Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse.

Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large ß barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a ß propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the ß propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.

Study of the optic nerve in patients with type 2 diabetic retinopathy by shear-wave elastography.

AIM: To investigate the clinical value of two-dimensional shear-wave elastography (2D-SWE) in detecting optic nerve elasticity and in-frame adipose tissue elasticity in patients with type 2 diabetic retinopathy (DR). MATERIALS AND METHODS: 2D-SWE was used to detect SWE values of the optic nerve and adipose tissue in adjacent optic nerve frames in 30 healthy participants, 30 patients with diabetic non-retinopathy (NDR), 35 patients with non-proliferative diabetic retinopathy (NPDR), and 30 patients with proliferative diabetic retinopathy (PDR). The correlation between SWE values and blood glucose, blood lipid, age, body mass index (BMI) was analysed. Receiver operating characteristic (ROC) curve analysis was performed for SWE values. RESULTS: The SWE values of the optic nerve and in-frame adipose tissue increased with the progression of DR, and analysis of variance was compared with groups: the SWE values of the optic nerve and in-frame adipose tissue in each group were significantly different (all p<0.001). The SWE values of the optic nerve and in-frame adipose tissue correlated positively with BMI, age, triglyceride, and fasting blood glucose, and correlated negatively with high-density lipoprotein. The SWE values of the optic nerve and in-frame adipose tissue had higher diagnostic efficacy. The combination of the two had higher diagnostic accuracy. CONCLUSION: The elastic modulus of optic nerve and in-frame adipose tissue can effectively predict and grade of DR, that is, 2D-SWE can be used as a non-invasive imaging diagnostic method for DR. The combined diagnostic efficacy of optic nerve SWE value and in-frame adipose tissue SWE value is significantly better than that of single use. This study found that increased BMI, age, triglyceride, and fasting blood glucose, and decreased high-density lipoprotein are risk factors for DR.

Cost-effectiveness analysis of five drugs for treating postmenopausal women in the United States with osteoporosis and a very high fracture risk.

PURPOSE: Five strategies were recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) guidelines for the treatment of postmenopausal osteoporosis (PMO) patients with a very high fracture risk. We aimed to assess their cost-effectiveness in the United States (US). METHODS: A microsimulation Markov model was created to compare the cost-effectiveness of five treatment strategies, including zoledronate, denosumab, abaloparatide, teriparatide, and romosozumab in PMO patients with a recent fracture from the healthcare perspective of the US. The data used in the model were obtained from published studies or online resources. Base-case analysis, one-way deterministic sensitivity analysis (DSA) and probability sensitivity analysis (PSA) were conducted for 65-, 70-, 75-, and 80-year-old patients. RESULTS: In base case, at 65 years, zoledronate was the cheapest strategy. The incremental cost-effectiveness ratios (ICER, which represent incremental costs per QALY gained) of denosumab, teriparatide, abaloparatide, and romosozumab against zoledronate were $13,020/QALY (quality-adjusted years), $477,331 /QALY, $176,287/QALY, and $98,953/QALY, respectively. Under a willing-to-pay (WTP, which means the highest price a consumer will pay for one unit of a good of service) threshold of $150,000/QALY, denosumab and romosozumab were cost-effective against zoledronate. The PSA results showed that denosumab was the most cost-effective option with WTP thresholds of $50,000/QALY, $100,000/QALY and $150,000/QALY. The results were similar in other age groups. The DSA results indicated that the most common parameters that have important influence on the outcome were drug persistence, incidence of adverse events, the efficacy of drugs on hip fractures and the cost of the drug. CONCLUSION AND RELEVANCE: Among PMO patients with a very high fracture risk in the US, zoledronate is the cheapest strategy and denosumab is the most cost-effective choice among these five strategies.

[Analysis of factors associated with futile recanalization after endovascular treatment for acute ischemic stroke with large vessels occlusion in anterior intracranial circulation].

Objective: To analyze the related factors of futile recanalization (FR) after emergency endovascular treatment of large artery occlusion in anterior circulation. Methods: Three studies on endovascular treatment of acute anterior circulation large vessels occlusion stroke were selected, and their data were merged for retrospective analysis. Patients were divided into the FR group and favorable prognosis group according to the functional prognosis. Risk factor analysis was conducted using multivariate logistic regression. Results: A total of 1 581 patients were finally included, with 858 (48.9%) patients in favorable prognosis group and 926 (51.91%) patients in FR group. Among them, there were 939 males and 642 females, with a mean age of (65±12) years. Multivariate logistic regression analysis showed that National Institute of Health Stroke Scale (NIHSS) score (OR=1.089,95%CI:1.066-1.113), puncture to recanalization time (OR=0.756, 95%CI:0.586-0.971), age (OR=1.04,95%CI:1.029-1.051), serum glucose (OR=1.101,95%CI:1.062-1.143), systolic blood pressure (OR=1.005,95%CI:1.001-1.010), passes≥3(OR=1.941,95%CI:1.294-2.941)Alberta stroke program early CT (ASPECT) score (OR=0.919,95%CI:0.847-0.996), occlusion site (M1 segment of middle cerebral artery, OR=0.744,95%CI:0.565-0.980) and collateral circulation [(2 points, OR=0.757, 95%CI:0.581-0.985); (3-4 points, adjusted OR=0.640, 95%CI: 0.472-0.866)] were independent factors of FR. Conclusion: The incidence of FR in patients with large artery occlusion in anterior circulation who achieve satisfied reperfusion after endovascular treatment is high. Higher NIHSS score, longer puncture to recanalization time, older age, higher serum glucose and systolic blood pressure are risk factors, while lower ASPECTS, occlusion in cerebral middle M1 segment, better collateral circulation are protective factors.

Micro-LED with red-green-blue super-pixel integration for simultaneous display and optical near field communication.

This work presents a novel all-in-one Micro-LED pixel (µLEDP) technology by integrating red-green-blue super-pixels (RGBSP) in a single unit cell. Measurement results show that the proposed µLEDP delivers excellent optical and electrical characteristics, including wide color gamut (109% NTSC), wide correlated color temperature range (2831.7-10016.8 K), and high modulation system bandwidth (58-62 MHz). To the best of our knowledge, the proposed integrated µLEDP achieves the highest data rate compared to published results based on other multi-color low-capacitance high-bandwidth LEDs. The maximum simulated non-return-to-zero (NRZ) and 4-level pulse-amplitude-modulation (PAM-4) data rates of 0.3-Gb/s and 1.1-Gb/s, respectively.

[Surgical management of nipple areola complex in central breast cancer].

Objective: To explore the surgical strategy of nipple areola complex (NAC) management in central breast cancer. Methods: A retrospective analysis was conducted on 164 cases of central breast cancer who underwent surgery treatment from December 2017 to December 2020 in the Breast Center of Beijing Tongren Hospital, Capital Medical University. Prior to the surgery, the tumor-nipple distance (TND) and the maximum diameter of the tumor were measured by magnetic resonance imaging (MRI). The presence of nipple invagination, nipple discharge, and nipple ulceration (including nipple Paget's disease) were recorded accordingly. NAC was preserved in patients with TND≥0.5 cm, no signs of NAC invasion (nipple invagination, nipple ulceration) and negative intraoperative frozen pathological margin. All patients with signs of NAC involvement, TND<0.5 cm or positive NAC basal resection margin confirmed by intraoperative frozen pathology underwent NAC removal. χ(2) test or Fisher exact test was used to analyze the influencing factors. Results: Of the 164 cases of central breast cancer, 73 cases underwent breast-conserving surgery, 43 cases underwent nipple-areola complex sparing mastectomy (NSM), 34 cases underwent total mastectomy, and the remaining 14 cases underwent skin sparing mastectomy (SSM). Among the 58 cases of NAC resection (including 34 cases of total mastectomy, 14 cases of SSM, and 10 cases of breast-conserving surgery), 25 cases were confirmed tumor involving NAC (total mastectomy in 12 cases, SSM in 9 cases, and breast-conserving surgery in 4 cases). The related factors of NAC involvement included TND (P=0.040) and nipple invagination (P=0.031). There were no correlations between tumor size (P=0.519), lymph node metastasis (P=0.847), bloody nipple discharge (P=0.742) and NAC involvement. During the follow-up period of 12 to 48 months, there was 1 case of local recurrence and 3 cases of distant metastasis. Conclusions: For central breast cancer, data suggest that patients with TND≥0.5cm, no signs of NAC invasion (nipple invagination, nipple ulceration) and negative NAC margin in intraoperative frozen pathology should be treated with NAC preservation surgery, whereas for those with TND<0.5 cm or accompanied by signs of NAC invasion, NAC should be removed. In addition, nipple reconstruction can be selected to further improve the postoperative appearance of patients with central breast cancer.

[The level distribution of serum AMH in different clinical manifestations of women of childbearing age].

To investigate the distribution and diagnostic value of serum anti-Müllerian hormone (AMH) in healthy women of childbearing age, women with polycystic ovary syndrome (PCOS), ovarian dysfunction (DOR) and premature ovarian failure (POF). This study retrospectively selected female patients of childbearing age who were treated in the affiliated Obstetrics and Gynecology Hospital of Fudan University from January to December 2019. According to different clinical manifestations, they were divided into 133 cases in PCOS group, 120 cases in DOR group and 134 cases in POF group. 125 healthy women in the same period were selected as the control group. The values of serum AMH, estradiol (E2), follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) were measured in the four groups. Single sample Kolmogorov-Smirnov test, one-way ANOVA, independent sample t-test, Kruskal-Wallis H test, Mann-Whitney U test, logistic regression analysis and ROC curve were used for comparative analysis. The serum AMH levels of PCOS group, DOR group, POF group and control group were 9.10 (6.67, 11.49) ng/ml, 0.11 (0.05, 0.29) ng/ml, 0.03 (0.02, 0.06) ng/ml and 2.99 (1.57, 4.98) ng/ml, respectively [M(Q1,Q3)], the differences were statistically significant (P<0.001). The basal endocrine levels including E2, FSH, LH and T also had significant differences between groups (P<0.001). The results of multiple comparisons showed that there were significant differences in AMH and LH between DOR, POF and PCOS groups and the control group. The T level of PCOS group was significantly higher than that of the control group, the E2, LH and T levels of DOR group were significantly higher than that of the control group, and the FSH level of POF group was significantly higher than that of the control group (P<0.05). The area under the curve (AUC) of AMH and AMH+LH in the diagnosis of PCOS were 0.905 and 0.922, the sensitivity was 82.7% and 85.0%, and the specificity was 88.0% and 88.8%. The AUC of DOR was 0.861 and 0.971, the sensitivity was 89.0% and 92.5%, and the specificity was 63.0% and 92.0%. The AUC of POF was 0.950 and 0.998, the sensitivity was 98.3% and 99.2%, and the specificity was 75.9% and 97.0%, respectively. The AUC of AMH and AMH+LH combined indexes in the differential diagnosis of DOR and POF were 0.768 and 0.937, the sensitivity was 70.3% and 95.5%, and the specificity was 73.9% and 80.8%.

[Clinicopathological characteristics of SMARCB1(INI1)-deficient sinonasal carcinoma].

Objective: To investigate the clinicopathological characteristics, diagnosis, differential diagnosis and prognostic factors of SMARCB1 (INI1)-deficient sinonasal carcinoma (SDSC). Methods: Sixteen cases of SDSC diagnosed in the Department of Pathology, Beijing Tongren Hospital from January 2016 to September 2020 were enrolled. Ninety-nine cases of small round cell malignant tumors of the head and neck were selected as the control, including poorly-differentiated squamous cell carcinoma (n=10), poorly-differentiated adenocarcinoma (n=5), undifferentiated carcinoma (SNUC, n=4), NUT carcinoma (n=5), neuroendocrine carcinoma (n=10), and other non-epithelial tumors [olfactory neuroblastoma (n=10), rhabdomyosarcoma (n=10), NK/T-cell lymphoma (n=10), malignant melanoma (n=10), Ewing's sarcoma/primitive neuroectodermal tumor (EWS/PNET, n=5)] and non-keratinizing undifferentiated nasopharyngeal carcinoma (n=20). The clinical and pathologic characteristics of SDSC, and immunohistochemical (IHC) expression of broad-spectrum CKpan, CK7, CK8/18, CK5/6, p63, p40, p16, INI1, NUT and neuroendocrine markers (Syn, CgA, CD56) were evaluated. In situ hybridization (ISH) was used to detect EBER and fluorescence in situ hybridization (FISH) to detect INI1 gene deletion. Results: The 16 cases of SDSC accounted for 1.3% (16/1 218) of all malignant sinonasal tumors in the author's unit during this time period, and 2.4% (16/657) of all malignant epithelial tumors. Microscopically, there was no clear squamous and adenomatous differentiation, but "rhabdoid-like" cells, are often seen. All SDSC cases were positive for CKpan and CK8/18, negative for INI1; Epstein-Barr virus was not detected by ISH; and INI1 gene deletion was observed in all 11 SDSC patients with FISH. Twelve cases were followed up for 3-47 months. One died of tumor-related diseases half a year after diagnosis, and the remaining patients were alive with tumor, the longest survival time was 47 months. Conclusion: SDSC should be differentiated from a variety of poorly-differentiated tumors in the sinonasal area. Histologically, SDSC has no clear differentiation, but the tumor cells are characteristically basal-like or rhabdoid-like, with non-specific vacuoles, translucent or vacuolar nuclei, prominent nucleoli and necrotic foci. They are negative for INI1 IHC staining, and FISH demonstrates INI1 gene deletion. The clinical prognosis is still unclear, further studies on its biologic behavior and treatment methods are warranted.

Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus.

PURPOSE: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. METHODS: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. RESULTS: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. CONCLUSION: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.

Absence of iron-responsive element-binding protein 2 causes a novel neurodegenerative syndrome.

Disruption of cellular iron homeostasis can contribute to neurodegeneration. In mammals, two iron-regulatory proteins (IRPs) shape the expression of the iron metabolism proteome. Targeted deletion of Ireb2 in a mouse model causes profoundly disordered iron metabolism, leading to functional iron deficiency, anemia, erythropoietic protoporphyria, and a neurodegenerative movement disorder. Using exome sequencing, we identified the first human with bi-allelic loss-of-function variants in the gene IREB2 leading to an absence of IRP2. This 16-year-old male had neurological and haematological features that emulate those of Ireb2 knockout mice, including neurodegeneration and a treatment-resistant choreoathetoid movement disorder. Cellular phenotyping at the RNA and protein level was performed using patient and control lymphoblastoid cell lines, and established experimental assays. Our studies revealed functional iron deficiency, altered post-transcriptional regulation of iron metabolism genes, and mitochondrial dysfunction, as observed in the mouse model. The patient's cellular abnormalities were reversed by lentiviral-mediated restoration of IRP2 expression. These results confirm that IRP2 is essential for regulation of iron metabolism in humans, and reveal a previously unrecognized subclass of neurodegenerative disease. Greater understanding of how the IRPs mediate cellular iron distribution may ultimately provide new insights into common and rare neurodegenerative processes, and could result in novel therapies.

[Application of indocyanine green in complex upper urinary tract repair surgery].

OBJECTIVE: To evaluate the clinical application of indocyanine green (ICG) visualization by near infrared fluorescence laparoscopy (NIFL) in complex upper urinary tract reconstructions surgery. METHODS: This was a retrospective study of 7 patients who underwent complex surgeries of ureteral reconstruction between May 2019 and October 2019. There were 6 males and 1 female with the age ranging from 24 to 57 years (median age was 47 years). There were 5 cases of right ureteral strictures, of which 3 were proximal ureteral strictures and 2 were multiple and long ureteral strictures caused by radiotherapy. There were 2 cases of left ureteral strictures, of which 1 was ureteropelvic junction stricture and 1 was proximal ureteral stricture. There were 4 cases of secondary repair operations and 3 cases of primary operations. All the patients underwent laparoscopic surgery via the abdominal approach. ICG was injected into the ureter via nephrostomy tube during the operations, and the diseased ureter was identified by NIFL. Among the patients, 2 cases underwent IUPU (Institute of Urology, Peking University) modified ileal ureter replacement, 2 cases underwent ureteroureterostomy, 2 cases underwent appendiceal onlay flap ureteroplasty, and 1 case underwent lingual mucosa onlay flap ureteroplasty. RESULTS: All the operations were successfully completed without open conversion. The localization and separation of ureteral lesions were completed under NIFL. The mean operative time was 187 (135-300) min. The duration of ureteral separation was 15-27 min, and the mean time was 18 min. The estimated blood loss was 15-200 mL, the mean estimated blood loss was 50 mL. There was one patient with ileal ureter replacement who had fever after surgery and responded well to antibiotics. The mean (range) length of postoperative hospital stay was 7 (6-10) days and no postoperative complications of a high grade (Clavien-Dindo Ⅲ and Ⅳ) occurred. Up to now, the mean follow-up duration was 9 (6-11) months, and no indocyanine green toxicity occurred. All D-J stents and nephrostomy were removed successfully 2 months after the operation. Ultrasound showed no obvious hydronephrosis, and CTU (computed tomography urography) showed that the urinary tract was unobstructed and the kidney function was normal. CONCLUSION: The application of ICG in the complex upper urinary tract reconstructive surgery is a safe and easy method to help surgeon to identify the ureter which may reduce the risk of iatrogenic damage and protect the ureteral blood supply.

[The 462nd case: chronic watery diarrhea and acute kidney injury].

A 60-year-old man presented with severe watery diarrhea for 2 months complicated with weight loss and acute kidney injury. He did not respond well to antidiarrheal medicines, empirical antibiotics and dietary exclusion of gluten or even complete bowel rest. The final diagnosis of autoimmune enteropathy (AIE) was made based on histopathologic findings of endoscopic biopsy from duodenal mucosa after excluding neoplastic disease, inflammatory bowel disease, and infectious diarrhea, etc. Chronic diarrhea and oliguria alleviated after the administration of corticosteroids.

[Analysis of vaccination situation of orial live attenuated rotavirus vaccine (LLR strain) among children in 6 provinces of China].

Objective: To analyze vaccination situation of oral live attenuated rotavirus vaccine (LLR strain) among children from six provinces in China. Methods: In 2014, we selected 12 counties in Guangdong, Jiangsu, Chongqing, Jiangxi, Heilongjiang and Gansu provinces by using stratified cluster random sampling method and extract information of children born from January 1, 2008 to December 31, 2012 from Children's Immunization Information System. We investigated ten children of each birth cohort in each county by checking the vaccination certification, and a total of 606 children were investigated. A survey was conducted to check the information of the children's vaccination certification with the data of Children's Immunization Information System by questionnaire including the basic information (province, county, name, gender, birth date, etc) and the rotavirus vaccination (vaccination date, dose, etc) to analyze the rotavirus vaccination situation. Results: 340 of 606 children were male. There were 121, 124, 122, 119 and 120 children born in 2008-2012, respectively. The proportions of the first and the second dose of rotavirus vaccination were 32.8% (199) and 9.7% (59). The proportion of the third dose of rotavirus vaccination among children born between 2008 and 2010 was 3.5% (13) since children born in 2011 and 2012 did not reach the age of third dose vaccination. The proportion of the first dose of rotavirus vaccination in high, middle and low per capita disposable income areas was 45.0% (91), 37.7% (77) and 15.5% (31) respectively (χ(2)= 43.15, P<0.001). Among 199 children vaccinated with the first dose of vaccine, the vaccination age mainly concentrated in 2 to 21 months, of which the peak was 5 to 13 months (66.8%, 133). The intervals between 2 doses of vaccination were mainly from 12 to 13 months (42.4%, 25) among the 59 children who received at least 2 doses of vaccine. In the 13 children vaccinated with 3 doses, the intervals between the second and the third dose were 12 months (5). Of the 271 doses of rotavirus vaccine vaccinated during 2008-2014, 34.7% (94 doses) were vaccinated in June-August, 88 were vaccinated simultaneously with 18 other vaccines, accounting for 32.5% of the total. Of the 18 other vaccines, inactivated vaccines such as diphtheria vaccine (30 doses), Hib vaccine (14 doses), group A meningitis vaccine (10 doses) were predominant. Conclusion: The proportion of rotavirus vaccination was low and the vaccination age was relatively late. The vaccination mode was different from the recommendation of WHO. It is recommended that routine immunization of rotavirus vaccines should be carried out in early-months of children.

Preoperative Thrombocytosis Predicts Shortened Survival in Patients with Malignant Peritoneal Mesothelioma Undergoing Operative Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: This study was designed to determine the clinical significance of preoperative thrombocytosis in patients with malignant peritoneal mesothelioma (MPM) undergoing operative cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). CRS and HIPEC have been associated with prolonged survival in patients with MPM and is the preferred treatment in select patients. However, patient selection criteria remain ill-defined for this operation that is also associated with significant morbidity and mortality. Preoperative thrombocytosis has been associated with poor outcomes in various malignancies but never studied in MPM. METHODS: Between January 2006 and December 2015, 100 patients with high-grade epithelioid MPM were evaluated and selected for CRS and HIPEC at our center (M: 53, F: 47; mean age: 54 years [range 17-81 years]). We analyzed various patient and treatment related factors potentially associated with overall survival (OS). RESULTS: The median actuarial overall survival was 32.8 months; the actuarial 1-, 3-, 5-year survivals were 70, 49, and 36%, respectively. On multivariate analysis, suboptimal resection (CCR > 1), high tumor burden (PCI > 20), and elevated preoperative platelet count (>367,000/mm3) were independently associated with shortened OS (P < 0.05). Median OS in patients with elevated versus normal platelet counts were 13 and 58 months, respectively (P < 0.001). Compared with patients with normal platelet counts, patients with elevated counts had significantly greater residual disease after operation (P = 0.008). CONCLUSIONS: Elevated preoperative platelet count is independently associated with poor outcome. Notably, thrombocytosis reflects aggressive tumor biology and should be considered a factor in patient selection for CRS and HIPEC.

pLARmEB: integration of least angle regression with empirical Bayes for multilocus genome-wide association studies.

Multilocus genome-wide association studies (GWAS) have become the state-of-the-art procedure to identify quantitative trait nucleotides (QTNs) associated with complex traits. However, implementation of multilocus model in GWAS is still difficult. In this study, we integrated least angle regression with empirical Bayes to perform multilocus GWAS under polygenic background control. We used an algorithm of model transformation that whitened the covariance matrix of the polygenic matrix K and environmental noise. Markers on one chromosome were included simultaneously in a multilocus model and least angle regression was used to select the most potentially associated single-nucleotide polymorphisms (SNPs), whereas the markers on the other chromosomes were used to calculate kinship matrix as polygenic background control. The selected SNPs in multilocus model were further detected for their association with the trait by empirical Bayes and likelihood ratio test. We herein refer to this method as the pLARmEB (polygenic-background-control-based least angle regression plus empirical Bayes). Results from simulation studies showed that pLARmEB was more powerful in QTN detection and more accurate in QTN effect estimation, had less false positive rate and required less computing time than Bayesian hierarchical generalized linear model, efficient mixed model association (EMMA) and least angle regression plus empirical Bayes. pLARmEB, multilocus random-SNP-effect mixed linear model and fast multilocus random-SNP-effect EMMA methods had almost equal power of QTN detection in simulation experiments. However, only pLARmEB identified 48 previously reported genes for 7 flowering time-related traits in Arabidopsis thaliana.

[Analysis of the clinical characteristics and efficacy of 20 cases of extranodal Rosai-Dorfman disease in head and neck].

Objective: To analyze the clinical characteristics and efficacy of extranodal Rosai-Dorfman disease in head and neck. Methods: Clinical and pathological features and follow-up of patients who were diagnosed as RDD at Beijing Tongren Hospital of Capital Medical University between May 2008 and November 2016 were analyzed retrospectively. Results: There were a total of 20 extranodal RDD patients in head and neck including 14 females and 6 males, aged from 27 to 86 years (mean 52.5 years). Nose (14 cases) and throat (5 cases) were most commonly involved organs and 5 patients had 2 or more organs involved. Diagnosis depends on biopsy. Histopathologically, the lesions of RDD were characterized by the presence of large histiocytes with emperipolesis. The large sinus histiocytes were positive for S-100 and CD68 protein staining. Diagnostic Errors in 13 patients and operations in all patients were happened. More than 1 operation was performed in 9 recurrence patients. Eight patients were treated by Glucocorticoids and immunosuppressive agents. All the patients were alive until Feb 2017. Conclusion: Extranodal RDD in head and neck is known as a rare benign idiopathic proliferative disease. Nose is the most common site involved, and recurrence easily. It is diagnosis depending on histopathological report. Operation is first choice in diagnosis and treatment now. Glucocorticoids and immunosuppressive agents are effective in recurrence patients.

RNA∶DNA hybrids initiate quasi-palindrome-associated mutations in highly transcribed yeast DNA.

RNase H enzymes promote genetic stability by degrading aberrant RNA:DNA hybrids and by removing ribonucleotide monophosphates (rNMPs) that are present in duplex DNA. Here, we report that loss of RNase H2 in yeast is associated with mutations that extend identity between the arms of imperfect inverted repeats (quasi-palindromes or QPs), a mutation type generally attributed to a template switch during DNA synthesis. QP events were detected using frameshift-reversion assays and were only observed under conditions of high transcription. In striking contrast to transcription-associated short deletions that also are detected by these assays, QP events do not require Top1 activity. QP mutation rates are strongly affected by the direction of DNA replication and, in contrast to their elevation in the absence of RNase H2, are reduced when RNase H1 is additionally eliminated. Finally, transcription-associated QP events are limited by components of the nucleotide excision repair pathway and are promoted by translesion synthesis DNA polymerases. We suggest that QP mutations reflect either a transcription-associated perturbation of Okazaki-fragment processing, or the use of a nascent transcript to resume replication following a transcription-replication conflict.

[Primary penoscrotal extra-mammary Paget's disease: analysis of 22 cases].

OBJECTIVE: To investigate the clinical characteristics, treatment and prognosis of primary penoscrotal extra-mammary Paget's disease (PSPD). METHODS: The clinical and pathological data of 22 cases of primary PSPD were retrospectively reviewed. Survival rate of the overall patients, the invasive patients, and the patients with positive surgical margin or negative surgical margin were analyzed with Kaplan-Meier survival curve method. RESULTS: Among all the patients with primary PSPD, the median age of onset was 64.5 (39-84) years, the median time of disease duration was 40 (2-300) months, and the median long diameter of lesion was 4.75 (1-10) cm. In the study, 12 patients (54.5%) were in pathological stage A1, 6 patients (27.3%) were in pathological stage A2, and 4 patients (18.2%) were in pathological stage B. Scrotum and penile of most patients (n=12, 54.5%) were involved, 5 patients (22.7%) were scrotum only, and 5 patients (22.7%) were penile only. Erythema (n=18, 81.8%), itchiness (n=16, 72.7%), ulcerate (n=12, 54.5%), exudation (n=11, 50.0%), and pain (n=4, 18.2%) were the major manifestations. All the patients with primary PSPD were treated with wide surgical excision. The rate of invasive patients was 77.3% (n=17). Of them, 6 patients had positive surgical margin. The surgical margins of non-invasive patients were all negative. Twelve patients exhibited local recurrence or/and metastases, and the status of surgical margins (P=0.015) and the depth of invasion (P=0.010) were important risk factors. Inguinal lymph nodes were generally involved. The difference of the delay of diagnosis between metastasis and non-metastasis was significant (P=0.040). The 5-year survival rates of the overall and invasive patients were 33.7% and 27.9%, respectively. The patients with positive surgical margin had poor prognosis. CONCLUSION: Primary PSPD, with the characteristics of long duration, high invasive tendency and high incidence of local recurrence or metastases, generally occurs in the elderly. Surgery should be performed at first. The delay of diagnosis, positive surgical margins and the involvement of inguinal lymph node are important risk factors. Biopsy, frozen section and inguinal lymph node biopsy (ILNB) can standardize diagnosis and treatment.

[Primary penoscrotal extra-mammary Paget's disease: analysis of 22 cases].

OBJECTIVE: To investigate the clinical characteristics, treatment and prognosis of primary penoscrotal extra-mammary Paget's disease (PSPD). METHODS: The clinical and pathological data of 22 cases of primary PSPD were retrospectively reviewed. Survival rate of the overall patients, the invasive patients, and the patients with positive surgical margin or negative surgical margin were analyzed with Kaplan-Meier survival curve method. RESULTS: Among all the patients with primary PSPD, the median age of onset was 64.5 (39-84) years, the median time of disease duration was 40 (2-300) months, and the median long diameter of lesion was 4.75 (1-10) cm. In the study, 12 patients (54.5%) were in pathological stage A1, 6 patients (27.3%) were in pathological stage A2, and 4 patients (18.2%) were in pathological stage B. Scrotum and penile of most patients (n=12, 54.5%) were involved, 5 patients (22.7%) were scrotum only, and 5 patients (22.7%) were penile only. Erythema (n=18, 81.8%), itchiness (n=16, 72.7%), ulcerate (n=12, 54.5%), exudation (n=11, 50.0%), and pain (n=4, 18.2%) were the major manifestations. All the patients with primary PSPD were treated with wide surgical excision. The rate of invasive patients was 77.3% (n=17). Of them, 6 patients had positive surgical margin. The surgical margins of non-invasive patients were all negative. Twelve patients exhibited local recurrence or/and metastases, and the status of surgical margins (P=0.015) and the depth of invasion (P=0.010) were important risk factors. Inguinal lymph nodes were generally involved. The difference of the delay of diagnosis between metastasis and non-metastasis was significant (P=0.040). The 5-year survival rates of the overall and invasive patients were 33.7% and 27.9%, respectively. The patients with positive surgical margin had poor prognosis. CONCLUSION: Primary PSPD, with the characteristics of long duration, high invasive tendency and high incidence of local recurrence or metastases, generally occurs in the elderly. Surgery should be performed at first. The delay of diagnosis, positive surgical margins and the involvement of inguinal lymph node are important risk factors. Biopsy, frozen section and inguinal lymph node biopsy (ILNB) can standardize diagnosis and treatment.

The implant infection paradox: why do some succeed when others fail? Opinion and discussion paper.

Biomaterial-implants are frequently used to restore function and form of human anatomy. However, the presence of implanted biomaterials dramatically elevates infection risk. Paradoxically, dental-implants placed in a bacteria-laden milieu experience moderate failure-rates, due to infection (0.0-1.1%), similar to the ones of joint-arthroplasties placed in a near-sterile environment (0.1-1.3%). Transcutaneous bone-fixation pins breach the immune-barrier of the epidermis, exposing underlying sterile-tissue to an unsterile external environment. In contrast to dental-implants, also placed in a highly unsterile environment, these pins give rise to relatively high infection-associated failure-rates of up to 23.0%. Herein, we attempt to identify causes as to why dental-implants so often succeed, where others fail. The major part of all implants considered are metal-made, with similar surface-finishes. Material choice was therefore discarded as underlying the paradox. Antimicrobial activity of saliva has also been suggested as a cause for the success of dental-implants, but was discarded because saliva is the implant-site-fluid from which viable bacteria adhere. Crevicular fluid was discarded as it is largely analogous to serum. Instead, we attribute the relative success of dental-implants to (1) ability of oral tissues to heal rapidly in the continuous presence of commensal bacteria and opportunistic pathogens, and (2) tolerance of the oral immune-system. Inability of local tissue to adhere, spread and grow in presence of bacteria and an intolerant immune-system are identified as the likely main causes explaining the susceptibility of other implants to infection-associated failure. In conclusion, it is the authors' belief that new anti-infection strategies for a wide range of biomaterial-implants may be derived from the relative success of dental-implants.