PIPS: Pathogenicity Island Prediction Software

The adaptability of pathogenic bacteria to hosts is influenced by the genomic plasticity of the bacteria, which can be increased by such mechanisms as horizontal gene transfer. Pathogenicity islands play a major role in this type of gene transfer because they are large, horizontally acquired regions that harbor clusters of virulence genes that mediate the adhesion, colonization, invasion, immune system evasion, and toxigenic properties of the acceptor organism. Currently, pathogenicity islands are mainly identified in silico based on various characteristic features: (1) deviations in codon usage, G+C content or dinucleotide frequency and (2) insertion sequences and/or tRNA genetic flanking regions together with transposase coding genes. Several computational techniques for identifying pathogenicity islands exist. However, most of these techniques are only directed at the detection of horizontally transferred genes and/or the absence of certain genomic regions of the pathogenic bacterium in closely related non-pathogenic species. Here, we present a novel software suite designed for the prediction of pathogenicity islands (pathogenicity island prediction software, or PIPS). In contrast to other existing tools, our approach is capable of utilizing multiple features for pathogenicity island detection in an integrative manner. We show that PIPS provides better accuracy than other available software packages. As an example, we used PIPS to study the veterinary pathogen Corynebacterium pseudotuberculosis, in which we identified seven putative pathogenicity islands

Evidence for Reductive Genome Evolution and Lateral Acquisition of Virulence Functions in Two Corynebacterium pseudotuberculosis Strains

Ruiz JC, D'Afonseca V, Silva A, et al. Evidence for Reductive Genome Evolution and Lateral Acquisition of Virulence Functions in Two Corynebacterium pseudotuberculosis Strains. PLoS ONE. 2011;6(4): e18551.Background: Corynebacterium pseudotuberculosis, a Gram-positive, facultative intracellular pathogen, is the etiologic agent of the disease known as caseous lymphadenitis (CL). CL mainly affects small ruminants, such as goats and sheep; it also causes infections in humans, though rarely. This species is distributed worldwide, but it has the most serious economic impact in Oceania, Africa and South America. Although C. pseudotuberculosis causes major health and productivity problems for livestock, little is known about the molecular basis of its pathogenicity. Methodology and Findings: We characterized two C. pseudotuberculosis genomes (Cp1002, isolated from goats; and CpC231, isolated from sheep). Analysis of the predicted genomes showed high similarity in genomic architecture, gene content and genetic order. When C. pseudotuberculosis was compared with other Corynebacterium species, it became evident that this pathogenic species has lost numerous genes, resulting in one of the smallest genomes in the genus. Other differences that could be part of the adaptation to pathogenicity include a lower GC content, of about 52%, and a reduced gene repertoire. The C. pseudotuberculosis genome also includes seven putative pathogenicity islands, which contain several classical virulence factors, including genes for fimbrial subunits, adhesion factors, iron uptake and secreted toxins. Additionally, all of the virulence factors in the islands have characteristics that indicate horizontal transfer. Conclusions: These particular genome characteristics of C. pseudotuberculosis, as well as its acquired virulence factors in pathogenicity islands, provide evidence of its lifestyle and of the pathogenicity pathways used by this pathogen in the infection process. All genomes cited in this study are available in the NCBI Genbank database (http://www.ncbi.nlm.nih.gov/genbank/) under accession numbers CP001809 and CP001829

Evolution of Burkholderia pseudomallei in Recurrent Melioidosis

Burkholderia pseudomallei, the etiologic agent of human melioidosis, is capable of causing severe acute infection with overwhelming septicemia leading to death. A high rate of recurrent disease occurs in adult patients, most often due to recrudescence of the initial infecting strain. Pathogen persistence and evolution during such relapsing infections are not well understood. Bacterial cells present in the primary inoculum and in late infections may differ greatly, as has been observed in chronic disease, or they may be genetically similar. To test these alternative models, we conducted whole-genome comparisons of clonal primary and relapse B. pseudomallei isolates recovered six months to six years apart from four adult Thai patients. We found differences within each of the four pairs, and some, including a 330 Kb deletion, affected substantial portions of the genome. Many of the changes were associated with increased antibiotic resistance. We also found evidence of positive selection for deleterious mutations in a TetR family transcriptional regulator from a set of 107 additional B. pseudomallei strains. As part of the study, we sequenced to base-pair accuracy the genome of B. pseudomallei strain 1026b, the model used for genetic studies of B. pseudomallei pathogenesis and antibiotic resistance. Our findings provide new insights into pathogen evolution during long-term infections and have important implications for the development of intervention strategies to combat recurrent melioidosis

Insulinoma in pregnancy (a case presentation and systematic review of the literature)

Insulinomas are rare, benign and functional tumors that coincidentally may become overt during pregnancy or in the post-partum period. As the general symptoms of a pregnancy might cover the clinical presentation, diagnosing remains challenging. We present one additional case of a post-partum insulinoma, combined with a systematic review of the literature to sum up relevant details in diagnosis and treatment. A systematic request of Pubmed/Medline was conducted using the following terms: "insulinoma AND pregnancy" and "insulinoma" for a second request of ClinicalTrials.gov. All publications concerning pregnant or post-partum women with insulinoma were included. Thirty-six cases could be identified for analysis. Each publication was reviewed for demographic, diagnostic and therapeutic data. The most frequent clinical signs were unconsciousness and neurological symptoms. 64.9% were diagnosed during early pregnancy and 35.1% post-partum. 91.9% underwent surgery with a third resected during pregnancy without severe influence on fetal or maternal outcome. Three patients died of metastatic disease or misdiagnosing, two of them miscarried. Insulinoma in pregnancy is rare but should be considered in case of unclear hyperinsulinemic hypoglycemia. Surgery can be performed during the second trimester or post-partum with promising outcome

Is There a Gender Difference in Clinical Presentation of Renal Hyperparathyroidism and Outcome after Parathyroidectomy?

Introduction: Gender has been proven to influence the pathophysiology and treatment of numerous diseases, including kidney diseases and hormonal dysfunction like hyperparathyroidism. Thus, higher parathormone levels have been demonstrated in women with end-stage kidney disease, when compared to men. Objectives: We questioned whether female gender is associated with an increased risk for parathyroid nodular hyperplasia and necessary parathyroidectomy in dialysis patients and assessed demographics as well as outcome data for women and men undergoing parathyroidectomy for renal hyperparathyroidism. Patients and Methods: One hundred and thirty patients (men = 75, female = 55) with end-stage renal disease on chronic dialysis and advanced secondary hyperparathyroidism who underwent parathyroidectomy between 2008 and 2014 at our center were analyzed retrospectively. Perioperative characteristics and short-term outcome were evaluated with respect to biological gender. Results: No differences could be demonstrated for patient demography, comorbidities and the perioperative course between males and females. Only preoperative calcium levels were lower in female than in male patients (2.3 +/- 0.19 vs. 2.3 +/- 0.26, p = 0.04). There were more women, however, with cerebrovascular complications during follow-up (p = 0.04). There was no postoperative mortality, and all complications and comorbidities with exception of cerebrovascular diseases were equally distributed between female and male patients. Conclusion: Overall, we could not demonstrate many significant differences between male and female patients with end-stage renal diseases, chronic dialysis and operated secondary hyperparathyroidism. Only preoperative electrolyte levels were higher in male than in female patients, and cerebrovascular complications developed more often in females than in males during long-term follow-up

Association between obesity after liver transplantation and steatosis, inflammation, and fibrosis of the graft

Background Nonalcoholic steatohepatitis has become one of the leading causes of liver transplantation. The development of steatosis, as well as the link to inflammation and fibrosis, after transplantation remain poorly understood. The aim of this analysis was to evaluate the influence of obesity on histopathological changes of the graft during long-term follow-up. Methods A total of 1494 longitudinal liver biopsies of 271 recipients were evaluated during a follow-up period of 5 to 10 years. Clinical and laboratory parameters as well as histopathological categories of steatosis, inflammation, and fibrosis were explored by routine protocol biopsies. Results The BMI and prevalence of diabetes mellitus significantly increased after transplantation (P < .01). Diabetes and de novo obesity were significantly associated with the degree of graft steatosis. There was no correlation between former steatosis and inflammation or fibrosis. Inflammation was a precursor of fibrosis, and fibrosis increased over the first 3 years (P < .01). No severe graft dysfunction was observed. Conclusion Obesity and diabetes mellitus correlated with higher grades of steatosis and de novo steatosis after transplantation. Metabolic syndrome must be considered as a serious post-transplant complication that can cause histopathological alteration. However, the progress from steatosis to steatohepatitis is not as common as expected

Influence of Gender on Therapy and Outcome of Neuroendocrine Tumors of Gastroenteropancreatic Origin: A Single-Center Analysis

Introduction: Gender-specific treatment is gaining growing attention in various fields of medicine. In gastrointestinal cancer, influence of sex on outcome has been discussed, while this has not been the case in neuroendocrine tumors. Overall, the incidence of neuroendocrine neoplasms is rising, especially for appendiceal neuroendocrine neoplasms in women. Also, women seem to have a slight advantage in response to therapy, especially for liver metastases. Objectives: This single-center analysis aimed to investigate gender-specific differences in our cohort related to distribution, therapy, and outcome. Methods: Patients from the NET registry as well as the clinic database were evaluated retrospectively concerning overall survival and response to therapy with respect to gender. A subgroup analysis was carried out for patients with low grading and response to chemotherapy, as well as for patients with good and moderate grading receiving peptide receptor radionuclide therapy and for a group of patients with liver surgery. Results: No specific differences could be detected for overall survival or response to therapy between male and female patients. Mean survival was estimated with 242.2 months (+/- 10.39 SD) altogether and 221.7 months (+/- 13.02 SD) for male patients and 253.5 months (+/- 15.24 SD) for female patients from the NET registry from initial diagnosis. There was no significant difference between female and male patients (p = 0.136). For patients receiving chemotherapy, overall survival from initial diagnosis was calculated with 26 months (+/- 2.59) and did not show any significant differences between female and male patients 24.8 months (+/- 2.81 SD) vs. 27.8 months (+/- 3.86 SD, p = 0.87). Patients undergoing peptide receptor radionuclide therapy showed a median progression-free survival of 26.9 months (+/- 2.82 SD), with 16.9 (+/- 5.595 SD) and 26.9 months (+/- 3.019 SD) for male and female patients, respectively (p = 0.2). In the group of patients with liver surgery, female patients reached an estimated overall survival of 64.7 months (+/- 4.16 SD), male patients 65.1 months (+/- 2.79 SD, p = 0.562). Conclusion: Our cohort did not reveal significant differences in outcome and response to therapy with regards to gender

Speckle Tracking Analysis Reveals Altered Left Atrial and Ventricular Myocardial Deformation in Patients with End-Stage Liver Disease

Background: Cardiac function can be influenced by liver cirrhosis and should be thoroughly evaluated before liver transplantation. We investigated left ventricular (LV) and, for the first time, left atrial (LA) strain and strain rate in end-stage liver cirrhosis patients of different etiologies. Methods: This retrospective, cross-sectional study evaluated left heart function in 80 cirrhosis patients and 30 controls using standardized echocardiographic techniques and speckle tracking technology (STE) analysis. Serum markers of liver function were used for correlation analysis. Results: While conventional parameters demonstrated no alteration in systolic function, speckle tracking analysis showed a significant increase in LV longitudinal strain throughout all cardiac layers, with significant correlation to model of end-stage liver disease (MELD) score. LA reservoir and conduit strain as well as LA strain rate in all phases were significantly reduced in end-stage liver disease (ESLD) patients compared to control. STE for the evaluation of LA phasic function seemed to be more sensitive than volumetric methods. Kaplan-Meier curves showed a trend towards reduced post-transplant survival in patients with a reduced LA reservoir and conduit strain. Conclusion: STE analysis detected increased LV and decreased LA deformation in cirrhosis patients, thus proving to be highly sensitive to cardiac changes and useful for more precise cardiac evaluation