Detecting the footprint of selection on the genomes of Murciano-Granadina goats.

Artificial selection is one of the major forces modifying the genetic composition of livestock populations. Identifying genes under selection could be useful to elucidate their impact on phenotypic variation. We aimed to identify genomic regions targeted by selection for dairy and pigmentation traits in Murciano-Granadina goats. Performance of a selection scan based on the integrated haplotype score test in a population of 1183 Murciano-Granadina goats resulted in the identification of 77 candidate genomic regions/SNPs. The most significant selective sweeps mapped to chromosomes 1 (69.86 Mb), 4 (41.80-49.95 Mb), 11 (65.74 Mb), 12 (31.24 and 52.51 Mb), 17 (34.76-37.67 Mb), 22 (31.75 Mb), and 26 (26.69-31.05 Mb). By using previously generated RNA-Seq data, we built a catalogue of 6414 genes that are differentially expressed across goat lactation (i.e. 78 days post-partum, early lactation; 216 days post-partum, late lactation; 285 days post-partum, dry period). Interestingly, 183 of these genes mapped to selective sweeps and several of them display functions related with lipid, protein, and carbohydrate metabolism, insulin signaling, cell proliferation, as well as mammary development and involution. Of particular interest are the CSN3 and CSN1S2 genes, which encode two major milk proteins. Additionally, we found three pigmentation genes (GLI3, MC1R, and MITF) co-localizing with selective sweeps. Performance of a genome-wide association study and Sanger sequencing and TaqMan genotyping experiments revealed that the c.801C>G (p.Cys267Trp) polymorphism in the melanocortin 1 receptor (MC1R) gene is the main determinant of the black (GG or GC genotypes) and brown (CC genotypes) colorations of Murciano-Granadina goats.

[Research Progress on Estimation of Postmortem Submersion Interval].

ABSTRACT: Postmortem interval （PMI） estimation is one of the most important and difficult academic tasks in forensic sciences. Due to the influence of the corpse itself and the water environment, corpses in water have unique corruption phenomenon and laws. Based on the experience of traditional PMI studies of corpses on land, forensic practitioners across the world have proposed a variety of practical methods for estimating postmortem submersion interval （PMSI）. This paper summarizes the literatures related to PMSI in recent years, and introduces methods to infer PMSI according to the phenomenon of corpses, the development of insects, the succession pattern of aquatic organisms, and the changes of other physical and chemical indexes of corpses, in order to provide some reference for the study of PMSI of corpses in water.

Guide to the Forensic Pathology Practice on Death Cases Related to Corona Virus Disease 2019 （COVID-19） （Trial Draft）.

Abstract: Autopsy is of great significance to the elucidation of the pathological changes, pathogeneses and causes of death of corona virus disease 2019 （COVID-19） and can provide theoretical basis for more scientific and accurate prevention and control of the outbreak. Based on related laws and regulations, such as the Law of the People's Republic of China on Prevention and Control of Infectious Diseases, the clinical manifestations and epidemiological characteristics of COVID-19, and the related guidelines on the prevention and control of the outbreak, combined with the practical work of forensic pathology examination, the Guide to the Forensic Pathology Practice on Death Cases Related to Corona Virus Disease 2019 （COVID-19） （Trial Draft） has been developed. This guide includes information on the background investigation of the cases, autopsy room requirements, personal prevention and protections, external examinations, autopsy, auxiliary examinations, and so on. This guide can be used as a reference by forensic and pathological examination institutions, as well as examination staff.

Genomic analysis of the origins of extant casein variation in goats.

The variation in the casein genes has a major impact on the milk composition of goats. Even though many casein polymorphisms have been identified so far, we do not know yet whether they are evolutionarily ancient (i.e., they existed before domestication) or young (i.e., they emerged after domestication). Herewith, we identified casein polymorphisms in a data set of 106 caprine whole-genome sequences corresponding to bezoars (Capra aegagrus, the ancestor of domestic goats) and 4 domestic goat (Capra hircus) populations from Europe, Africa, the Far East, and the Near East. Domestic and wild goat populations shared a substantial number of casein SNP, from 36.1% (CSN2) to 55.1% (CSN1S2). The comparison of casein variation among bezoars and the 4 domestic goat populations demonstrated that more than 50% of the casein SNP are shared by 2 or more populations, and 18 to 44% are shared by all populations. Moreover, the majority of casein alleles reported in domestic goats also segregate in the bezoar, including several alleles displaying significant associations with milk composition (e.g., the A/B alleles of the CSN1S1 and CSN3 genes, the A allele of the CSN2 gene). We conclude that much of the current diversity of the caprine casein genes comes from ancient standing variation segregating in the ancestor of modern domestic goats.

Research Progress?on?Age?Determination?of?Venous?Thrombosis in Forensic Medicine.

ABSTRACT: Pulmonary thromboembolism （PTE）, which is caused by detachment of venous thrombosis, is a common cause of sudden death in forensic practice. In the cases which die of PTE after trauma or die of PTE during non-thrombosis disease hospitalization, forensic pathologists are required to analyze the time sequence between trauma or medical practice and venous thrombosis, and then analyze their causal relationship. This review summarizes the history of thrombus age estimation and recent advances in forensic medicine, and then gives a brief outlook for future research to provide reference for forensic identification of PTE and guide follow-up studies.

Relationship between Expression Changes of CB2R and Wound Age of Brain Contusion in Mice.

ABSTRACT: Objective To investigate the expression of cannabinoid type 2 receptor （CB2R） at different time points after brain contusion and its relationship with wound age of mice. Methods A mouse brain contusion model was established with PCI3000 Precision Cortical Impactor. Expression changes of CB2R around the injured area were detected with immunohistochemical staining, immunofluorescent staining and Western blotting at different time points. Results Immunohistochemical staining results showed that only a few cells in the cerebral cortex of the sham operated group had CB2R positive expression. The ratio of CB2R positive cells gradually increased after injury and reached the peak twice at 12 h and 7 d post-injury, followed by a decrease to the normal level 28 d post-injury. The results of Western blotting were consistent with the immunohistochemical staining results. Immunofluorescent staining demonstrated that the changes of the ratio of CB2R positive cells in neurons, CB2R positive cells in monocytes and CB2R positive cells in astrocytes to the total cell number showed a single peak pattern, which peaked at 12 h, 1 d and 7 d post-injury, respectively. Conclusion The expression of CB2R after brain contusion in neurons, monocytes and astrocytes in mice suggests that it is likely to be involved in the regulation of the biological functions of those cells. The changes in CB2R are time-dependent, which suggests its potential applicability as a biological indicator for wound age estimation of brain contusion in forensic practice.

Relationship between Changes of Pericyte Number and Wound Age during Repair of Skeletal Muscle Contusion in Mice.

ABSTRACT: Objective To observe the change pattern of pericyte number at different time periods after mice skeletal muscle contusion and discuss its role in wound age estimation. Methods A mice gastrocnemius muscle contusion model was established. The form and number changes of pericytes at 1, 3, 5, 7, 9, 14, and 28 d post-injury were detected by multiple immunofluorescence staining. Results Compared with the slender shape of pericytes in normal skeletal muscles, pericytes in the contusion area had increased volume, rounder form and a round nuclei. Part of pericytes were found to express satellite cell markers paired-box transcription factor （Pax7） or myoblast determination 1 （MyoD1）. The changes of pericyte number in skeletal muscles after contusion were time-dependant, and showed unimodal distribution with the extension of wound age. In the central contusion area, the number of pericytes peaked at 5 d post-injury while in the peripheral contusion area, the number of pericytes peaked at 5 d and 7 d post-injury. Conclusion The number of pericytes in contusion area varies time-dependently after skeletal muscle contusion in mice and might be a reference index for muscle wound age estimation, and is involved in the repair and regeneration of skeletal muscle injury.

Expression of Nrf2 in Different Cells after Human Cerebral Cortex Contusion.

ABSTRACT: Objective To observe the expression changes of nuclear factor-erythroid derived 2-related factors （Nrf2） in different cells at different time points after human cerebral cortex contusion, and to discuss its application in brain wound age estimation. Methods Thirty-six human brain tissues were selected, of which 6 were for control and 30 were cortical contusion at different time points post-injury, which were divided into 0-1 h, 3-6 h, 1-3 d, 5-7 d, and 10-14 d post-injury groups, with 6 cases in each group. Based on paraffin embedded sections, HE staining was used to observe the morphological changes post-injury, and double immunofluorescence staining was used to detect the expression of Nrf2 in neurons, astrocytes, and microglia. The number of positive cells was counted and statistical analysis was made. Results The number of neurons decreased 1-3 d post-injury. The expression of Nrf2 cells in neurons increased after injury, and the rate of positive cells peaked at 1-3 d post-injury. Glial cells were activated 1-3 d post-injury, and the activation peaked at 5-7 d post-injury. The cerebromalacia began to form at 10-14 d post-injury. Glial fibrillary acidic protein （GFAP） positive cells in mice increased gradually after injury and peaked at 5-7 d post-injury, while the proportion of Nrf2 in GFAP positive cells was relatively stable. After injury, ionized calcium-binding adapter molecule 1 （IBA1） positive cells increased and activated gradually. The expression proportion of Nrf2 in IBA1 positive cells increased gradually, reached its peak at 5-7 d post-injury, and then decreased. Conclusion The expression of Nrf2 in different cells involves in the biological function of different cells post-injury, and the dynamic expression of single cells has a time-dependent pattern. This may provide a new reference index for the wound age estimation of brain contusion in human.

Relationship between the Degeneration and Regeneration of Neuromuscular Junction and Wound Age during the Repair of Mouse Skeletal Muscle Contusion.

ABSTRACT: Objective To investigate the morphological changes in the degeneration and regeneration of neuromuscular junctions （NMJ） during the repair of mouse skeletal muscle contusion and discuss the correlation between the degeneration and regeneration of NMJ and wound age. Methods A total of 50 healthy adult male mice were randomly divided into 10 groups, including 9 experimental groups and 1 control group. Immunofluorescent staining was applied, and neurofilament was marked with neurofilament protein-H （NF-H）, presynaptic membrane was marked with synaptophysin （Syn）, presynaptic membrane was marked with acetylcholine receptor （AChR）. Morphological changes of NMJ regeneration at different time points after mouse skeletal muscle contusion were detected. Results The neurofilament and presynaptic membrane of NMJ at the junction of contusion zones began to degrade after contusion, and completed degradation at about 3 d post-injury. Then they gradually regenerated, roughly completing the regeneration at about 21 d and basically reaching the control group level. The ratio of presynaptic membrane quantity to presynaptic membrane quantity showed a trend of decreasing then rising and finally reaching the control level. Conclusion During the repair of mouse skeletal muscle contusion, the morphological changes and wound age of the NMJ at the junction of contusion zones have a close correlation, which is expected to be one of the biological indicators for forensic skeletal muscle wound age estimation.

Statistical Analysis of the Heart and Lung Mass in Forensic Anatomical Cases and Its Forensic Significance.

ABSTRACT: Objective To investigate the differences of heart mass and lung mass in forensic autopsy cases and to explore their application value in forensic identification. Methods The data from 1 614 autopsy cases accepted by center of Medico-legal Investigation of China Medical University between 2007 to 2016 were collected. The correlation of heart and lung mass with age, height, body weight, and body mass index （BMI）, as well as differences in different causes of death were analyzed by GraphPad Prism 6.0 software. Results The heart mass and lung mass of males were higher than those of females （P<0.05）. The heart mass of males and females was positively correlated with age, height, body weight and body mass index （BMI） （P<0.05）. The heart mass of patients dying from sudden cardiac death （SCD） was significantly higher than those dying from other causes of death. The lung mass of patients dying from drowning and delayed treatment was higher than those dying from other causes of death （P<0.05）. Conclusion In forensic practice, measurement of the heart mass and lung mass has certain significance for differential diagnosis and diagnosis of different causes of death.

Thymoquinone protects against cerebral small vessel disease: Role of antioxidant and anti-inflammatory activities.

Cerebral small vessel disease (CSVD) is a leading cause of progressive decline of cognition and a major risk factor for stroke. Thymoquinone (TQ) is the major biological component of Nigella sativa (N. sativa) and its extracts. We explored the possible protective effect of TQ against CSVD in strokeprone spontaneously hypertensive SHRsp rats. Morris water maze and novel object recognition tests were conducted to evaluate memory and cognitive function. mRNA expression of inflammatory factors were determined and oxidative stress was evaluated. We showed that TQ markedly decreased the level of systolic blood pressure in SHRsp rats. TQ reduced the escape latency time and the time spent in the target quadrant in the Morris water maze test in SHRsp rats. TQ also decreased the time spent with the novel object in SHRsp rats in both short- and long-term memory tests. TQ markedly increased the capacity to distinguish between familiar objects and novel objects in the SHRsp rats in the short- and long-term memory tests. The mRNA expression of IL-1ß, IL-6, monocyte chemoattractant protein-1 and cyclooxygenase-2 in the brain of SHRsp rats was remarkably decreased by TQ, indicating the reduction of inflammation. Moreover, TQ increased the activities of superoxide dismutase and catalase, decreased the malondialdehyde level and increased glutathione level in the brain of SHRsp rats, indicating the attenuation of oxidative stress. In summary, we found that TQ could effectively attenuate the blood pressure and the injury of memory and cognition under the condition of CSVD. The anti-inflammatory and antioxidant activities of TQ may be responsible for its protective effect. We demonstrate that TQ is a novel candidate for the treatment of CSVD and its neurological outcome.

Effects of ALA-PDT on HPV16-immortalized cervical epithelial cell.

Current treatments for high-grade cervical intraepithelial neoplasia (CIN) and persistent infection with high-risk human papillomavirus (HR-HPV) type are mainly surgical interventions. However, such treatments are associated with adverse side effects and pose risks for future pregnancies. In order to reduce the requirement for excisional procedures, an effective and noninvasive therapy is needed for women at reproductive age. ALA-PDT has proved to be effective in the treatment of HPV-associated disease in several clinical investigations. In this study, the anti-proliferative effect of ALA-PDT was investigated in HPV16-immortalized cervical epithelial H8 cells. CCK-8 assay was used to measure cytotoxicity in H8 cells. The IC50 of ALA-PDT on H8 cells was about 120.75 ± 1.18 µM. We have now evaluated the mechanism by which ALA-PDT induces cell death. Annexin V-FITC/PI staining showed a significant dose-dependent induction of apoptosis by ALA-PDT in H8 cells, associated with accumulation of the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitor p21. Furthermore, ALA-PDT down-regulates expression of HPV E6/E7 oncogene as well as up-regulate tumor suppressor RbAp48 protein. Together, our data provides a basis for understanding and developing ALA-PDT as a cure for HPV infection-associated diseases and prevention of cervical cancer.

[Forensic Analysis of 6 Cases of Sudden Death due to Hyperthyroid Heart Disease].

OBJECTIVES: To analyse the cases of sudden death due to hyperthyroid heart disease, and explore the general information of deaths and the forensic pathological characteristics to provide reference evidence for forensic identification of such cases. METHODS: Six cases of sudden death due to hyperthyroid heart disease between 2001 and 2016 were selected from School of Forensic Medicine, China Medical University. The general information （gender and age）, clinical manifestations, medical history, anatomical and histopathological findings, biochemical parameters and cause of death were analysed retrospectively. RESULTS: Most of the 6 patients had definite history of hyperthyroidism, and they all showed certain degrees of symptoms of cardiovascular disease; had obvious incentive factors of death; histopathological examination of thyroid conformed to the performances of diffuse toxic goiter; with increase of cardiac weight, dilatation of cardiac chambers, myocardial hypertrophy and focal necrosis; postmortem biochemical analyses of pericardial fluid could be used as an additional method for diagnostic of sudden death due to hyperthyroid heart disease. CONCLUSIONS: The identification of death due to hyperthyroid heart disease should be based on the clinical history and the results of autopsy, histopathological examination, postmortem toxicology tests. The postmortem biochemical detection of thyroid and cardiac function should be performed if necessary.

[Abnormality of TOP2A expression and its gene copy number variations in neuroblastic tumors].

Objective: To detect TOP2A protein expression and gene copy number alterations, and to analyze related clinical and pathological implications in pediatric neuroblastic tumors (NT). Methods: Immunohistochemistry was used to detect TOP2A protein expression. Fluorescence in situ hybridization (FISH) was used to detect numerical aberrations of TOP2A. Results: TOP2A protein was expressed in 59.1%(52/88) of cases, which was associated with differentiation (P=0.006), Ki-67 index (P<0.01) and MKI (P=0.001). Twenty-eight cases (35.0%, 28/88) showed TOP2A gene amplification, which was correlated with the age (P<0.01), clinical stage (P=0.028), high risk group (P=0.001), Ki-67 index (P=0.040) and differentiation (P=0.014). Survival analysis showed that TOP2A expression was related to survival rate. Multivariate analyses showed that TOP2A expression was an independent predictor for poor prognosis (P=0.010). Conclusions: More than half of the cases show TOP2A expression, which is more likely associated with NB, high Ki-67 index and high MKI. Cases with TOP2A expression have shorter survivals and poorer prognosis. TOP2A amplification is seen in 35% and likely occurs in patients older than 18 months and at advanced INSS stages (Ⅲ and Ⅳ). As a target of the anthracycline-based adjuvant drugs, TOP2A test can be used to select patient with NT for the therapy.

Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Insights into tribofilm formation on Ti-6V-4Al in a bioactive environment: Correlation between surface modification and micro-mechanical properties.

Ti-6Al-4V has been used as a surgical implant material for a long time because of its combination of strength, corrosion resistance and biocompatibility. However, there remains much that is not understood about how the surface reacts with the environment under tribocorrosion conditions. In particular, the conditions under which tribofilms form and their role on friction and wear are not clear. To evaluate the complicated nature of the dynamic surface microstructural changes on the wear track, high resolution transmission electron microscopy (TEM), scanning transmission electron microscope (STEM) and electron energy loss spectroscopy (EELS) have been used to characterise the structure and chemical composition of the tribofilm. Detailed analysis of the formation and structure of the tribofilm and the metal surface deformation behaviour were studied as a function of applied potential and the role of proteins in the lubricant. For the first time, graphitic and onion-like carbon structures from wear debris were found in the testing solution. The presence of carbon nanostructures in the tribocorrosion process and the formation of the tribofilm leads to an improved tribocorrosion behaviour of the system, in particular a reduction in wear and friction. A detailed, quantitative, analysis of surface deformation was undertaken, in particular, the geometrically necessary dislocation (GND) density was quantified using precession electron diffraction (PET). A clear correlation between applied potential, tribofilm formation and the surface strain was established. STATEMENT OF SIGNIFICANCE: The formation of tribofilm and microstructure modification of the Ti-6Al-4V surface during tribocorrosion in a physiological environment is not fully understood. In particular, the correlation between microstructural changes and electrochemical conditions is not clear. This study presents a detailed investigation of the structure and chemical composition of tribofilms at the nanoscale during tribocorrosion tests in simulated body fluid and gives a detailed and quantitative description of the evolved surface structure. A clear correlation between applied potential, tribofilm formation and the surface strain was established. Moreover, particular attention is paid to the wear debris particles captured from the lubricating solution, including nanocarbon onion structures. The implications for tribocorrosion of the alloy in its performance as an implant are discussed.

Sex Moderates the Association between Frailty and Mild Behavioral Impairment.

BACKGROUND: Frailty has been associated with cognitive markers of dementia but its relationship with behavioral markers of dementia are poorly understood. OBJECTIVES: To investigate the association between frailty and mild behavioral impairment (MBI), and whether this association is moderated by sex. DESIGN: Cross-sectional observational study. PARTICIPANTS/SETTING: 219 non-dementia participants (cognitively normal and mild cognitive impairment) from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. MEASUREMENTS: Frailty was measured using the frailty index (FI) with higher scores indicating more health deficits/greater frailty. MBI symptoms were derived from Neuropsychiatric Inventory Questionnaire scores using a published algorithm with a cut-off of >0 indicating MBI symptom presence and higher scores indicating greater severity. Multivariable logistic and linear regressions adjusted for age, sex, education, and cognitive diagnosis were used to test the association between FI and MBI symptom presence and severity, respectively, with MBI as the outcome variable. An FI-by-sex interaction term was included to test for sex-dependent effects. RESULTS: The FI mean and SD across the entire cohort was 0.14 ± 0.06 (median = 0.14, IQR = 0.09-0.17, range = 0.02-0.38). Higher FI scores were associated with the presence of MBI symptoms both globally and in the domains of decreased motivation, affective dysregulation, and psychosis. Higher FI scores were also associated with more severe MBI symptoms in a sex-dependent manner: both sexes reported similarly low MBI symptom severity at low (-1 SD) levels of FI but males reported 1.9x higher MBI symptom severity relative to females at high (+1 SD) levels of FI. CONCLUSIONS: The FI is associated with both the presence and severity of MBI, especially for males. This suggests that screening for early dementia risk should incorporate assessments of MBI for patients with frailty, and assessments of frailty for patients with MBI.

Environmentally vulnerable or sensitive groups exhibiting varying concerns toward air pollution can drive government response to improve air quality.

Air pollution seriously threatens human health, and its consequences are particularly prevalent among environmentally vulnerable or sensitive groups. However, whether the concerns among these groups are different and how they affect air pollution governance remain unclear. Here, we extract 3.8 million haze-related posts from China's Sina Weibo and analyze the concerns raised by these groups by constructing an air pollution notability index. The results show that protection is the key theme for women aged 20-35 years, while elderly individuals are easily influenced by haze-related product ads yet lack awareness of scientific-based protection. Concerns shared by young individuals are more effective in pressuring the government in cities that experience higher levels of pollution. Concerns shared by women are more effective in cities that experience lower levels of pollution. This study evidences the influence of the public concerns conveyed via social media on air pollution governance in China.

[Clinical features and risk factors for early relapse of pediatric ulcerative colitis].

Objective: To investigate the clinical features of pediatric ulcerative colitis (UC) and analyze the risk factors of disease relapse. Methods: The clinical data of 79 children with UC diagnosed in Beijing Children's Hospital, Capital Medical University from January 2016 to February 2021 were retrospectively analyzed. They were divided into early relapse group and non-early relapse group according to the clinical relapse within 12 months after diagnosis. T-test, rank sum test, χ2 test or Fisher's exact test were used to compare the variables between the 2 groups, including the clinical features, laboratory examination results and treatments. The Logistic regression was used to analyze the risk factors of early relapse. The cumulative relapse rate during follow-up was calculated by Kaplan-Meier method. Results: Among the 79 UC children, 46 were males and 33 were females, and the age of onset was 10.6 (6.4, 12.7) years. The children were mainly characterized by extensive disease (E3) and pancolitis (E4) (51/79, 65%), moderate to severe activity (48/79, 61%) and moderate to severe inflammation of colonic mucosa (71/79, 90%). Thirty-eight (48%) patients had atypical phenotype and 17 (22%) had extraintestinal manifestations. The follow-up period was 43.9 (22.8, 61.3) months, and of the 41 patients rechecked with colonoscopy, 7 (17%) had disease progression. According to Kaplan-Meier analysis, the cumulative relapse rate of the 79 cases at 3 months, 6 months, 1 year and 2 years after diagnosis were 27% (21/79), 47% (37/79), 57% (45/79) and 73% (53/73), respectively. There were 45 children (57%) in early relapse group and 34 (43%) in non-early relapse group. In early relapse group, hemoglobin and mucosal healing rate were both significantly lower (105 (87, 122) vs. 120 (104, 131) g/L, 28% (7/25) vs. 7/9, Z=-2.38, χ²=4.87, both P<0.05). The rate of steroid-dependent, E3 and step-up therapy during the induction period were all significantly higher than those in non-early relapse group (11/19 vs. 1/12, 24% (11/45) vs. 6% (2/34), 29% (13/45) vs. 6% (2/34), χ²=5.67, 4.85, 6.66, all P<0.05). Multivariate Logistic regression analysis showed that extraintestinal manifestations (OR=4.33, 95%CI 1.05-17.83), E3 (OR=8.27, 95%CI 1.47-46.46) and step-up therapy during the induction period (OR=5.58, 95%CI 1.01-30.77) were independent risk factors for early relapse. Conclusions: Pediatric UC is usually extensive and severe, with atypical phenotype, a high rate of relapse and a risk of disease progression. Extraintestinal manifestations, E3 and step-up therapy during the induction period are independent risk factors for early relapse.

Contributions of Kv7-mediated potassium current to sub- and suprathreshold responses of rat layer II/III neocortical pyramidal neurons.

After block of Kv1- and Kv2-mediated K(+) currents in acutely dissociated neocortical pyramidal neurons from layers II/III of rat somatosensory and motor cortex, the remaining current is slowly activating and persistent. We used whole cell voltage clamp to show that the Kv7 blockers linopirdine and XE-991 blocked a current with similar kinetics to the current remaining after combined block of Kv1 and Kv2 channels. This current was sensitive to low doses of linopirdine and activated more slowly and at more negative potentials than Kv1- or Kv2-mediated current. The Kv7-mediated current decreased in amplitude with time in whole cell recordings, but in most cells the current was stable for several minutes. Current in response to a traditional M-current protocol was blocked by muscarine, linopirdine, and XE-991. Whole cell slice recordings revealed that the Q10 for channel deactivation was ∼2.5. Sharp electrode current-clamp recordings from adult pyramidal cells demonstrated that block of Kv7-mediated current with XE-991 reduced rheobase, shortened the latency to firing to near rheobase current, induced more regular firing at low current intensity, and increased the rate of firing to a given current injection. XE-991 did not affect single action potentials or spike frequency adaptation. Application of XE-991 also eliminated subthreshold voltage oscillations and increased gain for low-frequency inputs (<10 Hz) without affecting gain for higher frequency inputs. These data suggest important roles for Kv7 channels in subthreshold regulation of excitability, generation of theta-frequency subthreshold oscillations, regulation of interspike intervals, and biasing selectivity toward higher frequency inputs.