 participants aged ≥50 years. Subjects were diagnosed with pPD according to the MDS criteria. Overall, 39 pPD and 22 healthy controls underwent comprehensive clinical and neuropsychological assessment. MCI was also diagnosed by the MDS criteria. Next, we investigated the relationship between clinical factors and cognition. RESULTS: Among the 2,663 dementia-free and Parkinson disease (PD)-free participants, 55 met the criteria for pPD (2.1%) and 23 pPD met the criteria for MCI. Memory, attention/working memory, and executive function were the most frequent impaired domains, and amnestic MCI multidomain phenotype was the most frequent MCI subtype (69.57%) in pPD. Additionally, correlation analysis revealed that the global cognitive performance was negatively related to UPDRS-III score (r = -0.456, p = 0.004). CONCLUSION: MCI, specifically impairment in memory, attention/working memory, and executive domain, is present at the prodromal stage of PD. In addition, cognitive performance is correlated with motor symptoms in pPD. Our results reflect that cognitive profile, combined with motor symptoms, can help clinicians to identify individuals with pPD early, as those would be the optimal candidates for neuroprotective therapy.

High-resolution computed tomography findings independently predict epidermal growth factor receptor mutation status in ground-glass nodular lung adenocarcinoma.

BACKGROUND: For lung adenocarcinoma with epidermal growth factor receptor (EGFR) gene mutation, small molecule tyrosine kinase inhibitors are more effective. Some patients could not obtain enough histological specimens for EGFR gene mutation detection. Specific imaging features can predict EGFR mutation status to a certain extent. AIM: To assess the associations of EGFR mutations with high-resolution computerized tomography (HRCT) features in ground-glass nodular lung adenocarcinoma. METHODS: This study retrospectively assessed patients with ground-glass nodular lung adenocarcinoma diagnosed between January 2011 and March 2017. EGFR gene mutations in exons 18-21 were detected. The patients were classified into mutant EGFR and wild-type groups, and general data and HRCT image characteristics were assessed. RESULTS: Among 98 patients, 31 (31.6%) and 67 (68.4%) had mutated and wild-type EGFR in exons 18-21, respectively. Gender, age, smoking history, location of lesions, morphology, edges, borders, pleural indentations, and associations of nodules with bronchus and blood vessels were comparable in both groups (all P > 0.05). Patients with mutant EGFR had larger nodules than those with the wild-type (17.19 ± 6.79 and 14.37 ± 6.30 mm, respectively; P = 0.047). Meanwhile, the vacuole/honeycomb sign was more frequent in the mutant EGFR group (P = 0.011). The logistic regression prediction model included the combination of nodule size and vacuole/honeycomb sign (OR = 1.120, 95%CI: 1.023-1.227, P = 0.014) revealed a sensitivity of 83.9%, a specificity of 52.2% and an AUC of 0.698 (95%CI: 0.589-0.806; P = 0.002). CONCLUSION: Nodule size and vacuole/honeycomb features could independently predict EGFR mutation status in ground-glass nodular lung adenocarcinoma.

Cardiorespiratory arrest after iso-osmolar iodinated contrast injection: A case report of contrast-induced encephalopathy following contrast-enhanced computed-tomography.

RATIONALE: Contrast-induced encephalopathy (CIE) is a rare complication caused by administration of intravascular contrast media and characterized by acute reversible neurological disturbance. Most of the CIE cases are reported after arterial administration of contrast media such as during cerebral or coronary angiographies, yet only a few articles have reported CIE secondary to intravenous contrast. A case of CIE secondary to intravenous contrast administration is reported here. PATIENT CONCERNS: A 68-year-old man was admitted to our hospital for contrast-enhanced chest computed-tomography (CT) examination due to suspected pulmonary nodules. After CT examination, the patient lost consciousness and experienced a cardiorespiratory arrest. An emergency plain brain CT was done immediately which showed abnormal cortical contrast enhancement and cerebral sulci hyperdensity. DIAGNOSES: After excluding other differential diagnoses such as electrolytes imbalance, hypo/hyperglycemia, cardiogenic pathologies and other neurological emergencies such as cerebral hemorrhage, cerebral infarction, the final diagnosis of CIE was made. INTERVENTIONS: The patient was admitted to the intensive care unit for further management. A series of supportive treatments were arranged. OUTCOMES: Follow-up visits at the outpatient clinic showed no lasting neurological deficits. LESSONS: CIE should be considered as 1 of the differential diagnoses for a patient with acute neurologic symptoms after iodinate contrast administration. Neuroradiological imaging examinations are essential to rule out other etiologies such as acute cerebral infarction or intracranial hemorrhage.

Experiences of living with juvenile idiopathic arthritis: a qualitative systematic review protocol.

OBJECTIVE: The objective of this review is to identify, critically appraise and synthesize the available qualitative evidence to understand the experiences of children, young adults and their carers living with juvenile idiopathic arthritis in any setting. INTRODUCTION: Juvenile idiopathic arthritis is the most common rheumatic disease in childhood. Despite the availability of effective treatments, the disease still has negative impacts on patients' and carers' lives. Patients' and carers' experiences of living with juvenile idiopathic arthritis have been recognized as important in the measurement of health status and treatment implementation. Addressing these needs will facilitate more effective management and treatment of the disease. This protocol describes a method for a systematic review regarding the perspectives from patients and carers in order to highlight the needs of families throughout their juvenile idiopathic arthritis journey. INCLUSION CRITERIA: Studies on the experiences of patients aged <21 years who have been diagnosed with juvenile idiopathic arthritis according to the International League of Associations for Rheumatology criteria, as well as the experiences of their carers, will be considered. Papers included in this review will include, but not be limited to, designs such as phenomenology, grounded theory and ethnography. METHODS: A comprehensive search using PubMed, CINAHL, Embase, PsycINFO and Web of Science was undertaken in August 2019. Available studies published in English from 2001 to 2019 will be included. The recommended JBI method for study selection, critical appraisal, data extraction and data synthesis will be used. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO (CRD42019133165).

Firing activity of locus coeruleus noradrenergic neurons decreases in necdin-deficient mice, an animal model of Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by multiple respiratory, cognitive, endocrine, and behavioral symptoms, such as central apnea, intellectual disabilities, exaggerated stress responses, and temper tantrums. The locus coeruleus noradrenergic system (LC-NE) modulates a diverse range of behaviors, including arousal, learning, pain modulation, and stress-induced negative affective states, which are possibly correlated with the pathogenesis of PWS phenotypes. Therefore, we evaluated the LC-NE neuronal activity of necdin-deficient mice, an animal model of PWS. METHODS: Heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygotes (+m/-p) animals, which were examined of LC-NE neuronal activity, developmental reflexes, and plethysmography. RESULTS: On slice electrophysiology, LC-NE neurons of Ndntm1ky mice with necdin deficiency showed significantly decreased spontaneous activities and impaired excitability, which was mediated by enhanced A-type voltage-dependent potassium currents. Ndntm1ky mice also exhibited the neonatal phenotypes of PWS, such as hypotonia and blunt respiratory responses to hypercapnia. CONCLUSIONS: LC-NE neuronal firing activity decreased in necdin-deficient mice, suggesting that LC, the primary source of norepinephrine in the central nervous system, is possibly involved in PWS pathogenesis.

Inhibitory interneurons regulate phasic activity of noradrenergic neurons in the mouse locus coeruleus and functional implications.

KEY POINTS: The locus coeruleus (LC) contains noradrenergic (NA) neurons that respond to novel stimuli in the environment with phasic activation to initiate an orienting response; phasic LC activation is also triggered by stimuli, representing the outcome of task-related decision processes, to facilitate ensuing behaviours and help optimize task performance. Here, we report that LC-NA neurons exhibit bursts of action potentials in vitro resembling phasic LC activation in vivo, and the activity is gated by inhibitory interneurons (I-INs) located in the peri-LC. We also observe that inhibition of peri-LC I-INs enhances prepulse inhibition and axons from cortical areas that play important roles in evaluating the cost/reward of a stimulus synapse on both peri-LC I-INs and LC-NA neurons. The results help us understand the cellular mechanisms underlying the generation and regulation of phasic LC activation with a focus on the role of peri-LC I-INs. ABSTRACT: Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behaviour or stimuli representing the outcome of task-related decision processes to facilitate ensuing behaviours and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. We report here that LC-NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation-pause profile observed in animals. The activity was referred to as phasic-like activity (PLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory-inhibitory balance of the circuit. In support of this notion, we located a population of inhibitory interneurons (I-INs) in the medial part of the peri-LC that exerted feedforward inhibition of LC-NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri-LC I-INs with chemogenetic methods could enhance PLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri-LC I-INs and LC-NA neurons. These observations demonstrate functional roles of peri-LC I-INs in integrating inputs of the frontal cortex onto LC-NA neurons and gating the phasic LC output.