BackgroundCombination therapy is one of the most effective tools for limiting the emergence of drug resistance in pathogens. Despite the widespread adoption of combination therapy across diseases, drug resistance rates continue to rise, leading to failing treatment regimens. The mechanisms underlying treatment failure are well studied, but the processes governing successful combination therapy are poorly understood. We address this question by studying the population dynamics of Mycobacterium tuberculosis within tuberculosis patients undergoing treatment with different combinations of antibiotics.ResultsBy combining very deep whole genome sequencing (~1000-fold genome-wide coverage) with sequential sputum sampling, we were able to detect transient genetic diversity driven by the apparently continuous turnover of minor alleles, which could serve as the source of drug-resistant bacteria. However, we report that treatment efficacy has a clear impact on the population dynamics: sufficient drug pressure bears a clear signature of purifying selection leading to apparent genetic stability. In contrast, M. tuberculosis populations subject to less drug pressure show markedly different dynamics, including cases of acquisition of additional drug resistance.ConclusionsOur findings show that for a pathogen like M. tuberculosis, which is well adapted to the human host, purifying selection constrains the evolutionary trajectory to resistance in effectively treated individuals. Nonetheless, we also report a continuous turnover of minor variants, which could give rise to the emergence of drug resistance in cases of drug pressure weakening. Monitoring bacterial population dynamics could therefore provide an informative metric for assessing the efficacy of novel drug combinations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1196-0) contains supplementary material, which is available to authorized users.

GADD45, MyD118, and CR6 (also termed GADD45␣, ␤, and ␥) comprise a family of genes that encode for related proteins playing important roles in negative growth control, including growth suppression. Data accumulated suggest that MyD118/GADD45/CR6 serve similar but not identical functions along different apoptotic and growth suppressive pathways. It is also apparent that individual members of the MyD118/GADD45/CR6 family are differentially induced by a variety of genetic and environmental stress agents. The MyD118, CR6, and GADD45 proteins were shown to predominantly localize within the cell nucleus. Recently, we have shown that both MyD118 and GADD45 interact with proliferating cell nuclear antigen (PCNA), a protein that plays a central role in DNA replication, DNA repair, and cell cycle progression, as well as with the universal cyclin-dependent kinase inhibitor p21. In this work we show that also CR6 interacts with PCNA and p21. Moreover, it is shown that CR6 interacts with PCNA via a domain that also mediates interaction of both GADD45 and MyD118 with PCNA. Importantly, evidence has been obtained that interaction of CR6 with PCNA impedes the function of this protein in negative growth control, similar to observations reported for MyD118 and GADD45 (1).

The ideal surgical treatment of giant liver hemangioma is still controversial. This study aims to compare the outcomes of enucleation with those of resection for liver hemangioma larger than 10 cm in different locations of the liver and establish the preoperative predictors of increased intraoperative blood loss.Eighty-six patients underwent enucleation or liver resection for liver hemangioma larger than 10 cm was retrospectively reviewed. Patient demographic, tumor characteristics, surgical indications, the outcomes of both surgical treatment, and the clinicopathological parameters influencing intraoperative blood loss were analyzed.Forty-six patients received enucleation and 40 patients received liver resection. Mean tumor size was 14.1 cm with a range of 10–35 cm. Blood loss, blood product usage, operative time, hepatic vascular occlusion time and frequency, complications and postsurgical hospital stay were similar between liver resections and enucleation for right-liver and left-liver hemangiomas. There was no surgery-related mortality in either group. Bleeding was more related to adjacency of major vascular structures than the size of hemangioma. Adjacency to major vascular structures and right or bilateral liver hemangiomas were independently associated with blood loss >550 mL (P = 0.000 and 0.042, respectively).Both enucleation and liver resection are safe and effective surgical treatments for liver hemangiomas larger than 10 cm. The risk of intraoperative blood loss is related to adjacency to major vascular structures and the location of hemangioma.

In a retrospective analysis of POEM procedures, we found that 100 cases were required to decrease the risk of technical failure, adverse events, and clinical failure (the learning curve). Seventy cases can be considered the threshold for decreasing procedure time.

LTF seems to be as safe and effective on the long-term as LNF, but with a lower incidence of postoperative dysphagia (ChiCTR-TRC-13003945).

Demonstration of reduced levels in the expression of POSTN, an ECM gene, following resolution of disease, implicates POSTN, a potential pathogenesis indicator or biomarker of CRS disease activity and responsiveness to treatment.

Objective (1) To describe the demographics and clinical course of children with intracranial complications of sinusitis. (2) To elucidate factors that predict revision surgery in this population, such as type of initial surgery. Study Design Case series with chart review. Setting Tertiary care academic children's hospital. Subjects and Methods A 15-year retrospective review identified 71 patients with intracranial complications of acute sinusitis. Primary outcome was need for revision surgery. Secondary outcomes were readmission, length of hospitalization, and long-term complications. Results This study is the largest to date examining this disease process. Overall, 69 (97%) patients had surgery; 33 (46%) required revision surgery. Half of the patients with frontal sinus opacification underwent frontal sinus surgery at presentation (endoscopic, trephination, or cranialization). There was no difference in revision surgery between patients who had frontal sinus surgery and those who did not. Patients with frontal sinus surgery did not have a higher rate of complications or chronic sinusitis ( P > .05). Subdural abscess was associated with multiple surgical procedures (odds ratio, 20.0; P < .01). Thirty-four patients (49%) required neurosurgery. These patients had a longer length of stay (odds ratio, 11.0; P < .01) and a higher readmission rate ( P = .02). During the mean 92-month follow-up, 22 patients (33%) had long-term complications, and there was 1 death (1.4%). Conclusion Almost half of this cohort required multiple surgical procedures. In particular, patients with subdural abscess had significantly higher rates of revision surgery. Type of frontal sinus surgery was not correlated with need for revision surgery and was not associated with an increased rate of complications.

Interleukin-12 is an important regulator of other cytokines. Although interleukin-12 is considered to act primarily on lymphocytes, provoking a shift from T helper 2 to T helper 1 cells and an increase in lymphocyte-derived tumor necrosis factor alpha, we hypothesized that interleukin-12 might also affect tumor necrosis factor alpha secretion from skin cells. In this study, keratinocytes were treated with ultraviolet-B, ultraviolet-A, or sham irradiation, without or with exogenous interleukin-12. Remarkably, the exogenous interleukin-12 totally blocked ultraviolet-B-induced tumor necrosis factor alpha production. Both ultraviolet-A and ultraviolet-B were capable of inducing interleukin-12 production. To determine the molecular mechanism of this effect, we used a chloramphenicol acetyl transferase reporter under the control of a 1.2 kb fragment of the wild-type (-308G) human tumor necrosis factor alpha promoter and found significant suppression of promoter activity with interleukin-12. Studies using the -308A variant of the human tumor necrosis factor alpha promoter showed much higher promoter activity overall, but also a greater sensitivity to suppression by interleukin-12. The mechanism did not involve blockage of the interleukin-1 receptor, because interleukin-12 did not suppress interleukin-1-mediated induction of collagenase mRNA. To determine the role of endogenous interleukin-12, we found that anti-interleukin-12 antibodies enhanced ultraviolet-B-induced tumor necrosis factor alpha secretion. Thus, interleukin-12 strongly inhibits tumor necrosis factor alpha production by noninflammatory skin cells, mostly or entirely through inhibition of gene transcription via an element within the first 1.2 kb of the tumor necrosis factor alpha promoter. The result is a shift in tumor necrosis factor alpha production from noninflammatory cells to T helper 1 cells. Because tumor necrosis factor alpha is central to the pathogenesis of several photosensitive skin diseases and certain forms of immune suppression, interleukin-12 may have important physiologic, pathophysiologic, and therapeutic roles.