[Update points for the 2022 edition of the European Association for the Study of Liver Diseases Clinical Practice Guidelines for the Management of Hepatic Encephalopathy and comparison with China's 2018 edition guidelines].

The European Association for the Study of Liver Diseases issued the "Clinical Practice Guidelines for the Management of Hepatic Encephalopathy" in 2022, which included recommendations for clinical diagnosis, assessment, treatment, management, and prevention. The Society's "Hepatic Encephalopathy Clinical Practice Guidelines in Chronic Liver Disease," which was last published in 2014, and the "Guidelines for the Diagnosis and Treatment of Hepatic Encephalopathy in Cirrhosis," which the Chinese Society of Hepatology, Chinese Medical Association, released in 2018, have certain differences and updates in terms of comparison to terminology, grading and classification, diagnosis, clinical evaluation and treatment, management, and prevention. Herein, the updated points of this guideline and the differences between it and our nation's guidelines are summarized in order to refine and understand the guiding role of the new version of the guideline for the clinical treatment of hepatic encephalopathy and provide aid for standardizing clinical diagnosis and treatment.

[A meta-analysis on prevalence of primary angle-closure glaucoma in the middle-aged and elderly chinese population].

Objective: To evaluate the prevalence and relevant factors of primary angle-closure glaucoma (PACG) in the middle-aged and elderly (40 years old and above) Chinese population. Methods: Epidemiological literature (of English and/or Chinese language) on prevalence of PACG in China between 2000 and 2022 were retrieved from PubMed, Embase, Web of Science, CNKI, and Wanfang database. Two researchers conducted the process of document retrieval, inclusion, quality assessment and data extraction independently based on inclusion and exclusion criteria. Disagreement was resolved by consensus with a third researcher. The heterogeneity among studies was assessed by using the I2 statistics, and a corresponding model was used for the meta-analysis. Subgroup analysis (gender, age, survey date, place of residence, diagnostic criteria, and temperature zone), as well as sensitivity analysis and publication bias analysis, were conducted. Results: Twenty-three studies were included in this research. Among them, eight were of high-quality and fifteen were of middle-quality. In the past 20 years, the PACG prevalence in middle-aged and elderly (40 years and older) Chinese population was 1.35% (95%CI:1.08% to 1.61%). Chinese women (1.40%) were more likely to have PACG than men (0.96%, P<0.01). The PACG prevalence had a positive correlation with age (P<0.01). The prevalence was similar between urban (1.3%) and rural (1.2%, P=0.61) areas. The PACG prevalence from studies in which the diagnostic criteria of PACG requested the symptom of vision or optic nerve damage (1.1%) was lower than that those without such requirement (1.7%, P<0.01). In mid-temperate zone, the prevalence was higher (1.7%, P=0.02). Conclusions: The PACG prevalence in middle-aged and elderly (40 years old and above) Chinese population was 1.35% in the last 20 years. The prevalence of PACG varies across age, regions, and other variations. This risk is higher in the elderly, women, and people in cold regions among Chinese population.

[Efficacy of the XEN gel stent on intraocular pressure lowering in glaucoma patients].

Objective: To evaluate the efficacy and safety of the XEN gel implant in the treatment of glaucoma. Methods: It was a retrospective case series study. Eight patients (8 eyes) in the First Affiliated Hospital of Fujian Medical University from January 2020 to September 2020 were included, including six males and two females, aged 29 to 74 years. The patients treated with the XEN gel implanting for glaucoma. After detailed ophthalmic examination, all the patients met the surgical indications for the XEN gel implanting. Preoperative and postoperative intraocular pressure (IOP), anterior segment and fundus examination results, medication, and surgical complications were evaluated. Results: There were seven patients with primary open-angle glaucoma and one patient with glaucomatocyclitic syndrome. Five patients had received anti-glaucoma surgeries, and the remaining three patients had not received surgical treatment. All XEN gel stents were implanted successfully. All patients were followed up for 4 to 12 months. The preoperative maximum IOP ranged from 11 to 44 mmHg (median, 28 mmHg, 1 mmHg=0.133 kPa), and the IOP was 10 to 18 mmHg (median, 13 mmHg) at the last follow-up. Two to 4 types of medication were used for glaucoma preoperatively (median, 3), while 0 to 2 types (median, 0) were used at the last follow-up. During the follow-up, 7 cases were completely successful and only one case failed. Intraoperative hemorrhage occurred in two patients, and after effective treatment, the IOP decreased to below 20 mmHg. One patient was found to have an increased IOP with the XEN luminal obstruction, and the XEN drainage tube was recanalized. The IOP was about 10 mmHg at the last follow-up, and no anti-glaucoma drugs were used, but the surgery was assessed as failure by standard. The remaining patients had no other serious complications. Conclusion: This preliminary study shows that the XEN gel drainage may be a safe and effective treatment for patients with glaucoma. (Chin J Ophthalmol, 2021, 57: 679-684).

[Model for end-stage liver disease combined with arterial blood lactate to assess the prognosis of hepatitis B virus-associated acute-on-chronic liver failure: a retrospective analysis of 97 cases].

Objective: To explore the prognostic value of model for end-stage liver disease (MELD) combined with arterial blood lactate (Lac) in admitted patients with hepatitis B virus-associated acute- on-chronic liver failure (HBV-ACLF). Methods: Clinical data of 97 cases with hepatitis B virus-associated acute- on-chronic liver failure (HBV-ACLF) admitted to the First Affiliated Hospital of Suzhou University between March 2016 and March 2018 was retrospectively analyzed. Age, gender, complications, MELD score, lactic acid (Lac), total bilirubin (TBil), creatinine (Cr), serum albumin (Alb), high-sensitivity C-reactive protein (CRP), white blood cell count (WBC), platelet count (PLT), hematocrit (Hct), quantification of HBV DNA and HBsAg, and organ support treatment (artificial liver support system, renal replacement therapy and mechanical ventilation ) were documented after admission. The primary endpoint of treatment was death due to ineffective medical treatment during hospitalization, abandonment of medical treatment due to deterioration of the health condition, and switch to liver transplantation for patients with poor medical treatment. The risk factors for primary endpoint of treatment were analyzed by binary logistic regression. Hosmer-Lemeshow test was used to evaluate the goodness of fit for the scoring system, and the ROC to predict the prognosis of MELD-Lac. Results: Ninety-seven cases with HBV-ACLF were included, 56 cases had good prognosis, and 41 cases had bad prognosis (including two cases with poor medical treatment and liver transplantation). The overall improvement rate was 57.7%. MELD score and Lac value in treated group was significantly lower than non-treated group. Bivariable and multivariable logistic regression analysis showed that the MELD score [odds ratio (OR = 1.806)], and Lac score [odds ratio (OR = 1.820)] was the risk factor for hospitalization and mortality in patients with liver failure (P < 0.05). The area under the ROC curve (AUC) and the 95% confidence interval (95% CI) of prognostic patients with MELD-Lac were significantly better than Lac and MELD scores [0.923 (0.84 to 1.00) vs. 0.804 (0.067 to 0.942) and 0.864 (0.75). 0.977)], P < 0.05. When the MELD-Lac Youden index was set at 0.746, the optimal threshold was 18.36, and the sensitivity and specificity were 91.3% and 83.3%, respectively. Conclusion: MELD-Lac score has a high prognostic value in HBV-ACLF patients.

[The safety of decitabine as bridging pretreatment regimen before hematopoietic stem cell transplantation in pediatric hematological malignancies].

The safety of decitabine as bridging treatment before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with refractory hematological malignancies was evaluated. All 11 cases succeeded in hematopoietic reconstitution. The main adverse reaction was hematological toxicity. Neither did infections occur, nor drug-induced liver damage and renal impairment during decitabine administration. Most cases showed grade Ⅰ-Ⅱgastrointestinal adverse events. One case was diagnosed as severe acute graft versus host disease and died of intracranial hemorrhage on day 61 after allo-HSCT. The other 10 patients survived. Decitabine bridge is a safe regimen before allo-HSCT in children with refractory hematological malignancies.

Dual-channel compressed ultrafast photography for Z-pinch dynamic imaging.

The compressed ultrafast photography (CUP) can capture non-repetitive time-evolving events at 7 × 1013 fps, which is anticipated to find a diverse range of applications in physics, biomedical imaging, and materials science. The feasibility of diagnosing ultrafast phenomenon of Z-pinch by using the CUP has been analyzed in this article. Specifically, a dual-channel CUP design has been adopted for acquiring high quality reconstructed images and the strategies of identical masks, uncorrelated masks, and complementary masks have been compared. Furthermore, the image of the first channel was rotated by 90° to balance the spatial resolution between the sweep direction and the non-sweep direction. Both five synthetic videos and two simulated Z-pinch videos were chosen as the ground truth to validate this approach. The average peak signal to noise ratio of the reconstruction results is 50.55 dB for the self-emission visible light video and 32.53 dB for the laser shadowgraph video with unrelated masks (rotated channel 1). The simulation results show that the time-space-evolving process of plasma distribution can be well retold, and the phenomenon of plasma instability can be accurately diagnosed by the dual-channel CUP with unrelated masks (rotated channel 1). This study may promote the practical applications of the CUP in the field of accelerator physics.

[Efficacy and safety of total neoadjuvant therapy versus neoadjuvant chemoradiotherapy in the treatment of locally advanced rectal cancer: a meta-analysis].

Objective: To systematically evaluate the efficacy and safety of total neoadjuvant therapy (TNT) in the comprehensive treatment of locally advanced rectal cancer. Methods: Literatures were screened from PubMed, Embase, Web of Science, Cochrane Library, CBM, Wanfang Data, VIP and CNKI from the inception date to May 2021 to collect the randomized controlled clinical trials (RCTs) of TNT followed by total mesorectal excision (TME) versus neoadjuvant chemotherapy (nCRT) followed by TME in the treatment of locally advanced rectal cancer. The data of overall survival, disease-free survival, R0 radical resection rate, pathological complete response (pCR) rate, T downstaging rate, the incidence of adverse events ≥ grade III, including neutropenia, nausea and vomiting, diarrhea, radiation dermatitis and nervous system toxicity, and the morbidity of complications within postoperative 30 days of the two groups were extracted from the included literatures. Review Manager 5.3 software was utilized for statistical meta-analysis. Results: Nine RCTs were finally enrolled including 2430 patients. Meta-analysis results showed that compared with nCRT group, patients in TNT group had longer overall survival (HR=0.80, 95%CI: 0.65-0.97, P=0.03) and higher pCR rate (RR=1.73, 95%CI: 1.44-2.08, P<0.01) with significant differences. Besides, there were no significant differences between two groups in disease-free survival (HR=0.86, 95%CI:0.71-1.05, P=0.14), R0 radical resection rate (RR=1.02, 95%CI: 0.99-1.06, P=0.17) and T downstaging rate (RR=1.04, 95%CI: 0.89-1.22, P=0.58) between two groups. In terms of treatment safety, the incidence of adverse events ≥ grade III (RR=1.09, 95%CI: 0.70-1.70, P=0.70) and morbidity of complications within postoperative 30 days (RR=1.07, 95%CI: 0.97-1.18, P=0.19) did not significantly differ between two groups. Conclusions: In the treatment of locally advanced rectal cancer, TNT may bring more survival benefits than nCRT and does not increase the incidence of adverse events and postoperative complications. Therefore, TNT could be used as a recommended treatment for patients with locally advanced rectal cancer.

Clinical characteristics and microbiology of nosocomial enterococcal bloodstream infections in a tertiary-level hospital: a retrospective study, 2007-2019.

BACKGROUND: Enterococci are important pathogens causing nosocomial bloodstream infections (BSIs) and cannot be treated with appropriate timely empirical antibiotics due to their natural resistance to many kinds of antibiotics. AIM: To analyse the clinical characteristics and microbiological features of nosocomial bloodstream infections caused by enterococci. METHODS: The clinical characteristics and microbiological features of nosocomial enterococcal BSI patients in Xiamen University Zhongshan Hospital were examined in a case-controlled retrospective study. All patient information was collected through an electronic surveillance system. FINDINGS: A total of 199 cases were identified as nosocomial enterococcal BSIs over a period of 13 years. The incidence of BSIs fluctuated from 0.21% to 0.81%. In the distribution of wards, enterococcal BSIs in hepatobiliary surgery ranked first. Intra-abdominal diseases (odds ratio: 3.36; 95% confidence interval: 2.15-5.27; P < 0.001), chemotherapy history (4.37; 2.06-9.25; P < 0.001), and urinary catheterization (2.34; 1.52-3.61; P < 0.001) were risk factors for nosocomial enterococcal BSI acquisition. Vancomycin-resistant enterococci and linezolid-insensitive enterococci strains were not found. CONCLUSION: Patients with a history of intra-abdominal disease, chemotherapy and urinary catheterization are at higher risk of nosocomial enterococcal bloodstream infections. The enterococcus strains were still sensitive to commonly used antibiotics.

Cognitive impairment using education-based cutoff points for CMMSE scores in elderly Chinese people of agricultural and rural Shanghai China.

OBJECTIVES: To evaluate cognitive impairment (CI) in rural China using the Chinese version of the Mini-Mental Status Examination (CMMSE) and compare the prevalence of CI using two different cutoff points. MATERIALS & METHODS: A population-based survey was conducted of 2809 people aged 60 years and above in a community of two towns (Huaxin and Xujing) in the Qingpu district, located in the western suburb of Shanghai. Face-to-face interviews were carried out to collect relevant information with questionnaires. The Chinese version of the Mini-Mental State Examination with either a 23/24 cutoff point or a cutoff point varying according to education level (AEL) was used to screen subjects for CI. RESULTS: Among these subjects, the mean age was 70.6 years (SD = 6.6) and ranged from 60 to 92 years and included 1010 (36.0%) men and 1799 (64.0%) women. The mean age was 70.7 years (SD = 6.4) for men and 70.5 years (SD = 6.7) for women. Of the 2809 subjects, 2010 (71.5%) had no formal education, 607 (21.6%) completed 1-6 years of education, and 173 (6.2%) completed more than 6 years of school education. The prevalence of CI was 35.6% (95% CI: 33.8-37.4) for both genders when the cutoff point of 23/24 was used. However, when the cutoff point was altered with respect to different education levels, the prevalence of CI was 7.0%. For each item of the CMMSE, increased years of education correlated with a higher item score, with the exception of the 'Naming' item score. CONCLUSIONS: This study demonstrates that screening of CI using the AEL cutoff scores is feasible in a low-education population. Determining whether the 23/24 cutoff point is suitable for the Chinese people requires future prospective studies in a large Chinese population.

Tubulointerstitial nephritis and uveitis syndrome (TINU) with Fanconi's syndrome.

We report a 57-year-old woman with concurrent tubulointerstitial nephritis and uveitis syndrome (TINU) and Fanconi's syndrome. She presented with sudden onset of bilateral ocular pain, blurred vision, acute renal failure, glucosuria and proteinuria. Slit lamp examination revealed acute bilateral anterior uveitis. Tubulointerstitial nephritis was confirmed by kidney biopsy. Laboratory examination revealed normoglycemic glucosuria, proteinuria, normal anion-gap metabolic acidosis, phosphaturia, urinary uric acid wasting and kaliuresis leading to hypokalemia. Her vision and renal function improved gradually after systemic steroid therapy. There have been rare reports of TINU syndrome which had features of Fanconi's syndrome. The prevalence of TINU syndrome may be underestimated, and its association with Fanconi's syndrome requires further investigation.

[Clinical characteristics and distribution of peripheral T lymphocyte subsets in patients with schistosomal hepatic diseases in Suzhou City].

OBJECTIVE: To investigate the clinical characteristics and the distribution of peripheral blood T lymphocyte sub-sets in patients with schistosomal hepatic cirrhosis in Suzhou City. METHODS: A total of 32 inpatients with liver diseases due to advanced schistosomiasis at the Department of Infectious Diseases, The First Affiliated Hospital of Soochow University from January 2016 to January 2018 were recruited and assigned into the infection and non-infection groups according to presence of co-infections, and 20 old healthy volunteers served as controls. Venous blood samples were collected on the day of admission, and the proportions of CD4+ T cells, CD8+ T cells, regulatory T (Treg) cells and Th17 cells were detected in peripheral blood using flow cytometry. RESULTS: Most patients with liver disorders due to advanced schistosomiasis were admitted to hospital in Suzhou City because of portal hypertension-associated complications, with a high prevalence of co-infections (59.38%, 19/32). The proportions of peripheral CD4+ and CD8+ T cells and Th17 cells were all significantly lower in patients with liver disorders due to advanced schistosomiasis than in controls (t = -5.111, -4.470 and -2.749, all P < 0.05), and a higher proportion of Treg cells was detected in patients than in controls (t = 5.628, P < 0.05). In addition, there were significant differences among the infection group, non-infection group and controls in terms of the percentage of CD4+ T cells, CD8+ T cells, Th17 cells and Treg cells (F = 15.837, 16.594, 9.290 and 27.866, all P < 0.05). CONCLUSIONS: Portal hypertension-associated complications are predominantly seen in patients with liver diseases due to advanced schistosomiasis at admission in Suzhou City, and co-infections are common. Imbalance of peripheral T cell subsets is detected in patients with liver diseases due to advanced schistosomiasis in Suzhou City.

[Primary coenzyme Q10 deficiency-7: a case report and literature review].

Objective: To explore the clinical characteristics and gene variation of primary coenzyme Q10 deficiency-7 (COQ10D7) in children. Methods: Clinical data and genetic tests results of a COQ10D7 child caused by coenzyme Q4 (COQ4) gene variation at the First Affiliated Hospital of Xiamen University in March 2020 were collected and analyzed. A literature search with "primary coenzyme Q10 deficiency" or "COQ4 gene" as the keyword was conducted at Wanfang database, China national knowledge infrastructure(CNKI), PubMed, online Mendelian inheritance in man(OMIM), ClinVar database (up to April 2020), the clinical characteristics and gene variation of children with primary COQ10D7 were summarized. Results: A 5-month-old boy was diagnosed as "epilepsy" because of intermittent epileptic seizures in three months. He had feeding difficulties, growth retardation, hypotonia of limbs and increased lactic acid. His whole exon gene testing suggested a homozygous variation of COQ4 gene (c.370G>A). One article in Chinese and 9 articles in English were found, which made up the complete case data of 33 patients (including our case). There were 12 missense variations, 2 frameshift variations, 1 splicing variation, 1 nonsense variation and 1 deletion variation, among these variations c. 370G>A was found only in children in southern China.The age of onset was mostly in the neonatal period (22 cases). Among all patients, 20 cases had presented neonatal respiratory distress or respiratory insufficiency, 21 cases had seizures, 20 cases had hypertrophic cardiomyopathy, and 26 cases had elevated serum lactic acid or lactic acidosis. Brain dysplasia, brain atrophy, basal ganglia and other lesions were observed on brain magnetic resonance imaging in 28 cases. Most of them had a poor prognosis with a mortality rate of 20/33. The age of death ranged from 4 hours to 42 months old. Conclusions: The main clinical phenotypes of primary COQ10D7 are neonatal respiratory distress or respiratory insufficiency, epilepsy, myocardial hypertrophy and lactic acid elevation. Primary COQ10D7 is caused by homozygous or compound heterozygous variation in the COQ4 gene, and c.370G>A may be the hotspot variation in children in southern China.

Curcumin inhibits hypoxia inducible factor-1α-induced inflammation and apoptosis in macrophages through an ERK dependent pathway.

OBJECTIVE: Atherosclerosis, a kind of peripheral arterial disease with chronic inflammation, leads to the dysfunction of the vascular system and many other diseases. Hypoxia has been proven to participate in the progression of atherosclerosis, while curcumin can inhibit hypoxia-inducible factor 1α (HIF-1α). However, the underlying mechanisms are still elusive. PATIENTS AND METHODS: qRT-PCR was used to examine the expression of HIF-1α, IL-6 and TNFα of macrophages under hypoxic condition. Western blot was applied to examine the changes of HIF-1α, ERK and p-ERK after treatment with curcumin. Oli Red O staining and enzymatic assay were used to examine the lipid and total cholesterol in macrophages, respectively. ELISA was used to examine the release of IL-6 and TNFα by macrophages. FACS and MTT assays were applied to examine the apoptosis and proliferation of macrophages. RESULTS: Here, we found curcumin inhibited the expression of HIF-1α at the protein level in macrophages under hypoxic condition and curcumin and HIF-1α inhibitors repressed the total cholesterol and lipid level in macrophage under hypoxic condition. Moreover, curcumin also decreased the expression of HIF-1α downstream genes, VEGF, HMOX1, ROS and PDGF. Then, the data show the HIF-1α-induced apoptosis and inflammation of macrophages were inhibited by curcumin. Curcumin also rescued the proliferation defect of macrophages caused by hypoxia. Furthermore, we found it inhibited the expression of HIF-1α via ERK signaling pathway. CONCLUSIONS: We describe that curcumin inhibited the HIF-1α-induced apoptosis and inflammation of macrophages via ERK signaling pathways. These results suggest curcumin can be used for the treatment of atherosclerosis.

[Treatment of four cases of Fanconi anemia by allogeneic hematopoietic stem cell transplantation with low intensity conditional regimen].

Objective: To evaluate the efficiency and safety of low intensity conditional regimen for children with Fanconi anemia (FA) receiving allogenic hematopoietic stem cells transplantation (allo-HSCT). Methods: Four patients diagnosed as Fanconi anemia were enrolled in this study. One patient received HLA-identical sibling donor hematopoietic stem cell transplantation, two patients underwent unrelated donor matched (UD) HSCT, and one patient received unrelated cord blood transplantation. The conditional regimen consisted of Busulfan with low dose of cyclophosphamide. Results: All 4 cases succeeded in allo-HSCT. The median time for neutrophils engraftment was 11(9-15) day, median time to platelets (PLT) engraftment was 12 (8-28) day. One case occurred with grade I of aGVHD, 1 case with hemorrhagic cystitis. No patient happened with hepatic veno-occlusive disease (VOD). Conclusion: Low intensity of conditional regimen is efficient and safe which should be recommended for FA patients with HSCT.

[A multicenter, retrospective study of pathogenic bacteria distribution and drug resistance in febrile neutropenic patients with hematological diseases in Shanghai].

Objective: To investigate the pathogen spectrum distribution and drug resistance of febrile neutropenic patients with hematological diseases in Shanghai. Methods: A retrospective study was conducted on the clinical isolates from the febrile neutropenic patients hospitalized in the departments of hematology in 12 general hospitals in Shanghai from January 2012 to December 2014. The drug susceptibility test was carried out by Kirby-Bauer method. WHONET 5.6 software was used to analyze pathogenic bacteria and drug susceptibility data. Results: A total of 1 260 clinical isolates were collected from the febrile neutropenic patients. Gram-positive bacteria accounted for 33.3% and Gram-negative bacteria accounted for 66.7%. Klebsiella pneumoniae (12.5%) , Stenotrophomonas maltophilia (9.5%) , Escherichia coli (9.1%) , Pseudomonas aeruginosa (8.7%) , Acinetobacter baumannii (6.6%) , Staphylococcus aureus (5.6%) and Enterococcus faecium (5.0%) were ranked in the first 7 of all pathogens. In the respiratory tract secretions specimens, non-fermented strains accounted for 56.2%. Stenotrophomonas maltophilia accounted for 15.2%. Enterobacteriaceae and coagulase-negative Staphylococci accounted for 42.3% (104/246) and 32.6% (85/246) respectively in blood samples. Enterobacteriaceae and Enterococcus bacteria accounted for 39.4% (76/193) and 28.5% (55/193) respectively in pus specimens. The detection rates of methicillin resistant Staphylococcus aureus (MRSA) and methicillin resistant coagulase negative Staphylococci (MRCNS) were 54.3% and 82.5%, respectively. Staphylococcus bacterial strain was not found to be resistant to linezolid, vancomycin and teicoplanin. The detection rate of Enterococcus vancomycin-resistant strains was 8.9%. Enterococcus was not detected resistance to oxazolidinone strains. Enterobacteriaceae bacteria were highly sensitive to carbapenems. The resistance rate of Pseudomonas aeruginosa to imipenem and meropenem was 34.1% and 15.8%, respectively. Stenotrophomonas maltophilia was more sensitive to minocycline hydrochloride, levofloxacin and sulfamethoxazole. The resistance rate of Acinetobacter baumannii only to cefoperazone-sulbactam was less than 10.0%. The antibiotic resistance rate of Klebsiella pneumoniae, Stenotrophomonas maltophilia, Pseudomonas aeruginosa and Acinetobacter baumanii to most of common antibiotics was lower than that of the CHINET surveillance. Conclusions: The pathogenic strain distribution in common infection sites of febrile neutropenic patients was characterized. Bacterial resistance surveillance was better than the CHINET nationwide large sample surveillance in China.

Reduced Penetrance of PRRT2 Mutation in a Chinese Family With Infantile Convulsion and Choreoathetosis Syndrome.

Paroxysmal kinesigenic dyskinesia is a rare episodic movement disorder that can be isolated or associated with benign infantile seizures as part of choreoathetosis syndrome. Mutations in the PRRT2 gene have been recently identified as a cause of paroxysmal kinesigenic dyskinesia and infantile convulsion and choreoathetosis (ICCA). We reported a PRRT2 heterozygous mutation (c.604-607delTCAC, p.S202Hfs*25) in a 3-generation Chinese family with infantile convulsion and choreoathetosis and paroxysmal kinesigenic dyskinesia. The mutation was present in 5 family members, of which 4 were clinically affected and 1 was an obligate carrier with reduced penetrance of PRRT2. The affected carriers of this mutation presented with a similar type of infantile convulsion during early childhood and developed additional paroxysmal kinesigenic dyskinesia symptoms later in life. In addition, they all had a dramatic clinical response to oxcarbazepine/phenytoin therapy. Reduced penetrance of the PRRT2 mutation in this family could warrant genetic counseling.

Electrophilic alpha-methylene-gamma-lactone and isothiocyanate opioid ligands related to etorphine.

Isothiocyanate and alpha-methylene-gamma-lactone analogues of 6,14-endo-ethenotetrahydrothebaine and -oripavine were prepared with the electrophilic groups being located at C-19 in the C-7 alpha-side chain. Isothiocyanates were prepared in the N-Me and N-CPM (N-cyclopropylmethyl) series, both as the phenols and 3-O-methyl ethers from the diastereomeric amines formed from reductive amination of thevinone (2) and N-(cyclopropylmethyl)northevinone (13). Although addition of the organozinc reagent from methyl alpha-bromomethacrylate to 25 failed, addition to 3-O-protected aldehydes 27 and 35 produced, after subsequent deprotection, alpha-methylene-gamma-lactones 29 and 37, respectively. In the opioid receptor displacement assays against [3H]bremazocine as the radiolabeled ligand, the phenolic compounds were most potent with N-CPM isothiocyanates 20 and 21 showing IC50s of 0.32 and 0.76 nM, respectively, and N-CPM alpha-methylene-gamma-lactone 37 having an IC50 = 1.0 nM. Compound 37 showed irreversible effects in the binding assay which were mu-selective, as demonstrated by analogous experiments using [3H]DAGO, and naloxone was found to protect against the irreversible effects. This observation suggests that a receptor-bound nucleophile is located at a position where it can readily reach the alpha-methylene group of lactone 37.

Conjugate addition ligands of opioid antagonists. Methacrylate esters and ethers of 6 alpha- and 6 beta-naltrexol.

Alpha- and beta-naltrexol derived esters 9 and 10 and ethers 11 and 12, each containing the alpha, beta-unsaturated ester functionality, were prepared as conformationally more flexible analogues of spiro-alpha-methylene-gamma-lactones 5 and 6. All were active in the opioid radioreceptor binding assay against [3H]bremazocine and more active against [3H]DAGO, indicating mu-subtype selectivity, but only ether 12 showed significant irreversible activity. We conclude that small structural changes, made in very closely related electrophilic opioids, lead to changes in receptor binding. All four compounds were long-acting antagonists to morphine in mice, with ester 10 being approximately equipotent with naltrexone.