Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats.

BACKGROUND & AIMS: In advanced cirrhosis, gut bacterial translocation is the consequence of intestinal barrier disruption and leads to bacterial infection. Bile acid abnormalities in cirrhosis could play a role in the integrity of the intestinal barrier and the control of microbiota, mainly through the farnesoid X receptor. We investigated the long-term effects of the farnesoid X receptor agonist, obeticholic acid, on gut bacterial translocation, intestinal microbiota composition, barrier integrity and inflammation in rats with CCl4-induced cirrhosis with ascites. METHODS: Cirrhotic rats received a 2-week course of obeticholic acid or vehicle starting once ascites developed. We then determined: bacterial translocation by mesenteric lymph node culture, ileum expression of antimicrobial peptides and tight junction proteins by qPCR, fecal albumin loss, enteric bacterial load and microbiota composition by qPCR and pyrosequencing of ileum mucosa-attached contents, and intestinal inflammation by cytometry of the inflammatory infiltrate. RESULTS: Obeticholic acid reduced bacterial translocation from 78.3% to 33.3% (p<0.01) and upregulated the expression of the farnesoid X receptor-associated gene small heterodimer partner. Treatment improved ileum expression of antimicrobial peptides, angiogenin-1 and alpha-5-defensin, tight junction proteins zonulin-1 and occludin, and reduced fecal albumin loss and liver fibrosis. Enteric bacterial load normalized, and the distinctive mucosal microbiota of cirrhosis was reduced. Gut immune cell infiltration was reduced and inflammatory cytokine and Toll-like receptor 4 expression normalized. CONCLUSIONS: In ascitic cirrhotic rats, obeticholic acid reduces gut bacterial translocation via several complementary mechanisms at the intestinal level. This agent could be used as an alternative to antibiotics to prevent bacterial infection in cirrhosis.

Leprosy in Spain: A Descriptive Study of Admissions at Fontilles Sanatorium between 1909 and 2020.

BACKGROUND: The study aimed to characterize patients with leprosy admitted to Fontilles throughout the 20th and 21st centuries, focusing on differences across three periods (I, II, and III). It also explored variables linked to patient survival. METHODS: This was a retrospective descriptive study analyzing the medical records of Fontilles patients from 1909 to 2020. It assessed 26 clinical, sociodemographic, and temporal variables (n = 2652). RESULTS: Most patients were male, single, multibacillary (MB), and farmers, from Andalusia and the Valencian Community. The origin of patients shifted over time towards being mostly foreign-born in period III. More than a half were previously admitted and had family members with leprosy. While leprosy reactions decreased over time, neurological symptoms were increasingly diagnosed. The age at onset, admission, and death increased progressively over time. The survival of patients with leprosy at Fontilles depended on the age at admission and the period. CONCLUSIONS: Improved knowledge, services, and awareness regarding leprosy led to increased age at onset and more favorable outcomes. The prolonged time between symptom onset and diagnosis indicates that leprosy is still a neglected disease. Although MB forms are more severe, leprosy classification did not significantly impact the survival rates of patients at Fontilles.

Critical role of the liver in the induction of systemic inflammation in rats with preascitic cirrhosis.

UNLABELLED: Systemic activation of the inflammatory immune system contributes to the progression of cirrhosis with ascites. Immune cells become activated after interacting at the mesenteric lymph nodes (MLNs) with bacteria translocated from the gut, and thereafter reach the bloodstream through recirculation. It is unknown whether systemic activation of the immune system is present in pre-ascitic cirrhosis, in which gut bacterial translocation has not been described. The purpose of this study was to determine whether systemic activation of the immune system initiates in rats with compensated carbon tetrachloride (CCl(4))-induced cirrhosis, and if so to establish the activation site of immune cells. We studied the activation status of immune cells in peripheral blood, MLNs, and hepatic lymph nodes (HLNs). Systemic inflammation was present in rats with cirrhosis, as shown by expansion (P < 0.01) of circulating total and inflammatory monocytes and recently activated CD134(+) T helper (T(h)) cells. The same populations of cells were increased (P < 0.01) in MLNs and HLNs. Bacterial translocation was absent in rats with cirrhosis or control rats, but bacterial DNA fragments were present in the MLNs of 54% of rats with cirrhosis. The liver was the source of activated immune cells present in the blood, as shown by the direct correlation between activated T(h) cells in the blood and HLNs, but not in MLNs, and the normalization by gut decontamination with antibiotics of activated cells in MLNs, but not in the blood or HLNs. CONCLUSION: In experimental cirrhosis, systemic activation of the immune system occurs before ascites development and is driven by recirculation of cells activated in HLNs. In addition, in compensated cirrhosis, bacterial DNA fragments reach the MLNs, where they elicit a local inflammatory response.

The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis.

BACKGROUND: An inflammatory immune system response ensues in the liver and in the systemic circulation in cirrhosis, where it contributes to hepatic fibrosis and peripheral vasodilation. Modulation of the inflammatory response without increasing susceptibility to infection is a therapeutic target in cirrhosis. AM3 is a low-toxicity biological response modifier with regulatory effects on innate and adaptative immunity, and the ability to normalise the production of tumour necrosis factor alpha (TNFalpha). AIMS: This was an experimental study to investigate the effects of oral AM3 on the systemic and hepatic inflammatory response, liver fibrosis and on the haemodynamic abnormalities of portal hypertension in rats with biliary cirrhosis. DESIGN: Bile-duct ligated rats received a 3-week oral course of AM3 or placebo. RESULTS: In cirrhotic rats, AM3 blunted the inflammatory switch of circulating and intrahepatic monocytes and T-cells to TNFalpha and interferon gamma (IFNgamma) production, respectively. AM3 modified the intrahepatic polarisation pattern of the regulatory cytokines, decreasing the mRNA expression of transforming growth factor beta1 (TGFbeta1), interleukin 4 (IL4), and IFNgamma, and increasing that of IL10. Total and IFNgamma-producing natural killer (NK) cells were lowered by AM3 in the peripheral blood and liver of cirrhotic rats. The immunomodulatory effects of AM3 led to reduced hepatic fibrogenesis in cirrhotic rats, as shown by decreased area of liver fibrosis, hydroxyproline content and mRNA expression of procollagen alpha1(I). Besides, AM3 lowered portal pressure and systemic hyperaemia. CONCLUSIONS: The biological response modifier AM3 reverses the concurrent inflammatory immune system activation in peripheral blood and liver of experimental established cirrhosis, which results in reductions of hepatic fibrosis, portal pressure and peripheral vasodilation.

Preliminary Evidence of Rickettsia slovaca and Rickettsia conorii Infection in the Sera of Sheep, Dogs and Deer from an Area of Northern Spain.

Limited information is available on the presence of rickettsial infection in animal reservoirs in Spain. Antibodies against Rickettsia slovaca and Rickettsia conorii were therefore sought in the sera of farm, domestic and wild animals (n = 223 samples) in an area of northern Spain. Indirect immunofluorescence assays showed: (A) 17/120 and 16/120 (14.2% and 13.3%) of serum samples from sheep (farm animals) reacted with R. slovaca and R. conorii antigens, respectively; (B) 10/73 and 10/73 (13.7% and 13.7%) of samples from dogs (domestic animals) did the same; (C) as did 22/30 and 20/30 (73.3% and 66.6%) of samples from deer (wild animals) (overall titre range: 1/40 to 1/1280). The prevalence of both types of infection was significantly greater in the wild animals than either the farm or domestic animals. The largest titres were recorded for R. slovaca in all three groups.

Epidemiological Study of Thogoto and Dhori Virus Infection in People Bitten by Ticks, and in Sheep, in an Area of Northern Spain.

There is little information on Thogoto virus (THOV) and Dhori virus (DHOV)infection in Spain. A total of 283 serum samples from 150 human subjects (78 males, 72 females) bitten by ticks, as well as samples from 120 sheep (one per animal), were studied by immunofluorescence assay. All human and animal subjects were from the province of Palencia in northern Spain. Eight human subjects had antibodies against THOV (seroprevalence: 5.3%) and six had antibodies against DHOV (seroprevalence: 4%); titers ranged between 1/32-1/256 and 1/32-1/128, respectively. No significant differences were seen in seroprevalence in terms of gender or age, although people with antibodies were significantly more likely to have had contact with livestock for professional reasons. One subject with an acute infection had IgM antibodies to both viruses and seroconverted to IgG. For the sheep, 24 serum samples were positive for antibodies to THOV (seroprevalence: 20%) and 32 for antibodies to DHOV (seroprevalence: 26.8%); titers ranged between 1/16 and 1/128. The seroprevalence of both viruses was significantly higher in animals < 4 years of age. Together, these results reveal the circulation of DHOV and THOV in humans and sheep in the province of Palencia. Sheep might be used as indicators of the presence of these organisms.

Wild Red Foxes (Vulpes vulpes) as Sentinels of Rodent-Borne Hantavirus and Lymphocytic Choriomeningitis Virus in the Province of Soria, Northern Spain.

Three hundred and fourteen red foxes (Vulpes vulpes) in the province of Soria, Spain, were examined for hantavirus and lymphocytic choriomeningitis virus (LCMV) infection (and were likely to have been infected by feeding on infected rodents). Immunofluorescence and western blot assays confirmed 3.5% (11/314) to have antibodies to hantaviruses, and the immune fluorescence assay showed 2.2% (7/314) to have antibodies to LCMV. The serologic status of the animals showed no statistically significant association with sex or age. Although studies on the prevalence of hantaviruses and LCMV normally focus on rodents, our results showed that foxes can provide complementary information in determined areas.

Independent lineage of lymphocytic choriomeningitis virus in wood mice (Apodemus sylvaticus), Spain.

To clarify the presence of lymphocytic choriomeningitis virus (LCMV) in Spain, we examined blood and tissue specimens from 866 small mammals. LCMV RNA was detected in 3 of 694 wood mice (Apodemus sylvaticus). Phylogenetic analyses suggest that the strains constitute a new evolutionary lineage. LCMV antibodies were detected in 4 of 10 rodent species tested.

Screening of Forestry Workers in Guadalajara Province (Spain) for Antibodies to Lymphocytic Choriomeningitis Virus, Hantavirus, Rickettsia spp. and Borrelia burgdorferi.

Exposure to Lymphocytic choriomeningitis virus (LCMV), hantaviruses, Rickettsia spp. and Borrelia burgdorferi among forestry workers from a province in central Spain (Guadalajara) was examined by serological screening. This is the first such study in this rural area, where people often live and work in proximity to domestic and wild animals. Immunofluorescent analyses of the serum of 100 forestry workers detected IgG antibodies to LCMV in 2% (CL 95% 0.55%-7.0%) of this population, to hantaviruses in 4% (CL 95% 1.6%-8.3%) for the serum amyloid A (SAA) serotype, and 2% (CL 95% 0.55%-7.0%) for the Seoul virus (SEO) serotype (samples also positive for SAA), to Rickettsia in 8% (CL 95% 4.1%-15%) (3% (CL 95% 1.0%-8.5%) for R. typhi and 5% (CL 95% 2.2%-11.2%) for R. slovaca, and to B. burgdorferi in 7% (CL 95% 3.4%-13.8%). The number of people who have been exposed to these organisms is commonly underestimated since most infections are asymptomatic. Greater epidemiological surveillance may therefore be recommended.

Prevalence of anti-hantavirus antibodies in patients with hypertransaminemia in Madrid (Spain).

The hantaviruses are involved in a number of clinical syndromes of different severity and prognosis. Hantaviruses are widely distributed around the world, but the spectrum of illnesses they cause outside recognized endemic areas is unclear. A retrospective analysis was performed to detect anti-hantavirus antibodies in the serum of patients with hypertransaminemia of unknown etiology and in that of healthy members of the general population of Madrid (Spain). Antibodies were detected by indirect immunofluorescence and enzyme immunoassay; positive results were confirmed by Western blotting. Of the 182 patients with hypertransaminemia, 11 (6%) were positive for anti-hantavirus IgG antibodies; Western blotting using recombinant Puumala virus N antigen showed one of these patients to have hantavirus-specific IgM antibodies. Among the 146 healthy subjects from the general population, 3 (2%) were positive for anti-hantavirus IgG antibodies. These results show that anti-hantavirus antibodies are more commonly detected in patients with hypertransaminemia than in healthy people.

Antibodies to Rickettsia spp. and Borrelia burgdorferi in Spanish Wild Red Foxes (Vulpes vulpes).

We examined 314 red foxes (Vulpes vulpes) from the province of Soria, Spain, for Rickettsia typhi, Rickettsia slovaca, and Borrelia burgdorferi infection. Immunofluorescence assays showed 1.9% had antibodies to R. typhi, 6.7% had antibodies to R. slovaca, and 8.3% had antibodies to B. burgdorferi. Serostatus was not correlated with sex or age. Because red foxes can be infected by Rickettsiae and B. burgdorferi, presence of red foxes may be and indicator for the presence of these pathogens.

Wild Red Foxes (Vulpes vulpes) as Sentinels of Parasitic Diseases in the Province of Soria, Northern Spain.

Four hundred red foxes (Vulpes vulpes) were examined for ecto- (arthropods) and endoparasites (Leishmania spp., Trichinella spp., and intestinal parasites). Different species of flea (total prevalence, 40.50%), tick (16.25%), mite (7.25%), and fly (1.50%) were identified. The most prevalent flea was Pulex irritans (found on 29% of the foxes); the most prevalent tick, mite, and fly were Ixodes canisuga (on 5%), Sarcoptes scabiei (on 5.25%), and Hippobosca equina (on 1%), respectively. The endoparasites identified included Leishmania spp. (found in 12% of the foxes), Trichinella spp. (in 15.5%, with T. britovi the most prevalent species in 15.25%), Cestoda (in 72.75%, with Mesocestoides spp. the most prevalent in 69.50%), and intestinal ascarids (in 73.25%, with Ancylostoma caninum the most prevalent in 12.50%). No animal was free of parasites. The present results suggest that foxes can act as sentinels of diseases transmitted by ecto- and endoparasites.

Hantavirus infections in Spain: analysis of sera from the general population and from patients with pneumonia, renal disease and hepatitis.

BACKGROUND: Hantaviruses are rodent borne viruses in the family Bunyaviridae that cause significant morbidity in large areas of Europe. There are only a few reports available on hantavirus infections from Spain. Although the results of these earlier studies indicated the presence of hantavirus infections, no confirmative or serotype-specific analyses have been performed. OBJECTIVES: To investigate whether hantaviruses cause human infection/disease in Spain. STUDY DESIGN: Ten thousand, four hundred and eighteen serum samples from the general population and 599 sera from 492 patients with potential hantavirus infections (renal disease, pneumonia or hepatitis) were initially screened by immunofluorescence assay (IFA) using Hantaan, Seoul and Puumala hantavirus antigens. Altogether 193 suspicious samples (165 from healthy people and 28 from patients) were selected for confirmation by quality-assured assays. RESULTS AND CONCLUSIONS: Of the 165 pre-screened serum samples from healthy individuals, only five could be confirmed by IFA for hantavirus-reactive antibodies (using Dobrava, Saaremaa, Hantaan or Puumala virus antigens). In addition, one serum was found weakly positive for hantavirus-reactive IgG by ELISA using recombinant Saaremaa virus (SAAV) nucleocapsid (N) antigen, and subsequently confirmed by immunoblotting. Thus, the results indicated a low (0.06%) total antibody prevalence to hantaviruses in Spain. Of 28 pre-screened serum samples from hospitalized patients, eight reacted as positive or showed border-line reactivities for hantavirus-specific IgM by ELISA using recombinant Saaremaa and Puumala virus N antigens. The IFA/ELISA reactive/border-line samples were subsequently analyzed by a focus reduction neutralization test, which revealed low titers (1:80) against SAAV in two samples from a patient with hepatic disease. The nature of the hantavirus(es) potentially involved remain, however, unknown, since none of the positive samples showed neutralizing titers of the expected range to any of the known European hantaviruses.

Molecular and serological study of rickettsial infection in humans, and in wild and farm animals, in the province of Burgos, Spain.

Limited information is available on the presence of rickettsial infection in humans and animal reservoirs in Spain. Exposure to spotted fever group rickettsia in healthy humans and in farm and wild animals in the Province of Burgos, Spain, was examined by serological methods. Rickettsial DNA was also sought by PCR in animal samples. Of 102 human serum samples examined by indirect immunofluorescence assays (IFA), 5.88% were positive for antibodies against Rickettsia conorii (titers 1/128-1/512). Significant differences were detected in human seroprevalence with respect to age. In further IFAs, 102 out of 375 (27.2%) serum samples from the wild animals reacted with R. conorii antigens (titers 1/64-1/1024); 32 out of 281 (11.38%) samples from farm animals were also positive for R. conorii (titers 1/64-1/2048). The prevalence detected among total wild animals was significantly higher than among total farm animals. No rickettsial DNA was found by PCR in any farm or wild animal sample.

A seventeen-year epidemiological surveillance study of Borrelia burgdorferi infections in two provinces of northern Spain.

This paper reports a 17-year seroepidemiological surveillance study of Borrelia burgdorferi infection, performed with the aim of improving our knowledge of the epidemiology of this pathogen. Serum samples (1,179) from patients (623, stratified with respect to age, sex, season, area of residence and occupation) bitten by ticks in two regions of northern Spain were IFA-tested for B. burgdorferi antibodies. Positive results were confirmed by western blotting. Antibodies specific for B. burgdorferi were found in 13.3% of the patients; 7.8% were IgM positive, 9.6% were IgG positive, and 4.33% were both IgM and IgG positive. Five species of ticks were identified in the seropositive patients: Dermacentor marginatus (41.17% of such patients) Dermacentor reticulatus (11.76%), Rhiphicephalus sanguineus (17.64%), Rhiphicephalus turanicus (5.88%) and Ixodes ricinus (23.52%). B. burgdorferi DNA was sought by PCR in ticks when available. One tick, a D. reticulatus male, was found carrying the pathogen. The seroprevalence found was similar to the previously demonstrated in similar studies in Spain and other European countries.

Seroepidemiological survey of hantavirus infection in healthy people in Vallès Occidental, Barcelona.

INTRODUCTION: Hantaviruses are the etiological agents of hemorrhagic fever with renal syndrome in Europe and Asia, and hantavirus pulmonary syndrome in America. Approximately 150,000 cases are reported annually worldwide. In Spain, some hantavirus infection cases have been described. Besides, rodents that have been described as hantavirus reservoirs are present. The aim of the present study was to determinate the seroprevalence of hantavirus in humans in the northeast of Spain. MATERIALS AND METHODS: During a 5-month period, 217 serum samples were collected. The study population was stratified by age, gender, and residential area. Age, gender, residential area, contact with pets, contact with wild animals, contact with farm animals, and occupation were surveyed. Immunoglobulin G antibodies to Hantaan virus, Seoul virus, or Puumala virus were examined by immunofluorescence assay. Titles ≥1/32 against any of the hantavirus were considered positive. RESULTS: Four (1.8%) positive samples were detected. Age ranged from 14 to 67 years. Two subjects were male. Three samples reacted to both Puumala virus and Hantaan virus. The other one reacted against all three hantavirus surveyed. Titles ranged from 32 to 1024. The highest titles were found against Seoul virus. CONCLUSIONS: Our data show serological evidence about hantavirus infection among population of Catalonia, northeast of Spain. Seroprevalence rate was (around 2%) similar to other regions of Spain.

Molecular detection of hemoprotozoa and Rickettsia species in arthropods collected from wild animals in the Burgos Province, Spain.

Limited information on the presence of bacterial and hematozoan infections in parasitic arthropods from Spain is available. In an attempt to address this issue, the prevalence of Theileria, Babesia, Hepatozoon, and Rickettsia species was investigated by polymerase chain reaction plus sequencing. In a survey for zoonotic pathogens in ectoparasites, 42 wild animals (which included rodents, carnivores, Sciuridae, and Cervidae) were captured in Burgos (Spain). A total of 256 arthropods (including 107 ticks, 76 fleas, and 73 mites) were collected from these mammals. Molecular diagnostic results showed that (i) Rickettsia felis was found in fleas (two Ctenocephalides felis), (ii) Hepatozoon sp. infected some fleas (two Ctenophtalmus sp. and a DNA pool of Ceratophyllus sciurorum) and Acari (one Neotrombicula sp.), and (iii) Theileria annae was found in Ixodes ricinus and I. hexagonus (each a single infected specimen). All microorganisms and parasites were genetically identical to pathogens already described in Spain or elsewhere. Infected arthropods were recovered from beech marten, bank vole, squirrel, wood mouse, and red fox. Our findings emphasize the potential risk for transmission of rickettsias to humans (namely, R. felis) in Burgos, since C. felis is capable to seek out humans for feeding. No hemoprotozoa with proven significance as human pathogens were found in the survey. However, finding T. annae in ticks recovered from wild canids suggests possible links of sylvatic and domestic cycles for some Piroplasmida.

Epidemiological study of rickettsial infections in patients with hypertransaminemia in Madrid (Spain).

A retrospective analysis was performed to detect anti-rickettsial antibodies in the serum of patients with hypertransaminemia of unknown etiology, and in that of healthy members of the general population of Madrid (Spain). Among 143 patients 16 (11.2%) were positive for anti-R. conorii IgG antibodies and 7% for R. typhi. PCR analysis was performed in patients with IgM antibodies. Among 143 healthy subjects from the general population, seven (4.9%) were positive for anti-R. conorii IgG antibodies, and 2.8% for R. typhi. These results show that anti-rickettsial antibodies are more commonly detected in patients with hypertransaminemia than in healthy people.

[Infection due to Hantavirus and other rodent-borne viruses]. / Infección por hantavirus y otros virus transmitidos por roedores.

The term "robovirus" (rodent-borne virus) refers to viruses belonging to the Bunyaviridae (genus Hantavirus) and Arenaviridae families, which are occasionally transmitted to human beings from rodents, their natural hosts. Hantaviruses cause two human diseases: hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. Arenaviruses produce hemorrhagic fevers or acute central nervous system disease in humans. This article reviews the biology, epidemiology, pathogenesis, clinical features, diagnostic methods, treatment and prevention of hantavirus and, more concisely, arenavirus infections.