1,5-Hydrogen atom transfer of α-iminyl radical cations: a new platform for relay annulation for pyridine derivatives and axially chiral heterobiaryls.

The exploitation of new reactive species and novel transformation modes for their synthetic applications have significantly promoted the development of synthetic organic methodology, drug discovery, and advanced functional materials. α-Iminyl radical cations, a class of distonic ions, exhibit great synthetic potential for the synthesis of valuable molecules. For their generation, radical conjugate addition to α,ß-unsaturated iminium ions represents a concise yet highly challenging route, because the in situ generated species are short-lived and highly reactive and they have a high tendency to cause radical elimination (ß-scission) to regenerate the more stable iminium ions. Herein, we report a new transformation mode of the α-iminyl radical cation, that is to say, 1,5-hydrogen atom transfer (1,5-HAT). Such a strategy can generate a species bearing multiple reactive sites, which serves as a platform to realize (asymmetric) relay annulations. The present iron/secondary amine synergistic catalysis causes a modular assembly of a broad spectrum of new structurally fused pyridines including axially chiral heterobiaryls, and exhibits good functional group tolerance. A series of mechanistic experiments support the α-iminyl radical cation-induced 1,5-HAT, and the formation of several radical species in the relay annulations. Various synthetic transformations of the reaction products demonstrate the usefulness of this relay annulation protocol for the synthesis of significant molecules.

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Preparation and characterization of a novel composite acellular matrix/hyaluronic acid thermosensitive hydrogel for interstitial cystitis/bladder pain syndrome.

Bladder mucosa damage that causes harm to the interstitium is a recognized pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). The intravesical instillation of drugs is an important second-line therapy, but it is often necessary to use drugs repeatedly in the clinic because of their short residence time in the bladder cavity, which alters the therapeutic effect. To overcome this drawback, this study developed a novel composite acellular matrix/hyaluronic acid (HA) thermosensitive hydrogel (HA-Gel) using rabbit small intestinal submucosa extracellular matrix (ECM) as the thermosensitive material and HA as the drug component and examined its composition, microstructure, thermodynamic properties, temperature sensitivity, rheological properties, biocompatibility, drug release, hydrogel residue, and bacteriostatic properties. The study showed HA-Gel was liquid at temperatures of 15-37.5°C and solid at 37.5-50°C, its swelling rate decreased with increasing temperature, and its lower critical solution temperature occurred at approximately 37.5°C. This property made the hydrogel liquid at room temperature convenient for intravesical perfusion and turned into a solid about 1 min after entering the body and rising to body temperature to increase its residence time. Subsequent experiments also proved that the gel residue time of HA-Gel in vivo and the drug release time of HA in vivo could reach more than 5 days, which was significantly higher than that of HA alone, and it had good biocompatibility and antibacterial properties. Therefore, this hydrogel possesses the proper characteristics to possibly make it an ideal dosage form for IC/BPS intravesical instillation therapy.

The effects of a psychiatric clerkship on stigmatizing attitudes toward mental disorders as held by German medical students.

Background: According to the United Nations, access to medical care is a fundamental human right. However, there is widespread stigmatization of severe mental illnesses and this appears to seriously hamper the quality of healthcare in people with psychiatric co-morbidity. Thus, interventions that help reduce stigma among healthcare providers are urgently needed. Purpose: The objective of the current study was to investigate the effects of a psychiatric clerkship on stigmatizing attitudes toward mental disorders held by medical students. Methods: Between 2018 and 2019, a total of 256 third- and fourth-year students from Marburg University Medical School (Germany) completed two surveys-one before and one after a 2 week clerkship program that was designed to prioritize direct interaction with the patients. For measuring stigma, the questionnaires contained questions about students' attitudes toward psychiatry (ATP), including the Opening Minds Scale for Healthcare Providers (OMS-HC), Community Attitudes Toward the Mentally Ill (CAMI), and measurements according to the Stereotype-Content Model (SCM). We conducted pre-vs.-post comparisons using the Wilcoxon signed rank test with continuity correction or paired t-test and employed the Spearman method for correlational analysis. We considered p < 0.05 significant and adjusted all p-values reported here using the Benjamini-Hochberg procedure to account for family-wise error. Results: After the clerkship, a significantly reduced stigma was found, as assessed with ATP (mean p < 0.001), OMS-HC (sum and subscale "attitudes" p < 0.001; subscale "disclosure" p = 0.002), and both SCM subscales (p < 0.001). Moreover, we observed significant associations between stigma expression (e.g., OMS-HC sum) and the willingness of students to choose psychiatric residency after finishing medical school (before clerkship: p < 0.001; ρ = -0.35; change after clerkship: p = 0.004; ρ = -0.2). Conclusion: Our findings indicate that a psychiatric clerkship that involves students in direct interaction with patients may effectively reduce stigma. Therefore, we advocate the incorporation of components of direct interaction in medical education to combat stigma and unequal treatment, as this could improve outcomes in patients with severe mental illnesses.

Comparison of Flexion Relaxation Phenomenon After Single-Level and Multi-Level Anterior Cervical Discectomy and Fusion.

BACKGROUND: This prospective cohort study aimed to assess the influence of the number of fused segments in cervical paravertebral muscles by comparing the changes of the cervical flexion relaxation phenomenon (FRP) after single-level versus multilevel anterior cervical discectomy and fusion (ACDF). METHODS: A total of 115 patients who had undergone ACDF were retrospectively recruited and divided into a 1-level group (n = 44), a 2-level group (n = 40) and a 3- to 4-level group (n = 31). The flexion relaxation experiment was carried out 3 days preoperatively and 12 months postoperatively by surface electromyography (SEMG). Patients were examined using the neck visual analog scale, cervical Japanese Orthopedic Association score, Neck Disability Index, and C2-C7 range of motion (ROM). RESULTS: There was a significant difference in the time-related changes in flexion relaxation ratio (FRR) among the 3 study groups before and after surgery (F = 85.701; P < .001). Thirty-five patients (79.55%) with 1-level ACDF and 11 patients (27.5%) with 2-level ACDF had FRP were restored to normal at 12 months postoperatively; however, only 1 patient (3.33%) had normalized FRP after 3- to 4-level ACDF. There were significant differences in the time-related changes of the normalized SEMG root mean square values in each phase before and after surgery (P = .018, <.001, <.001, and <.001). A significant correlation was found between the changes in C2-C7 ROM and FRR in the 3 study groups (P = .007 for 1 level, P = .003 for 2 levels, and P = .036 for 3-4 levels). CONCLUSIONS: Single-level ACDF contributes to normalizing the FRP of cervical paravertebral muscles, which is not ideally recovered by 2-level ACDF. In contrast, 3- or 4-level ACDF could not normalize the cervical FRP. Our research supports the passive structure hypothesis.

Safety and efficacy of percutaneous electrocoagulation haemostasis in the treatment of grade IV haemorrhagic cystitis after allogeneic haematopoietic stem cell transplantation in children: a retrospective analysis.

BACKGROUND: To investigate the efficacy and safety of endoscopic electrocoagulation haemostasis via a percutaneous transhepatic approach for the treatment of grade IV haemorrhagic cystitis (HC) after allogeneic haematopoietic stem cell transplantation (allo-HSCT) in children. METHODS: The clinical data of 14 children with severe HC, who were admitted to Hebei Yanda Hospital between July 2017 and January 2020, were analysed retrospectively. There were nine males and five females, with an average age of 8.6 years (range: 3 to 13 years). After an average of 39.6 (7 to 96) days of conservative treatment in the hospital's haematology department, the bladders of all patients were filled with blood clots. A small 2-cm incision was made in the suprapubic area to enter the bladder and quickly clear the blood clots, and a percutaneous transhepatic approach to electrocoagulation and haemostasis was performed. RESULTS: In the 14 children, a total of 16 operations were performed, with an average operation time of 97.1 (31 to 150) min, an average blood clot of 128.1 (80 to 460) mL and an average intraoperative blood loss of 31.9 (20 to 50) mL. There were three cases of postoperative bladder spasm remission after conservative treatment. During the follow-up period of 1 to 31 months, one patient improved after one operation, 11 patients were cured after one operation, and two patients were cured after recurrent haemostasis by secondary electrocoagulation, four of whom died of postoperative non-surgical blood-related diseases and severe lung infections. CONCLUSION: Percutaneous electrocoagulation haemostasis can quickly remove blood clots in the bladders of children after allo-HSCT with grade IV HC. It is a safe and effective minimally invasive treatment.

Flow Pattern Study and Pressure Drop Prediction of Two-Phase Boiling Process in Different Surface Wettability Microchannel.

An experimental study of two-phase flow pressure drop using R-134a is conducted on three types of different surface wettability microchannels with superhydrophilic (contact angle of 0°), hydrophilic (contact angle of 43°) and common (contact angle of 70°, unmodified) surfaces, all with a hydraulic diameter of 0.805 mm. Experiments were conducted using a mass flux of 713-1629 kg/m2s and a heat flux of 7.0-35.1 kW/m2. Firstly, the bubble behavior during the two-phase boiling process in the superhydrophilic and common surface microchannel is studied. Through a large number of flow pattern diagrams under different working conditions, it is found that the bubble behavior shows different degrees of order in microchannels with different surface wettability. The experimental results show that the hydrophilic surface modification of microchannel is an effective method to enhance heat transfer and reduce friction pressure drop. Through the data analysis of friction pressure drop and C parameter, it is found that the three most important parameters affecting the two-phase friction pressure drop are mass flux, vapor quality, and surface wettability. Based on flow patterns and pressure drop characteristics obtained from the experiments, a new parameter, named flow order degree, is proposed to account for the overall effects of mass flux, vapor quality, and surface wettability on two-phase frictional pressure drop in microchannels, and a newly developed correlation based on the separated flow model is presented. In the superhydrophilic microchannel, the mean absolute error of the new correlation is 19.8%, which is considerably less than the error of the previous models.

A Novel Drug with Potential to Treat Hyperbilirubinemia and Prevent Liver Damage Induced by Hyperbilirubinemia: Carbon Dots Derived from Platycodon grandiflorum.

Platycodon grandiflorum (PG) is a traditional Chinese medicine with a long history, but its active compounds have not been reported. In this study, novel carbon dots (CDs), PG-based CDs (PGC-CDs), were discovered and prepared from PG via calcinations and characterized by transmission electron microscopy; high-resolution transmission electron microscopy; X-ray diffraction, fluorescence, ultraviolet-visible, and Fourier-transform infrared spectrometers; X-ray photoelectron spectroscopy; and high-performance liquid chromatography. In addition, the safety and antioxidant activity of PGC-CDs was evaluated by RAW264.7 cells and LO2 cells. The therapeutic effects of PGC-CDs on hyperbilirubinemia and liver protection were evaluated in a bilirubin-induced hyperbilirubinemia mice model. The experiment confirmed that the diameter range of PGC-CDs was from 1.2 to 3.6 nm. PGC-CDs had no toxicity to RAW264.7 cells and LO2 cells at a concentration of 3.91 to 1000 µg/mL and could reduce the oxidative damage of cells caused by H2O2. PGC-CDs could inhibit the increase levels of bilirubin and inflammation factors and increase the levels of antioxidants and survival rate, demonstrating that PGC-CDs possessed anti-inflammatory and anti-oxidation activity. PGC-CDs may reduce the content of bilirubin, so as to reduce a series of pathological lesions caused by bilirubin, which has potential in treating hyperbilirubinemia and preventing liver damage induced by hyperbilirubinemia.

Metastatic parotid gland malignancy: A preliminary study in an eastern Chinese population.

OBJECTIVE: This study aimed to determine the incidence and clinicopathological patterns of metastatic carcinoma of the parotid gland. METHOD: Ninety patients with parotid gland metastases admitted to our hospital between January 2003 and December 2018 were included in this study. Clinical and pathological data were obtained from the medical records and follow-ups. Kaplan-Meier analysis was used to assess overall survival of patients. RESULTS: Among the 90 patients, parotid gland metastases originated from the head and neck in 86 (95.6%), from non-head and neck in 4 (4.4%), from the oral cavity in 30(33.3%), and from the eyelid in 21 (23.3%). Among the 85 cases with parotid gland lymph node metastasis, 45 (52.9%) were diagnosed with extra-lymph node metastasis. The capsule of the parotid lymph nodes was thinner than that of the cervical lymph nodes (P < 0.05). Hematogenous metastases to the parotid gland (only five cases) were rare, mainly from the non-head and neck malignancies. Patients with oral squamous cell carcinoma and meibomian adenocarcinoma with parotid metastatic disease had poorer overall survival (P < 0.05). CONCLUSION: Eastern China population analysis showed that parotid gland metastases usually arise from oral squamous cell carcinoma and eyelid, but rarely from cutaneous squamous cell carcinoma. Most cases metastasize to the parotid lymph nodes via the lymphatic system and are prone to extranodal extension with little or no facial nerve involvement. These findings have important implications for the treatment of metastatic parotid malignancies.

Sometimes I feel the fear of uncertainty: How intolerance of uncertainty and trait anxiety impact fear acquisition, extinction and the return of fear.

It is hypothesized that the ability to discriminate between threat and safety is impaired in individuals with high dispositional negativity, resulting in maladaptive behavior. A large body of research investigated differential learning during fear conditioning and extinction protocols depending on individual differences in intolerance of uncertainty (IU) and trait anxiety (TA), two closely-related dimensions of dispositional negativity, with heterogenous results. These might be due to varying degrees of induced threat/safety uncertainty. Here, we compared two groups with high vs. low IU/TA during periods of low (instructed fear acquisition) and high levels of uncertainty (delayed non-instructed extinction training and reinstatement). Dependent variables comprised subjective (US expectancy, valence, arousal), psychophysiological (skin conductance response, SCR, and startle blink), and neural (fMRI BOLD) measures of threat responding. During fear acquisition, we found strong threat/safety discrimination for both groups. During early extinction (high uncertainty), the low IU/TA group showed an increased physiological response to the safety signal, resulting in a lack of CS discrimination. In contrast, the high IU/TA group showed strong initial threat/safety discrimination in physiology, lacking discriminative learning on startle, and reduced neural activation in regions linked to threat/safety processing throughout extinction training indicating sustained but non-adaptive and rigid responding. Similar neural patterns were found after the reinstatement test. Taken together, we provide evidence that high dispositional negativity, as indicated here by IU and TA, is associated with greater responding to threat cues during the beginning of delayed extinction, and, thus, demonstrates altered learning patterns under changing environments.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

The Clinical Study of Bladder Flap Ureteroplasty (Psoas Hitch) in the Treatment of Lower Ureteral Injuries and Strictures (19 Cases).

Objective: The aim of this study was to investigate the efficacy and safety of bladder flap ureteroplasty (psoas hitch) in the treatment of lower ureteral injuries and strictures. Methods: 19 patients with lower ureteral injuries and strictures scheduled for a bladder flap ureteroplasty (psoas hitch) in our hospital from January 2020 to January 2021 were recruited. The outcome measures included treatment efficacy and safety. Results: The operative time, intraoperative bleeding, catheter extubation time, hospital stay, extubation time of ureteral stent, and follow-up time were (125.36 ± 15.38) min, (75.37 ± 11.09) ml, (7.25 ± 1.04) d, (8.76 ± 1.11) d, (46.34 ± 7.66) d, and(19.27 ± 1.27) months, respectively. No serious perioperative adverse reactions were observed, and all the symptoms of patients were relieved. Conclusion: Bladder flap ureteroplasty (psoas hitch) is safe and effective for the treatment of lower ureteral injuries, with advantages such as less intraoperative bleeding and trauma and rapid recovery, so it is worthy of promotion. This was a retrospective study supervised by the Ethics Committee of Hebei Yanda Hospital.This trial is registered with no. hebYD076.

Neural Correlates of Facial Emotion Recognition in Non-help-seeking University Students With Ultra-High Risk for Psychosis.

Background: Since the introduction of the neurodevelopmental perspective of schizophrenia research on individuals at ultra-high risk for psychosis (UHR) has gained increasing interest, aiming at early detection and intervention. Results from fMRI studies investigating behavioral and brain functional changes in UHR during facial emotion recognition, an essential component of social cognition, showed heterogenous results, probably due clinical diversity across these investigations. This fMRI study investigated emotion recognition in a sub-group of the UHR spectrum, namely non-help-seeking, drug-naïve UHR with high cognitive functioning to reveal the neurofunctional underpinnings of their social functioning in comparison to healthy controls. Methods: Two large cohorts of students from an elite University (n 1 = 4,040, n 2 = 4,364) were screened firstly with the Prodromal Questionnaires and by surpassing predefined cut-offs then interviewed with the semi-structured Interview for Psychosis-Risk Syndromes to verify their UHR status. Twenty-one identified non-help-seeking UHR and 23 non-UHR control subjects were scanned with functional magnetic resonance imaging while classifying emotions (i.e., neutral, happy, disgust and fear) in a facial emotion recognition task. Results: Behaviorally, no group differences were found concerning accuracy, reaction times, sensitivity or specificity, except that non-help-seeking UHR showed higher specificity when recognizing neutral facial expressions. In comparison to healthy non-UHR controls, non-help-seeking UHR showed generally higher activation in the superior temporal and left Heschl's gyrus as well as in the somatosensory, insular and midcingulate cortex than the control subjects during the entire recognition task regardless of the emotion categories. In an exploratory analysis, in the non-help-seeking UHR group, functional activity in the left superior temporal gyrus was significantly correlated with deficits in the ability to experience emotions at uncorrected statistical thresholds. Conclusions: Compared to healthy controls, non-help-seeking UHR show no behavioral deficits during facial emotion recognition, but functional hyperactivities in brain regions associated with this cognitive process. Our study may inspire future early intervention and provide loci for treatment using neural stimulation.

The impact of microplastic pollution on ecological environment: a review.

Microplastic pollution and its impact on the ecological environment have attracted worldwide attention. The strong adsorption capacity of the microplastic surface plays an important role in the migration of microplastics throughout the environment. Synergistic effects between microplastics and persistent organic pollutants increase the toxicity of pollutants to organisms. In addition, microplastics cause different degrees of harm to aquatic organisms with different nutritional levels. However, the toxic effects of microplastics and organic pollutants on organisms, the distribution of microplastics in higher aquatic organisms, and the nutrient transfer in complex aquatic food webs require further research. Therefore, studying the impact of microplastics on the ecological environment would provide insights into controlling microplastic pollution. This paper in-depth discusses the source, distribution, and transmission of microplastics and summarizes the current situation of the impact of microplastics on the ecological environment, including physical, chemical, and biological effects. This paper also suggests topics for further research on the influence of microplastics on various aspects of the ecological environment.

Clinical study on the pattern of lower-level lymphatic metastasis in primary tongue squamous cell carcinoma.

OBJECTIVES: To study and analyze the clinical patterns of lower-level lymph node (Ⅳ and Ⅴ) metastasis in primary tongue squamous cell carcinoma, and establish a reference for the decision-making of the lower-level neck dissection in tongue squamous cell carcinoma. METHODS: A total of 203 patients with primary tongue squamous cell carcinoma were recruited. These patients underwent simultaneous/secondary comprehensive neck (level Ⅰ-Ⅴ) dissection in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine from January 2010 to December 2015. Their clinicopathological and follow-up data were obtained and analyzed to reveal the prognosis and risk factors of primary tongue squamous cell carcinoma with lower-level lymph node metastasis. RESULTS: Among the 203 patients, the metastasis rates of levels Ⅳ and Ⅴ are 14.78% and 4.93%, respectively. Level Ⅳ metastasis is more prevalent in males than females (P=0.04); non-smokers are more likely to have level Ⅴ metastasis than smokers (P=0.046). Lymph node status in levels Ⅲ and Ⅳ are significantly associated with the risk of metastasis in level Ⅴ (P=0.001). Patients with extracapsular invasion in level Ⅲ have a significantly increased risk of metastasis in levels Ⅳ (P=0.014) and Ⅴ (P=0.026). The 5-year survival rate of patients with lower lymph node (Ⅳ/Ⅴ) metastasis is only 14.70%, which is an independent poor prognostic factor for patients with primary tongue squamous cell carcinoma (P<0.000 1). CONCLUSIONS: Most primary tongue squamous cell carcinoma metastases occur in levels Ⅰ-Ⅲ. However, the rate of lower-level lymph node metastasis is rather low. For the cN0 and cN+ patients with levels Ⅰ-Ⅱ lymph node metastases without extracapsular invasion, the strategy for level Ⅴ management may be observation rather than dissection.

Efficacy and safety of transurethral resection of bladder tumor for superficial bladder cancer.

The purpose of this study was to explore the efficacy and safety of transurethral resection of bladder tumor (TURBT) in the treatment of superficial bladder cancer (SBC). In this retrospective study, we included 103 patients with SBC who were admitted to the Hebei Yanda Hospital from March 2015 to May 2019. Among them, 53 patients were treated by TURBT and assigned to the research group. The rest, 50 patients, were treated by partial cystectomy (PC) and were included in the control group. The two groups were compared in terms of curative efficacy, complications, operation-related indexes, 2-year recurrence and survival, quality of life, and serum tumor markers. The operation-related indexes mainly included intraoperative blood loss, the time of operation, bladder flushing, catheter indwelling, and hospitalization. The quality of life of patients was assessed by the 36-Item Short-Form Health Survey (SF-36). The data revealed that compared with the control group, the overall response rate and the scores of various dimensions of the SF-36 were significantly higher in the research group. The complication rate, surgical indicators, and 2-year recurrence were significantly lower in the research group, with a better survival. Serum levels of tumor marker cancer antigen 125 (CA125), carcinoembryonic antigen (CEA), and neuron specific enolase (NSE) in the research group were significantly lower than those in the control group after treatment. TURBT is effective and safe in the treatment of patients with SBC.

Neural adaptation of cingulate and insular activity during delayed fear extinction: A replicable pattern across assessment sites and repeated measurements.

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24 h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.

The modulating impact of cigarette smoking on brain structure in panic disorder: a voxel-based morphometry study.

Cigarette smoking increases the likelihood of developing anxiety disorders, among them panic disorder (PD). While brain structures altered by smoking partly overlap with morphological changes identified in PD, the modulating impact of smoking as a potential confounder on structural alterations in PD has not yet been addressed. In total, 143 PD patients (71 smokers) and 178 healthy controls (62 smokers) participated in a multicenter magnetic resonance imaging (MRI) study. T1-weighted images were used to examine brain structural alterations using voxel-based morphometry in a priori defined regions of the defensive system network. PD was associated with gray matter volume reductions in the amygdala and hippocampus. This difference was driven by non-smokers and absent in smoking subjects. Bilateral amygdala volumes were reduced with increasing health burden (neither PD nor smoking > either PD or smoking > both PD and smoking). As smoking can narrow or diminish commonly observed structural abnormalities in PD, the effect of smoking should be considered in MRI studies focusing on patients with pathological forms of fear and anxiety. Future studies are needed to determine if smoking may increase the risk for subsequent psychopathology via brain functional or structural alterations.

Neural correlates of NOS1 ex1f-VNTR allelic variation in panic disorder and agoraphobia during fear conditioning and extinction in fMRI.

Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.

Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures.

Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients' pretreatment extinction learning performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment procedures. Therefore, we developed an extinction-training protocol highly tailored to the procedure of exposure therapy and tested it in two samples of 46 subjects in total. By using instructed fear acquisition training, including a consolidation period overnight, we wanted to ensure that the conditioned fear response was well established prior to extinction training, which is the case in patients with anxiety disorders prior to treatment. Moreover, the extinction learning process was analyzed on multiple response levels, comprising unconditioned stimulus (US) expectancy ratings, autonomic responses, defensive brain stem reflexes, and neural activation using functional magnetic resonance imaging. Using this protocol, we found robust fear conditioning and slow-speed extinction learning. We also observed within-group heterogeneity in extinction learning, albeit a stable fear response at the beginning of the extinction training. Finally, we found discordance between different response systems, suggesting that multiple processes are involved in extinction learning. The paradigm presented here might help to ameliorate the association between extinction learning performance assessed in the laboratory and therapy outcomes and thus facilitate translational science in anxiety disorders.