Paired Primary and Recurrent Rhabdoid Meningiomas: Cytogenetic Alterations, BAP1 Gene Expression Profile and Patient Outcome.

Rhabdoid meningiomas (RM) are a rare meningioma subtype with a heterogeneous clinical course which is more frequently associated with recurrence, even among tumors undergoing-complete surgical removal. Here, we retrospectively analyzed the clinical-histopathological and cytogenetic features of 29 tumors, from patients with recurrent (seven primary and 14 recurrent tumors) vs. non-recurrent RM (n = 8). Recurrent RM showed one (29%), two (29%) or three (42%) recurrences. BAP1 loss of expression was found in one third of all RM at diagnosis and increased to 100% in subsequent tumor recurrences. Despite both recurrent and non-recurrent RM shared chromosome 22 losses, non-recurrent tumors more frequently displayed extensive losses of chromosome 19p (62%) and/or 19q (50%), together with gains of chromosomes 20 and 21 (38%, respectively), whereas recurrent RM (at diagnosis) displayed more complex genotypic profiles with extensive losses of chromosomes 1p, 14q, 18p, 18q (67% each) and 21p (50%), together with focal gains at chromosome 17q22 (67%). Compared to paired primary tumors, recurrent RM samples revealed additional losses at chromosomes 16q and 19p (50% each), together with gains at chromosomes 1q and 17q in most recurrent tumors (67%, each). All deceased recurrent RM patients corresponded to women with chromosome 17q gains, although no statistical significant differences were found vs. the other RM patients.

Dynamic Changes in Non-Invasive Markers of Liver Fibrosis Are Predictors of Liver Events after SVR in HCV Patients.

Objectives: The course of progressive liver damage after achieving sustained virological response (SVR) with direct-acting antivirals (DAAs) remains undetermined. We aimed to determine risk factors associated with the development of liver-related events (LREs) after SVR, focusing on the utility of non-invasive markers. Methods: An observational, retrospective study that included patients with advanced chronic liver disease (ACLD) caused by hepatitis C virus (HCV), who achieved SVR with DAAs between 2014 and 2017. Patients were followed-up until December 2020. LREs were defined as the development of portal hypertension decompensation and the occurrence of hepatocellular carcinoma (HCC). Serological markers of fibrosis were calculated before treatment and one and two years after SVR. Results: The study included 321 patients, with a median follow-up of 48 months. LREs occurred in 13.7% of patients (10% portal hypertension decompensation and 3.7% HCC). Child-Pugh [HR 4.13 (CI 95% 1.74; 9.81)], baseline FIB-4 [HR 1.12 (CI 95% 1.03; 1.21)], FIB-4 one year post-SVR [HR 1.31 (CI 95% 1.15; 1.48)] and FIB-4 two years post-SVR [HR 1.42 (CI 95% 1.23; 1.64)] were associated with portal hypertension decompensation. Older age, genotype 3, diabetes mellitus and FIB-4 before and after SVR were associated with the development of HCC. FIB-4 cut-off values one and two years post-SVR to predict portal hypertension decompensation were 2.03 and 2.21, respectively, and to predict HCC were 2.42 and 2.70, respectively. Conclusions: HCV patients with ACLD remain at risk of developing liver complications after having achieved SVR. FIB-4 evaluation before and after SVR may help to predict this risk, selecting patients who will benefit from surveillance.

Surgical treatment for recurrent cholangiocarcinoma: a single-center series.

Purpose: The present study aims to assess the results obtained after surgical treatment of cholangiocarcinoma (CC) recurrences. Methods: We carried out a single-center retrospective study, including all patients with recurrence of CC. The primary outcome was patient survival after surgical treatment compared with chemotherapy or best supportive care. A multivariate analysis of variables affecting mortality after CC recurrence was performed. Results: Eighteen patients were indicated surgery to treat CC recurrence. Severe postoperative complication rate was 27.8% with a 30-day mortality rate of 16.7%. Median survival after surgery was 15 months (range 0-50) with 1- and 3-year patient survival rates of 55.6% and 16.6%, respectively. Patient survival after surgery or CHT alone, was significantly better than receiving supportive care (p< 0.001). We found no significant difference in survival when comparing CHT alone and surgical treatment (p=0.113). Time to recurrence of <1 year, adjuvant CHT after resection of the primary tumor and undergoing surgery or CHT alone versus best supportive care were independent factors affecting mortality after CC recurrence in the multivariate analysis. Conclusion: Surgery or CHT alone improved patient survival after CC recurrence compared to best supportive care. Surgical treatment did not improve patient survival compared to CHT alone.

Urinary cystatin C and N-acetyl-beta-D-glucosaminidase (NAG) as early biomarkers for renal disease in dogs with leishmaniosis.

Canine leishmaniasis (CanL) is a disease caused by Leishmania infantum that can vary from a subclinical infection to a severe disease. Dogs affected with CanL present varying degrees of renal dysfunction. Unfortunately, traditional biomarkers such as urea and creatinine detect renal damage in advanced stages of the disease, so more accurate biomarkers are needed. Hence, we aimed to study how urinary cystatin C (CysC) and N-acetyl-beta-D-glucosaminidase (NAG), behave in dogs with CanL at different stages of the disease. Eighty-six CanL infected dogs were classified according to LeishVet stages: LI (16 dogs), LIIa (12 dogs), LIIb (12 dogs), LIII (16 dogs) and LIV (30 dogs); as a control, 17 healthy dogs were studied. Blood samples were collected for complete haematological and biochemistry analysis including plasma cystatin C. Urine analysis included urine specific gravity (USG), urine protein to creatinine ratio (UPC), CysC and NAG expressed as a ratio with creatinine uCysCc (µg/g) and uNAGc (IU/g). The haematological, biochemical and urinary analysis coincided with the LeishVet guidelines. The statistical study of the uCysCc ratio and the uNAGc, showed significant increase when compared against control starting from group LI (p < 0.05). Interestingly, when the cut-off values were calculated using the ROC curve, uCysCc (258.85 µg/g) and uNAGc (2.25 IU/g) 75 % of the dogs included in LI groups surpassed the threshold. Hence our study indicates that uCysCc and uNAGc, could help to detect early renal damage in CanL affected dogs.

[Utility of the intraoperative neurophysiological monitoring as a prognostic value of postoperative facial paresis in vestibular schwannomas]. / Utilidad de la monitorización neurofisiológica intraoperatoria como valor pronóstico de la parálisis facial posquirúrgica en schwannomas vestibulares.

BACKGROUND AND OBJECTIVE: Intraoperative neurophysiological monitoring allows us to predict the functional status of the facial nerve after vestibular schwannoma surgery. Due to the great variability of the neurophysiological protocols used for it, the goal of this study is to determine the prognostic ability of our neurophysiological protocol. MATERIAL AND METHODS: We have performed a statistical analysis of the neurophysiological monitoring data collected from patients operated between March 2009 and July 2021 at the Neurosurgery Service of Salamanca according to their functional status, both in the immediate post-surgical period and one year after surgery. RESULTS: A number of 51 patients between 46 and 63 years old (median: 54) were analyzed. We have found significant differences studying the threshold value of the stimulation intensity of the facial nerve and the variation of the Cortico-bulbar Evoked Motor Potentials (P=0.043 and P=0.011, respectively) between the patients with good and bad clinical situation after surgery. The most discriminating intensity threshold value was 0.35mA (Sensitivity: 85%; Specificity: 48%). No statistical relationship was found in the study group one year after surgery. CONCLUSIONS: Our intraoperative monitoring protocol allows us to predict the clinical situation of patients in the immediate postoperative period and improve information for the patient and her relatives after surgery. We cannot, however, use these parameters to predict the functional situation one year after surgery and make clinical decisions in this regard.

Clinical, Histopathologic and Genetic Features of Rhabdoid Meningiomas.

Rhabdoid meningiomas (RM) shows heterogeneous histological findings, and a wide variety of chromosomal copy number alterations (CNA) are associated with an unpredictable course of the disease. In this study, we analyzed a series of 305 RM samples from patients previously reported in the literature and 33 samples from 23 patients studied in our laboratory. Monosomy 22-involving the minimal but most common recurrent region loss of the 22q11.23 chromosomal region was the most observed chromosomal alteration, followed by losses of chromosomes 14, 1, 6, and 19, polysomies of chromosomes 17, 1q, and 20, and gains of 13q14.2, 10p13, and 21q21.2 chromosomal regions. Based on their CNA profile, RM could be classified into two genetic subgroups with distinct clinicopathologic features characterized by the presence of (1) chromosomal losses only and (2) combined losses and gains of several chromosomes. The latter displays a higher frequency of WHO grade 3 tumors and poorer clinical outcomes.

Renoportal Anastomosis and Its Complications: A Complex Case Report.

BACKGROUND: Renoportal anastomosis (RPA) is an effective technique in cases of complex portal vein thrombosis with the presence of a splenorenal shunt. The objective of this report is to describe the possible complications related to RPA. CASE REPORT: A 50-year-old man with alcohol-related and hepatitis C-related cirrhosis and 2 hepatocellular carcinomas underwent liver transplant. He presented a portal vein thrombosis Yerdel IV, a splenorenal shunt, and another shunt between the inferior mesenteric vein (IMV) and the perirectal plexus. During surgery, the flow of the left renal vein was 891 mL/min, and this rose to 1050 mL/min after IMV clamping. RPA was made through iliac vein graft interposition, and the IMV was ligated. Portal flow was 832 mL/min but drastically decreased because of mesenteric root compression. After finishing the liver transplant, a renoiliac graft percutaneous transhepatic stent was put in place. The patient presented graft dysfunction and acute kidney injury. On postoperative day +18, a second stent was put in place because of a thrombosis in the splenomesenteric confluence. The patient subsequently presented partial distal rethrombosis and a pancreaticoduodenal arteriovenous fistula, which required several embolizations. The patient developed ascites, recurrent gastrointestinal bleeding, and persistent bacterial peritonitis. Finally, a modified Sugiura procedure (without splenectomy) was performed, achieving a portal flow of 1800 mL/min. However, the patient developed sepsis and multiorgan failure, and died on postoperative day +70. CONCLUSIONS: Despite long-term patient and graft survival within accepted limits after LT, RPA is a challenging technique not exempt from complications.

Blood cadmium, lead, manganese, mercury, and selenium levels in American Indian populations: The Strong Heart Study.

BACKGROUND: Many American Indian (AI) communities are in areas affected by environmental contamination, such as toxic metals. However, studies assessing exposures in AI communities are limited. We measured blood metals in AI communities to assess historical exposure and identify participant characteristics associated with these levels in the Strong Heart Study (SHS) cohort. METHOD: Archived blood specimens collected from participants (n = 2014, all participants were 50 years of age and older) in Arizona, Oklahoma, and North and South Dakota during SHS Phase-III (1998-1999) were analyzed for cadmium, lead, manganese, mercury, and selenium using inductively coupled plasma triple quadrupole mass spectrometry. We conducted descriptive analyses for the entire cohort and stratified by selected subgroups, including selected demographics, health behaviors, income, waist circumference, and body mass index. Bivariate associations were conducted to examine associations between blood metal levels and selected socio-demographic and behavioral covariates. Finally, multivariate regression models were used to assess the best model fit that predicted blood metal levels. FINDINGS: All elements were detected in 100% of study participants, with the exception of mercury (detected in 73% of participants). The SHS population had higher levels of blood cadmium and manganese than the general U.S. population 50 years and older. The median blood mercury in the SHS cohort was at about 30% of the U.S. reference population, potentially due to low fish consumption. Participants in North Dakota and South Dakota had the highest blood cadmium, lead, manganese, and selenium, and the lowest total mercury levels, even after adjusting for covariates. In addition, each of the blood metals was associated with selected demographic, behavioral, income, and/or weight-related factors in multivariate models. These findings will help guide the tribes to develop education, outreach, and strategies to reduce harmful exposures and increase beneficial nutrient intake in these AI communities.

Antitumoral Effect of Plocabulin in High Grade Serous Ovarian Carcinoma Cell Line Models.

Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation.

Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.

BACKGROUND: Inherited kidney diseases are one of the leading causes of chronic kidney disease (CKD) that manifests before the age of 30 years. Precise clinical diagnosis of early-onset CKD is complicated due to the high phenotypic overlap, but genetic testing is a powerful diagnostic tool. We aimed to develop a genetic testing strategy to maximize the diagnostic yield for patients presenting with early-onset CKD and to determine the prevalence of the main causative genes. METHODS: We performed genetic testing of 460 patients with early-onset CKD of suspected monogenic cause using next-generation sequencing of a custom-designed kidney disease gene panel in addition to targeted screening for c.428dupC MUC1. RESULTS: We achieved a global diagnostic yield of 65% (300/460), which varied depending on the clinical diagnostic group: 77% in cystic kidney diseases, 76% in tubulopathies, 67% in autosomal dominant tubulointerstitial kidney disease, 61% in glomerulopathies and 38% in congenital anomalies of the kidney and urinary tract. Among the 300 genetically diagnosed patients, the clinical diagnosis was confirmed in 77%, a specific diagnosis within a clinical diagnostic group was identified in 15%, and 7% of cases were reclassified. Of the 64 causative genes identified in our cohort, 7 (COL4A3, COL4A4, COL4A5, HNF1B, PKD1, PKD2 and PKHD1) accounted for 66% (198/300) of the genetically diagnosed patients. CONCLUSIONS: Two-thirds of patients with early-onset CKD in this cohort had a genetic cause. Just seven genes were responsible for the majority of diagnoses. Establishing a genetic diagnosis is crucial to define the precise aetiology of CKD, which allows accurate genetic counselling and improved patient management.

Totally laparoscopic simultaneous resection of colorectal cancer and synchronous liver metastases: a single-center case series.

BACKGROUND: The aim of the study is to analyze the feasibility, the safety and short- and medium-term survival of totally laparoscopic simultaneous resections (LSR) of colorectal cancer (CRC) and synchronous liver metastases (LM). METHODS: This is a retrospective study of a single-center series. Patients ASA IV, ECOG ≥ 2, major hepatectomies (≥ 3 segments), symptomatic CRC as well as low rectal tumors were excluded from indication. The difficulty level of all liver resections was classified as low or intermediate according to the Iwate Criteria. Dindo-Clavien classification for postoperative complications evaluation was used. RESULTS: 15 Patients with 21 liver lesions were included. Laparoscopic liver surgery was performed first in every case. Median size of the lesions was 20 mm (r 8-69). Major complications (Dindo-Clavien ≥ 3) occurred in 3 patients (20%); median hospital stay was 7 days (r 4-35), and only one patient (6.6%) was readmitted upon the first month from the surgery. 90-day mortality rate was 0%. After a median follow-up of 24 months (r 7-121), disease-free survival at 1, 2 and 3 years was 58%, 36% and 24%, respectively; overall survival at 1, 2 and 3 years was 92.3%. CONCLUSIONS: In selected patients, LSR of CRC and LM is technically feasible and has an acceptable morbidity rate and mid-term survival.

Influencias de los discursos cisnormativos en el cuidado físico y psicoemocional de jóvenes trans de México / The influence of cisnormative discourses on the physical and psycho-emotional care of trans youth in Mexico

RESUMEN La cisnormatividad en el ámbito de la salud ha implicado la patologización de identidades que no se identifican con los criterios de la lógica binaria del género. El objetivo de este estudio fue analizar el alcance y la influencia que los discursos cisnormativos tienen en el cuidado y la salud de las y los jóvenes trans. Entre marzo de 2021 y mayo de 2022, se llevaron a cabo entrevistas semiestructuradas que se analizaron a la luz de la perspectiva socioconstruccionista. Participaron cinco jóvenes trans (dos mujeres trans y tres varones trans), de entre los 20 y 29 años. Los resultados mostraron la incorporación en sus relatos de aspectos del discurso cisnormativo del género; no obstante, a la par generan narrativas alternativas, en las que el cuidado psicoemocional y del cuerpo les lleva a posicionarse lejos de tropos narrativos como la disforia y "el cuerpo equivocado". Concluimos que este trabajo contribuye a desmantelar la visión médica de las personas trans, mostrando cómo a través de sus recursos, adoptan prácticas de autocuidado. Asimismo, refleja la importancia de construir diálogos con las personas trans que permitan generar más y mejores estrategias de atención.

ABSTRACT Cisnormativity in the health field has involved the pathologization of identities that do not align with gender binaries. The aim of this study was to analyze the scope and influence of cisnormative discourses on the care and health of trans youth. Semi-structured interviews were carried out between March 2021 and May 2022, and results were analyzed from a social constructivist approach. Five young trans people between 20 and 29 years old participated in the study (2 trans women and 3 trans men). Results showed that aspects of cisnormative gender discourse were evident in their narratives; however, at the same time they generated alternative narratives, where psycho-emotional and bodily care led them to position themselves outside of common tropes such as dysphoria and "the wrong body". We conclude that this study contributes to dismantling the medical view of trans people by showing how they adopt self-care practices by mobilizing their own resources. Furthermore, it reflects the importance of building dialogues with trans people that will allow more and better care strategies to be generated.

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

BACKGROUND: Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). METHODS: In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. RESULTS: Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. CONCLUSIONS: Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

Effects of Allogeneic Mesenchymal Stem Cell Transplantation in Dogs with Inflammatory Bowel Disease Treated with and without Corticosteroids.

Mesenchymal stem cells have proven to be a promising alternative to conventional steroids to treat canine inflammatory bowel disease (IBD). However, their administration requires a washout period of immunosuppressive drugs that can lead to an exacerbation of the symptoms. Therefore, the feasibility and effects of the combined application of stem cells and prednisone in IBD-dogs without adequate response to corticosteroids was evaluated for the first time in this study over a long- term follow up. Two groups of dogs with IBD, one without treatment and another with prednisone treatment, received a single infusion of stem cells. The clinical indices, albumin and cobalamin were determined prior to the infusion and after one, three, six and 12 months. In both groups, all parameters significantly improved at each time point. In parallel, the steroid dosage was gradually reduced until it was suppressed in all patients a year after the cell therapy. Therefore, cell therapy can significantly and safely improve the disease condition in dogs with IBD receiving or not receiving prednisone. Furthermore, the steroid dosage can be significantly reduced or cancelled after the stem cell infusion. Their beneficial effects are stable over time and are long lasting.

Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma.

Low-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently, CTNNB1 exon 3 mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of CTNNB1 mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers. CTNNB1 exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in CTNNB1 exon 3. Nuclear beta-catenin and LEF1 were significantly associated with CTNNB1 mutation, showing nuclear beta-catenin a better specificity and positive predictive value for CTNNB1 mutation. Tumours with CTNNB1 exon 3 mutation were associated with reduced disease-free survival (p = 0.010), but no impact on overall survival was found (p = 0.807). The risk of relapse in tumours with CTNNB1 exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion. CTNNB1 exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for CTNNB1 exon 3 mutation in these tumours.

Experiencia de una niña de nueve años ante la separación parental / Effects of parental separation: listening to a nine-year-old girl / Efeitos da separação parental: ouvindo uma menina de nove anos

Resumen (analítico) En este estudio cualitativo se describen y analizan los efectos de la separación parental, a través de la mirada y voz de una niña de nueve años. Se empleó como instrumento una entrevista semiestructurada y un análisis de resultados de tipo categórico. Las repercusiones observadas se clasificaron en efectos individuales como el manejo de la información y la construcción de explicaciones, así como una mayor independencia y mejora en su autoconcepto; y efectos en su entorno familiar, tales como la modificación en los vínculos afectivos con sus padres, dinámicas familiares más consistentes y mayores momentos de bienestar. Concluyendo que los infantes son participantes activos en la construcción de sus significados y que la separación de los padres puede permitir la generación de experiencias de crecimiento.

Abstract (analytical) In this qualitative study, the effects of parental separation are described and analyzed through the voice and point of view of a nine-year-old girl. The authors used a semi-structured interview and categorical data analysis to identify these effects. The identified repercussions of the parental separation were classified into individual effects, such as information management and construction of explanations, as well as higher levels of independence and improvements in self-awareness. The authors also identified effects on the family environment such as modification of affective bonding with parents, more consistent family dynamics and increased moments of wellbeing. The study concludes that children perform an active role in the construction of their meaning and parental separation can facilitate the generation of self-growth experiences.

Resumo (analítico) Neste estudo qualitativo, são descritos e analisados os efeitos da separação parental através da visão e da voz de uma menina de nove anos. Utilizou-se como instrumento uma entrevista semiestruturada e uma análise dos resultados categóricos. As repercussões observadas foram classificadas em efeitos individuais, como gerenciamento de informações e construção de explicações, além de maior independência e melhoria de seu autoconceito; Os efeitos no ambiente familiar, como mudanças nos laços emocionais com os pais, dinâmicas familiares mais consistentes e mais momentos de bem-estar, concluindo que as crianças são participantes ativas na construção de seus significados. E, por último, que a separação dos pais pode gerar experiências de crescimento.

Non-malignant portal vein thrombosis in a cohort of cirrhotic patients: Incidence and risk factors.

AIM: Non-malignant portal vein thrombosis (PVT) is a complication of liver cirrhosis. The aim of this study was to evaluate the annual incidence of PVT and related risk factors. METHODS: We retrospectively reviewed clinical, laboratory, and radiological data collected prospectively from September 2016 to September 2017. A follow-up of 36 months was performed in a subset of patients to determine the cumulative incidence of PVT and related complications. RESULTS: The study included 567 patients. The incidence of PVT at 12, 24, and 36 months was 3.7%, 0.8%, and 1.4%, respectively. Patients with PVT were compared with patients without PVT, and showed differences in albumin (p = 0.04), aspartate aminotransferase (p = 0.04), hemoglobin (p = 0.01), and prothrombin activity (p = 0.01). The presence of hydropic decompensation (57.1% vs. 30.1%; p 0.004), gastroesophageal varices (76.2% vs. 39.5%; p = 0.05), variceal bleeding (52.4% vs. 22.7%; p < 0.001), hepatic encephalopathy (38.1% vs. 9.9%; p = 0.01), spontaneous bacterial peritonitis (9.5% vs. 1.7%; p < 0.001), and use of beta-blockers (71.4% vs. 27.7%; p < 0.001) were significantly associated. In the multivariate analysis, use of beta-blockers and hepatic encephalopathy appeared as risk factors, and high albumin levels a protective factor. CONCLUSIONS: The incidence of PVT was 3.7%. Beta-blockers and hepatic encephalopathy were risks factors. High albumin levels were a protective factor.

Characterization of the Metabolic Pathways of 4-Chlorobiphenyl (PCB3) in HepG2 Cells Using the Metabolite Profiles of Its Hydroxylated Metabolites.

The characterization of the metabolism of lower chlorinated PCB, such as 4-chlorobiphenyl (PCB3), is challenging because of the complex metabolite mixtures formed in vitro and in vivo. We performed parallel metabolism studies with PCB3 and its hydroxylated metabolites to characterize the metabolism of PCB3 in HepG2 cells using nontarget high-resolution mass spectrometry (Nt-HRMS). Briefly, HepG2 cells were exposed for 24 h to 10 µM PCB3 or its seven hydroxylated metabolites in DMSO or DMSO alone. Six classes of metabolites were identified with Nt-HRMS in the culture medium exposed to PCB3, including monosubstituted metabolites at the 3'-, 4'-, 3-, and 4- (1,2-shift product) positions and disubstituted metabolites at the 3',4'-position. 3',4'-Di-OH-3 (4'-chloro-3,4-dihydroxybiphenyl), which can be oxidized to a reactive and toxic PCB3 quinone, was a central metabolite that was rapidly methylated. The resulting hydroxylated-methoxylated metabolites underwent further sulfation and, to a lesser extent, glucuronidation. Metabolomic analyses revealed an altered tryptophan metabolism in HepG2 cells following PCB3 exposure. Some PCB3 metabolites were associated with alterations of endogenous metabolic pathways, including amino acid metabolism, vitamin A (retinol) metabolism, and bile acid biosynthesis. In-depth studies are needed to investigate the toxicities of PCB3 metabolites, especially the 3',4'-di-OH-3 derivatives identified in this study.

Bayesian toxicokinetic modeling of cadmium exposure in Chinese population.

Cadmium (Cd) is a toxic heavy metal widely present in the environment. Estimating its internal levels for a given external exposure using toxicokinetic (TK) models is key to the human health risk assessment of Cd. In this study, existing Cd TK models were adapted to develop a one-compartment TK model and a multi-compartment physiologically based toxicokinetic (PBTK) model by estimating the characteristics of Cd kinetics based on Cd exposure data from 814 Chinese residents. Both models not only considered the effect of gender difference on Cd kinetics, but also described the model parameters in terms of distributions to reflect individual variability. For both models, the posterior distributions of sensitive parameters were estimated using the Markov chain-Monte Carlo method (MCMC) and the approximate Bayesian computation-MCMC algorithm (ABC-MCMC). Validation with the test dataset showed 1.4-22.5% improvement in the root mean square error (RMSE) over the original models. After a systematic literature search, the optimized models showed acceptable prediction on other Chinese datasets. The study provides a method for parameter optimization of TK models under different exposure environment, and the validated models can serve as new quantitative assessment tools for the risk assessment of Cd in the Chinese population.

Early tacrolimus exposure does not impact long-term outcomes after liver transplantation.

BACKGROUND: Tacrolimus trough levels (TTL) during the first weeks after liver transplantation (LT) have been related with long-term renal function and hepatocellular carcinoma recurrence. Nevertheless, the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate. AIM: To evaluate the effect of TTL during the first month on the long-term outcomes after LT. METHODS: One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied. Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy. Patients were classified into 2 groups according to their mean TTL within the first month after transplantation: ≤ 10 (n = 98) and > 10 ng/mL (n = 57). Multivariate analyses were performed to assess risk factors for patient mortality. RESULTS: Mean levels within the first month post-transplant were 7.4 ± 1.7 and 12.6 ± 2.2 ng/mL in the ≤ 10 and > 10 groups, respectively. Donor age was higher in the high TTL group 62.9 ± 16.8 years vs 45.7 ± 17.5 years (P = 0.002) whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7% vs 15.8% (P = 0.02). Recipient features were generally similar across groups. After a median follow-up of 52.8 mo (range 2.8-81.1), no significant differences were observed in: Mean estimated glomerular filtration rate (P = 0.69), hepatocellular carcinoma recurrence (P = 0.44), de novo tumors (P = 0.77), new-onset diabetes (P = 0.13), or biopsy-proven acute rejection rate (12.2% and 8.8%, respectively; P = 0.50). Eighteen patients died during the follow-up and were evenly distributed across groups (P = 0.83). Five-year patient survival was 90.5% and 84.9%, respectively (P = 0.44), while 5-year graft survival was 88.2% and 80.8%, respectively (P = 0.42). Early TTL was not an independent factor for patient mortality in multivariate analyses. CONCLUSION: Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.