A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase.

Immunomodulatory drugs bind to cereblon (CRBN) to confer differentiated substrate specificity on the CRL4(CRBN) E3 ubiquitin ligase. Here we report the identification of a new cereblon modulator, CC-885, with potent anti-tumour activity. The anti-tumour activity of CC-885 is mediated through the cereblon-dependent ubiquitination and degradation of the translation termination factor GSPT1. Patient-derived acute myeloid leukaemia tumour cells exhibit high sensitivity to CC-885, indicating the clinical potential of this mechanism. Crystallographic studies of the CRBN-DDB1-CC-885-GSPT1 complex reveal that GSPT1 binds to cereblon through a surface turn containing a glycine residue at a key position, interacting with both CC-885 and a 'hotspot' on the cereblon surface. Although GSPT1 possesses no obvious structural, sequence or functional homology to previously known cereblon substrates, mutational analysis and modelling indicate that the cereblon substrate Ikaros uses a similar structural feature to bind cereblon, suggesting a common motif for substrate recruitment. These findings define a structural degron underlying cereblon 'neosubstrate' selectivity, and identify an anti-tumour target rendered druggable by cereblon modulation.

Multimodal Assessments of Altered Sensation after Transoral Endoscopic Thyroidectomy.

BACKGROUND: Transoral endoscopic thyroidectomy, a novel technique, uses oral vestibule as the entry point and leaves no scar on the body surface. However, because the incisions are close to the mental nerve, nerve damage and the associated sensory impairment are concerning. Herein, we evaluated sensory alteration after transoral endoscopic thyroidectomy and determined factors associated with the prolonged sensory alteration. METHODS: Patients who underwent transoral endoscopic thyroidectomy were enrolled. Sensation over the lower lip, chin, and neck was evaluated before and after the surgery. A self-assessment questionnaire, Semmes-Weinstein monofilament test, and two-point discrimination test were used to subjectively and objectively evaluate sensory changes. RESULTS: Fifty-one patients were enrolled; most of them reported altered sensation, with chin (72.5%) being the most common site, followed by lower lip (52.9%), upper neck (33.3%), and lower neck (5.9%) on postoperative day 2. The sensory disturbance resolved within 3 months. Factors associated with prolonged sensory alteration are male sex and old age. Fourteen patients (27.5%) experienced mild drooling from the mouth, which was usually self-limiting in 1 month. Sensory impairments in light touch pressure threshold and two-point discrimination were significant in the chin and neck on postoperative day 2 and at 1 week. The ability to discern two-point was also compromised in the lower lip on postoperative day 2. All these significant changes normalized to preoperative baseline at 1 month. CONCLUSIONS: There was an altered sensation after transoral endoscopic thyroidectomy with the most common and disturbed in the chin. Sensory impairment was usually transient and recovered in 3 months.

Outcome Comparison between Endoscopic Transoral and Bilateral Axillo-Breast Approach Thyroidectomy Performed by a Single Surgeon.

BACKGROUND: The transoral approach and the bilateral axillo-breast approach (BABA) are remote access approaches for endoscopic thyroidectomy. Both follow a symmetric design and use CO2 insufflation to maintain the working space. The outcome differences between the techniques are rarely compared in the literature. METHODS: All patients who underwent endoscopic transoral (n = 72) and BABA (n = 63) thyroidectomy between October 2018 and August 2020 by a single surgeon were retrospectively reviewed. The following peri-operative data were collected and compared: operative time, blood loss, postoperative drainage amount, hospital stay, pain score, number of retrieved lymph nodes, and complications. RESULTS: Patients in the transoral group were younger (44.7 vs. 49.3 years, p = 0.022) and had smaller tumors (2.4 vs. 2.8 cm, p = 0.020) than those in the BABA group. The operative times were significantly longer in the transoral group than in the BABA group (lobectomy, 194.1 vs. 177.0 min, p = 0.026; total thyroidectomy, 246.0 vs. 214.3 min, p = 0.042). Nevertheless, the time difference became insignificant after completing the initial 20 cases of transoral thyroidectomy. The drainage fluid collected after the surgery was serosanguinous, and a lower drainage volume was observed in the transoral group than that in the BABA group (64.9 vs. 78.5 ml, p = 0.017). However, there was no significant difference regarding the blood loss, hospital stay, postoperative pain score, and lymph nodes retrieved. The rate of postoperative complications, such as hypoparathyroidism and vocal cord palsy was comparable between the two groups. CONCLUSIONS: Transoral approach and BABA are comparable with regard to surgical outcomes. Selected patients may choose either technique based on their preferences.

Vocal cord granuloma after transoral thyroidectomy using oral endotracheal intubation: two case reports.

BACKGROUND: Transoral thyroidectomy can be performed using nasal or oral intubation. Recently, we encountered two cases of vocal cord granuloma that were suspected to result from intraoperative compression by the oral endotracheal tube. CASES PRESENTATION: Two women underwent transoral endoscopic thyroidectomy with oral endotracheal tubes fixed at the mouth angle. Their initial postoperative recovery was uneventful, but they developed hoarseness 2 months after the surgery. Subsequent strobolaryngoscopy revealed vocal cord granulomas at the side of contact of the endotracheal tube. One patient received medication and voice therapy, and her granuloma shrank significantly one month later. The other patient underwent granuloma resection. Thereafter, the symptoms improved in both the patients. CONCLUSIONS: Oral intubation with tube placement at the mouth angle might result in the formation of vocal cord granulomas. Therefore, we suggest positioning the tube at the midline to avoid excessive irritation on one side of the vocal cord.

In vitro antibacterial activity of rifampicin in combination with imipenem, meropenem and doripenem against multidrug-resistant clinical isolates of Pseudomonas aeruginosa.

BACKGROUND: Multidrug-resistant Pseudomonas aeruginosa has emerged as one of the most important healthcare-associated pathogens. Colistin is regarded as the last-resort antibiotic for multidrug-resistant Gram-negative bacteria, but is associated with high rates of acute kidney injury. The aim of this in vitro study is to search for an alternative treatment to colistin for multidrug-resistant P. aeruginosa infections. METHODS: Multidrug and carbapenem-resistant P. aeruginosa isolates were collected between January 2009 and December 2012 at MacKay Memorial Hospital. Minimal inhibitory concentrations (MICs) were determined for various antibiotic combinations. Carbapenemase-producing genes including bla VIM, other ß-lactamase genes and porin mutations were screened by PCR and sequencing. The efficacy of carbapenems (imipenem, meropenem, doripenem) with or without rifampicin was correlated with the type of porin mutation (frameshift mutation, premature stop codon mutation) in multidrug-resistant P. aeruginosa isolates without carbapenemase-producing genes. RESULTS: Of the 71 multidrug-resistant clinical P. aeruginosa isolates, only six harboured the bla VIM gene. Imipenem, meropenem and doripenem were significantly more effective (reduced fold-change of MICs) when combined with rifampicin in bla VIM-negative isolates, especially in isolates with porin frameshift mutation. CONCLUSIONS: Imipenem + rifampicin combination has a low MIC against multidrug-resistant P. aeruginosa, especially in isolates with porin frameshift mutation. The imipenem + rifampicin combination may provide an alternative treatment to colistin for multidrug -resistant P. aeruginosa infections, especially for patients with renal insufficiency.

Group B streptococcal serine-rich repeat proteins promote interaction with fibrinogen and vaginal colonization.

Group B streptococcus (GBS) can cause severe disease in susceptible hosts, including newborns, pregnant women, and the elderly. GBS serine-rich repeat (Srr) surface glycoproteins are important adhesins/invasins in multiple host tissues, including the vagina. However, exact molecular mechanisms contributing to their importance in colonization are unknown. We have recently determined that Srr proteins contain a fibrinogen-binding region (BR) and hypothesize that Srr-mediated fibrinogen binding may contribute to GBS cervicovaginal colonization. In this study, we observed that fibrinogen enhanced wild-type GBS attachment to cervical and vaginal epithelium, and that this was dependent on Srr1. Moreover, purified Srr1-BR peptide bound directly to host cells, and peptide administration in vivo reduced GBS recovery from the vaginal tract. Furthermore, a GBS mutant strain lacking only the Srr1 "latching" domain exhibited decreased adherence in vitro and decreased persistence in a mouse model of GBS vaginal colonization, suggesting the importance of Srr-fibrinogen interactions in the female reproductive tract.

Types and prevalence of carbapenem-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex in Northern Taiwan.

The frequency of the carbapenem-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii (CRACB) complex increases annually in our hospitals. However, the types and prevalence of carbapenemases among isolates still remain unclear. In this study, we identified and collected 672 carbapenem-resistant isolates from a medical center in Northern Taiwan between April and December of 2010. There were 577 genospecies 2 (Acinetobacter baumannii), 79 genospecies 13TU, and 16 genospecies 3 isolates. The isolates had an acquired blaOXA-24-like gene, which was confirmed by sequencing for the encoded OXA-72 carbapenemase, and were often associated with high-level carbapenem resistance. These CRACB complex isolates remained susceptible to colistin (100%). The genotyping of isolates was conducted using pulsed-field gel electrophoresis with ApaI digestion. In most clonally related groups, patients were from both branch hospitals. The results indicate that interhospital dissemination of clones occurred. This study provides updated data on the types and prevalence of the CRACB complex. In addition, it presents a warning on the emergence and spread of CRACB complex harboring blaOXA-24-like genes in northern Taiwan.

Group B Streptococcus CovR regulation modulates host immune signalling pathways to promote vaginal colonization.

Streptococcus agalactiae (Group B Streptococcus, GBS) is a frequent commensal organism of the vaginal tract of healthy women. However, GBS can transition to a pathogen in susceptible hosts, but host and microbial factors that contribute to this conversion are not well understood. GBS CovR/S (CsrR/S) is a two component regulatory system that regulates key virulence elements including adherence and toxin production. We performed global transcription profiling of human vaginal epithelial cells exposed to WT, CovR deficient, and toxin deficient strains, and observed that insufficient regulation by CovR and subsequent increased toxin production results in a drastic increase in host inflammatory responses, particularly in cytokine signalling pathways promoted by IL-8 and CXCL2. Additionally, we observed that CovR regulation impacts epithelial cell attachment and intracellular invasion. In our mouse model of GBS vaginal colonization, we further demonstrated that CovR regulation promotes vaginal persistence, as infection with a CovR deficient strainresulted in a heightened host immune response as measured by cytokine production and neutrophil activation. Using CXCr2 KO mice, we determined that this immune alteration occurs, at least in part, via signalling through the CXCL2 receptor. Taken together, we conclude that CovR is an important regulator of GBS vaginal colonization and loss of this regulatory function may contribute to the inflammatory havoc seen during the course of infection.

Clinical and molecular characteristics and risk factors for patients acquiring carbapenemase-producing and non-carbapenemase-producing carbapenem-nonsusceptible-Enterobacterales bacteremia.

BACKGROUND/PURPOSE: Carbapenem-nonsusceptible Enterobacterales (CNSE) are a growing global threat. Carbapenemases are often produced by plasmids, which allow rapid transmission. This study aimed to investigate (1) the bacterial type (2) resistant genes (3) antimicrobial susceptibility and (4) risk factors for acquisition of carbapenemase-producing carbapenem-nonsusceptible Enterobacterales (CP-CNSE) and non-carbapenemase-producing carbapenem-nonsusceptible Enterobacterales (non-CP-CNSE) bacteremia. METHODS: There were a total of 113 isolates of Enterobacterales from 2013 to 2018. After excluding nonblood isolates and including only one sample from each patient, 99 isolates were analyzed and the medical charts of these patients were reviewed. Carbapenemase genes, ß-lactamase genes and antimicrobial susceptibility of the isolates were determined. Multilocus sequence typing (MLST) was performed on CP-CNSE isolates. RESULTS: CP-CNSE carried more blaSHV (P = 0.004) and were more resistant to imipenem than non-CP-CNSE (P < 0.001). In the univariate analyses, we found that CP-CNSE bloodstream infection was associated with patient <65 years of age (odds ratio, 3.90; 95% confidence interval [CI], 1.16 to 13.10; P = 0.027), mechanical ventilation at the time of bloodstream infection (BSI) (odds ratio, 3.85; 95% CI, 1.16-12.78; P = 0.028) and exposure to piperacillin/tazobactam (odds ratio, 3.96; 95% CI, 1.09-14.38; P = 0.037). However, on multivariate analyses, no independent predictor for CP-CNSE was identified in this study. CONCLUSION: CP-CNSE carried more blaSHV and were more resistant to imipenem when compared to non-CP-CNSE. No independent predictor for CP-CNSE was identified after multivariate analysis. This is the first study conducted in Taiwan comparing risk factors between CP-CNSE and non-CP-CNSE from both clinical and molecular aspects.

Aconitum pendulum and Aconitum flavum: A narrative review on traditional uses, phytochemistry, bioactivities and processing methods.

ETHNOPHARMACOLOGICAL RELEVANCE: Composed of dried Aconitum pendulum and Aconitum flavum roots, Tiebangchui, is an important Tibetan medicine and has been traditionally and widely used as a remedy for cold and pain for thousands of years because of its extraordinary pharmacological activities. The toxicity and efficacy of Tiebangchui as a typical toxic traditional Tibetan medicine, are interdependent, and thus to make sure its safe use in clinics is also noteworthy. AIM OF THE STUDY: This review aims to document and summarize critical and comprehensive information about traditional uses, phytochemistry, pharmacology, toxicology and processing methods of Tiebangchui. Perspectives for possible future investigations have been discussed. MATERIALS AND METHODS: Relevant information about Tiebangchui (A. pendulum and A. flavum) was collected from internationally recognized electronic scientific databases, such as Web of Science, PubMed, Science Direct, Springer Link, ACS, and CNKI. Then, classic Tibetan medical books, such as Four Medical Tantra, and Jing Zhu Materia Medica, and official drug standards were reviewed. RESULTS: A total of 95 chemical constituents have been isolated and identified from Tiebangchui, and most of them were diterpenoid alkaloids. These phytochemicals showed a wide range of pharmacological properties, such as anti-inflammation, anti-rheumatoid arthritis, analgesic, local anesthetic, anti-cancer and anti-bacterial activities. Hence, Tiebangchui is broadly used in hundreds of preparations to treat fever, arthritis, rheumatic arthralgia, traumatic injury, furuncle and swelling. Cardiotoxicity, neurotoxicity and gastrointestinal toxicity are the main toxic effects caused by the Aconitum alkaloids of Tiebangchui. Various processing methods, including steaming, decocting and sand-frying, and traditional Tibetan medicine processing methods, such as processing with Hezi decoction, Qingke wine and Zanba, are effective in attenuating toxicity while retaining efficacy. CONCLUSIONS: The present review provides primary information of Tiebangchui, particularly for its traditional uses, botanical characteristics, phytochemicals, outstanding bioactivities and processing methods. However, studies that explored the in vivo pharmacokinetics and mechanism of Tiebangchui, as well as its quality markers, qualitative and quantitative analysis are still insufficient. Processing methods that attenuate toxicities, evaluations of efficacy, in vivo processes and biological effects, the mechanisms of processed products should be further explored.

Serine-rich repeat proteins and pili promote Streptococcus agalactiae colonization of the vaginal tract.

Streptococcus agalactiae (group B streptococcus [GBS]) is a Gram-positive bacterium found in the female rectovaginal tract and is capable of producing severe disease in susceptible hosts, including newborns and pregnant women. The vaginal tract is considered a major reservoir for GBS, and maternal vaginal colonization poses a significant risk to the newborn; however, little is known about the specific bacterial factors that promote GBS colonization and persistence in the female reproductive tract. We have developed in vitro models of GBS interaction with the human female cervicovaginal tract using human vaginal and cervical epithelial cell lines. Analysis of isogenic mutant GBS strains deficient in cell surface organelles such as pili and serine-rich repeat (Srr) proteins shows that these factors contribute to host cell attachment. As Srr proteins are heavily glycosylated, we confirmed that carbohydrate moieties contribute to the effective interaction of Srr-1 with vaginal epithelial cells. Antibody inhibition assays identified keratin 4 as a possible host receptor for Srr-1. Our findings were further substantiated in an in vivo mouse model of GBS vaginal colonization, where mice inoculated with an Srr-1-deficient mutant exhibited decreased GBS vaginal persistence compared to those inoculated with the wild-type (WT) parental strain. Furthermore, competition experiments in mice showed that WT GBS exhibited a significant survival advantage over the ΔpilA or Δsrr-1 mutant in the vaginal tract. Our results suggest that these GBS surface proteins contribute to vaginal colonization and may offer new insights into the mechanisms of vaginal niche establishment.

Indocyanine Green Angiography for Parathyroid Gland Evaluation during Transoral Endoscopic Thyroidectomy.

Indocyanine green (ICG) angiography, a real-time intraoperative imaging technique, is associated with better parathyroid identification and functional evaluation during open thyroidectomy. However, the benefits of ICG fluorescence imaging application in transoral endoscopic thyroidectomy are not well-documented. Consecutive patients who underwent transoral endoscopic thyroidectomy were retrospectively reviewed. Parathyroid glands were assessed with visual inspection followed by ICG angiography. The fluorescence intensity of all parathyroid glands was recorded. In total, 158 parathyroid glands from 60 patients (41 underwent lobectomy and 19 underwent total thyroidectomy) were eligible for evaluation. A total of 135 parathyroid glands (85.4%) were identified, including nine glands (5.7%) that were solely localized because of ICG angiography. Incidental parathyroidectomy occurred in 12 patients with predominant inferior gland (83.3%) and associated with central neck dissection (66.7%). Among patients receiving total thyroidectomy, patients who retained at least one well-perfused parathyroid gland had higher parathyroid hormone (PTH) level and were less likely to develop hypoparathyroidism on postoperative day one than those without any well-perfused ICG-enhanced parathyroid gland (p = 0.038). In addition, the duration of calcium supplementation to maintain normocalcemia was also shorter. ICG angiography is a feasible adjunct procedure for parathyroid identification and postoperative functional prediction in transoral endoscopic thyroidectomy.

Extreme Lake-Effect Snow from a GPM Microwave Imager Perspective: Observational Analysis and Precipitation Retrieval Evaluation.

This study focuses on the ability of the Global Precipitation Measurement (GPM) passive microwave sensors to detect and provide quantitative precipitation estimates (QPE) for extreme lake-effect snowfall events over the U.S. lower Great Lakes region. GPM Microwave Imager (GMI) high-frequency channels can clearly detect intense shallow convective snowfall events. However, GMI Goddard Profiling (GPROF) QPE retrievals produce inconsistent results when compared with the Multi-Radar Multi-Sensor (MRMS) ground-based radar reference dataset. While GPROF retrievals adequately capture intense snowfall rates and spatial patterns of one event, GPROF systematically underestimates intense snowfall rates in another event. Furthermore, GPROF produces abundant light snowfall rates that do not accord with MRMS observations. Ad hoc precipitation-rate thresholds are suggested to partially mitigate GPROF's overproduction of light snowfall rates. The sensitivity and retrieval efficiency of GPROF to key parameters (2-m temperature, total precipitable water, and background surface type) used to constrain the GPROF a priori retrieval database are investigated. Results demonstrate that typical lake-effect snow environmental and surface conditions, especially coastal surfaces, are underpopulated in the database and adversely affect GPROF retrievals. For the two presented case studies, using a snow-cover a priori database in the locations originally deemed as coastline improves retrieval. This study suggests that it is particularly important to have more accurate GPROF surface classifications and better representativeness of the a priori databases to improve intense lake-effect snow detection and retrieval performance.

Inhibition of Cancer Cell Adhesion, Migration and Proliferation by a Bispecific Antibody that Targets two Distinct Epitopes on αv Integrins.

Members of the αv family of integrins regulate activation of transforming growth factor beta (TGFß) and are directly involved in pro-tumorigenic phenotypes. Thus, αv integrins may be therapeutic targets for fibrosis and cancer, yet the isolation of selective inhibitors is currently a challenge. We generated synthetic antibodies selective for αv integrins by phage display selections on cell lines that displayed integrin heterodimers. We identified antibodies that targeted two distinct epitopes on cell-surface αv integrins and partially inhibited cell adhesion mediated by interactions between integrins and the latency-associated peptide, part of the pro-form of TGFß. Using the isolated antibody paratope sequences we engineered a bispecific antibody capable of binding to both epitopes simultaneously; this antibody potently and completely inhibited cell adhesion mediated by integrins αvß1, αvß3 and αvß5. In addition, the bispecific antibody inhibited proliferation and migration of lung carcinoma lines, where the highest and lowest potencies observed correlated with integrin-αv cell surface expression levels. Taken together, our results demonstrate that phage display selections with live cells can yield high quality anti-integrin antibodies, which we used as biparatopic building blocks to construct a bispecific antibody that strongly inhibited integrin function and may be a therapeutic candidate for cancer and fibrosis.

Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs.

The Wnt/ß-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of ß-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/ß-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl4)-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of ß-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/ß-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis.

Incarcerated Hiatal Hernia with Perforation after Laparoscopic Total Gastrectomy with Roux-en-Y Reconstruction: a Case Report.

The occurrence of hiatal hernia after total gastrectomy with Roux-en-Y reconstruction is rare. We report the case of a 76-year-old man who presented with dyspnea, vomiting, and fever around 8 days after total gastrectomy with Roux-en-Y reconstruction. Abdominal computed tomography revealed a hiatal hernia containing part of the small intestine in the left thoracic cavity. Emergent reduction and repair of the hiatal hernia were performed later. Operative findings revealed that the Roux limb was incarcerated in the left pleural cavity. Esophagojejunostomy leakage, perforation of the small intestine with transient ischemic change, and pyothorax were also found. Thus, feeding jejunostomy, thoracoscopic decortication, and diversion T-tube esophagostomy were performed. Considering that the main cause of hiatal hernia is blunt dissection with division of the phrenoesophageal membrane, approximating the crus with 1 or 2 figure-8 sutures, according to the size of the defect, to prevent the incidence of hiatal hernia after total gastrectomy may be performed.

Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography.

OBJECTIVE: To determine if specific mutations were present in Asian patients with progressive familial intrahepatic cholestasis (PFIC) type 2 caused by defects in bile salt export pump (BSEP), encoded by ABCB11. STUDY DESIGN: A combination of denaturing high-performance liquid chromatography (DHPLC) and direct sequencing was used to screen ABCB11 mutations in 18 Taiwanese patients with low gamma-glutamyltransferase PFIC or benign recurrent intrahepatic cholestasis (BRIC). Polymorphisms were also analyzed in patients with PFIC (n = 21), neonatal cholestasis (n = 23), and control subjects (n = 88). RESULTS: Seven mutations in 4 of 16 patients with PFIC from different families were detected by DHPLC, including M183V, V284L, R303K, R487H, W493X, G1004D, and 1145delC. G1004D was found in a patient with BRIC. L827I was found in another patient with neonatal cholestasis. Absent or defective BSEP staining was found in the liver of patients with mutations. Polymorphisms V444A and A865V, with an allele frequencies 75.6% and 0.6%, respectively, were found in our population. No differences were found between patients with cholestasis and control subjects. CONCLUSIONS: One-fourth of Taiwanese patients with PFIC/BRIC had compound heterozygous or single heterozygous ABCB11 mutations without hot spots. All of the mutations were different from those detected in Western countries.

Prenatal diagnosis of progressive familial intrahepatic cholestasis type 2.

BACKGROUND AND AIM: Progressive familial intrahepatic cholestasis type 2 (PFIC2) results from genetic defects of the hepatobiliary bile salt export pump (BSEP, ABCB11) at chromosome 2q24. Patients with progressive cholestasis and liver cirrhosis usually need liver transplantation in the first decade. Mutations in ABCB11 are also associated with benign recurrent intrahepatic cholestasis type 2 and intrahepatic cholestasis of pregnancy in adult patients. We aimed to make the prenatal diagnosis of PFIC2. METHODS: Genetic diagnosis was performed by genomic DNA analysis. Prenatal genetic diagnosis was made by fetal amniotic DNA and chorionic DNA analysis. RESULTS: We report on two families of PFIC2 with inherited compound heterozygous mutations of ABCB11 (M183V and R303K in Family 1, V284L and 1145delC in Family 2) from the parents. An infant with heterozygous M183V mutation was later born healthy in Family 1. A fetus with compound heterozygous missense mutation V284L and 1145delC was terminated in Family 2. CONCLUSION: Prenatal diagnosis of PFIC2 was helpful to prevent further affected children in families with this fatal disease.

[Industrial VOCs Emission in Qinhuangdao].

This study established a VOC emissions inventory for Qinhuangdao City using the data on the product yield, raw material use, the concentration of VOCs, the discharge flow, and activities of 609 enterprises. The amount of annual VOC emissions obtained from direct measurements and emission factor methods was 8420.07 t; 48.9% of which was from the economechnological development district, which is the major industrial source of VOCs in the region. Benzene, lipids, alkanes, and ketones were the main industrial VOC components. For important VOC-emitting industries, processing of petroleum, coking, processing of nuclear fuel contributed 30.35% of total VOCs emissions in Qinhuangdao, and manufacture of chemical raw materials, chemical products contributed 14.42%. Solvent use was the most important emission link, which accounted for 37% of total industrial VOCs emissions. About 109 of 609 investigated plants have VOC treatment facilities, 69% of which are based on adsorption technology.