An integrated in-silico approach for drug target identification in human pathogen Shigella dysenteriae.

Shigella dysenteriae, is a Gram-negative bacterium that emerged as the second most significant cause of bacillary dysentery. Antibiotic treatment is vital in lowering Shigella infection rates, yet the growing global resistance to broad-spectrum antibiotics poses a significant challenge. The persistent multidrug resistance of S. dysenteriae complicates its management and control. Hence, there is an urgent requirement to discover novel therapeutic targets and potent medications to prevent and treat this disease. Therefore, the integration of bioinformatics methods such as subtractive and comparative analysis provides a pathway to compute the pan-genome of S. dysenteriae. In our study, we analysed a dataset comprising 27 whole genomes. The S. dysenteriae strain SD197 was used as the reference for determining the core genome. Initially, our focus was directed towards the identification of the proteome of the core genome. Moreover, several filters were applied to the core genome, including assessments for non-host homology, protein essentiality, and virulence, in order to prioritize potential drug targets. Among these targets were Integration host factor subunit alpha and Tyrosine recombinase XerC. Furthermore, four drug-like compounds showing potential inhibitory effects against both target proteins were identified. Subsequently, molecular docking analysis was conducted involving these targets and the compounds. This initial study provides the list of novel targets against S. dysenteriae. Conclusively, future in vitro investigations could validate our in-silico findings and uncover potential therapeutic drugs for combating bacillary dysentery infection.

Identification of vaccine and drug targets in Shigella dysenteriae sd197 using reverse vaccinology approach.

Shigellosis is characterized as diarrheal disease that causes a high mortality rate especially in children, elderly and immunocompromised patients. More recently, the World Health Organization advised safe vaccine designing against shigellosis due to the emergence of Shigella dysenteriae resistant strains. Therefore, the aim of this study is to identify novel drug targets as well as the design of the potential vaccine candidates and chimeric vaccine models against Shigella dysenteriae. A computational based Reverse Vaccinology along with subtractive genomics analysis is one of the robust approaches used for the prioritization of drug targets and vaccine candidates through direct screening of genome sequence assemblies. Herein, a successfully designed peptide-based novel highly antigenic chimeric vaccine candidate against Shigella dysenteriae sd197 strain is proposed. The study resulted in six epitopes from outer membrane WP_000188255.1 (Fe (3+) dicitrate transport protein FecA) that ultimately leads to the construction of twelve vaccine models. Moreover, V9 construct was found to be highly immunogenic, non-toxic, non-allergenic, highly antigenic, and most stable in terms of molecular docking and simulation studies against six HLAs and TLRS/MD complex. So far, this protein and multiepitope have never been characterized as vaccine targets against Shigella dysenteriae. The current study proposed that V9 could be a significant vaccine candidate against shigellosis and to ascertain that further experiments may be applied by the scientific community focused on shigellosis.

Evaluation of the Anti-Shigellosis Activity of Dietary Isothiocyanates in Galleria mellonella Larvae.

Cruciferous vegetables, widely present in daily diets, are a rich source of organosulfur compounds with proven health benefits, especially chemopreventive or antioxidative effects. Isothiocyanate derivatives (ITCs) exhibit a broad spectrum of biological and pharmacological activity and recently, their antibacterial properties have been of particular importance. Here, we have focused on the anti-shigellosis activity of sulforaphane (SFN) and phenethyl ITC (PEITC). The genus Shigella causes gastroenteritis in humans, which constitutes a threat to public health. Production of a potent Stx toxin by S. dysenteriae type 1 results not only in more severe symptoms but also in serious sequela, including the hemolytic uremic syndrome. Here, we present evidence that two aliphatic and aromatic ITCs derivatives, SFN and PEITC, have an effective antibacterial potency against S. dysenteriae, also negatively regulating the stx gene expression. The molecular mechanism of this effect involves induction of the global stress-induced stringent response. ITCs also inhibit bacterial virulence against the Vero and HeLa cells. We present evidence for the therapeutic effect of sulforaphane and phenethyl ITC against a S. dysenteriae infection in the Galleria mellonella larvae model. Thus, our results indicate that isothiocyanates can be effectively used to combat dangerous bacterial infections.

The heme-binding protein PhuS transcriptionally regulates the Pseudomonas aeruginosa tandem sRNA prrF1,F2 locus.

Pseudomonas aeruginosa is an opportunistic pathogen requiring iron for its survival and virulence. P. aeruginosa can acquire iron from heme via the nonredundant heme assimilation system and Pseudomonas heme uptake (Phu) systems. Heme transported by either the heme assimilation system or Phu system is sequestered by the cytoplasmic protein PhuS. Furthermore, PhuS has been shown to specifically transfer heme to the iron-regulated heme oxygenase HemO. As the PhuS homolog ShuS from Shigella dysenteriae was observed to bind DNA as a function of its heme status, we sought to further determine if PhuS, in addition to its role in regulating heme flux through HemO, functions as a DNA-binding protein. Herein, through a combination of chromatin immunoprecipitation-PCR, EMSA, and fluorescence anisotropy, we show that apo-PhuS but not holo-PhuS binds upstream of the tandem iron-responsive sRNAs prrF1,F2. Previous studies have shown the PrrF sRNAs are required for sparing iron for essential proteins during iron starvation. Furthermore, under certain conditions, a heme-dependent read through of the prrF1 terminator yields the longer PrrH transcript. Quantitative PCR analysis of P. aeruginosa WT and ΔphuS strains shows that loss of PhuS abrogates the heme-dependent regulation of PrrF and PrrH levels. Taken together, our data show that PhuS, in addition to its role in extracellular heme metabolism, also functions as a transcriptional regulator by modulating PrrF and PrrH levels in response to heme. This dual function of PhuS is central to integrating extracellular heme utilization into the PrrF/PrrH sRNA regulatory network that is critical for P. aeruginosa adaptation and virulence within the host.

Epidemic and molecular characterization of fluoroquinolone-resistant Shigella dysenteriae 1 isolates from calves with diarrhea.

BACKGROUND: The widespread distribution of antimicrobial-resistant Shigella has become a recurrent challenge in many parts of the developing world. Previous studies indicate that the host of Shigella has expanded from humans to animals. This study aimed to investigate the prevalence of fluoroquinolone resistance and associated molecular characterization of S. dysenteriae 1 isolated from calves. RESULTS: All 38 unduplicated S. dysenteriae 1 isolates were collected from calves in Gansu Province from October 2014 to December 2016. According to MLST and PFGE analysis, these isolates were separated into 4 and 28 genotypes, respectively. The most common STs identified were ST228 (34.21%, 13/38) and ST229 (39.47%, 15/38), which were first found in the present study. All isolates harbored virulence genes, and the incidence of the seven virulence genes were ipaH (100%), ipaBCD (92.11%), stx (73.68%), ial (57.89%), sen (28.95%), set1A and set1B (0%). According to the results of antimicrobial susceptibilities, 76.32% (29/38) were resistant to fluoroquinolone and showed multidrug resistance. In a study on the polymorphism of quinolone resistance-determining region (QRDR) of gyrA/B and parC/E genes, we identified two mutations in gyrA (Ser83 → Leu and Asp87 → Asn) and parC (Ser80 → Ile and Ser83 → Leu), respectively. Among them, 55.17% (16/29) of resistant strains had the gyrA point mutations (Ser83 → Leu) and parC point mutation (Ser83 → Leu). Moreover, 41.38% (12/29) of isolates had all five point mutations of gyrA and parC. In addition, the prevalence of the plasmid-mediated quinolone resistance (PMQR) determinant genes was also investigated. All 29 fluoroquinolone-resistant isolates were positive for the aac (6')-Ib-cr gene but negative for qepA, except for SD001. In addition, only 6 (20.69%, 6/29) isolates harbored the qnr gene, including two with qnrB (6.90%, 2/29) and four with qnrS (13.79%, 4/29). CONCLUSION: Given the increased common emergence of multidrug resistant isolates, uninterrupted surveillance will be necessary to understand the actual epidemic burden and control this infection.

Impact of insertion sequences on convergent evolution of Shigella species.

Shigella species are specialised lineages of Escherichia coli that have converged to become human-adapted and cause dysentery by invading human gut epithelial cells. Most studies of Shigella evolution have been restricted to comparisons of single representatives of each species; and population genomic studies of individual Shigella species have focused on genomic variation caused by single nucleotide variants and ignored the contribution of insertion sequences (IS) which are highly prevalent in Shigella genomes. Here, we investigate the distribution and evolutionary dynamics of IS within populations of Shigella dysenteriae Sd1, Shigella sonnei and Shigella flexneri. We find that five IS (IS1, IS2, IS4, IS600 and IS911) have undergone expansion in all Shigella species, creating substantial strain-to-strain variation within each population and contributing to convergent patterns of functional gene loss within and between species. We find that IS expansion and genome degradation are most advanced in S. dysenteriae and least advanced in S. sonnei; and using genome-scale models of metabolism we show that Shigella species display convergent loss of core E. coli metabolic capabilities, with S. sonnei and S. flexneri following a similar trajectory of metabolic streamlining to that of S. dysenteriae. This study highlights the importance of IS to the evolution of Shigella and provides a framework for the investigation of IS dynamics and metabolic reduction in other bacterial species.

Regulation of OmpA Translation and Shigella dysenteriae Virulence by an RNA Thermometer.

RNA thermometers are cis-acting riboregulators that mediate the posttranscriptional regulation of gene expression in response to environmental temperature. Such regulation is conferred by temperature-responsive structural changes within the RNA thermometer that directly result in differential ribosomal binding to the regulated transcript. The significance of RNA thermometers in controlling bacterial physiology and pathogenesis is becoming increasingly clear. This study combines in silico, molecular genetics, and biochemical analyses to characterize both the structure and function of a newly identified RNA thermometer within the ompA transcript of Shigella dysenteriae First identified by in silico structural predictions, genetic analyses have demonstrated that the ompA RNA thermometer is a functional riboregulator sufficient to confer posttranscriptional temperature-dependent regulation, with optimal expression observed at the host-associated temperature of 37°C. Structural studies and ribosomal binding analyses have revealed both increased exposure of the ribosomal binding site and increased ribosomal binding to the ompA transcript at permissive temperatures. The introduction of site-specific mutations predicted to alter the temperature responsiveness of the ompA RNA thermometer has predictable consequences for both the structure and function of the regulatory element. Finally, in vitro tissue culture-based analyses implicate the ompA RNA thermometer as a bona fide S. dysenteriae virulence factor in this bacterial pathogen. Given that ompA is highly conserved among Gram-negative pathogens, these studies not only provide insight into the significance of riboregulation in controlling Shigella virulence, but they also have the potential to facilitate further understanding of the physiology and/or pathogenesis of a wide range of bacterial species.

Immunological detection assays for recombinant Shiga toxin & Shigella dysenteriae.

Background & objectives: : Shiga toxin (Stx) is produced by Shigella dysenteriae, a Gram-negative, facultative anaerobic bacillus that causes shigellosis, haemolytic uraemic syndrome (HUS) and Reiter's syndrome. The detection methods for shiga toxin needs to be rapid, accurate, reliable and must be extensively evaluated under field conditions. The aim of this study was to develop rapid, sensitive and specific detection method for Stx. Methods: : Mice and rabbits were immunized with purified recombinant Shiga toxin B (rStxB). Using these antibodies dot ELISA, sandwich ELISA and flow through assay were developed. Results: : The high-titre antibodies specifically reacted with purified rStxB. Dot-ELISA, sandwich ELISA and flow-through assay were developed and standardized that could detect StxB with limit of detection (LOD) of 9.75, 9.7 ng/ml and 0.46 µg/cassette, respectively. Interpretation & conclusions: : The rStxB was used to produce antibodies to avoid handling of pathogen. The Flow through assay 'developed was specific, rapid and field amenable.

Isolation, characterization, and PCR-based molecular identification of a siphoviridae phage infecting Shigella dysenteriae.

BACKGROUND: Shigella dysenteriae is one of the members of Shigella genus which was the main responsible of different Shigellosis outbreaks worldwide. The increasing consumption of antibiotics has led to the emergence and spreading of antibiotic-resistant strains. Therefore, finding new alternatives for infection control is essential, one of which is using bacteriophages. MATERIALS AND METHODS: Lytic bacteriophage against Shigella dysenteriae was isolated from petroleum refinery wastewater. Phage morphological and genetic characteristics were studied using TEM, and sequencing, respectively. In addition, the genome size was estimated, and phage resistance to different temperatures and pH, host range, adsorption rate, and one-step growth were investigated. RESULTS: According to the morphology and genetic results, this phage was named vB-SdyS-ISF003. Sequencing of the PCR products revealed that the vB-SdyS-ISF003 phage belongs to the species T1virus, subfamily Tunavirinae of family Siphoviridae. This was the first detected bacteriophage against S. dysenteriae, which belongs to the family Siphoviridae. In addition, its host range was limited to S. dysenteriae. The genome size was about 62 kb. vB-SdyS-ISF003 phage has a number of desirable characteristics including the limited host range to S. dysenteriae, very short connection time, a relatively wide range of temperature tolerance -20 to 50 °C, pH tolerance of 7-9 without significant reduction in the phage titer. CONCLUSION: vB-SdyS-ISF003 is a novel virulent T1virus phage and has the appropriate potential for being used in bio controlling of S. dysenteriae in different condition.

Experimental In Vivo Models of Bacterial Shiga Toxin-Associated Hemolytic Uremic Syndrome.

Shiga toxins (Stxs) are the main virulence factors expressed by the pathogenic Stx-producing bacteria, namely, Shigella dysenteriae serotype 1 and certain Escherichia coli strains. These bacteria cause widespread outbreaks of bloody diarrhea (hemorrhagic colitis) that in severe cases can progress to life-threatening systemic complications, including hemolytic uremic syndrome (HUS) characterized by the acute onset of microangiopathic hemolytic anemia and kidney dysfunction. Shiga toxicosis has a distinct pathogenesis and animal models of Stx-associated HUS have allowed us to investigate this. Since these models will also be useful for developing effective countermeasures to Stx-associated HUS, it is important to have clinically relevant animal models of this disease. Multiple studies over the last few decades have shown that mice injected with purified Stxs develop some of the pathophysiological features seen in HUS patients infected with the Stx-producing bacteria. These features are also efficiently recapitulated in a non-human primate model (baboons). In addition, rats, calves, chicks, piglets, and rabbits have been used as models to study symptoms of HUS that are characteristic of each animal. These models have been very useful for testing hypotheses about how Stx induces HUS and its neurological sequelae. In this review, we describe in detail the current knowledge about the most well-studied in vivo models of Stx-induced HUS; namely, those in mice, piglets, non-human primates, and rabbits. The aim of this review is to show how each human clinical outcome-mimicking animal model can serve as an experimental tool to promote our understanding of Stx-induced pathogenesis.

Adaptations in the physiological heterogeneity and viability of Shigella dysenteriae, Shigella flexneri and Salmonella typhimurium, after exposure to simulated gastric acid fluid.

Stomach acidity is an important barrier of the human body to protect itself from microbial pathogens entering the small intestine and causing infection. This study examined the survival adaptations of non-acid adapted diarrheal Shigella and Salmonella strains in an environment mimicking the human stomach. The bacterial responses to the challenge of acidic simulated gastric fluid were studied using flow cytometry physiological heterogeneity, membrane integrity and survival (culturability) respectively. Flow cytometry showed that bacterial cells, when exposed to gastric fluid, transformed distinctly, into physiologically heterogeneous sub-populations: intact, stressed and damaged cells, when stained with propidium iodide and thiazole orange. Shigella and Salmonella cells became membrane compromised during initial acid shock (0-30 min), and 80% of these cells shifted to the stressed state throughout gastric fluid exposure. Approximately 10-30% of bacterial strains remained culturable after 60 min of gastric fluid exposure at pH 2.5-4.5, with the percentage increasing with an inoculum size of 102 CFU/ml. This ability of non-acid adapted Shigella and Salmonella sp. to adapt and survive low pH gastric fluid, even though the bacterial numbers decreased or changed to a stressed state, further supports the possible risk of infection when consumed.

Remediation of intramacrophageal Shigella dysenteriae type 1 by probiotic lactobacilli isolated from human infants' stool samples.

BACKGROUND & OBJECTIVES: Shigella dysenteriae is one of the most virulent pathogens causing bacillary dysentery and is responsible for high mortality in infants. To reduce the load of antibiotic therapy for treating shigellosis, this study was carried out to assess the ex vivo effect of novel probiotic lactobacilli, isolated from infant's stool samples, on killing S. dysenteriae type 1 residing in the rat macrophages. METHODS: Stool samples from infants were collected, processed for the isolation of lactobacilli and screened for the probiotic attributes (acid tolerance, bile tolerance, ability to adhere intestinal cells and anti-S. dysenteriae activity). The effect of cell-free supernatant of lactobacilli on Shigella- infected macrophages in terms of phagocytic ability, extent of lipid peroxidation, nitrite, superoxide dismutase and glutathione levels was evaluated. RESULTS: Based on the probiotic attributes, three lactobacilli were isolated from the stool samples of infants. Using classical and molecular tools, these isolates were identified as Lactobacillus pentosus, L. Paraplantarum and L. rhamnosus. All the three lactobacilli had the ability to kill intramacrophage S. dysentriae type 1. The anti-Shigella activity of the probiotic lactobacilli was attributed to increased antioxidative ability and decreased free radical production by the infected macrophages. INTERPRETATION & CONCLUSIONS: Probiotic cocktail of L. pentosus, L. paraplantarum and L. rhamnosus showed ex vivo killing of S. dysenteriae residing inside the rat macrophages significantly. This cocktail has the potential to be used as a natural alternative for treating S. dysenteriae infection, especially in infants, however, further studies need to be done to confirm these finding in vivo.

[Hemolytic and uremic syndrome and related thrombotic microangiopathies: Treatment and prognosis]. / Syndromes hémolytiques et urémiques (SHU) et syndromes de microangiopathie thrombotique apparentés : traitement et pronostic.

Major achievements in the understanding of thrombotic microangiopathies (TMA) have not only resulted in a reclassification of TMA but most of all they have culminated in the design of new treatments and have enabled clinicians to better delineate their prognosis. Recent multicenter studies have improved our understanding of the prognosis of atypical hemolytic and uremic syndromes (aHUS). More specifically, they have highlighted the role of genetic testing on predicting the recurrence of aHUS, the risk of chronic kidney disease and the recurrence following kidney transplantation. A major advance consisted of the identification of the alternative complement pathway in the pathogenesis of aHUS, thus paving the way for the use of the C5a inhibitor eculizumab in this indication. Eculizumab has thereafter dramatically improved the management of patients affected with aHUS. During spring 2011, a great epidemic of entero-hemorrhagic Escherichia coli (EHEC) associated HUS occurred in Germany, providing clinicians the opportunity to examine the relevance of antibiotic prophylaxis, plasma exchange and eculizumab in EHEC-associated HUS. In this work, we herein present advances achieved in the setting of therapeutic management and prognosis in HUS and other related TMA syndromes.

Protection against Shiga Toxins.

Shiga toxins consist of an A-moiety and five B-moieties able to bind the neutral glycosphingolipid globotriaosylceramide (Gb3) on the cell surface. To intoxicate cells efficiently, the toxin A-moiety has to be cleaved by furin and transported retrogradely to the Golgi apparatus and to the endoplasmic reticulum. The enzymatically active part of the A-moiety is then translocated to the cytosol, where it inhibits protein synthesis and in some cell types induces apoptosis. Protection of cells can be provided either by inhibiting binding of the toxin to cells or by interfering with any of the subsequent steps required for its toxic effect. In this article we provide a brief overview of the interaction of Shiga toxins with cells, describe some compounds and conditions found to protect cells against Shiga toxins, and discuss whether they might also provide protection in animals and humans.

Shigella Diversity and Changing Landscape: Insights for the Twenty-First Century.

Shigella is a pathovar of Escherichia coli comprising four groups, Shigella flexneri, Shigella sonnei, Shigella dysenteriae, and Shigella boydii, each of them, with the exception of S.sonnei, comprising several serotypes. Shigella accounts for the majority of dysentery causing infections occurring world-wide each year. Recent advancements in the Shigella field have led to a better understanding of the molecular mechanisms underlying host epithelial cell invasion and immune cell function manipulation, mainly using S. flexneri as a model. Host-cell invasion is the final step of the infection process, as Shigella's virulence strategy relies also on its ability to survive hostile conditions during its journey through the gastro-intestinal tract, to compete with the host microbiota and to cross the intestinal mucus layer. Hence, the diversity of the virulence strategies among the different Shigella species has not yet been deeply investigated, which might be an important step to understand the epidemiological spreading of Shigella species worldwide and a key aspect for the validation of novel vaccine candidates. The recent development of high-throughput screening and sequencing methods will facilitate these complex comparison studies. In this review we discuss several of the major avenues that the Shigella research field has taken over the past few years and hopefully gain some insights into the questions that remain surrounding this important human pathogen.

Immunization of Mice with a Live Transconjugant Shigella Hybrid Strain Induced Th1 and Th17 Cell-Mediated Immune Responses and Confirmed Passive Protection Against Heterologous Shigellae.

An avirulent, live transconjugant Shigella hybrid (LTSHΔstx) strain was constructed in our earlier study by introducing a plasmid vector, pPR1347, into a Shiga toxin gene deleted Shigella dysenteriae 1. Three successive oral administrations of LTSHΔstx to female adult mice produced comprehensive passive heterologous protection in their offspring against challenge with wild-type shigellae. Production of NO and different cytokines such asIL-12p70, IL-1ß and IL-23 in peritoneal mice macrophages indicated that LTSHΔstx induced innate and adaptive immunity in mice. Furthermore, production of IFN-γ, IL-10 and IL-17 in LTSH-primed splenic CD4+ T cell suggested that LTSHΔstx may induce Th1 and Th17 cell-mediated immune responses. Exponential increase of the serum IgG and IgA titre against whole shigellae was observed in immunized adult mice during and after the immunization with the highest peak on day 35. Antigen-specific sIgA was also determined from intestinal lavage of immunized mice. The stomach extracts of neonates from immunized mice, mainly containing mother's milk, contained significant levels of anti-LTSHΔstx immunoglobulin. These studies suggest that the LTSHΔstx could be a new live oral vaccine candidate against shigellosis in the near future.

Controlling the cytokine storm in severe bacterial diarrhoea with an oral Toll-like receptor 4 antagonist.

Shigella dysenteriae causes the most severe of all infectious diarrhoeas and colitis. We infected rhesus macaques orally and also treated them orally with a small and non-absorbable polypropyletherimine dendrimer glucosamine that is a Toll-like receptor-4 (TLR4) antagonist. Antibiotics were not given for this life-threatening infection. Six days later, the clinical score for diarrhoea, mucus and blood was 54% lower, colon interleukin-8 and interleukin-6 were both 77% lower, and colon neutrophil infiltration was 75% less. Strikingly, vasculitis did not occur and tissue fibrin thrombi were reduced by 67%. There was no clinical toxicity or adverse effect of dendrimer glucosamine on systemic immunity. This is the first report in non-human primates of the therapeutic efficacy of a small and orally bioavailable TLR antagonist in severe infection. Our results show that an oral TLR4 antagonist can enable controlled resolution of the infection-related-inflammatory response and can also prevent neutrophil-mediated gut wall necrosis in severe infectious diarrhoeas.

[Molecular targets of bacterial effectors and toxins that underlie vulnerability to diseases].

Pathogenic bacteria produce a variety of effectors and/or toxins, which subvert target cell/tissue functions in the infected hosts. Some of those effectors/toxins also perturb host defense mechanism, thereby making up more complicated pathophysiological conditions. Such bacterial effectors/toxins may have been positively selected during evolution because they directly strike vulnerable points in the host system. In turn, this indicates that systemic exploration of molecules and signaling pathways targeted by bacterial effectors/toxins provides a powerful tool in digging up an unexpected Achilles' heel(s), malfunctioning of which gives rise to disorders not restricted to infectious diseases. Based on this viewpoint, this review shows molecular basis underlying host susceptibility and vulnerability to diseases through the studies of host molecules targeted by bacterial effectors and toxins.

Análisis del patrón epidemiológico de la shigelosis en Barcelona entre 1988 y 2012: ¿es una infección de transmisión sexual emergente? / Analysis of the epidemiological pattern of Shigellosis in Barcelona between 1988 and 2012: is it an emerging sexually transmitted infection?

INTRODUCCIÓN: El objetivo de este estudio fue describir la evolución y las características epidemiológicas de los pacientes con shigelosis durante 25 años en una gran ciudad. MÉTODOS: La shigelosis es una enfermedad de declaración obligatoria en España desde 1988. Se analizan los casos de residentes en Barcelona incluidos en el registro entre 1988-2012. Se presenta un análisis descriptivo según sexo, edad, vía de transmisión y especies de Shigella. Se realizó un análisis de tendencias y de series temporales. RESULTADOS: De los 559 casos analizados, el 60,15% correspondían a hombres. Se observó un incremento sostenido de la tendencia en hombres desde 2008 (p < 0,05), sobre todo a expensas de los de hombres que no tenían antecedentes de toXIInfección alimentaria ni de viajes a zonas endémicas. El incremento de la tendencia fue mayor en hombres de 21 a 60 años, tanto para S. flexneri (desde 2009) como para S. sonnei (desde 2003). En 2012 se observó que, en los hombres con S. flexneri, el 63% tenían sexo con hombres. CONCLUSIONES: Se detectó un incremento de la tendencia en los casos en hombres que no tenían antecedentes de toXIInfección alimentaria ni de viajes a zonas endémicas. Este incremento apunta a un cambio en el patrón de la shigelosis, pasando a ser predominantemente masculina, y cuyo mecanismo principal serían las relaciones sexuales

INTRODUCTION: The aim of the study was to analyze the incidence, management and cost associated to hematological and dermatological adverse effects (AE) in chronic hepatitis C patients on triple therapy (TT) with telaprevir (TVR) or boceprevir (BOC). METHODS: An analysis was made on the data recorded on patients who started treatment with TVR or BOC associated with peginterferon alfa and ribavirin in a 12-week follow-up period. RESULTS: Fifty-three patients were included (TVR n = 36; BOC n = 17). Thrombocytopenia (83% TVR vs. 88% BOC) followed by neutropenia (89% TVR vs. 82% BOC) were the most common AE. Dermatological AE were observed in 32% of patients. Eleven patients required treatment discontinuation (all of them received TVR), and toxicity was the main reason for discontinuation (64%). The percentage of patients who required supportive treatment for management of AE was 66%. The most used supportive treatment was erythropoietin. Eight patients required emergency health care, and 2 were hospitalized due to AE. Total cost of additional supportive resources was 32,522 Euros (625 [SD = 876] Euros/patient) (TVR 759 [SD = 1,022] Euros/patient vs. BOC 349 [SD = 327] Euros/patient; P > .05). Patients with grade iii-iv toxicity required greater supportive care with higher costs, compared to patients with grade i-ii toxicity (849 [SD = 1,143] Euros/patient vs. 387 [SD = 397] Euros/patient; P = .053). CONCLUSION: The addition of new protease inhibitors to conventional treatment leads to a higher incidence of hematological AE in our study, compared to data described in clinical trials. The elevated incidence of AE involves the use of supportive care, increasing total costs of therapy

The genome of Shigella dysenteriae strain Sd1617 comparison to representative strains in evaluating pathogenesis.

We sequenced and analyzed Shigella dysenteriae strain Sd1617 serotype 1 that is widely used as model strain for vaccine design, trials and research. A combination of next-generation sequencing platforms and assembly yielded two contigs representing a chromosome size of 4.34 Mb and the large virulence plasmid of 177 kb. This genome sequence is compared with other Shigella genomes in order to understand gene complexity and pathogenic factors.