A hypothesis for explaining single outbreaks (like the Black Death in European cities) of vector-borne infections

We propose a mechanism by which single outbreaks of vector-borne infections can happen even when the value of the basic reproduction number, R(o), of the infection is below one. With this hypothesis we have shown that dynamical models simulations demonstrate that the arrival of a relatively small (with respect to the host population) number of infected vectors can trigger a short-lived epidemic but with a huge number of cases. These episodes are characterized by a sudden outbreak in a previously virgin area that last from weeks to a few months, and then disappear without leaving vestiges. The hypothesis proposed in this paper to explain those single outbreaks of vector-borne infections, even when total basic reproduction number, Ro, is less than one (which explain the fact that those infections fail to establish themselves at endemic levels), is that the vector-to-host component of Ro is greater than one and that a sufficient amount of infected vectors are imported to the vulnerable area, triggering the outbreak. We tested the hypothesis by performing numerical simulations that reproduce the observed outbreaks of chikungunya in Italy in 2007 and the plague in Florence in 1348. The theory proposed provides an explanation for isolated outbreaks of vector-borne infections, ways to calculate the size of those outbreaks from the number of infected vectors arriving in the affected areas. Given the ever-increasing worldwide transportation network, providing a high degree of mobility from endemic to virgin areas, the proposed mechanism may have important implications for public health planning. (C) 2009 Elsevier Ltd. All rights reserved.

Implications of prevalent and incident diabetes mellitus on left ventricular geometry and function in the ageing heart: The MONICA/KORA Augsburg cohort study

Background and Aim: It is unclear to what extent diabetes modulates the ageing-related adaptations of cardiac geometry and function. Methods and Results: We examined 1005 adults, aged 25-74 years, from a population-based survey at baseline in 1994/5 and at follow-up in 2004/5. We compared persistently non-diabetic individuals (ND; no diabetes at baseline and at follow-up, n = 833) with incident (ID; non-diabetic at baseline and diabetic at follow-up, n = 36) and with prevalent diabetics (PD; diabetes at baseline and follow-up examination, n = 21). Left ventricular (LV) geometry and function were evaluated by echocardiography. Statistical analyses were performed with multivariate linear regression models. Over ten years the PD group displayed a significantly stronger relative increase of LV mass (+9.34% vs. +23.7%) that was mediated by a more pronounced increase of LV end-diastolic diameter (+0% vs. +6.95%) compared to the ND group. In parallel, LA diameter increased (+4.50% vs. +12.7%), whereas ejection fraction decreased (+3.02% vs. -4.92%) more significantly in the PD group. Moreover, at the follow-up examination the PD and ID groups showed a significantly worse diastolic function, indicated by a higher E/EM ratio compared with the ND group (11.6 and 11.8 vs. 9.79, respectively). Conclusions: Long-standing diabetes was associated with an acceleration of age-related changes of left ventricular geometry accumulating in an eccentric remodelling of the left ventricle. Likewise, echocardiographic measures of systolic and diastolic ventricular function deteriorated more rapidly in individuals with diabetes. (C) 2009 Elsevier B.V. All rights reserved.

Predictive models for diagnosis of pleural effusions secondary to tuberculosis or cancer

Background and objective: Tuberculosis (TB) and cancer are two of the main causes of pleural effusions which frequently share similar clinical features and pleural fluid profiles. This study aimed to identify diagnostic models based on clinical and laboratory variables to differentiate tuberculous from malignant pleural effusions. Methods: A retrospective study of 403 patients (200 with TB; 203 with cancer) was undertaken. Univariate analysis was used to select the clinical variables relevant to the models composition. Variables beta coefficients were used to define a numerical score which presented a practical use. The performances of the most efficient models were tested in a sample of pleural exudates (64 new cases). Results: Two models are proposed for the diagnosis of effusions associated with each disease. For TB: (i) adenosine deaminase (ADA), globulins and the absence of malignant cells in the pleural fluid; and (ii) ADA, globulins and fluid appearance. For cancer: (i) patient age, fluid appearance, macrophage percentage and presence of atypical cells in the pleural fluid; and (ii) as for (i) excluding atypical cells. Application of the models to the 64 pleural effusions showed accuracy higher than 85% for all models. Conclusions: The proposed models were effective in suggesting pleural tuberculosis or cancer.

Targeted Mutagenesis in Pathogenic Leptospira Species: Disruption of the LigB Gene Does Not Affect Virulence in Animal Models of Leptospirosis

The pathogenic mechanisms of Leptospira interrogans, the causal agent of leptospirosis, remain largely unknown. This is mainly due to the lack of tools for genetically manipulating pathogenic Leptospira species. Thus, homologous recombination between introduced DNA and the corresponding chromosomal locus has never been demonstrated for this pathogen. Leptospiral immunoglobulin-like repeat (Lig) proteins were previously identified as putative Leptospira virulence factors. In this study, a ligB mutant was constructed by allelic exchange in L. interrogans; in this mutant a spectinomycin resistance (Spc(r)) gene replaced a portion of the ligB coding sequence. Gene disruption was confirmed by PCR, immunoblot analysis, and immunofluorescence studies. The ligB mutant did not show decrease virulence compared to the wild-type strain in the hamster model of leptospirosis. In addition, inoculation of rats with the ligB mutant induced persistent colonization of the kidneys. Finally, LigB was not required to mediate bacterial adherence to cultured cells. Taken together, our data provide the first evidence of site-directed homologous recombination in pathogenic Leptospira species. Furthermore, our data suggest that LigB does not play a major role in dissemination of the pathogen in the host and in the development of acute disease manifestations or persistent renal colonization.

EFFECTS OF A POTENT PEROXYNITRITE DECOMPOSITION CATALYST IN MURINE MODELS OF ENDOTOXEMIA AND SEPSIS

Excessive free-radical production due to various bacterial components released during bacterial infection has been linked to cell death and tissue injury. Peroxynitrite is a highly reactive oxidant produced by the combination of nitric oxide (NO) and superoxide anion, which has been implicated in cell death and tissue injury in various forms of critical illness. Pharmacological decomposition of peroxynitrite may represent a potential therapeutic approach in diseases associated with the overproduction of NO and superoxide. In the present study, we tested the effect of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Mice were injected i.p. with LPS 40 mg/kg with or without FP15 [Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin] (0.1, 0.3, 1, 3, or 10 mg/kg per hour). Mice were killed 12 h later, followed by the harvesting of samples from the lung, liver, and gut for malondialdehyde and myeloperoxidase measurements. In other subsets of animals, blood samples were obtained by cardiac puncture at 1.5, 4, and 8 h after LPS administration for cytokine (TNF-alpha, IL-1 beta, and IL-10), nitrite/nitrate, alanine aminotransferase, and blood urea nitrogen measurements. Endotoxemic animals showed an increase in survival from 25% to 80% at the FP15 doses of 0.3 and 1 mg/kg per hour. The same dose of FP15 had no effect on plasma levels of nitrite/nitrate. There was a reduction in liver and lung malondialdehyde in the endotoxemic animals pretreated with FP15, as well as in hepatic myeloperoxidase and biochemical markers of liver and kidney damage (alanine aminotransferase and blood urea nitrogen). In a bacterial model of sepsis induced by cecal ligation and puncture, FP15 treatment (0.3 mg/kg per day) significantly protected against mortality. The current data support the view that peroxynitrite is a critical factor mediating liver, gut, and lung injury in endotoxemia and septic shock: its pharmacological neutralization may be of therapeutic benefit.

Nonhuman primate models and the failure of the Merck HIV-1 vaccine in humans

The adenovirus type 5 (Ad5)-based vaccine developed by Merck failed to either prevent HIV-1 infection or suppress viral load in subsequently infected subjects in the STEP human Phase 2b efficacy trial. Analogous vaccines had previously also failed in the simian immunodeficiency virus (SIV) challenge-rhesus macaque model. In contrast, vaccine protection studies that used challenge with a chimeric simian-human immunodeficiency virus (SHIV89.6P) in macaques did not predict the human trial results. Ad5 vector -based vaccines did not protect macaques from infection after SHIV89.6P challenge but did cause a substantial reduction in viral load and a preservation of CD4(+) T cell counts after infection, findings that were not reproduced in the human trials. Although the SIV challenge model is incompletely validated, we propose that its expanded use can help facilitate the prioritization of candidate HIV-1 vaccines, ensuring that resources are focused on the most promising candidates. Vaccine designers must now develop T cell vaccine strategies that reduce viral load after heterologous challenge.

A decision support system to facilitate management of patients with acute gastrointestinal bleeding

Objective: To develop a model to predict the bleeding source and identify the cohort amongst patients with acute gastrointestinal bleeding (GIB) who require urgent intervention, including endoscopy. Patients with acute GIB, an unpredictable event, are most commonly evaluated and managed by non-gastroenterologists. Rapid and consistently reliable risk stratification of patients with acute GIB for urgent endoscopy may potentially improve outcomes amongst such patients by targeting scarce health-care resources to those who need it the most. Design and methods: Using ICD-9 codes for acute GIB, 189 patients with acute GIB and all. available data variables required to develop and test models were identified from a hospital medical records database. Data on 122 patients was utilized for development of the model and on 67 patients utilized to perform comparative analysis of the models. Clinical data such as presenting signs and symptoms, demographic data, presence of co-morbidities, laboratory data and corresponding endoscopic diagnosis and outcomes were collected. Clinical data and endoscopic diagnosis collected for each patient was utilized to retrospectively ascertain optimal management for each patient. Clinical presentations and corresponding treatment was utilized as training examples. Eight mathematical models including artificial neural network (ANN), support vector machine (SVM), k-nearest neighbor, linear discriminant analysis (LDA), shrunken centroid (SC), random forest (RF), logistic regression, and boosting were trained and tested. The performance of these models was compared using standard statistical analysis and ROC curves. Results: Overall the random forest model best predicted the source, need for resuscitation, and disposition with accuracies of approximately 80% or higher (accuracy for endoscopy was greater than 75%). The area under ROC curve for RF was greater than 0.85, indicating excellent performance by the random forest model Conclusion: While most mathematical models are effective as a decision support system for evaluation and management of patients with acute GIB, in our testing, the RF model consistently demonstrated the best performance. Amongst patients presenting with acute GIB, mathematical models may facilitate the identification of the source of GIB, need for intervention and allow optimization of care and healthcare resource allocation; these however require further validation. (c) 2007 Elsevier B.V. All rights reserved.