EspA Acts as a Critical Mediator of ESX1-Dependent Virulence in Mycobacterium tuberculosis by Affecting Bacterial Cell Wall Integrity

Mycobacterium tuberculosis (Mtb) requires the ESX1 specialized protein secretion system for virulence, for triggering cytosolic immune surveillance pathways, and for priming an optimal CD8+ T cell response. This suggests that ESX1 might act primarily by destabilizing the phagosomal membrane that surrounds the bacterium. However, identifying the primary function of the ESX1 system has been difficult because deletion of any substrate inhibits the secretion of all known substrates, thereby abolishing all ESX1 activity. Here we demonstrate that the ESX1 substrate EspA forms a disulfide bonded homodimer after secretion. By disrupting EspA disulfide bond formation, we have dissociated virulence from other known ESX1-mediated activities. Inhibition of EspA disulfide bond formation does not inhibit ESX1 secretion, ESX1-dependent stimulation of the cytosolic pattern receptors in the infected macrophage or the ability of Mtb to prime an adaptive immune response to ESX1 substrates. However, blocking EspA disulfide bond formation severely attenuates the ability of Mtb to survive and cause disease in mice. Strikingly, we show that inhibition of EspA disulfide bond formation also significantly compromises the stability of the mycobacterial cell wall, as does deletion of the ESX1 locus or individual components of the ESX1 system. Thus, we demonstrate that EspA is a major determinant of ESX1-mediated virulence independent of its function in ESX1 secretion. We propose that ESX1 and EspA play central roles in the virulence of Mtb in vivo because they alter the integrity of the mycobacterial cell wall

The value of mastectomy flap fixation in reducing fluid drainage and seroma formation in breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Prolonged and excessive drainage of serous fluid and seroma formation constitute the most common complications after mastectomy for breast carcinoma. Seroma formation delays wound healing, increases susceptibility to infection, skin flap necrosis, persistent pain and prolongs convalescence. For this, several techniques have been investigated to improve primary healing and minimize seroma formation.</p> <p>Materials and methods</p> <p>Between June 2009 and July 2010 forty patients with breast carcinoma, scheduled for modified radical mastectomy, were randomly divided into 2 groups, the study group (20) and the control group (20). In the study group; the mastectomy flaps were fixed to the underlying muscles in raws, at various parts of the flap and at the wound edge using fine absorbable sutures. In the control group; the wound was closed in the conventional method at the edges. Closed suction drains were used in both groups. Patients, tumor characteristics and operative related factors were recorded. The amount and color of drained fluid were recorded daily. The drains were removed when the amount become less than 50 cc. The total amount and duration of drained fluid and the formation of seroma were recorded and the results were compared between the two groups.</p> <p>Results</p> <p>In the flap fixation group, the drain was removed in significantly shorter time compared to the control group (p < 0.001). Also, the total amount of fluid drained was significantly lower in the flap fixation group (p < 0.001). The flap fixation group showed a significantly lower frequency of seroma formation compared to the control group, both clinically (p = 0.028) and ultrasonographically (p = 0.047).</p> <p>Conclusions</p> <p>The mastectomy flap fixation technique is a valuable procedure that significantly decreases the incidence of seroma formation, and reduces the duration and amount of drained fluid. However, it should be tried on a much wider scale to prove its validity.</p

A multidisciplinary treatment of congenitally missing maxillary lateral incisors: a 14-year follow-up case report

Absence of the maxillary lateral incisor creates an aesthetic problem which can be managed in various ways. The condition requires careful treatment planning and consideration of the options and outcomes following either space closure or prosthetic replacement. Recent developments in restorative dentistry have warranted a re-evaluation of the approach to this clinical situation. Factors relating both to the patient and the teeth, including the presentation of malocclusion and the effect on the occlusion must be considered. The objective of this study was to describe the etiology, prevalence and alternative treatment modalities for dental agenesis and to present a clinical case of agenesis of the maxillary lateral incisors treated by the closure of excessive spaces and canine re-anatomization. A clinical case is presented to illustrate the interdisciplinary approach between orthodontics and restorative dentistry for improved esthetic results. In this report, the treatment of a girl with a Class II malocclusion of molars and canines with missing maxillary lateral incisors and convex facial profile is shown. Treatment was successfully achieved and included the space closure of the areas corresponding to the missing upper lateral incisors, through movement of the canines and the posterior teeth to mesial by fixed appliances as well as the canines transformation in the maxillary lateral incisors. This is a 14-year follow-up case report involving orthodontics and restorative dentistry in which pretreatment, posttreatment, and long-term follow-up records for the patient are presented

Axillary lymph node dissection for breast cancer utilizing Harmonic Focus®

<p>Abstract</p> <p>Background</p> <p>For patients with axillary lymph node metastases from breast cancer, performance of a complete axillary lymph node dissection (ALND) is the standard approach. Due to the rich lymphatic network in the axilla, it is necessary to carefully dissect and identify all lymphatic channels. Traditionally, these lymphatics are sealed with titanium clips or individually sutured. Recently, the Harmonic Focus^®, a hand-held ultrasonic dissector, allows lymphatics to be sealed without the utilization of clips or ties. We hypothesize that ALND performed with the Harmonic Focus^®will decrease operative time and reduce post-operative complications.</p> <p>Methods</p> <p>Retrospective review identified all patients who underwent ALND at a teaching hospital between January of 2005 and December of 2009. Patient demographics, presenting pathology, treatment course, operative time, days to drain removal, and surgical complications were recorded. Comparisons were made to a selected control group of patients who underwent similar surgical procedures along with an ALND performed utilizing hemostatic clips and electrocautery. A total of 41 patients were included in this study.</p> <p>Results</p> <p>Operative time was not improved with the use of ultrasonic dissection, however, there was a decrease in the total number of days that closed suction drainage was required, although this was not statistically significant. Complication rates were similar between the two groups.</p> <p>Conclusion</p> <p>In this case-matched retrospective review, there were fewer required days of closed suction drainage when ALND was performed with ultrasonic dissection versus clips and electrocautery.</p

Conditional Inactivation of Brca1, p53 and Rb in Mouse Ovaries Results in the Development of Leiomyosarcomas

Epithelial ovarian cancer (EOC) is thought to arise in part from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. To generate a model in which Brca1-mediated transformation can be studied, we previously inactivated Brca1 alone in murine OSE, which resulted in an increased accumulation of premalignant changes, but no tumor formation. In this study, we examined tumor formation in mice with conditionally expressed alleles of Brca1, p53 and Rb, alone or in combination. Intrabursal injection of adenovirus expressing Cre recombinase to inactivate p53 resulted in tumors in 100% of mice. Tumor progression was accelerated in mice with concomitant inactivation of Brca1 and p53, but not Rb and p53. Immunohistologic analyses classified the tumors as leiomyosarcomas that may be arising from the ovarian bursa. Brca1 inactivation in primary cultures of murine OSE cells led to a suppression of proliferation that could be rescued by concomitant inactivation of p53 and/or Rb. Brca1-deficient OSE cells displayed an increased sensitivity to the DNA damaging agent cisplatin, and this effect could be modulated by inactivation of p53 and/or Rb. These results indicate that Brca1 deficiency can accelerate tumor development and alter the sensitivity of OSE cells to chemotherapeutic agents. Intrabursal delivery of adenovirus intended to alter gene expression in the ovarian surface epithelium may, in some strains of mice, result in more rapid transformation of adjacent cells, resulting in leiomyosarcomas

Emotional design and human-robot interaction

Recent years have shown an increase in the importance of emotions applied to the Design field - Emotional Design. In this sense, the emotional design aims to elicit (e.g., pleasure) or prevent (e.g., displeasure) determined emotions, during human product interaction. That is, the emotional design regulates the emotional interaction between the individual and the product (e.g., robot). Robot design has been a growing area whereby robots are interacting directly with humans in which emotions are essential in the interaction. Therefore, this paper aims, through a non-systematic literature review, to explore the application of emotional design, particularly on Human-Robot Interaction. Robot design features (e.g., appearance, expressing emotions and spatial distance) that affect emotional design are introduced. The chapter ends with a discussion and a conclusion.info:eu-repo/semantics/acceptedVersio

The Receptor Tyrosine Kinase FGFR4 Negatively Regulates NF-kappaB Signaling

NFκB signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NFκB activation has not been previously described, although FGFs have been known to antagonize TNFα-induced apoptosis. assays. FGF19 stimulation of endogenous FGFR4 in TNFα-treated DU145 prostate cancer cells also leads to a decrease in IKKβ activity, concomitant reduction in NFκB nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNFα treatment of DU145 cells, in comparison with TNFα alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NFκB signaling.These results identify a compelling link between FGFR4 signaling and the NFκB pathway, and reveal that FGFR4 activation leads to a negative effect on NFκB signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NFκB signaling will not be limited to FGFR4 alone