gutSMASH predicts specialized primary metabolic pathways from the human gut microbiota.

The gut microbiota produce hundreds of small molecules, many of which modulate host physiology. Although efforts have been made to identify biosynthetic genes for secondary metabolites, the chemical output of the gut microbiome consists predominantly of primary metabolites. Here we introduce the gutSMASH algorithm for identification of primary metabolic gene clusters, and we used it to systematically profile gut microbiome metabolism, identifying 19,890 gene clusters in 4,240 high-quality microbial genomes. We found marked differences in pathway distribution among phyla, reflecting distinct strategies for energy capture. These data explain taxonomic differences in short-chain fatty acid production and suggest a characteristic metabolic niche for each taxon. Analysis of 1,135 individuals from a Dutch population-based cohort shows that the level of microbiome-derived metabolites in plasma and feces is almost completely uncorrelated with the metagenomic abundance of corresponding metabolic genes, indicating a crucial role for pathway-specific gene regulation and metabolite flux. This work is a starting point for understanding differences in how bacterial taxa contribute to the chemistry of the microbiome.

Generating lineage-resolved, complete metagenome-assembled genomes from complex microbial communities.

Microbial communities might include distinct lineages of closely related organisms that complicate metagenomic assembly and prevent the generation of complete metagenome-assembled genomes (MAGs). Here we show that deep sequencing using long (HiFi) reads combined with Hi-C binning can address this challenge even for complex microbial communities. Using existing methods, we sequenced the sheep fecal metagenome and identified 428 MAGs with more than 90% completeness, including 44 MAGs in single circular contigs. To resolve closely related strains (lineages), we developed MAGPhase, which separates lineages of related organisms by discriminating variant haplotypes across hundreds of kilobases of genomic sequence. MAGPhase identified 220 lineage-resolved MAGs in our dataset. The ability to resolve closely related microbes in complex microbial communities improves the identification of biosynthetic gene clusters and the precision of assigning mobile genetic elements to host genomes. We identified 1,400 complete and 350 partial biosynthetic gene clusters, most of which are novel, as well as 424 (298) potential host-viral (host-plasmid) associations using Hi-C data.

BiG-MAP: an Automated Pipeline To Profile Metabolic Gene Cluster Abundance and Expression in Microbiomes.

Microbial gene clusters encoding the biosynthesis of primary and secondary metabolites play key roles in shaping microbial ecosystems and driving microbiome-associated phenotypes. Although effective approaches exist to evaluate the metabolic potential of such bacteria through identification of these metabolic gene clusters in their genomes, no automated pipelines exist to profile the abundance and expression levels of such gene clusters in microbiome samples to generate hypotheses about their functional roles, and to find associations with phenotypes of interest. Here, we describe BiG-MAP, a bioinformatic tool to profile abundance and expression levels of gene clusters across metagenomic and metatranscriptomic data and evaluate their differential abundance and expression under different conditions. To illustrate its usefulness, we analyzed 96 metagenomic samples from healthy and caries-associated human oral microbiome samples and identified 252 gene clusters, including unreported ones, that were significantly more abundant in either phenotype. Among them, we found the muc operon, a gene cluster known to be associated with tooth decay. Additionally, we found a putative reuterin biosynthetic gene cluster from a Streptococcus strain to be enriched but not exclusively found in healthy samples; metabolomic data from the same samples showed masses with fragmentation patterns consistent with (poly)acrolein, which is known to spontaneously form from the products of the reuterin pathway and has been previously shown to inhibit pathogenic Streptococcus mutans strains. Thus, we show how BiG-MAP can be used to generate new hypotheses on potential drivers of microbiome-associated phenotypes and prioritize the experimental characterization of relevant gene clusters that may mediate them. IMPORTANCE Microbes play an increasingly recognized role in determining host-associated phenotypes by producing small molecules that interact with other microorganisms or host cells. The production of these molecules is often encoded in syntenic genomic regions, also known as gene clusters. With the increasing numbers of (multi)omics data sets that can help in understanding complex ecosystems at a much deeper level, there is a need to create tools that can automate the process of analyzing these gene clusters across omics data sets. This report presents a new software tool called BiG-MAP, which allows assessing gene cluster abundance and expression in microbiome samples using metagenomic and metatranscriptomic data. Here, we describe the tool and its functionalities, as well as its validation using a mock community. Finally, using an oral microbiome data set, we show how it can be used to generate hypotheses regarding the functional roles of gene clusters in mediating host phenotypes.

Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions.

To adopt prevention strategies in gastric cancer, it is imperative to develop robust biomarkers with acceptable costs and feasibility in clinical practice to stratified populations according to risk scores. With this aim, we applied an unbiased genome-wide CpG methylation approach to a discovery cohort composed of gastric cancer (n = 24), and non-malignant precursor lesions (n = 64). Then, candidate-methylation approaches were performed in a validation cohort of precursor lesions obtained from an observational longitudinal study (n = 264), with a 12-year follow-up to identify repression or progression cases. H. pylori stratification and histology were considered to determine their influence on the methylation dynamics. As a result, we ascertained that intestinal metaplasia partially recapitulates patterns of aberrant methylation of intestinal type of gastric cancer, independently of the H. pylori status. Two epigenetically regulated genes in cancer, RPRM and ZNF793, consistently showed increased methylation in intestinal metaplasia with respect to earlier precursor lesions. In summary, our result supports the need to investigate the practical utilities of the quantification of DNA methylation in candidate genes as a marker for disease progression. In addition, the H. pylori-dependent methylation in intestinal metaplasia suggests that pharmacological treatments aimed at H. pylori eradication in the late stages of precursor lesions do not prevent epigenome reprogramming toward a cancer signature.

The gutSMASH web server: automated identification of primary metabolic gene clusters from the gut microbiota.

Anaerobic bacteria from the human microbiome produce a wide array of molecules at high concentrations that can directly or indirectly affect the host. The production of these molecules, mostly derived from their primary metabolism, is frequently encoded in metabolic gene clusters (MGCs). However, despite the importance of microbiome-derived primary metabolites, no tool existed to predict the gene clusters responsible for their production. For this reason, we recently introduced gutSMASH. gutSMASH can predict 41 different known pathways, including MGCs involved in bioenergetics, but also putative ones that are candidates for novel pathway discovery. To make the tool more user-friendly and accessible, we here present the gutSMASH web server, hosted at https://gutsmash.bioinformatics.nl/. The user can either input the GenBank assembly accession or upload a genome file in FASTA or GenBank format. Optionally, the user can enable additional analyses to obtain further insights into the predicted MGCs. An interactive HTML output (viewable online or downloadable for offline use) provides a user-friendly way to browse functional gene annotations and sequence comparisons with reference gene clusters as well as gene clusters predicted in other genomes. Thus, this web server provides the community with a streamlined and user-friendly interface to analyze the metabolic potential of gut microbiomes.

Computational genomic discovery of diverse gene clusters harbouring Fe-S flavoenzymes in anaerobic gut microbiota.

The gut contains an enormous diversity of simple as well as complex molecules from highly diverse food sources, together with host-secreted molecules. This presents a large metabolic opportunity for the gut microbiota, but little is known about how gut microbes are able to catabolize this large chemical diversity. Recently, Fe-S flavoenzymes were found to be key in the transformation of bile acids, catalysing the key step in the 7α-dehydroxylation pathway that allows gut bacteria to transform cholic acid into deoxycholic acid, an exclusively microbe-derived molecule with major implications for human health. While this enzyme family has also been implicated in a limited number of other catalytic transformations, little is known about the extent to which it is of more global importance in gut microbial metabolism. Here, we perform a large-scale computational genomic analysis to show that this enzyme superfamily has undergone a remarkable expansion in Clostridiales, and occurs throughout a diverse array of >1000 different families of putative metabolic gene clusters. Analysis of the enzyme content of these gene clusters suggests that they encode pathways with a wide range of predicted substrate classes, including saccharides, amino acids/peptides and lipids. Altogether, these results indicate a potentially important role of this protein superfamily in the human gut, and our dataset provides significant opportunities for the discovery of novel pathways that may have significant effects on human health.

Early Postoperative Endoscopic Recurrence in Crohn's Disease Is Characterised by Distinct Microbiota Recolonisation.

BACKGROUND AND AIMS: Intestinal microbiota dysbiosis is implicated in Crohn's disease [CD] and may play an important role in triggering postoperative disease recurrence [POR]. We prospectively studied faecal and mucosal microbial recolonisation following ileocaecal resection to identify the predictive value of recurrence-related microbiota. METHODS: Mucosal and/or faecal samples from 121 CD patients undergoing ileocaecal resection were collected at predefined time points before and after surgery. Ileal biopsies were collected from 39 healthy controls. POR was defined by a Rutgeerts score ≥i2b. The microbiota was evaluated by 16S rRNA sequencing. Prediction analysis was performed using C5.0 and Random Forest algorithms. RESULTS: The mucosa-associated microbiota in CD patients was characterised by a depletion of butyrate-producing species (false discovery rate [FDR] <0.01) and enrichment of Proteobacteria [FDR = 0.009] and Akkermansia spp. [FDR = 0.02]. Following resection, a mucosal enrichment of Lachnospiraceae [FDR <0.001] was seen in all patients but in POR patients, also Fusobacteriaceae [FDR <0.001] increased compared with baseline. Patients without POR showed a decrease of Streptococcaceae [FDR = 0.003] and Actinomycineae [FDR = 0.06]. The mucosa-associated microbiota profile had good discriminative power to predict POR, and was superior to clinical risk factors. At Month 6, patients experiencing POR had a higher abundance of taxa belonging to Negativicutes [FDR = 0.04] and Fusobacteria [FDR = 0.04] compared with patients without POR. CONCLUSIONS: Microbiota recolonisation after ileocaecal resection is different between recurrence and non-recurrence patients, with Fusobacteria as the most prominent player driving early POR. These bacteria involved in the early recolonisation and POR represent a promising therapeutic strategy in the prevention of disease recurrence.

MIBiG 2.0: a repository for biosynthetic gene clusters of known function.

Fueled by the explosion of (meta)genomic data, genome mining of specialized metabolites has become a major technology for drug discovery and studying microbiome ecology. In these efforts, computational tools like antiSMASH have played a central role through the analysis of Biosynthetic Gene Clusters (BGCs). Thousands of candidate BGCs from microbial genomes have been identified and stored in public databases. Interpreting the function and novelty of these predicted BGCs requires comparison with a well-documented set of BGCs of known function. The MIBiG (Minimum Information about a Biosynthetic Gene Cluster) Data Standard and Repository was established in 2015 to enable curation and storage of known BGCs. Here, we present MIBiG 2.0, which encompasses major updates to the schema, the data, and the online repository itself. Over the past five years, 851 new BGCs have been added. Additionally, we performed extensive manual data curation of all entries to improve the annotation quality of our repository. We also redesigned the data schema to ensure the compliance of future annotations. Finally, we improved the user experience by adding new features such as query searches and a statistics page, and enabled direct link-outs to chemical structure databases. The repository is accessible online at https://mibig.secondarymetabolites.org/.

The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters.

Natural products originating from microorganisms are frequently used in antimicrobial and anticancer drugs, pesticides, herbicides or fungicides. In the last years, the increasing availability of microbial genome data has made it possible to access the wealth of biosynthetic clusters responsible for the production of these compounds by genome mining. antiSMASH is one of the most popular tools in this field. The antiSMASH database provides pre-computed antiSMASH results for many publicly available microbial genomes and allows for advanced cross-genome searches. The current version 2 of the antiSMASH database contains annotations for 6200 full bacterial genomes and 18,576 bacterial draft genomes and is available at https://antismash-db.secondarymetabolites.org/.

Genetic variation analysis in a follow-up study of gastric cancer precursor lesions confirms the association of MUC2 variants with the evolution of the lesions and identifies a significant association with NFKB1 and CD14.

Gastric carcinogenesis proceeds through a series of gastric cancer precursor lesions (GCPLs) leading to gastric cancer (GC) development. Although Helicobacter pylori infection initiates this process, genetic factors also play a role. We previously reported that genetic variability in MUC2 is associated with the evolution of GCPLs. In order to replicate previous results in an independent sample series and to explore whether genetic variability in other candidate genes plays a role in the evolution of GCPL, genomic DNA from 559 patients with GCPLs, recruited from 9 Spanish hospitals and followed for a mean of 12 years, was genotyped for 141 SNPs in 29 genes. After follow-up, 45.5% of the lesions remained stable, 37% regressed and 17.5% progressed to a more severe lesion. Genetic association with the evolution of the lesions (progression or regression) was analyzed by multinomial and binomial logistic regression. After correction for multiple comparisons, the results obtained confirmed the inverse association between MUC2 variants and the regression of the lesions. A significant association was also observed between NFKB1 and CD14 variants and the evolution of the lesions; interestingly, this association was with both progression and regression in the same direction, which could reflect the dual role of inflammation in cancer. Stratified analyses according to H. pylori virulence factors indicated some significant and differential effects but none of them passed the FDR test. These results confirm that genetic variability in MUC2, NFKB1 and CD14 may have a role in the evolution of the GCPLs along time and in gastric carcinogenesis.

Características clínicas del carcinoma hepatocelular en España. Comparación con el período 2008-2009 y análisis de las causas del diagnóstico fuera de cribado. Estudio de 686 casos en 73 centros / Clinical characteristics of hepatocellular carcinoma in Spain. Comparison with the 2008-2009 period and analysis of the causes of diagnosis out of screening programs. Analysis of 686 cases in 73 centers

Antecedentes y objetivo: En 2010 publicamos que en España el 53% de los carcinomas hepatocelulares (CHC) se diagnostican fuera de programas de cribado, lo que conlleva una menor supervivencia. El objetivo del presente estudio es evaluar la situación actual y las causas del diagnóstico fuera de cribado. Material y métodos: Registro prospectivo entre el 1 de octubre de 2014 y el 31 de enero de 2015 en 73 centros asistenciales españoles de segundo/tercer nivel. Se registraron las características basales y el primer tratamiento de los tumores primarios hepáticos incidentales de ese período. Resultados: Se incluyeron 720 pacientes: CHC (n=686), colangiocarcinoma intrahepático (n=29), hepatocolangiocarcinoma (n=2), otros (n=3). Los pacientes con CHC fueron varones en el 82% de los casos; media de 67 años; cirrosis en el 87%; etiología: alcohol 35%, VHC 30%, alcohol y VHC 15%, enfermedad hepática por depósito de grasa 6%; estadio tumoral: BCLC-0 11%, A 43%, B 19%, C 16% y D 11%; tratamiento inicial: quimioembolización transarterial (23%), ablación percutánea (22%), tratamiento sintomático (20%), resección (11%), sorafenib (11%). Se diagnosticaron fuera de cribado 356 pacientes (53%). Los motivos principales fueron la ausencia de diagnóstico previo de hepatopatía (76%) y la mala adherencia al cribado (18%). Estos pacientes eran predominantemente varones (p<0,001), de etiología alcohólica (p<0,001), con consumo activo de alcohol (p<0,001) y se diagnosticaron en estadios más avanzados (p<0,001), recibiendo menos tratamientos radicales (p<0,001). Conclusiones: En España, la principal causa del diagnóstico de CHC fuera del cribado es la ausencia de diagnóstico previo de enfermedad hepática, principalmente en varones con consumo de alcohol. La detección de hepatopatía en población asintomática y la mejora de la adherencia al cribado son los principales aspectos para mejorar la detección precoz (AU)

Background and objective: In 2010 we published that 53% of cases of hepatocellular carcinoma (HCC) detected in Spain were diagnosed outside the context of standard screening programs, which consequently leads to lower survival rates. The aim of this study was to analyze the current situation and the causes of diagnosis out of screening programs. Material and methods: Prospective registry of 73 second- and third-level Spanish healthcare centers carried out between October 1, 2014 and January 31, 2015. The baseline characteristics of the disease and the first treatment administered for the incidental primary liver tumors during such period were recorded. Results: A total of 720 patients were included in the study: HCC (n=686), intrahepatic cholangiocarcinoma (n=29), hepatic cholangiocarcinoma (n=2), other (n=3). HCC characteristics: male 82%; mean age 67 years; cirrhosis 87%; main etiologies: alcohol 35%, HCV 30%, alcohol and HCV 15%, non-alcoholic fatty liver disease 6%; tumor stage: BCLC-0 11%, A 43%, B 19%, C 16% and D 11%; first treatment: transarterial chemoembolization (23%), percutaneous ablation (22%), symptomatic treatment (20%), resection (11%), sorafenib (11%). Three hundred and fifty-six patients (53%) were diagnosed outside of screening programs, mainly owing to the fact that they suffered from an undiagnosed liver disease (76%) and to the poor adherence to the screening program (18%). These patients were mainly male (P<.001), with an alcoholic etiology (P<.001) and active alcohol consumption (P<.001). Moreover, the disease was predominantly diagnosed at more advanced stages (P<.001) and was addressed with less radical treatments (P<.001). Conclusions: In Spain, the main cause of diagnosis of a HCC outside the context of a screening program is the absence of a prior diagnosis of a liver disease, particularly in alcohol-consuming men. Detecting a liver disease in asymptomatic populations and improving adherence to screening programs are the main areas that must be subject to improvement in order to improve the early detection of HCC (AU)

Gene expression study and pathway analysis of histological subtypes of intestinal metaplasia that progress to gastric cancer.

BACKGROUND: Intestinal metaplasia (IM) is a precursor lesion that precedes gastric cancer (GC). There are two IM histological subtypes, complete (CIM) and incomplete (IIM), the latter having higher progression rates to GC. This study was aimed at analysing gene expression and molecular processes involved in the progression from normal mucosa to IM, and also from IM subtypes to GC. METHODOLOGY: We used expression data to compare the transcriptome of healthy gastric mucosa to that of IM not progressing to GC, and the transcriptome of IM subtypes that had progressed to GC to those that did not progress. Some deregulated genes were validated and pathway analyses were performed. RESULTS: Comparison of IM subtypes that had progressed to GC with those that did not progress showed smaller differences in the expression profiles than the comparison of IM that did not progress with healthy mucosa. New transcripts identified in IM not progressing to GC included TRIM, TMEM, homeobox and transporter genes and SNORD116. Comparison to normal mucosa identified non tumoral Warburg effect and melatonin degradation as previously unreported processes involved in IM. Overexpressed antigen processing is common to both IM-subtypes progressing to GC, but IIM showed more over-expressed oncogenic genes and molecular processes than CIM. CONCLUSIONS: There are greater differences in gene expression and molecular processes involved in the progression from normal healthy mucosa to IM than from IM to gastric cancer. While antigen processing is common in both IM-subtypes progressing to GC, more oncogenic processes are observed in the progression of IIM.

Clinical characteristics of hepatocellular carcinoma in Spain. Comparison with the 2008-2009 period and analysis of the causes of diagnosis out of screening programs. Analysis of 686 cases in 73 centers. / Características clínicas del carcinoma hepatocelular en España. Comparación con el período 2008-2009 y análisis de las causas del diagnóstico fuera de cribado. Estudio de 686 casos en 73 centros.

BACKGROUND AND OBJECTIVE: In 2010 we published that 53% of cases of hepatocellular carcinoma (HCC) detected in Spain were diagnosed outside the context of standard screening programs, which consequently leads to lower survival rates. The aim of this study was to analyze the current situation and the causes of diagnosis out of screening programs. MATERIAL AND METHODS: Prospective registry of 73 second- and third-level Spanish healthcare centers carried out between October 1, 2014 and January 31, 2015. The baseline characteristics of the disease and the first treatment administered for the incidental primary liver tumors during such period were recorded. RESULTS: A total of 720 patients were included in the study: HCC (n=686), intrahepatic cholangiocarcinoma (n=29), hepatic cholangiocarcinoma (n=2), other (n=3). HCC characteristics: male 82%; mean age 67 years; cirrhosis 87%; main etiologies: alcohol 35%, HCV 30%, alcohol and HCV 15%, non-alcoholic fatty liver disease 6%; tumor stage: BCLC-0 11%, A 43%, B 19%, C 16% and D 11%; first treatment: transarterial chemoembolization (23%), percutaneous ablation (22%), symptomatic treatment (20%), resection (11%), sorafenib (11%). Three hundred and fifty-six patients (53%) were diagnosed outside of screening programs, mainly owing to the fact that they suffered from an undiagnosed liver disease (76%) and to the poor adherence to the screening program (18%). These patients were mainly male (P<.001), with an alcoholic etiology (P<.001) and active alcohol consumption (P<.001). Moreover, the disease was predominantly diagnosed at more advanced stages (P<.001) and was addressed with less radical treatments (P<.001). CONCLUSIONS: In Spain, the main cause of diagnosis of a HCC outside the context of a screening program is the absence of a prior diagnosis of a liver disease, particularly in alcohol-consuming men. Detecting a liver disease in asymptomatic populations and improving adherence to screening programs are the main areas that must be subject to improvement in order to improve the early detection of HCC.

Incomplete type of intestinal metaplasia has the highest risk to progress to gastric cancer: results of the Spanish follow-up multicenter study.

BACKGROUND AND AIM: In high or moderate risk populations, periodic surveillance of patients at risk of progression from gastric precursor lesions (PL) to gastric cancer (GC) is the most effective strategy for reducing the burden of GC. Incomplete type of intestinal metaplasia (IIM) may be considered as the best candidate, but it is still controversial and more research is needed. To further assess the progression of subtypes of IM as predictors of GC occurrence. METHODS: A follow-up study was carried-out including 649 patients, diagnosed with PL between 1995-2004 in 9 participating hospitals from Spain, and who repeated the biopsy during 2011-2013. Medical information and habits were collected through a questionnaire. Based on morphology, IM was sub-classified as complete (small intestinal type, CIM) and incomplete (colonic type, IIM). Analyses were done using Cox (HR) models. RESULTS: At baseline, 24% of patients had atrophic gastritis, 38% CIM, 34% IIM, and 4% dysplasia. Mean follow-up was 12 years. 24 patients (3.7%) developed a gastric adenocarcinoma during follow-up. The incidence rate of GC was 2.76 and 5.76 per 1,000 person-years for those with CIM and IIM, respectively. The HR of progression to CG was 2.75 (95% CI 1.06-6.26) for those with IIM compared with those with CIM at baseline, after adjusting for sex, age, smoking, family history of GC and use of NSAIDs. CONCLUSIONS: IIM is the PL with highest risk to progress to GC. Sub-typing of IM is a valid procedure for the identification of high risk patients that require more intensive surveillance.

Carcinoma neuroendocrino de colon poco diferenciado con metástasis hepáticas / Poorly differentiated neuroendocrine carcinoma of the colon with liver metastases

Resumen Los tumores neuroendocrinos del tubo digestivo son lesiones muy poco frecuentes. Se presenta el caso de una mujer de 57 años de edad que consulta por síndrome tóxico, vómitos y diarrea de 3 meses de evolución, con diagnóstico final de tumor neuroendocrino pobremente diferenciado. A partir de esta observación clínica se revisan las características clínicas y procedimientos diagnósticos, los factores pronósticos y las posibilidades terapéuticas en este tipo de tumores. Ante una tumoración colónica con metástasis hepáticas hiperecogénicas se debe considerar siempre el diagnóstico de tumor neuroendocrino (AU)

Abstract Neuroendocrine tumors of the gastrointestinal tract are highly infrequent. We report the case of a 57-year-old woman who presented with toxic syndrome, vomiting and a 3-month history diarrhea, with a final diagnosis of poorly-differentiated neuroendocrine tumor. Based on this case, we review the clinical characteristics, diagnostic procedures, prognostic factors and therapeutic possibilities in this type of tumor. Neuroendocrine tumors should be considered in the diagnosis of colonic tumors with hyperechoic liver metastases (AU)

[Poorly differentiated neuroendocrine carcinoma of the colon with liver metastases]. / Carcinoma neuroendocrino de colon poco diferenciado con metástasis hepáticas.

Neuroendocrine tumors of the gastrointestinal tract are highly infrequent. We report the case of a 57-year-old woman who presented with toxic syndrome, vomiting and a 3-month history diarrhea, with a final diagnosis of poorly-differentiated neuroendocrine tumor. Based on this case, we review the clinical characteristics, diagnostic procedures, prognostic factors and therapeutic possibilities in this type of tumor. Neuroendocrine tumors should be considered in the diagnosis of colonic tumors with hyperechoic liver metastases.

Fiebre prolongada e ictericia en un paciente con hepatopatía alcohólica / Prolonged fever and jaundice in a patient with alcoholic liver disease

Presentamos el caso clínico de un varón de 40 años con hepatopatía alcohólica de base que presenta fiebre prolongada, ictericia e insuficiencia hepática asociados a infección por Coxiella burnetti. Tras el diagnóstico y el tratamiento antibiótico adecuado el paciente se recuperó por completo. Se documenta el caso adecuadamente y, a propósito del mismo, se revisa de forma práctica la literatura y se discute la importancia de esta infección, y la necesidad de insistir en su inclusión en el diagnóstico diferencial ante a esta situación clínica (AU)

We report the case of a 40-year-old man with underlying alcoholic liver disease who presented with prolonged fever, jaundice and liver failure associated with Coxiella burnetii infection. After diagnosis and appropriate antibiotic treatment, the patient made a complete recovery. We describe aspects of this case and provide a practical review of the literature on the topic. We also discuss the importance of this infection and the need for its inclusion in the differential diagnosis of this clinical picture (AU)

[Prolonged fever and jaundice in a patient with alcoholic liver disease]. / Fiebre prolongada e ictericia en un paciente con hepatopatía alcohólica.

We report the case of a 40-year-old man with underlying alcoholic liver disease who presented with prolonged fever, jaundice and liver failure associated with Coxiella burnetii infection. After diagnosis and appropriate antibiotic treatment, the patient made a complete recovery. We describe aspects of this case and provide a practical review of the literature on the topic. We also discuss the importance of this infection and the need for its inclusion in the differential diagnosis of this clinical picture.

Effects of propranolol on venous compliance in conscious rats with pre-hepatic portal hypertension.

BACKGROUND/AIMS: The venous system is the primary capacitance region in the body. However, the influence of active changes in the venous system on the hemodynamic alterations of portal hypertension is poorly understood. To investigate venous compliance (VC) in conscious partial portal vein ligated rats (PPVL) and the effect of propranolol on VC. METHODS: Venous compliance was derived from the relationship between changes in mean circulatory filling pressure (MCFP) and changes in blood volume (BV). Measurements were performed before and after i.v. propranolol (7.5 mg/Kg) or placebo in rats with portal hypertension due to PPVL and sham operated controls. RESULTS: PPVL rats had an increased VC when compared to Sham (4.9+/-1.4 vs. 3.7+/-0.9 ml kg-1 mm Hg-1; P<0.02). VC did not change after placebo but was significantly reduced by Propranolol in PPVL (-32.9+/-15.7%; P<0,007). Propranolol did not modify venous compliance in sham operated rats (+10.9+/-13.4%; P=ns). CONCLUSIONS: Venous compliance is increased in portal hypertensive rats, suggesting that the venous system contributes to the profound circulatory changes encountered in portal hypertension. The increased venous compliance is markedly attenuated by propranolol, suggesting that this abnormality is related to increased adrenergic activity.

Total effective vascular compliance in patients with cirrhosis. Effects of propranolol.

BACKGROUND: Total effective vascular compliance (TEVC), may be increased in cirrhosis. However, its significance is unclear. AIMS: To investigate TEVC in patients with cirrhosis, and the effects of propranolol. METHODS: Seven patients without liver disease and 44 cirrhotic patients were studied before and after double-blind administration of propranolol (n=33) or placebo (n=11). MEASUREMENTS: TEVC (right atrial pressure response to rapid central volume expansion), hepatic venous pressure gradient (HVPG) and systemic hemodynamics. RESULTS: TEVC (ml x mmHg(-1) x kg(-1)) was increased in cirrhotics (1.67 +/- 0.66 versus 1.33 +/- 0.32 in controls; P<0.05). TEVC was not modified by placebo, but was markedly reduced by propranolol (from 1.74 +/- 0.75 to 1.33 +/- 0.56; P<0.01). Propranolol decreased HVPG >10% in 20 patients ('responders': -20 +/- 9%) but <10% in 13 'non-responders'. TEVC was normalized by propranolol in HVPG 'responders' (from 1.76 +/- 0.88 to 1.21 +/- 0.51; P<0.01), but not in 'non-responders' (1.69 +/- 0.48 to 1.52 +/- 0.59; NS). Reduction of TEVC in responders was accompanied by increased free hepatic vein pressure (+21 +/- 20%, P=0.05; approximately 60% of the fall in HVPG), which was not observed in non-responders (+3 +/- 11%, NS). CONCLUSIONS: TEVC is increased in cirrhosis. This abnormality is corrected by propranolol in patients exhibiting a >10% fall in HVPG, suggesting that changes in vascular compliance may influence the portal pressure response to propranolol.