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Innovation is broadly defined as the act of introducing a new product, idea, or process. The field of surgery is built upon innovation, revolutionizing technology, science, and tools to improve patient care. While most innovative solutions are aimed at problems with a significant patient population, the process can also be used on orphan pathologies without obvious solutions. We present a case of tracheal agenesis, a rare congenital anomaly with an overwhelming mortality and few good treatment options, that benefited from the innovation process and achieved survival with no ventilator dependence at three years of age.Utilizing the framework of the innovation process akin to the Stanford Biodesign Program, 1) the parameters of the clinical problem wereA 3D-printed external bioresorbable splint was chosen as the solution. Our patient underwent airway reconstruction with "trachealization of the esophagus": esophageotracheal fistula resection, esophagotracheoplasty, and placement of a 3D-printed polycaprolactone (PCL) stent for external esophageal airway support at five months of age.The innovation process provided our team with the guidance and imperative steps necessary to develop an innovative device for the successful management of an infant survivor with Floyd Type I tracheal agenesis.We present a case of tracheal agenesis, a rare congenital anomaly with an overwhelming mortality and few good treatment options, that benefited from the innovation process and achieved survival with no ventilator dependence at three years of age.The importance of this report is to reveal how the innovation process, which is typically used for problems with significant patient population, can also be used on orphan pathologies without obvious solutions.

Pediatric dog bites are prevalent and often devastating. Population-based data on these injuries can aid public health intervention efforts. However, most existing literature comes from single institutions in urban settings. We assess a statewide cohort to compare injury characteristics in urban and rural regions and find predictors for inter-hospital transfer. Data from 1,007 injuries from 2000 to 2015 were analyzed. Patients in rural areas were younger, more likely to be white and low-income, and more likely to receive delayed patient care. Injuries occurring in public settings as opposed to the private residence were more likely to involve males, occur in low-income areas, and involve non-white patients. Patients who required inter-hospital transfer were more likely to require a surgical subspecialist and operative repair. Our population analysis reveals children living in rural areas as a previously unidentified vulnerable patient population that may be suitable targets for public health interventions.

Pediatric patients undergoing palatal surgery may experience significant postoperative pain. Undertreatment of acute postoperative pain may impact postoperative bleeding and recovery. The primary objectives of this study were to evaluate the severity of acute postoperative pain scores, analgesia management, and discharge times after palatal surgery.A retrospective chart review was performed for all patients aged18 years, born with cleft palate who underwent palatal surgery over a 1-year period. The primary outcome variable was the highest pain score recorded by the nursing staff at various time frames postoperatively.Overall, the infant/toddler group demonstrated higher postoperative pain scores throughout the first 24 hours (1- to 6-hour period, P = .015). The duration of hospital stay was significantly greater in the infant/toddler age group (P.001).The results of our study indicate that frequent pain monitoring, multimodal approach, and "round-the-clock" analgesics may be warranted in this vulnerable patient population.

Reconstruction of complex craniomaxillofacial (CMF) defects is challenging due to the highly organized layering of multiple tissue types. Such compartmentalization necessitates the precise and effective use of cells and other biologics to recapitulate the native tissue anatomy. In this study, intra-operative bioprinting (IOB) of different CMF tissues, including bone, skin, and composite (hard/soft) tissues, is demonstrated directly on rats in a surgical setting. A novel extrudable osteogenic hard tissue ink is introduced, which induced substantial bone regeneration, with approximate to 80% bone coverage area of calvarial defects in 6 weeks. Using droplet-based bioprinting, the soft tissue ink accelerated the reconstruction of full-thickness skin defects and facilitated up to 60% wound closure in 6 days. Most importantly, the use of a hybrid IOB approach is unveiled to reconstitute hard/soft composite tissues in a stratified arrangement with controlled spatial bioink deposition conforming the shape of a new composite defect model, which resulted in approximate to 80% skin wound closure in 10 days and 50% bone coverage area at Week 6. The presented approach will be absolutely unique in the clinical realm of CMF defects and will have a significant impact on translating bioprinting technologies into the clinic in the future.

Objective:This study aimed to determine whether intraoperative acetaminophen was able to decrease opioid consumption, pain scores, and length of stay while increasing oral intake in cleft palate surgery.Design/Setting/Patients:One hundred consecutive patients with cleft palate who underwent a von Langenbeck or 2-flap palatoplasty and intravelar veloplasty at a tertiary medical center by the 2 senior authors from 2010 to 2015 were reviewed.Interventions:Three intraoperative treatment groups were analyzed: intravenous (IV) acetaminophen, per rectal (PR) acetaminophen, and no acetaminophen. All patients received long-acting local anesthesia infiltration before incision. Additionally, all patients were admitted overnight and given weight-based per oral (PO) acetaminophen and oxycodone and IV morphine as needed based on pain scores.Outcomes Measured:The study outcomes included pain scores, opioid requirement, length of stay, and oral intake.Results:The treatment groups were comprised of 40 patients who received IV acetaminophen, 22 PR acetaminophen, and 35 none. Concerning demographic data, there was no statistical difference between treatment groups. There was no statistically significant difference for opioid intake, although both IV and PR acetaminophen groups had decreased pain scores ( P = .029). There was no difference in oral intake ( P = .13) or length of stay ( P = .31) between treatment groups.Conclusion:In this study, intraoperative administration of acetaminophen was associated with decreased pain scores, but no opioid-sparing effect. As other studies have shown an opioid-sparing effect with postoperative acetaminophen, we recommend withholding the intraoperative dose and beginning therapy in the immediate postoperative period.

Summary This paper makes a case for looking beyond the tropes that oversimplify the intellectual movement called Theory. It claims that this is necessary to get a glimpse of the sociocultural processes that shaped Theory and defined its moment in cultural history. This paper analyses the assumptions on which these tropes are based. Based on this analysis, it seeks to establish that Theory is not a coherent discourse that yielded knowledge of the process of reality-making, without being affected by the discourses on reality it engaged with to carve out its position. Theory is a fissured discourse whose "discoveries" were both enabled and delimited by the contexts of its articulation. In fact, Theory owes its shape to these contexts. This paper attempts to establish this thesis by studying Theory's stance vis-a-vis literature, one of the important "contexts" (for want of a better term) of Theory. Opsomming In hierdie artikel word gronde aangevoer waarom verder gekyk moet word as die trope wat die oorvereenvoudiging van die intellektuele beweging genaamd Theory tot gevolg het. Hierin word beweer dat dit noodsaaklik is om 'n vlugtige blik te kry op die sosiokulturele prosesse wat Theory beinvloed het, en waaraan sy hoogtepunt in die kultuurgeskiedenis te danke is. Die veronderstellings waarop die trope berus word in hierdie artikel ontleed. Op grond van die ontleding word betoog dat Theory nie 'n samehangende diskoers kan wees en kennis oor realiteitswording kan genereer sonder om beinvloed te word deur die realiteitsdiskoerse waaraan die beweging deelgeneem her, en waardeur hy sy posisie verwerf her nie. Theory is 'n gesplete diskoers, en die beweging se "ontdekkings" word moontlik gemaak en terselfdertyd beperk deur die kontekste waarin dit verwoord word. Theory het trouens sy vorm aan hierdie kontekste te danke. Die tese word getoets aan die hand van 'n studie van Theory se standpunt oor die letterkunde, wat (by gebrek aan 'n beter woord) een van sy belangrike "kontekste" is. ********** In literature alone, our ideas of author, audience, reading, writing, book, genre, critical theory, and of literature itself, have all suddenly become questionable--questionable but far firm invalid, reconstituting themselves in various ways. (Hassan 2009; my italics) 1 Now that the moment of high Theory has well and truly passed, it is both possible and necessary to look beyond the facile accounts that often misrepresent sociocultural phenomena like Theory. In the context of the post-Theory debates, this is the need to engage with the two dominant tropes or facile representations of Theory that are popular in the academy today: the leaven and the lump, and the organic intellectual. Interestingly, these two accounts are founded on the same assumption about Theory: doing Theory involves a new way of relating to reality. Theory gives a new handle on experience, helps us read experience against the grain. Theory, it is assumed, is like the laws of gravity that established the invisible connection among what used to be considered unrelated events, and turned common-sense notions about daily occurrences on their head thereby transforming people's experience of them. Theory's deconstruction of the foundationalist notions of "subject" and "object" of knowledge, its reconception of these essentialist categories as effects of a process, it is assumed, has not only transformed the way contemporary reality is perceived, but has empowered the Theorist to see the shape of things to come. This paper is an attempt to establish that both these accounts and the assumption underpinning them amount to an oversimplification of the phenomenon called Theory. Far from helping a student of Theory understand the dynamics of this phenomenon, they misrepresent this phenomenon in an effort to simplify it. This paper starts by making a case ['or looking beyond these "tropes" to get a glimpse of the sociocultural processes that shaped Theory and defined its moment in cultural history. …

English Studies today seems to be plagued by self-doubt. English Studies professionals appear to have lost the capacity for dialogue, as is evident from contemporary celebration of pluralism. The self-conception of Literary Studies as The 1001 Nights of literary analysis, for instance, is symptomatic of the loss of a common purpose and plan of action. The belief that good disciplinary fences make good neighbours of colleagues seems to be the foundation of practice in Literary Studies today. This new role that the discipline has scripted for itself is that of a victim, a far cry from its traditional self-image as a stakeholder in the process of social change through curricular reforms. This paper argues for the need to reinvent English Studies as a coherent discipline that can make a significant contribution to contemporary society. This paper claims that without such a self-conception, it would be difficult to profess English Studies. It invites English Studies professionals to view the recent development...

In this article it is shown that EGF stimulation leads to rapid activation of RhoG through Vav GEFs and the GEF PLEKHG6. Importantly, different cellular responses induced by EGF are determined by the available GEFs. Furthermore, this article presents results showing that EGF-stimulated cell migration and EGFR internalization are regulated by RhoG., RhoG is a member of the Rac-like subgroup of Rho GTPases and has been linked to a variety of different cellular functions. Nevertheless, many aspects of RhoG upstream and downstream signaling remain unclear; in particular, few extracellular stimuli that modulate RhoG activity have been identified. Here, we describe that stimulation of epithelial cells with epidermal growth factor leads to strong and rapid activation of RhoG. Importantly, this rapid activation was not observed with other growth factors tested. The kinetics of RhoG activation after epidermal growth factor (EGF) stimulation parallel the previously described Rac1 activation. However, we show that both GTPases are activated independently of one another. Kinase inhibition studies indicate that the rapid activation of RhoG and Rac1 after EGF treatment requires the activity of the EGF receptor kinase, but neither phosphatidylinositol 3-kinase nor Src kinases. By using nucleotide-free RhoG pull-down assays and small interfering RNA-mediated knockdown studies, we further show that guanine-nucleotide exchange factors (GEFs) of the Vav family mediate EGF-induced rapid activation of RhoG. In addition, we found that in certain cell types the recently described RhoG GEF PLEKHG6 can also contribute to the rapid activation of RhoG after EGF stimulation. Finally, we present results that show that RhoG has functions in EGF-stimulated cell migration and in regulating EGF receptor internalization.

Bathrocephaly is a posterior cranial deformity associated with failure of fusion of the mendosal suture. Infants are born with a prominent occipital bone. Here we discuss a case report of bathrocephaly in a newborn discussing management, imaging finding, differential diagnosis and relevant bony anatomy and development.

Resident dendritic cells (DC) within the T cell area of the lymph node take up soluble antigens that enter via the afferent lymphatics before antigen carrying DC arrive from the periphery. The reticular network within the lymph node is a conduit system forming the infrastructure for the fast delivery of soluble substances from the afferent lymph to the lumen of high endothelial venules (HEVs). Using high-resolution light microscopy and 3D reconstruction, we show here that these conduits are unique basement membrane-like structures ensheathed by fibroblastic reticular cells with occasional resident DC embedded within this cell layer. Conduit-associated DC are capable of taking up and processing soluble antigens transported within the conduits, whereas immigrated mature DC occur remote from the reticular fibers. The conduit system is, therefore, not a closed compartment that shuttles substances through the lymph node but represents the morphological equivalent to the filtering function of the lymph node.

FHL1, FHL2, and FHL3 are members of the four and one-half LIM domain protein subclass that are expressed in striated muscles. Here we show that FHL2 and FHL3 are novel α7β1 integrin-interacting proteins. They bind both the α- and the β-subunit as well as different splice isoforms. The minimal binding sites for FHL2 and FHL3 on β1A-chain overlap, whereas on α7A and α7B subunits they are situated adjacent. Determining the binding sites for integrins on FHL2 or FHL3 revealed that the suprastructure of the whole molecule is important for these associations, rather than any single LIM domain. Immunofluorescence studies with cells expressing full-length FHL proteins or their deletion mutants showed that FHL2 and FHL3 but not FHL1 colocalize with integrins at cell adhesion sites. Further, their recruitment to the membrane results from binding to either the α- or the β-chain of the integrin receptor. The association of FHL2 or FHL3 with integrin receptors neither influences attachment of cells to different substrates nor changes their migration capacity. However, in cardiac and skeletal muscles, FHL2 and FHL3, respectively, are colocalized with α7β1 integrin receptor at the periphery of Z-discs, suggesting a role in mechanical stabilization of muscle cells.

Supplemental Data Supplemental Figure S1 Characterization of WT and aPKC-deficient podocytes. A–C: Genomic DNA isolated from deficient and control cell lines was tested for the presence of Cre recombinase (A), floxed and WT alleles of PKCλ/ι (B), or WT and knockout alleles of PKCζ (C). As controls, genomic DNA samples of tail biopsies were used. D: Differentiated deficient or control cells were stained with antibodies against synaptopodin or WT-1. All used cell lines were positive for the tested podocyte markers. Scale bars = 50 μm. Download Supplemental Figure S2 Relative mRNA and protein expression of PKCλ/ι, PKCζ, and Def-6 in deficient and control podocytes. A–C: Real-time PCR measurements and Western blot analysis of PKCλ/ι- and PKCζ-deficient cells in comparison with control cells. A: PKCλ/ι mRNA and protein are reduced in the PKCλ/ι −/− cells. B: PKCζ mRNA and protein are reduced in the PKCζ −/− cells. C: Def-6 mRNA is up-regulated in the PKCλ/ι −/− cells but not in PKCζ −/− cells. mRNA level is normalized for HPRT-1. Def-6 protein expression is not changed. ∗∗P < 0.01. Download Supplemental Table S1 Download Supplemental Table S2 Download Supplemental Table S3 Download Supplemental Table S4 Download Supplemental Table S5 Download Supplemental Table S6 Download Supplemental Table S7 Download Supplemental Table S8 Download Supplemental Data Supplemental material for this article can be found at . The atypical protein kinase C (aPKC) isotypes PKCλ/ι and PKCζ are both expressed in podocytes; however, little is known about differences in their function. Previous studies in mice have demonstrated that podocyte-specific loss of PKCλ/ι leads to a severe glomerular phenotype, whereas mice deficient in PKCζ develop no renal phenotype. We analyzed various effects caused by PKCλ/ι and PKCζ deficiency in cultured murine podocytes. In contrast to PKCζ-deficient podocytes, PKCλ/ι-deficient podocytes exhibited a severe actin cytoskeletal phenotype, reduced cell size, decreased number of focal adhesions, and increased activation of small GTPases. Comparative microarray analysis revealed that the guanine nucleotide exchange factor Def-6 was specifically up-regulated in PKCλ/ι-deficient podocytes. In vivo Def-6 expression is significantly increased in podocytes of PKCλ/ι-deficient mice. Cultured PKCλ/ι-deficient podocytes exhibited an enhanced membrane association of Def-6, indicating enhanced activation. Overexpression of aPKCλ/ι in PKCλ/ι-deficient podocytes could reduce the membrane-associated expression of Def-6 and rescue the actin phenotype. In the present study, PKCλ/ι was identified as an important factor for actin cytoskeletal regulation in podocytes and Def-6 as a specific downstream target of PKCλ/ι that regulates the activity of small GTPases and subsequently the actin cytoskeleton of podocytes.

Focal adhesions have been intensely studied ever since their discovery in 1971. The last three decades have seen major advances in understanding the structure of focal adhesions and the functions they serve in cellular adhesion, migration, and other biological processes. In this chapter, we begin with a historical perspective of focal adhesions, provide an overview of focal adhesion biology, and highlight recent major advances in the field. Specifically, we review the different types of matrix adhesions and the role different Rho GTPases play in their formation. We discuss the relative contributions of integrin and syndecan adhesion receptors to the formation of focal adhesions. We also focus on new insights gained from studying focal adhesions on biomaterial surfaces and from the growing field of mechanotransduction. Throughout this chapter, we have highlighted areas of focal adhesion biology where major questions still remain to be answered.

Focal adhesions have been intensely studied ever since their discovery in 1971. The last three decades have seen major advances in understanding the structure of focal adhesions and the functions they serve in cellular adhesion, migration, and other biological processes. In this chapter, we begin with a historical perspective of focal adhesions, provide an overview of focal adhesion biology, and highlight recent major advances in the field. Specifically, we review the different types of matrix adhesions and the role different Rho GTPases play in their formation. We discuss the relative contributions of integrin and syndecan adhesion receptors to the formation of focal adhesions. We also focus on new insights gained from studying focal adhesions on biomaterial surfaces and from the growing field of mechanotransduction. Throughout this chapter, we have highlighted areas of focal adhesion biology where major questions still remain to be answered.

Integrin alpha7beta1 is the major laminin binding integrin receptor of muscle cells. The alpha7 chain occurs in several splice isoforms, of which alpha7A and alpha7B differ in their intracellular domains only. The fact that the expression of alpha7A and alpha7B is tightly regulated during skeletal muscle development suggests different and distinct roles for both isoforms. However, so far, functional properties and interacting proteins were described for the alpha7B chain only. Using a yeast two-hybrid screen, we have found that Def-6, a guanine nucleotide exchange factor for Rac1, binds to the intracellular domain of the alpha7A subunit. The specificity of the Def-6-alpha7A interaction has been shown by direct yeast two-hybrid binding assays and coprecipitation experiments. This is the first description of an alpha7A-specific and -exclusive interaction, because Def-6 did not bind to any other tested integrin cytoplasmic domain. Interestingly, the binding of Def-6 to alpha7A was abolished, when cells were cotransfected with an Src-related kinase, which is known to phosphorylate Def-6 and stimulate its exchange activity. We found expression of Def-6 was not only restricted to T-lymphocytes as described thus far but in a more widespread manner, including different muscle tissues. In cells, Def-6 is seen in newly forming cell protrusions and focal adhesions, and its localization partially overlaps with the alpha7A integrin receptor. C2C12 myoblasts overexpressing Def-6 show a delay of Rac1 inactivation during myogenic differentiation and abnormal myotube formation. Thus, our data suggest a role for Def-6 in the fine regulation of Rac1 during myogenesis with the integrin alpha7A chain guiding this regulation in a spatio-temporal manner.

During trans-endothelial migration (TEM), leukocytes use adhesion receptors such as intercellular adhesion molecule-1 (ICAM1) to adhere to the endothelium. In response to this interaction, the endothelium throws up dynamic membrane protrusions, forming a cup that partially surrounds the adherent leukocyte. Little is known about the signaling pathways that regulate cup formation. In this study, we show that RhoG is activated downstream from ICAM1 engagement. This activation requires the intracellular domain of ICAM1. ICAM1 colocalizes with RhoG and binds to the RhoG-specific SH3-containing guanine-nucleotide exchange factor (SGEF). The SH3 domain of SGEF mediates this interaction. Depletion of endothelial RhoG by small interfering RNA does not affect leukocyte adhesion but decreases cup formation and inhibits leukocyte TEM. Silencing SGEF also results in a substantial reduction in RhoG activity, cup formation, and TEM. Together, these results identify a new signaling pathway involving RhoG and its exchange factor SGEF downstream from ICAM1 that is critical for leukocyte TEM.

FHL1, FHL2, and FHL3 are members of the four and one-half LIM domain protein subclass that are expressed in striated muscles. Here we show that FHL2 and FHL3 are novel alpha(7)beta(1) integrin-interacting proteins. They bind both the alpha- and the beta-subunit as well as different splice isoforms. The minimal binding sites for FHL2 and FHL3 on beta(1A)-chain overlap, whereas on alpha(7A) and alpha(7B) subunits they are situated adjacent. Determining the binding sites for integrins on FHL2 or FHL3 revealed that the suprastructure of the whole molecule is important for these associations, rather than any single LIM domain. Immunofluorescence studies with cells expressing full-length FHL proteins or their deletion mutants showed that FHL2 and FHL3 but not FHL1 colocalize with integrins at cell adhesion sites. Further, their recruitment to the membrane results from binding to either the alpha- or the beta-chain of the integrin receptor. The association of FHL2 or FHL3 with integrin receptors neither influences attachment of cells to different substrates nor changes their migration capacity. However, in cardiac and skeletal muscles, FHL2 and FHL3, respectively, are colocalized with alpha(7)beta(1) integrin receptor at the periphery of Z-discs, suggesting a role in mechanical stabilization of muscle cells.