Strain-Specific Differences in the Genetic Control of Two Closely Related Mycobacteria

The host response to mycobacterial infection depends on host and pathogen genetic factors. Recent studies in human populations suggest a strain specific genetic control of tuberculosis. To test for mycobacterial-strain specific genetic control of susceptibility to infection under highly controlled experimental conditions, we performed a comparative genetic analysis using the A/J- and C57BL/6J-derived recombinant congenic (RC) mouse panel infected with the Russia and Pasteur strains of Mycobacterium bovis Bacille Calmette Guérin (BCG). Bacillary counts in the lung and spleen at weeks 1 and 6 post infection were used as a measure of susceptibility. By performing genome-wide linkage analyses of loci that impact on tissue-specific bacillary burden, we were able to show the importance of correcting for strain background effects in the RC panel. When linkage analysis was adjusted on strain background, we detected a single locus on chromosome 11 that impacted on pulmonary counts of BCG Russia but not Pasteur. The same locus also controlled the splenic counts of BCG Russia but not Pasteur. By contrast, a locus on chromosome 1 which was indistinguishable from Nramp1 impacted on splenic bacillary counts of both BCG Russia and Pasteur. Additionally, dependent upon BCG strain, tissue and time post infection, we detected 9 distinct loci associated with bacillary counts. Hence, the ensemble of genetic loci impacting on BCG infection revealed a highly dynamic picture of genetic control that reflected both the course of infection and the infecting strain. This high degree of adaptation of host genetics to strain-specific pathogenesis is expected to provide a suitable framework for the selection of specific host-mycobacteria combinations during co-evolution of mycobacteria with humans

Evaluation of PCR on Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Aspergillosis: A Bivariate Metaanalysis and Systematic Review

BACKGROUND: Nucleic acid detection by polymerase chain reaction (PCR) is emerging as a sensitive and rapid diagnostic tool. PCR assays on serum have the potential to be a practical diagnostic tool. However, PCR on bronchoalveolar lavage fluid (BALF) has not been well established. We performed a systematic review of published studies to evaluate the diagnostic accuracy of PCR assays on BALF for invasive aspergillosis (IA). METHODS: Relevant published studies were shortlisted to evaluate the quality of their methodologies. A bivariate regression approach was used to calculate pooled values of the method sensitivity, specificity, and positive and negative likelihood ratios. Hierarchical summary receiver operating characteristic curves were used to summarize overall performance. We calculated the post-test probability to evaluate clinical usefulness. Potential heterogeneity among studies was explored by subgroup analyses. RESULTS: Seventeen studies comprising 1191 at-risk patients were selected. The summary estimates of the BALF-PCR assay for proven and probable IA were as follows: sensitivity, 0.91 (95% confidence interval (CI), 0.79-0.96); specificity, 0.92 (95% CI, 0.87-0.96); positive likelihood ratio, 11.90 (95% CI, 6.80-20.80); and negative likelihood ratio, 0.10 (95% CI, 0.04-0.24). Subgroup analyses showed that the performance of the PCR assay was influenced by PCR assay methodology, primer design and the methods of cell wall disruption and DNA extraction. CONCLUSIONS: PCR assay on BALF is highly accurate for diagnosing IA in immunocompromised patients and is likely to be a useful diagnostic tool. However, further efforts towards devising a standard protocol are needed to enable formal validation of BALF-PCR

“Es fundamental que la información que se transmita sea confiable”

El flamante Doctor Honoris Causa de la UNLP, Emilio Luque Fadón, de la Universidad Autónoma de Barcelona, fue uno de los conferencistas de CACIC 2017. Durante su estadía por la ciudad de La Plata, el español habló acerca de las nuevas tecnologías, su tolerancia a los fallos y el consumo energético.Facultad de Informátic

Transient receptor potential ankyrin-1 has a major role in mediating visceral pain in mice

The excitatory ion channel transient receptor potential ankyrin-1 (TRPA1) is prominently expressed by primary afferent neurons and is a mediator of inflammatory pain. Inflammatory agents can directly activate [e.g., hydroxynonenal (HNE), prostaglandin metabolites] or indirectly sensitize [e.g., agonists of protease-activated receptor (PAR2)] TRPA1 to induce somatic pain and hyperalgesia. However, the contribution of TRPA1 to visceral pain is unknown. We investigated the role of TRPA1 in visceral hyperalgesia by measuring abdominal visceromotor responses (VMR) to colorectal distention (CRD) after intracolonic administration of TRPA1 agonists [mustard oil (MO), HNE], sensitizing agents [PAR2 activating peptide (PAR2-AP)], and the inflammatory agent trinitrobenzene sulfonic acid (TNBS) in trpa1+/+ and trpa1−/− mice. Sensory neurons innervating the colon, identified by retrograde tracing, coexpressed immunoreactive TRPA1, calcitonin gene-related peptide, and substance P, expressed TRPA1 mRNA and responded to MO with depolarizing currents. Intracolonic MO and HNE increased VMR to CRD and induced immunoreactive c-fos in spinal neurons in trpa1+/+ but not in trpa1−/− mice. Intracolonic PAR2-AP induced mechanical hyperalgesia in trpa1+/+ but not in trpa1−/− mice. TNBS-induced colitis increased in VMR to CRD and induced c-fos in spinal neurons in trpa1+/+ but not in trpa1−/− mice. Thus TRPA1 is expressed by colonic primary afferent neurons. Direct activation of TRPA1 causes visceral hyperalgesia, and TRPA1 mediates PAR2-induced hyperalgesia. TRPA1 deletion markedly reduces colitis-induced mechanical hyperalgesia in the colon. Our results suggest that TRPA1 has a major role in visceral nociception and may be a therapeutic target for colonic inflammatory pain