Publications by authors named "Leila Haddad"

49 Publications

A New Insight on Exophytic Serous Borderline Adnexal Tumors: Specific Sonographic Features.

J Ultrasound Med 2021 Sep 25. Epub 2021 Sep 25.

Obstetrics and Gynecology Ultrasound Unit, Bnai-Zion Medical Center, Haifa, Israel.

Objectives: To characterize and compare the sonographic features of exophytic serous borderline ovarian tumors (ESBOT) with those of high-grade serous carcinoma of the ovary (HGSC).

Methods: Seven patients with histological diagnosis of ESBOT diagnosed between 2011 and 2019 and 10 consecutive cases of HGSC detected during 2019, both depicting an exophytic growth pattern, were identified retrospectively. The sonographic imaging of the masses was reassessed and characterized according to the International Ovarian Tumor Analysis terms.

Results: A unilateral irregular solid adnexal mass was demonstrated in all patients with ESBOT. The mass typically wrapped an apparently normal ovary, with a clear demarcation line depicted between them and it contained tiny cystic inclusions and calcifications. On color Doppler study of all the ESBOT cases, a unique vascular pattern could be demonstrated: an intratumoral vascular bundle originating from the ovarian vessels and supplying a rich radial blood flow to the tumor periphery. These characteristic morphological and color Doppler features could not be observed in any of the HGSC cases (P < .001). In 42.8% of the patients with ESBOT, additional unilocular-solid components (ipsilateral or contralateral) could be detected, whereas all the HGSC patients presented with a multilocular-solid tumor morphology (P < .001). The interface of the external mass border with the adjacent pelvic walls was regular in all the cases with ESBOT, whereas in 80% of HGSC patients, it was irregular, suggesting invasiveness (P = .002).

Conclusions: ESBOT can mimic HGSC. Our results suggest that ESBOT has specific B-mode and color Doppler features, enabling differentiation from HGSC and planning appropriate intervention.
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http://dx.doi.org/10.1002/jum.15838DOI Listing
September 2021

Plasma and stool metabolomics to identify microbiota derived-biomarkers of metabolic dysfunction-associated fatty liver disease: effect of PNPLA3 genotype.

Metabolomics 2021 06 16;17(7):58. Epub 2021 Jun 16.

Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB) - CONICET - Instituto Universitario del Hospital Italiano (IUHI) - Hospital Italiano de Buenos Aires (HIBA), Potosí 4240, C1199ACL, Ciudad Autónoma de Buenos Aires, Argentina.

Introduction: Non-invasive biomarkers are needed for metabolic dysfunction-associated fatty liver disease (MAFLD), especially for patients at risk of disease progression in high-prevalence areas. The microbiota and its metabolites represent a niche for MAFLD biomarker discovery. However, studies are not reproducible as the microbiota is variable.

Objectives: We aimed to identify microbiota-derived metabolomic biomarkers that may contribute to the higher MAFLD prevalence and different disease severity in Latin America, where data is scarce.

Methods: We compared the plasma and stool metabolomes, gene patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP), diet, demographic and clinical data of 33 patients (12 simple steatosis and 21 steatohepatitis) and 19 healthy volunteers (HV). The potential predictive utility of the identified biomarkers for MAFLD diagnosis and progression was evaluated by logistic regression modelling and ROC curves.

Results: Twenty-four (22 in plasma and 2 in stool) out of 424 metabolites differed among groups. Plasma triglyceride (TG) levels were higher among MAFLD patients, whereas plasma phosphatidylcholine (PC) and lysoPC levels were lower among HV. The PNPLA3 risk genotype was related to higher plasma levels of eicosenoic acid or fatty acid 20:1 (FA(20:1)). Body mass index and plasma levels of PCaaC24:0, FA(20:1) and TG (16:1_34:1) showed the best AUROC for MAFLD diagnosis, whereas steatosis and steatohepatitis could be discriminated with plasma levels of PCaaC24:0 and PCaeC40:1.

Conclusion: This study identified for the first time MAFLD potential non-invasive biomarkers in a Latin American population. The association of PNPLA3 genotype with FA(20:1) suggests a novel metabolic pathway influencing MAFLD pathogenesis.
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http://dx.doi.org/10.1007/s11306-021-01810-6DOI Listing
June 2021

Detection of SARS-CoV-2 RNA using RT-LAMP and molecular beacons.

Genome Biol 2021 06 3;22(1):169. Epub 2021 Jun 3.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Background: Rapid spread of SARS-CoV-2 has led to a global pandemic, resulting in the need for rapid assays to allow diagnosis and prevention of transmission. Reverse transcription-polymerase chain reaction (RT-PCR) provides a gold standard assay for SARS-CoV-2 RNA, but instrument costs are high and supply chains are potentially fragile, motivating interest in additional assay methods. Reverse transcription and loop-mediated isothermal amplification (RT-LAMP) provides an alternative that uses orthogonal and often less expensive reagents without the need for thermocyclers. The presence of SARS-CoV-2 RNA is typically detected using dyes to report bulk amplification of DNA; however, a common artifact is nonspecific DNA amplification, which complicates detection.

Results: Here we describe the design and testing of molecular beacons, which allow sequence-specific detection of SARS-CoV-2 genomes with improved discrimination in simple reaction mixtures. To optimize beacons for RT-LAMP, multiple locked nucleic acid monomers were incorporated to elevate melting temperatures. We also show how beacons with different fluorescent labels can allow convenient multiplex detection of several amplicons in "single pot" reactions, including incorporation of a human RNA LAMP-BEAC assay to confirm sample integrity. Comparison of LAMP-BEAC and RT-qPCR on clinical saliva samples showed good concordance between assays. To facilitate implementation, we developed custom polymerases for LAMP-BEAC and inexpensive purification procedures, which also facilitates increasing sensitivity by increasing reaction volumes.

Conclusions: LAMP-BEAC thus provides an affordable and simple SARS-CoV-2 RNA assay suitable for population screening; implementation of the assay has allowed robust screening of thousands of saliva samples per week.
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http://dx.doi.org/10.1186/s13059-021-02387-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173101PMC
June 2021

Failure in all steps of hepatocellular carcinoma surveillance process is frequent in daily practice.

Ann Hepatol 2021 Apr 2;25:100344. Epub 2021 Apr 2.

Hospital de Clínicas José de San Martín (UBA), CABA, Argentina.

Introduction And Objectives: Failures at any step in the hepatocellular carcinoma (HCC) surveillance process can result in HCC diagnostic delays and associated worse prognosis. We aimed to estimate the prevalence of surveillance failure and its associated risk factors in patients with HCC in Argentina, considering three steps: 1) recognition of at-risk patients, 2) implementation of HCC surveillance, 3) success of HCC surveillance.

Methods: We performed a multi-center cross-sectional study of patients at-risk for HCC in Argentina seen between10.01.2018 and 10.30.2019. Multivariable logistic regression analysis was used to identify correlates of surveillance failure.

Results: Of 301 included patients, the majority were male (74.8%) with a mean age of 64 years old. At the time of HCC diagnosis, 75 (25%) patients were unaware of their diagnosis of chronic liver disease, and only 130 (43%) patients were under HCC surveillance. Receipt of HCC surveillance was significantly associated with follow-up by a hepatologist. Of 119 patients with complete surveillance, surveillance failure occurred in 30 (25%) patients. Surveillance failure was significantly associated with alpha fetoprotein ≥20 ng/mL (OR 4.0, CI 95% 1.43-11.55).

Conclusions: HCC surveillance failure was frequent in all the evaluated steps. These data should help guide strategies to improve the implementation and results of HCC surveillance in our country.
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http://dx.doi.org/10.1016/j.aohep.2021.100344DOI Listing
April 2021

Outbreak of hepatitis A in a post-vaccination era: High rate of co-infection with sexually transmitted diseases.

Ann Hepatol 2020 Nov - Dec;19(6):641-644. Epub 2020 Aug 21.

Hospital Privado de Rosario, Rosario, Santa Fe, Argentina. Electronic address:

Introduction And Objectives: After hepatitis A (HAV) mandatory immunization in 2005 in Argentina, the incidence of HAV declined drastically. However, several new autochthonous cases of HAV have been reported since 2017. We aimed to evaluate the clinical and epidemiological characteristics and possible transmission routes of affected patients.

Patients Or Materials And Methods: We performed a cross-sectional study of patients residing in Argentina with acute hepatitis A between 30.06.2017 and 31.12.2018.

Results: 66 cases of HAV were registered. Fifty-six patients (86%) were males, with a mean age of 34 ± 12 years old. The most likely routes of transmission were sexual intercourse of men with men, reported by 31 patients. Additionally, 23% and 26% of patients tested positive for HIV and syphilis, respectively. In total, 35% of patients required hospitalization. When assessing outcomes, 79% had a mild presentation and 21% had a severe/fulminant presentation: one patient underwent liver transplantation, and one patient died.

Conclusions: Our study describes that during the study period, HAV infection affected predominantly young adults, particularly men who have sex with men. An elevated proportion of them was diagnosed with a concomitant sexually transmitted disease, and several patients had a severe presentation of the disease.
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http://dx.doi.org/10.1016/j.aohep.2020.07.005DOI Listing
August 2020

Efficient process development for high-level production, purification, formulation, and characterization of recombinant mecasermin in Escherichia coli.

Biotechnol Appl Biochem 2021 Aug 7;68(4):776-788. Epub 2020 Aug 7.

Mycobacteriology Research Centre, National Research Institute of Tuberculosis and Lung Disease (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Overproduction of recombinant mecasermin was achieved by investigation of effect of three factors, temperature, inducer amount, and culture media, at three levels according to the Taguchi statistical design in Escherichia coli in a bench-scale bioreactor. In optimal conditions (induction temperature 28 °C, terrific broth with glucose (TB+G) medium, with 0.1 mM IPTG as inducer) 0.84 g/L mecasermin with expression levels of 38% of total protein and 4.13 g/L final dry cell biomass was produced, that is one of the highest values of recombinant protein has been reported in the batch system. The cell disruption was done by lysozyme pretreatment with sonication to the efficient purification of mecasermin. The isolated and washed inclusion bodies were solubilized in Gdn-HCl at pH 5.4 and folded with glutathione and purified with gel filtration. The purified rhIGF-1 (mecasermin) was formulated with arginine. Mecasermin protein remained t stable at 4 °C for up to 2 years. The quantitative and qualitative control indicated that mecasermin is expressed correctly (without the initial methionine by mass spectrometry), pure (without endotoxin and other protein impurities), correct folding (FTIR, RF-HPLC), monomer form (SEC-HPLC), and active (bioactivity test). Also, the purification results revealed that expression at low temperature results in the efficient purification of the overproduced mecasermin with high quantity and quality.
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http://dx.doi.org/10.1002/bab.1990DOI Listing
August 2021

Hepatitis E infection is an infrequent cause of acute hepatitis in the metropolitan area of Buenos Aires.

J Clin Virol 2020 05 6;126:104309. Epub 2020 Mar 6.

Unidad de Hígado y Trasplante Hepático, Hospital Universitario Austral, Pilar, Argentina; Latin American Liver Research, Educational and Awareness Network (LALREAN).

Background Argentina is considered a region of low seroprevalence of hepatitis E virus (HEV), however; no studies have evaluated its burden among acute hepatitis cases.

Objectives: We aimed to estimate the proportion of acute HEV and outcome in a cohort of patients with acute hepatitis from 6 liver units in the Metropolitan area of Buenos Aires (MABA).

Study Design: We performed a prospective cohort study including patients ≥18 years with acute hepatitis (increase in transaminases x 5 ULN) fromJuly 2016 to May 2018. Severe hepatitis was defined as acute hepatitis + INR> 1.5 and acute liver failure as severe hepatitis + encephalopathy. In patients in whom other etiologies were excluded, HEV tests were performed: anti-HEV IgM/G and HEV-RNA in serum and feces.

Results: Overall, 268 patients with acute hepatitis were included in the study. The most frequent etiologies of acute hepatitis were hepatitis B (67patients, 25 %), hepatotoxicity (65, 24 %) and autoimmune hepatitis (26, 10 %). Acute HEV infection was confirmed in 8 (2.98 %; 95 %CI 1.25-5.63) patients who tested positive for anti-HEV IgM. A total of 63 (23.5 %) patients were hospitalized and 9 (3.3 %) patients died. Overall, 48 (18 %) patients developed severe hepatitis, 6 (2.2 %) have acute liver failure, 6 (1.9 %) underwent liver transplantation and 9 (3.4 %) patients died.

Conclusions: the proportion of acute HEV in MABA was low during the period studied. We believe our findings will aid physicians prioritize other etiologies of acute hepatitis over HEV in order to optimize diagnostic resources and offer better care to their patients.
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http://dx.doi.org/10.1016/j.jcv.2020.104309DOI Listing
May 2020

Unexpected high seroprevalence of hepatitis E virus in patients with alcohol-related cirrhosis.

PLoS One 2019 24;14(10):e0224404. Epub 2019 Oct 24.

Instituto de Virología "Dr. J. M. Vanella", Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina.

Introduction: Little is known about hepatitis E virus (HEV) infection in patients with cirrhosis. The aim of the present study was to describe the frequency of HEV infection and associated risk factors in patients with cirrhosis from Argentina.

Materials And Methods: We evaluated HEV seroprevalence (IgG anti-HEV) and acute infections (IgM and RNA) in patients with cirrhosis (n = 140) vs. healthy controls (n = 300). Additionally, we compared the same outcomes in individuals with alcohol-related cirrhosis (n = 43) vs. patients with alcohol use disorder (without cirrhosis, n = 72).

Results: The overall HEV seroprevalence in the cohort of subjects with cirrhosis was 25% (35/140), compared to 4% in the healthy control group [12/300; OR = 8; (95% CI = 4-15.99); p<0.05]. HEV seropositivity was significantly higher in alcohol-related cirrhosis compared to other causes of cirrhosis [39.5% vs. 12.4%; OR = 4.71; (95% CI = 1.9-11.6); p<0.05] and to healthy controls [OR = 15.7; (95% CI = 6.8-36.4); p = 0.0001]. The HEV seroprevalence in alcoholic-related cirrhosis vs. with alcohol use disorder was 39.5% vs. 12.5% [OR = 4.58; (95% CI = 1.81-11.58); p<0.001].

Conclusion: We found a high seroprevalence of HEV in patients with cirrhosis and in individuals with alcohol use disorder. The simultaneous presence of both factors (cirrhosis + alcohol) showed more association to HEV infection. Larger studies with prospective follow up are needed to further clarify this interaction.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224404PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812777PMC
March 2020

B.A.R.C.O.S. (Brazilian Argentine Hepatitis C Collaborative Observational Study): Effectiveness and clinical outcomes of HCV treatment with daclatasvir and sofosbuvir with or without ribavirin.

J Viral Hepat 2019 10 19;26(10):1200-1209. Epub 2019 Jun 19.

Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Presidente Derqui, Buenos Aires, Argentina.

Real-world data evaluating the effectiveness of direct-acting antivirals (DAAs) in hepatitis C virus (HCV) treatment have been reported from different regions. Our aim was to evaluate the effectiveness and clinical outcomes of daclatasvir (DCV) and sofosbuvir (SOF) ± ribavirin (RBV) in a prospective multicentre cohort study including patients from Argentina and Brazil who received DCV/SOF ± RBV for 12 or 24 weeks from 2015 to 2018. Multivariable logistic regression models were carried out to identify factors associated with failure to achieve sustained virologic response (SVR) as a primary end point, and to death, decompensation, hepatocellular carcinoma (HCC) or liver transplantation (LT) as a composite secondary end point. From a total of 1517 patients treated with DCV/SOF, 906 completed 12 weeks post-treatment evaluation and were included in the analysis. Overall SVR12 rate was 96.1% (95% CI: 94.6%-97.2%), and 95% (95% CI: 92.8%-96.6%) in patients with cirrhosis. LT recipients and presence of cirrhosis were independently associated with failure to achieve SVR. During post-SVR12 follow-up, cumulative incidence of the secondary end point was 2.4% (95% CI: 1.5%-3.6%); two patients died from nonliver-related causes and two from HCC, five underwent LT, 12 developed HCC and 17 patients developed hepatic decompensation. Independent variables associated with these composite secondary end points were prior to HCV treatment and presence of cirrhosis. In conclusion, although the high pangenotypic effectiveness of DCV/SOF ± RBV was confirmed in our real-life cohort, patients with compensated and decompensated cirrhosis showed higher risk of non-SVR and complication appearance during treatment or after achieving SVR.
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http://dx.doi.org/10.1111/jvh.13148DOI Listing
October 2019

Chronic hepatitis B: The interplay between intrahepatic lymphocyte population and viral antigens in relation to liver damage.

J Viral Hepat 2019 06 5;26(6):727-737. Epub 2019 Mar 5.

Laboratorio de Biología Molecular, División Patología, Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP- CONICET-GCBA), Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.

In Chronic hepatitis B (CHB) infection, virus and immune response interplay is thought to be responsible for pathogenesis. Yet, the impact of each immune cell population and viral protein expression in liver damage is still unknown. Our aim was to study the interplay between intrahepatic immune response and viral activity in relation to CHB liver damage. Immunostaining was performed in 29 liver biopsies from untreated CHB patients to characterize liver infiltrate [Th (CD4+), CTL (CD8+), Treg (FoxP3+), Th17 (IL-17A+) and Th1 (T-bet+)] and viral antigen expression (HBsAg and HBcAg). Inflammatory activity and fibrosis were assessed using the HAI and METAVIR scoring system. All studied populations were identified in the portal-periportal (P-P) areas with a CD4+ lymphocyte predominance, while only CD8+ and FoxP3+ cells were observed in the intralobular area. Both P-P CD4+ and intralobular CD8+ cell frequencies were increased among severe hepatitis cases. Concerning HBsAg and HBcAg expression, a mutually exclusive pattern was observed. HBcAg was mainly detected among HBeAg-positive patients and was associated with hepatitis severity and higher frequency of P-P FoxP3+, intralobular CD8+ and FoxP3+ cells. HBsAg was identified among HBeAg-negative cases with less severe hepatitis grade and lower frequency of P-P CD4+ and intralobular FoxP3+ lymphocytes. In conclusion, the HBV antigen profile expression seen during CHB infection may be reflecting different stages of viral replication which impacts the host immune response and liver damage process. While HBcAg might be an inducer of a regulatory microenvironment, the intralobular CTL population seemed to have a key role in hepatitis severity.
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http://dx.doi.org/10.1111/jvh.13078DOI Listing
June 2019

Prevalence and Factors Related to Natural Resistance-Associated Substitutions to Direct-Acting Antivirals in Patients with Genotype 1 Hepatitis C Virus Infection.

Viruses 2018 12 21;11(1). Epub 2018 Dec 21.

Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB), CONICET, Instituto Universitario del Hospital Italiano (IUHI), Hospital Italiano (HIBA), C1199ACL Buenos Aires, Argentina.

This study aimed to assess the prevalence of natural resistance-associated substitutions (RASs) to NS3, NS5A and NS5B inhibitors in 86 genotype 1 Hepatitis C Virus (HCV)-infected patients from Buenos Aires, Argentina, and to determine their effect on therapy outcome. Additionally, virological, clinical and host genetic factors were explored as predictors of the presence of baseline RASs. RASs (39.2%) were more prevalent than RASs (25%) and RASs (8.9%). In the three regions, the frequencies of RASs were significantly higher in HCV-1b than in HCV-1a. The prevalence of Y93H, L159F and Q80K were 1.3%, 6.3% and 2.5%, respectively. IFNL3 CC genotype was identified as an independent predictor of the presence of baseline RASs in and genes ( = 0.0005 and = 0.01, respectively). Sustained virologic response was achieved by 93.3% of the patients after receiving direct-acting antivirals (DAAs), although 48.7% of them showed baseline RASs related to the DAA-regimen. Notably, the prevalence of clinically relevant RASs in the three genes was lower than that observed around the world. The baseline presence of RASs in both subtypes did not appear to affect therapy outcome. These results support the need to evaluate resistance patterns in each particular country since RASs´ prevalence significantly vary worldwide.
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http://dx.doi.org/10.3390/v11010003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356817PMC
December 2018

Complete Genome Sequence of Cluster J Mycobacteriophage Superphikiman.

Genome Announc 2018 Feb 1;6(5). Epub 2018 Feb 1.

Department of Biology, Drexel University, Philadelphia, Pennsylvania, USA.

Mycobacteriophage Superphikiman is a cluster J bacteriophage which was isolated from soil collected in Philadelphia, PA. Superphikiman has a 109,799-bp genome with 239 predicted genes, including 2 tRNA genes.
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http://dx.doi.org/10.1128/genomeA.01538-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794948PMC
February 2018

Effectiveness and safety of original and generic sofosbuvir for the treatment of chronic hepatitis C: A real world study.

J Med Virol 2018 05 15;90(5):951-958. Epub 2018 Feb 15.

Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.

We report the first real-world prospective multicenter cohort study that evaluated the effectiveness and safety of original or generic sofosbuvir-based regimens in patients with chronic hepatitis C in Latin America. The main endpoints were assessment of sustained virological response and serious adverse events rates. A total of 321 patients with chronic hepatitis C treated with the following regimens were included: sofosbuvir plus daclatasvir for 12 (n = 34) or 24 (n = 135) weeks, sofosbuvir plus daclatasvir plus ribavirin for 12 (n = 84) or 24 (n = 56) weeks, or sofosbuvir plus ribavirin for 12 (n = 8) or 24 (n = 2) weeks. Patients received either original sofosbuvir (Sovaldi , Gilead Sciences, n = 135) or generic sofosbuvir (Probirase , Laboratorios RICHMOND, n = 184) which were randomly assigned by the National Ministry of Health. Overall, 292 (91%) patients had cirrhosis, 136 (42%) were treatment experienced, and 240 (75%) genotype 1. The overall sustained virological response was 90% (95% CI 86-93%); 91% (95% CI 84-95%) in patients who received Sovaldi , and 89% (95% CI 84-93%) in patients who received Probirase . Anemia was the most common adverse event and was reported in 52 (17%) patients. Bacterial infection, gastrointestinal bleeding, worsening of ascites or encephalopathy occurred in less than 5% of the patients. During the study, seven (2%) patients died, four of whom died of cirrhosis-related complications. In summary, we observed similar sustained virological response rates than prior studies, both in patients who received Sovaldi or Probirase . Serious adverse events were infrequent, in line with prior studies that included patients with cirrhosis treated with protease-inhibitor-free regimes.
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http://dx.doi.org/10.1002/jmv.25033DOI Listing
May 2018

Spontaneous bacteremia and spontaneous bacterial peritonitis share similar prognosis in patients with cirrhosis: a cohort study.

Hepatol Int 2018 Mar 9;12(2):181-190. Epub 2017 Dec 9.

Liver Unit, Hospital Italiano, Juan Domingo Perón 4190, 1181ACH, Buenos Aires, Argentina.

Background And Aims: Spontaneous bacteremia is a poorly characterized infection in patients with cirrhosis. We compared the incidence of mortality and acute kidney injury in patients with spontaneous bacterial peritonitis and spontaneous bacteremia, and identified risk factors for mortality and acute kidney injury in patients with spontaneous bacteremia.

Methods: We performed a retrospective cohort study of patients with cirrhosis and spontaneous bacteremia or spontaneous bacterial peritonitis from 2008 to 2016 at Hospital Italiano, Buenos Aires. We compared the cumulative incidence of acute kidney injury and death between the two infections, and identified risk factors for these outcomes in patients with spontaneous bacteremia.

Results: Seventy-one patients with spontaneous bacteremia and 55 patients with spontaneous bacterial peritonitis were included. Most infections were nosocomial. Overall, 26% of bacteria were resistant and 11% multi-resistant. We found no significant association between acute kidney injury [subhazard ratio (sHR) 1.05 (95% confidence interval, CI 0.67-1.63, p = 0.83)] or death [sHR 1.15 (95% CI 0.60-2.20, p = 0.68)] and type of spontaneous infection in multivariate analyses adjusting for basal Model for End-Stage Liver Disease (MELD) score. In patients with spontaneous bacteremia, baseline MELD score was independently associated with acute kidney injury [sHR 1.07 (95% CI 1.03-1.11, p = 0.001)] and death [sHR 1.07 (95% CI 1.02-1.15, p = 0.03)].

Conclusions: Short-term acute kidney injury and mortality rates were similar in patients with spontaneous bacteremia and spontaneous bacterial peritonitis. Risk assessment of patients with spontaneous bacteremia can be performed with baseline MELD score.
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http://dx.doi.org/10.1007/s12072-017-9837-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104019PMC
March 2018

Ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin is safe and effective in HCV-infected patients in a real-life cohort from Latin America.

J Med Virol 2017 09 6;89(9):1590-1596. Epub 2017 Jun 6.

Unidad de Hígado y Trasplante Hepático, Hospital Universitario Austral, Pilar, Argentina.

Information about the use of ombitasvir/paritaprevir/ritonavir/dasabuvir ± ribavirin (OBV/PTV/r/DSV ± RBV) in real-clinical practice in Latin America is scarce. We aimed to confirm safety and effectiveness of OBV/PTV/r/DSV ± RBV therapy in real-world setting. We analyzed a cohort of patients with genotype 1 infection treated with OBV/PTV/r/DSV ± RBV. Data on demographics, clinical features, safety, and virological response were retrospectively collected from 21 centers in Latin America. A total of 96 patients received OBV/PTV/r/DSV, associated with RBV in 68% of the cases. Most were genotype 1b (80%), 56 (58%) had cirrhosis, and 45 (47%) failed prior HCV treatment. Adverse events occurred in 62% of patients. The most common adverse events were pruritus (21%), hyperbilirubinemia (17%), and asthenia (17%). Five patients discontinued therapy prematurely due to hepatic decompensation, three of them were Child-Pugh B at baseline and one patient died due to multi-organ failure. Follow up HCV-RNA 12 weeks after completion of therapy was evaluated in all the patients and sustained virologic response rate was 97%. No virologic breakthrough was detected. Our study confirms that OBV/PTV/r/DSV treatment is highly effective in patients with chronic HCV without cirrhosis or with Child-Pugh A cirrhosis in non-European populations. Adverse events were often mild and rarely led to treatment discontinuation except for patients with Child-Pugh B cirrhosis or with previous history of hepatic decompensation. These results can support the development of public strategies to expand the access of OBV/PTV/r + DSV and other DAAs combinations in order to reduce the burden of HCV infection in our region.
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http://dx.doi.org/10.1002/jmv.24816DOI Listing
September 2017

Role of HLA-DP and HLA-DQ on the clearance of hepatitis B virus and the risk of chronic infection in a multiethnic population.

Liver Int 2017 10 30;37(10):1476-1487. Epub 2017 Mar 30.

Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina.

Background & Aims: HBV infection exhibits geographical variation in its distribution in South America. While HBV rates are low in central Argentina, the north-western region exhibits intermediate HBV rates. Unfortunately, the reasons that could explain this difference are still unknown.

Methods: A total of 1440 Argentines were recruited and grouped into HBV patients, HBV-resolved individuals and healthy controls. Genetic ancestry was assessed by analysis of biparental lineages and ancestry autosomal typing. SNPs of HLA-DPA1 (rs3077), HLA-DPB1 (rs9277542), HLA-DQB1 (rs2856718) and HLA-DQB2 (rs7453920) were determined, and HBV genotyping was performed by phylogenetic analysis in HBV patients.

Results: Native American ancestry prevailed in the north-western region when compared with central Argentina (P<.0001). However, no differences were observed among the three groups of each region. The distribution of HBV genotypes revealed significant differences (P<.0001). Three SNPs (rs3077, rs9277542 and rs7453920) showed a significant association with protection against chronic HBV and viral clearance in both regions. The remaining SNP showed a significant association with susceptibility to chronic HBV. The frequency rates of rs3077-T, related to protection against chronic HBV and viral clearance, were lower in north-western Argentina when compared with central Argentina. The same uneven frequency rates were observed for SNP rs9277542.

Conclusions: This is the first study addressing the associations between the HLA-DP and HLA-DQ loci and the protection against chronic HBV and viral clearance in a multiethnic South American population. The uneven distribution of HLA-DP and HLA-DQ supports the HBV epidemiological differences observed in these two regions of Argentina with dissimilar ancestry genetic background.
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http://dx.doi.org/10.1111/liv.13405DOI Listing
October 2017

Sex-specific association between functional neuropeptide S receptor gene (NPSR1) variants and cortisol and central stress responses.

Psychoneuroendocrinology 2017 02 10;76:49-56. Epub 2016 Nov 10.

Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany; Institute of Experimental Psychology, University of Regensburg, Germany. Electronic address:

The brain neuropeptide S (NPS) system has recently generated substantial interest and may be of major relevance for central stress regulation. The NPS receptor (NPSR1) is highly expressed in the limbic system, exogenous NPS exerts pronounced anxiolytic and fear-attenuating effects in rodents and extensive close crosstalk between the NPS system and the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated. In humans, associations between NPSR1 variants and anxiety and panic disorder, as well as amygdala responsiveness to fear- relevant faces and prefrontal cortex activity in a fear conditioning paradigm have been reported. Moreover, a NPSR1 sequence variant was found to be associated with cortisol stress responses in males. Here, we performed a haplotype-based analysis covering three functional NPSR1 single nucleotide polymorphisms in the promoter (rs2530547), in exon 3 (rs324981) and exon 6 (rs727162) in 277 healthy subjects who were exposed to the Trier Social Stress Test (TSST). A significant sex-specific association with salivary cortisol responses to acute psychosocial stress was detected for the common TTC haplotype 2 (frequency of about 20%). In an additional study using an imaging genetics approach, 65 healthy subjects were exposed to a stress paradigm for scanner environments (“ScanSTRESS”). We found a significant and, again, sex-specific interaction between rs324981 (whose minor T-allele is harbored by haplotype 2) and the neural stress response in a cluster close to the parahippocampal gyrus (whole brain corrected). Moreover, as in the TSST sample, NPSR1 variation was associated with salivary cortisol responses (on a trend level) in a sex-specific way. In summary, our preliminary findings in two independent cohorts exposed to different stress paradigms suggest that the NPS system significantly influences acute stress responses and that sequence variation in NPSR1 may contribute to sex differences in stress regulation.
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http://dx.doi.org/10.1016/j.psyneuen.2016.10.027DOI Listing
February 2017

Dynamic brain network reconfiguration as a potential schizophrenia genetic risk mechanism modulated by NMDA receptor function.

Proc Natl Acad Sci U S A 2016 11 17;113(44):12568-12573. Epub 2016 Oct 17.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany;

Schizophrenia is increasingly recognized as a disorder of distributed neural dynamics, but the molecular and genetic contributions are poorly understood. Recent work highlights a role for altered N-methyl-d-aspartate (NMDA) receptor signaling and related impairments in the excitation-inhibitory balance and synchrony of large-scale neural networks. Here, we combined a pharmacological intervention with novel techniques from dynamic network neuroscience applied to functional magnetic resonance imaging (fMRI) to identify alterations in the dynamic reconfiguration of brain networks related to schizophrenia genetic risk and NMDA receptor hypofunction. We quantified "network flexibility," a measure of the dynamic reconfiguration of the community structure of time-variant brain networks during working memory performance. Comparing 28 patients with schizophrenia, 37 unaffected first-degree relatives, and 139 healthy controls, we detected significant differences in network flexibility [F(2,196) = 6.541, P = 0.002] in a pattern consistent with the assumed genetic risk load of the groups (highest for patients, intermediate for relatives, and lowest for controls). In an observer-blinded, placebo-controlled, randomized, cross-over pharmacological challenge study in 37 healthy controls, we further detected a significant increase in network flexibility as a result of NMDA receptor antagonism with 120 mg dextromethorphan [F(1,34) = 5.291, P = 0.028]. Our results identify a potential dynamic network intermediate phenotype related to the genetic liability for schizophrenia that manifests as altered reconfiguration of brain networks during working memory. The phenotype appears to be influenced by NMDA receptor antagonism, consistent with a critical role for glutamate in the temporal coordination of neural networks and the pathophysiology of schizophrenia.
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http://dx.doi.org/10.1073/pnas.1608819113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098640PMC
November 2016

Implementation of the ECHO telementoring model for the treatment of patients with hepatitis C.

J Med Virol 2017 04 1;89(4):660-664. Epub 2016 Sep 1.

Hospital Italiano, Buenos Aires, Argentina.

We aimed to implement the Extension for Community Healthcare Outcomes (ECHO) telementoring model for hepatitis C and to evaluate its outcomes in the health providers. Following the ECHO model, an hepatitis C teleECHO clinic was established at the Hospital Italiano in Argentina. The teleECHO clinic provides support and training to physicians from Patagonia who treat patients with hepatitis C. In order to evaluate the teleECHO clinic outcomes, physicians completed a survey focused on skills and competence in hepatitis C before and after 6 months of participating in the project. The survey consisted of 10 questions, which participants rated from 1 to 7 (1 no ability; 7 highest ability). To analyze the difference before and after participation in the project, Wilcoxon signed-rank test was used. During the first 6 months of implementation of the model, a total of 14 physicians from 12 sites in Patagonia agreed to participate in the survey. The median age of the participants was 42 years. Participants' primary specialties were Hepatology (55%), Infectious Diseases (25%), General Practice (10%), and other (10%). A significant improvement was observed in all the evaluated fields after 6 month of the participation in the teleECHO clinic, namely fibrosis staging, determining appropriate candidates for treatment, and selecting appropriate HCV treatment. In addition, their general interest in hepatitis C increased. We successfully replicated and implemented the first teleECHO clinic in Argentina. Physicians improved their ability to provide best practice care for patients with Hepatitis C. J. Med. Virol. 89:660-664, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jmv.24668DOI Listing
April 2017

Altered Functional Subnetwork During Emotional Face Processing: A Potential Intermediate Phenotype for Schizophrenia.

JAMA Psychiatry 2016 06;73(6):598-605

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Importance: Although deficits in emotional processing are prominent in schizophrenia, it has been difficult to identify neural mechanisms related to the genetic risk for this highly heritable illness. Prior studies have not found consistent regional activation or connectivity alterations in first-degree relatives compared with healthy controls, suggesting that a more comprehensive search for connectomic biomarkers is warranted.

Objectives: To identify a potential systems-level intermediate phenotype linked to emotion processing in schizophrenia and to examine the psychological association, task specificity, test-retest reliability, and clinical validity of the identified phenotype.

Design, Setting, And Participations: The study was performed in university research hospitals from June 1, 2008, through December 31, 2013. We examined 58 unaffected first-degree relatives of patients with schizophrenia and 94 healthy controls with an emotional face-matching functional magnetic resonance imaging paradigm. Test-retest reliability was analyzed with an independent sample of 26 healthy participants. A clinical association study was performed in 31 patients with schizophrenia and 45 healthy controls. Data analysis was performed from January 1 to September 30, 2014.

Main Outcomes And Measures: Conventional amygdala activity and seeded connectivity measures, graph-based global and local network connectivity measures, Spearman rank correlation, intraclass correlation, and gray matter volumes.

Results: Among the 152 volunteers included in the relative-control sample, 58 were unaffected first-degree relatives of patients with schizophrenia (mean [SD] age, 33.29 [12.56]; 38 were women), and 94 were healthy controls without a first-degree relative with mental illness (mean [SD] age, 32.69 [10.09] years; 55 were women). A graph-theoretical connectivity approach identified significantly decreased connectivity in a subnetwork that primarily included the limbic cortex, visual cortex, and subcortex during emotional face processing (cluster-level P corrected for familywise error = .006) in relatives compared with controls. The connectivity of the same subnetwork was significantly decreased in patients with schizophrenia (F = 6.29, P = .01). Furthermore, we found that this subnetwork connectivity measure was negatively correlated with trait anxiety scores (P = .04), test-retest reliable (intraclass correlation coefficient = 0.57), specific to emotional face processing (F = 17.97, P < .001), and independent of gray matter volumes of the identified brain areas (F = 1.84, P = .18). Replicating previous results, no significant group differences were found in face-related amygdala activation and amygdala-anterior cingulate cortex connectivity (P corrected for familywise error =.37 and .11, respectively).

Conclusions And Relevance: Our results indicate that altered connectivity in a visual-limbic subnetwork during emotional face processing may be a functional connectomic intermediate phenotype for schizophrenia. The phenotype is reliable, task specific, related to trait anxiety, and associated with manifest illness. These data encourage the further investigation of this phenotype in clinical and pharmacologic studies.
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http://dx.doi.org/10.1001/jamapsychiatry.2016.0161DOI Listing
June 2016

The effect of cell disruption techniques and chaotropic agents on the downstream purification process of mecasermin produced as inclusion body in E. coli.

Res Pharm Sci 2015 Nov-Dec;10(6):553-61

Department of Biochemistry, Isfahan Pharmaceutical Sciences Research Center and Bioinformatics Research Center, School of Pharmacy, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.

The isolation of the target protein from inclusion bodies (IBs) is a preliminary step to increase protein titer and to maintain its biological activity. In the present study, the effects of various cell lysis methods and the expression temperature was investigated on the improvement of the subsequent purification steps of mecasermin produced in IB. We also investigated the solubilization profile of the top-notch IB in 6 M guanidine hydrochloride (Gdn-HCl) and 8 M urea at different pH ranges. Mecasermin was expressed at various temperatures (25, 28, 30, and 37 °C) and the Escherichia coli cells were lysed by different cell lysis methods. The purity and quality of harvested IBs was evaluated with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Finally, mecasermin was refolded and purified using gel filtration chromatography. The profile of SDS-PAGE analysis showed higher quality and purity after application of sonication coupled with lysozyme pretreatment for expressed mecasermin at 37 °C. Besides, from dithiothreitol application in washing step, we achieved a manifold enriched secondary IB for further purification of mecasermin. Mecasermin exhibited optimized solubility in 6 M Gdn-HCl at pH of 5.4. The findings of this study indicate an important role for cell disruption techniques to efficient purification of mecasermin. The study presents the most efficient techniques for improvement of downstream purification of mecasermin.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698866PMC
January 2016

Dynamic reconfiguration of frontal brain networks during executive cognition in humans.

Proc Natl Acad Sci U S A 2015 Sep 31;112(37):11678-83. Epub 2015 Aug 31.

Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104; Department of Electrical and Systems Engineering, University of Pennsylvania, Philadelphia, PA 19104

The brain is an inherently dynamic system, and executive cognition requires dynamically reconfiguring, highly evolving networks of brain regions that interact in complex and transient communication patterns. However, a precise characterization of these reconfiguration processes during cognitive function in humans remains elusive. Here, we use a series of techniques developed in the field of "dynamic network neuroscience" to investigate the dynamics of functional brain networks in 344 healthy subjects during a working-memory challenge (the "n-back" task). In contrast to a control condition, in which dynamic changes in cortical networks were spread evenly across systems, the effortful working-memory condition was characterized by a reconfiguration of frontoparietal and frontotemporal networks. This reconfiguration, which characterizes "network flexibility," employs transient and heterogeneous connectivity between frontal systems, which we refer to as "integration." Frontal integration predicted neuropsychological measures requiring working memory and executive cognition, suggesting that dynamic network reconfiguration between frontal systems supports those functions. Our results characterize dynamic reconfiguration of large-scale distributed neural circuits during executive cognition in humans and have implications for understanding impaired cognitive function in disorders affecting connectivity, such as schizophrenia or dementia.
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http://dx.doi.org/10.1073/pnas.1422487112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577153PMC
September 2015

Segregation of face sensitive areas within the fusiform gyrus using global signal regression? A study on amygdala resting-state functional connectivity.

Hum Brain Mapp 2015 Oct 14;36(10):4089-103. Epub 2015 Jul 14.

Division of Mind and Brain Research, Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

The application of global signal regression (GSR) to resting-state functional magnetic resonance imaging data and its usefulness is a widely discussed topic. In this article, we report an observation of segregated distribution of amygdala resting-state functional connectivity (rs-FC) within the fusiform gyrus (FFG) as an effect of GSR in a multi-center-sample of 276 healthy subjects. Specifically, we observed that amygdala rs-FC was distributed within the FFG as distinct anterior versus posterior clusters delineated by positive versus negative rs-FC polarity when GSR was performed. To characterize this effect in more detail, post hoc analyses revealed the following: first, direct overlays of task-functional magnetic resonance imaging derived face sensitive areas and clusters of positive versus negative amygdala rs-FC showed that the positive amygdala rs-FC cluster corresponded best with the fusiform face area, whereas the occipital face area corresponded to the negative amygdala rs-FC cluster. Second, as expected from a hierarchical face perception model, these amygdala rs-FC defined clusters showed differential rs-FC with other regions of the visual stream. Third, dynamic connectivity analyses revealed that these amygdala rs-FC defined clusters also differed in their rs-FC variance across time to the amygdala. Furthermore, subsample analyses of three independent research sites confirmed reliability of the effect of GSR, as revealed by similar patterns of distinct amygdala rs-FC polarity within the FFG. In this article, we discuss the potential of GSR to segregate face sensitive areas within the FFG and furthermore discuss how our results may relate to the functional organization of the face-perception circuit.
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http://dx.doi.org/10.1002/hbm.22900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868984PMC
October 2015

Neural Correlates of the Cortisol Awakening Response in Humans.

Neuropsychopharmacology 2015 Aug 17;40(9):2278-85. Epub 2015 Mar 17.

Central Institute for Mental Health, University of Heidelberg/Medical Faculty Mannheim, J5, Mannheim, Germany.

The cortisol rise after awakening (cortisol awakening response, CAR) is a core biomarker of hypothalamic-pituitary-adrenal (HPA) axis regulation related to psychosocial stress and stress-related psychiatric disorders. However, the neural regulation of the CAR has not been examined in humans. Here, we studied neural regulation related to the CAR in a sample of 25 healthy human participants using an established psychosocial stress paradigm together with multimodal functional and structural (voxel-based morphometry) magnetic resonance imaging. Across subjects, a smaller CAR was associated with reduced grey matter volume and increased stress-related brain activity in the perigenual ACC, a region which inhibits HPA axis activity during stress that is implicated in risk mechanisms and pathophysiology of stress-related mental diseases. Moreover, functional connectivity between the perigenual ACC and the hypothalamus, the primary controller of HPA axis activity, was associated with the CAR. Our findings provide support for a role of the perigenual ACC in regulating the CAR in humans and may aid future research on the pathophysiology of stress-related illnesses, such as depression, and environmental risk for illnesses such as schizophrenia.
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http://dx.doi.org/10.1038/npp.2015.77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613622PMC
August 2015

Amygdala habituation: a reliable fMRI phenotype.

Neuroimage 2014 Dec 2;103:383-390. Epub 2014 Oct 2.

Central Institute of Mental Health, Department of Psychiatry and Psychotherapy, University of Heidelberg/Medical Faculty Mannheim, Mannheim, Germany.

Amygdala function is of high interest for cognitive, social and psychiatric neuroscience, emphasizing the need for reliable assessments in humans. Previous work has indicated unsatisfactorily low within-subject reliability of amygdala activation fMRI measures. Based on basic science evidence for strong habituation of amygdala response to repeated stimuli, we investigated whether a quantification of habituation provides additional information beyond the usual estimate of the overall mean activity. We assessed the within-subject reliability of amygdala habituation measures during a facial emotion matching paradigm in 25 healthy subjects. We extracted the amygdala signal decrement across the course of the fMRI run for the two test-retest measurement sessions and compared reliability estimates with previous findings based on mean response amplitude. Retest-reliability of the session-wise amygdala habituation was significantly higher than the evoked amygdala mean amplitude (intraclass correlation coefficients (ICC)=0.53 vs. 0.16). To test the task-specificity of this finding, we compared the retest-reliability of amygdala habituation across two different tasks. Significant amygdala response decrement was also seen in a cognitive task (n-back working memory) that did not per se activate the amygdala, but was totally unreliable in that context (ICC~0.0), arguing for task-specificity. Together the results show that emotion-dependent amygdala habituation is a robust and considerably more reliable index than the mean amplitude, and provides a robust potential endpoint for within-subject designs including pharmaco-fMRI studies.
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http://dx.doi.org/10.1016/j.neuroimage.2014.09.059DOI Listing
December 2014

Ultra-sensitive procalcitonin may help rule out bacterial infections in patients with cirrhosis.

Ann Hepatol 2014 Sep-Oct;13(5):541-7

Liver Unit, Hospital Italiano, Buenos Aires, Argentina.

Background: Bacterial infections are frequent complications in patients with cirrhosis. Since they are associated with poor outcomes, antibiotics are frequently over-prescribed. Surrogate markers of bacterial infections, like procalcitonin, are needed to better discriminate between infected and not infected patients.

Aims: To evaluated the diagnostic accuracy of an ultra-sensitive procalcitonin assay for the diagnosis of bacterial infections in patients with cirrhosis.

Material And Methods: In a single-center prospective study, we determined the basal levels of procalcitonin in 106 episodes of admissions to the emergency department in 84 cirrhotic patients. Patients were classified as infected or not infected by two independent hepatologists blinded to the procalcitonin result.

Results: The prevalence of bacterial infection was 28% (29 episodes). The median procalcitonin was significantly higher in the infected group than in the not infected group (0.45 vs. 0.061 ng/mL, p < 0.001). The diagnostic accuracy of procalcitonin for bacterial infection estimated by the ROC curve was 0.95 (CI: 95%, 0.91-0.99). When selecting a cutoff value of 0.098 ng/mL a sensitivity of 97% and a negative predictive value 98% were found.

Conclusions: The use of an ultra-sensitive procalcitonin assay identifies patients with cirrhosis at very low risk of bacterial infections.
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May 2015

Larger amygdala volume in first-degree relatives of patients with major depression.

Neuroimage Clin 2014 2;5:62-8. Epub 2014 Jun 2.

Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Charité Campus Mitte, Berlin, Germany.

Objective: Although a heritable contribution to risk for major depressive disorder (MDD) has been established and neural alterations in patients have been identified through neuroimaging, it is unclear which brain abnormalities are related to genetic risk. Studies on brain structure of high-risk subjects - such as individuals carrying a familial liability for the development of MDD - can provide information on the potential usefulness of these measures as intermediate phenotypes of MDD.

Methods: 63 healthy first-degree relatives of patients with MDD and 63 healthy controls underwent structural magnetic resonance imaging. Regional gray matter volumes were analyzed via voxel-based morphometry (VBM).

Results: Whole-brain analysis revealed significantly larger gray matter volume in the bilateral amygdala in first-degree relatives of patients with MDD. Furthermore, relatives showed significantly larger gray matter volume in anatomical structures found relevant to MDD in previous literature, specifically in the bilateral hippocampus and amygdala as well as the left dorsolateral prefrontal cortex (DLPFC). Bilateral DLPFC volume correlated positively with the experience of negative affect.

Conclusions: Larger gray matter volume in healthy relatives of MDD patients point to a possible vulnerability mechanism in MDD etiology and therefore extend knowledge in the field of high-risk approaches in MDD.
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http://dx.doi.org/10.1016/j.nicl.2014.05.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081974PMC
February 2015

Identification of gene ontologies linked to prefrontal-hippocampal functional coupling in the human brain.

Proc Natl Acad Sci U S A 2014 Jul 16;111(26):9657-62. Epub 2014 Jun 16.

Departments of Psychiatry and Psychotherapy and

Functional interactions between the dorsolateral prefrontal cortex and hippocampus during working memory have been studied extensively as an intermediate phenotype for schizophrenia. Coupling abnormalities have been found in patients, their unaffected siblings, and carriers of common genetic variants associated with schizophrenia, but the global genetic architecture of this imaging phenotype is unclear. To achieve genome-wide hypothesis-free identification of genes and pathways associated with prefrontal-hippocampal interactions, we combined gene set enrichment analysis with whole-genome genotyping and functional magnetic resonance imaging data from 269 healthy German volunteers. We found significant enrichment of the synapse organization and biogenesis gene set. This gene set included known schizophrenia risk genes, such as neural cell adhesion molecule (NRCAM) and calcium channel, voltage-dependent, beta 2 subunit (CACNB2), as well as genes with well-defined roles in neurodevelopmental and plasticity processes that are dysfunctional in schizophrenia and have mechanistic links to prefrontal-hippocampal functional interactions. Our results demonstrate a readily generalizable approach that can be used to identify the neurogenetic basis of systems-level phenotypes. Moreover, our findings identify gene sets in which genetic variation may contribute to disease risk through altered prefrontal-hippocampal functional interactions and suggest a link to both ongoing and developmental synaptic plasticity.
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http://dx.doi.org/10.1073/pnas.1404082111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4084419PMC
July 2014

Brain structure correlates of urban upbringing, an environmental risk factor for schizophrenia.

Schizophr Bull 2015 Jan 3;41(1):115-22. Epub 2014 Jun 3.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Medical Faculty Mannheim, Mannheim, Germany;

Urban upbringing has consistently been associated with schizophrenia, but which specific environmental exposures are reflected by this epidemiological observation and how they impact the developing brain to increase risk is largely unknown. On the basis of prior observations of abnormal functional brain processing of social stress in urban-born humans and preclinical evidence for enduring structural brain effects of early social stress, we investigated a possible morphological correlate of urban upbringing in human brain. In a sample of 110 healthy subjects studied with voxel-based morphometry, we detected a strong inverse correlation between early-life urbanicity and gray matter (GM) volume in the right dorsolateral prefrontal cortex (DLPFC, Brodmann area 9). Furthermore, we detected a negative correlation of early-life urbanicity and GM volumes in the perigenual anterior cingulate cortex (pACC) in men only. Previous work has linked volume reductions in the DLPFC to the exposure to psychosocial stress, including stressful experiences in early life. Besides, anatomical and functional alterations of this region have been identified in schizophrenic patients and high-risk populations. Previous data linking functional hyperactivation of pACC during social stress to urban upbringing suggest that the present interaction effect in brain structure might contribute to an increased risk for schizophrenia in males brought up in cities. Taken together, our results suggest a neural mechanism by which early-life urbanicity could impact brain architecture to increase the risk for schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbu072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266290PMC
January 2015
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