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Clear cell carcinoma (CCC) of the vulva is extremely rare. We report a case of a 54-year-old woman who presented with a 5 cm mass of the mons pubis. She underwent needle biopsy demonstrating CCC. She then underwent radical vulvectomy with bilateral inguinofemoral lymph node dissection. Surgical pathology revealed CCC of the vulva with lymphovascular space invasion (LVSI) and metastatic carcinoma in 1/7 inguinal lymph nodes. The patient has a history of endometriosis, raising suspicion that her CCC could have arisen from endometriosis in the mons. She completed adjuvant treatment with cisplatin and concurrent external beam radiation therapy with radiographic evidence of complete response. However, short-interval imaging demonstrated multi-focal recurrence, which was confirmed with supraclavicular lymph node biopsy. She then completed 8 cycles carboplatin, paclitaxel, and biosimilar bevacizumab-bvzr with favorable response on imaging. She was continued on bevacizumab maintenance. She was later started on pembroluzimab for disease progression based on new mediastinal adenopathy and worsening retroperitoneal lymphadenopathy. She received eight cycles of pembrolizumab with ongoing disease progression before enrolling in hospice and discontinuing cancer-directed treatment. As described in the related literature which we summarize here, the majority of reported cases of vulvar CCC arise from endometriosis implants at the site of prior episiotomy or from the Bartholin's gland. This patient had clinical history of endometriosis; prior tissue sampling was not performed to support the diagnosis. Given the absence of data regarding this rare type of primary vulvar cancer, treatment of this patient's disease was based on existing data specific to squamous cell carcinoma of the vulva and extrapolated from treatment guidelines for CCC of the ovary and endometrium. Continued research is needed on this rare form of vulvar carcinoma to determine the risk factors, prognostic factors, and treatment recommendations specific to this disease.

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BACKGROUND: The goals of our study were to describe the types of family accommodation for parents of hospitalized children and to examine their influence on the pediatric hospital experience. METHODS: This multi-site cohort survey included 10 hospitals in Ontario Province, Canada. Participants were parents of inpatient children (n = 1240). Main outcome measures included ratings of three parent-reported measures of hospital experience: overall hospital experience; willingness to recommend the hospital to family or friends; and how much the accommodation type helped parent stay involved in their child's hospital care. RESULTS: Parents most often stayed in the child's room (74.7%), their own home (12.3%), hotel (4.0%) or a Ronald McDonald House (3.0%). Accommodation varied based on hospital, parent and child factors. Length of stay and the child's health status were significant predictors for overall hospital experience and recommending the hospital to family or friends, but accommodation type was not. Families who stayed at a Ronald McDonald House reported greater involvement in their child's care compared with other accommodation types (odds ratio: 1.54-20.73 for contrasted accommodation types). CONCLUSION: Use of different overnight accommodations for families of hospitalized pediatric patients in Canada is similar to a previous report of U.S. family hospital accommodations. In contrast to the previous U.S. findings, Canadian hospital experience scores were lower and accommodation type was not a significant predictor of overall hospital experience or willingness to recommend the hospital. In Canada, as in the U.S., families who stayed at a Ronald McDonald House reported that this accommodation type significantly improved their ability to be involved in their child's care.

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Enhancing the endogenous regenerative capacity of the mammalian heart is a promising strategy that can lead to potential treatment of injured cardiac tissues. Studies on heart regeneration in zebrafish and neonatal mice have shown that cardiomyocyte proliferation is essential for replenishing myocardium. We will review recent advancements that have demonstrated the importance of Neuregulin 1/ErbB2 and innervation in regulating cardiomyocyte proliferation using both adult zebrafish and neonatal mouse heart regeneration models. Emerging findings suggest that different populations of macrophages and inflammation might contribute to regenerative versus fibrotic responses. Finally, we will discuss variation in the severity of the cardiac injury and size of the wound, which may explain the range of outcomes observed in different injury models.

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PURPOSE: The purpose of this paper is to describe an international survey of hospital executives and administrators' perspectives on the contributions of their affiliation with a Ronald McDonald House (RMH) as an example of accommodation in family-centered care to the hospital's mission, operations and patient experience. DESIGN/METHODOLOGY/APPROACH: RMHs worldwide provided the names and e-mail addresses of the people holding key leadership positions in their main hospital partner, who in turn were invited to complete an internet-based survey (530 participants; response rate of 54.5 percent). FINDINGS: Hospital leaders reported very positive opinions about the contributions of their RMHs affiliation to their ability to serve seriously ill children and their families. This included such important outcomes as increasing family integrity and family participation in care decisions; and decreasing psychosocial stress and hospital social work resource burdens associated with lodging, food, transportation and sibling support. Hospital chief executive offices (CEOs) and medical directors reported very strong and positive opinions regarding the value-added of their RMHs affiliation in many areas, including enhanced marketing of hospital specialty services and reduced length of stay. RESEARCH LIMITATIONS/IMPLICATIONS: Survey response bias is a limitation, although the results are still useful in terms of identifying multiple ways in which RMHs are perceived as contributing to hospitals' operations and provision of family-centered care. PRACTICAL IMPLICATIONS: Overall, the results suggest that, internationally, hospital leaders believe that RMHs play a key and valued role in their provision of family-centered care to seriously ill children and their families. SOCIAL IMPLICATIONS: Family accommodation is more than the simple provision of lodging and plays an integral role how hospitals approach family-centered care. ORIGINALITY/VALUE: This international study contributes to the general literature on the role of family accommodation in hospitals' provision of family-centered care and the specific and very sparse literature on RMHs in particular.

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Patient and family experiences are important indicators of quality of care and little is known about how family accommodation affects hospital experience. We added questions about accommodation to standardized inpatient pediatric and neonatal intensive care unit family experience surveys at 10 U.S. hospitals to determine the accommodation types used by families, compare characteristics across accommodation types and explore accommodation-type influences on overall hospital experience outcomes. Parents of inpatient children (n = 5,105; 93.4%) most often stayed in the child's room (76.8%). Parents of neonatal intensive care unit infants (n = 362; 6.6%) most often stayed overnight in their own home or with relatives/friends (47.2%). Accommodation varied based on hospital, parent, and child factors. Accommodation type was a significant predictor for most hospital experience outcomes, with families who stayed at a Ronald McDonald House reporting more positive overall hospital experiences (odds ratios: ranging from 1.83 to 4.86 for contrasted accommodation types and three experience outcomes).

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Neonatal mouse hearts fully regenerate after ventricular resection similar to adult zebrafish. We established cryoinjury models to determine if different types and varying degrees of severity in cardiac injuries trigger different responses in neonatal mouse hearts. In contrast to ventricular resection, neonatal mouse hearts fail to regenerate and show severe impairment of cardiac function post transmural cryoinjury. However, neonatal hearts fully recover after non-transmural cryoinjury. Interestingly, cardiomyocyte proliferation does not significantly increase in neonatal mouse hearts after cryoinjuries. Epicardial activation and new coronary vessel formation occur after cryoinjury. The profibrotic marker PAI-1 is highly expressed after transmural but not non-transmural cryoinjuries, which may contribute to the differential scarring. Our results suggest that regenerative medicine strategies for heart injuries should vary depending on the nature of the injury.

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BACKGROUND: Embryonic lung development is instructed by crosstalk between mesenchyme and epithelia, which results in activation of transcriptional factors, such as Sox9, in a temporospatial manner. Sox9 is expressed in both distal lung epithelium and proximal lung mesenchyme. Here, we investigated the effect of lung mesenchyme-specific inducible deletion of Sox9 during murine lung development. RESULTS: Transgenic mice lacking Sox9 expression were unable to breathe and died at birth, with noticeable tracheal defects. Cartilage rings were missing, and the tracheal lumen was collapsed in the mutant trachea. In situ hybridization showed an altered expression pattern of Tbx4, Tbx5 and Fgf10 genes and marked reduction of Collagen2 expression in the tracheal mesenchyme. The tracheal phenotype was increasingly severe, with longer duration of deletion. Lymphatic vasculature was underdeveloped in the mutant trachea: Prox1, Lyve1, and Vegfr3 were decreased after Sox9 knockout. We also found that compared with normal tracheal epithelium, the mutant tracheal epithelium had an altered morphology with fewer P63-positive cells and more CC10-positive cells, fewer goblet cells, and downregulation of surfactant proteins A and C. CONCLUSION: The appropriate temporospatial expression of Sox9 in lung mesenchyme is necessary for appropriate tracheal cartilage formation, lymphatic vasculature system development, and epithelial differentiation. We uncovered a novel mechanism of lung epithelium differentiation: tracheal cartilage rings instruct the tracheal epithelium to differentiate properly during embryonic development. Thus, besides having a mechanical function, tracheal cartilage also appears to be a local signaling structure in the embryonic lung.

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Family accommodation programs, such as Ronald McDonald House® (RMH), aim to facilitate family proximity and family-centered care during a child's hospitalization, yet little is known about how the programs influence family experience. The aim of this study was to investigate the perspectives of families regarding the impact of the RMH stay on the family and their hospital experience and to explore the influence of demographic and clinical factors on family member views about their experience and outcome of their child's hospitalization. Family members who spent one or more nights at an RMH in Southern California completed a cross-sectional, self-report survey that included descriptive information about the family and the hospital experience. The 2,081 respondents (53% mothers, 24% fathers, 7% other family members, and 15% multiple family members) generally reported positive experiences at RMH. Although effect sizes were small, families who stayed together for at least a portion of their stay believed more strongly that their ability to stay nearby improved their child's recovery and that RMH helped their family to stay together. Cultural differences were also evident, with Hispanic families believing more strongly that RMH shortened their child's hospital stay. A family's ability to stay together and in close proximity during a pediatric hospital stay is facilitated by accommodations such as RMH and provides important benefits in terms of family experience, psychosocial well-being, and perceptions of child recovery. These services also contribute meaningfully to the priority of providing family-centered care.

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Unlike zebrafish and newt hearts, mammalian hearts have limited capacity to regenerate. Upon injury or disease, the adult mammalian hearts form a fibrotic scar. Recently, it was shown that neonatal mouse hearts can regenerate similarly to adult zebrafish hearts. However, this capacity quickly decreases after postnatal day 7 (P7). Understanding the molecular mechanisms underlying neonatal heart regeneration might lead to therapeutic approaches for regenerating adult mammalian hearts. In this study, we utilized an inducible transgenic mouse model to determine the effects of FGF10 growth factor over expression on neonatal mouse heart regeneration/repair. Over expression of FGF10 in myocardium enhanced the expansion of Wt1 positive epicardial cells at 21 days after heart injury through increased proliferation. However, this expansion of epicardial cells did not lead to increased epithelial-to-mesenchymal transition or affect fibroblast formation or fibrosis, as seen by vimentin expression, after heart injury. Furthermore, neither continuous nor transient expression of FGF10 did not affect scar thickness or length after heart injury in neonatal hearts. Our results suggest that FGF10 can regulate epicardial cell expansion of neonatal mouse hearts after injury; however, FGF10 alone is not sufficient to cause beneficial effects on heart repair.

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Epithelial to mesenchymal transition (EMT) is a key process during embryonic development and disease development and progression. During EMT, epithelial cells lose epithelial features and express mesenchymal cell markers, which correlate with increased cell migration and invasion. Transforming growth factor-ß (TGF-ß) is a multifunctional cytokine that induces EMT in multiple cell types. The TGF-ß pathway is regulated by microRNAs (miRNAs), which are small non-coding RNAs regulating the translation of specific messenger RNAs.Herein, we identified mir-99a and mir-99b as two novel TGF-ß target miRNA genes, the expression of which increased during TGF-ß induced EMT of NMUMG cells. Mir-99a and mir-99b inhibition decreased TGF-ß activity by inhibiting SMAD3 phosphorylation, resulting in decreased migration and increased proliferation in response to TGF-ß. However, mir-99a and mir-99b inhibition was insufficient to block TGF-ß induced EMT of NMUMG cells.Mir-99a and mir-99b over-expression in epithelial NMUMG cells resulted in increased proliferation, migration and fibronectin expression, while E-cadherin and ZO-1 expression were negatively regulated.In conclusion, we identified mir-99a and mir-99b as two novel modulators of TGF-ß pathway that alter SMAD3 phosphorylation, in turn altering cell migration and adhesion of mesenchymal NMUMG cells. The effect of mir-99a and mir-99b over-expression on NMUMUG proliferation is dependent upon the epithelial or mesenchymal status of the cells. Our study suggests that mir-99a and mir-99b may function as modulators within a complex network of factors regulating TGF-ß induced breast epithelial to mesenchymal transition, as well as proliferation and migration of breast cancer cells, providing a possible target for future translationally oriented studies in this area.

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We describe here a protocol for culturing epicardial cells from adult zebrafish hearts, which have a unique regenerative capacity after injury. Briefly, zebrafish hearts first undergo ventricular amputation or sham operation. Next, the hearts are excised and explanted onto fibrin gels prepared in advance in a multiwell tissue culture plate. The procedure allows the epicardial cells to outgrow from the ventricle onto a fibrin matrix in vitro. This protocol differs from those used in other organisms by using a fibrin gel to mimic blood clots that normally form after injury and that are essential for proper cell migration. The culture procedure can be accomplished within 5 h; epicardial cells can be obtained within 24-48 h and can be maintained in culture for 5-6 d. This protocol can be used to investigate the mechanisms underlying epicardial cell migration, proliferation and epithelial-to-mesenchymal transition during heart regeneration, homeostatic cardiac growth or other physiological processes.

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Mammary gland development starts in utero with one or several pairs of mammary rudiments (MRs) budding from the surface ectodermal component of the mammalian embryonic skin. Mice develop five pairs, numbered MR1 to MR5 from pectoral to inguinal position. We have previously shown that Gli3(Xt-J/Xt-J) mutant embryos, which lack the transcription factor Gli3, do not form MR3 and MR5. We show here that two days after the MRs emerge, Gli3(Xt-J/Xt-J) MR1 is 20% smaller, and Gli3(Xt-J/Xt-J) MR2 and MR4 are 50% smaller than their wild type (wt) counterparts. Moreover, while wt MRs sink into the underlying dermis, Gli3(Xt-J/Xt-J) MR4 and MR2 protrude outwardly, to different extents. To understand why each of these five pairs of functionally identical organs has its own, distinct response to the absence of Gli3, we determined which cellular mechanisms regulate growth of the individual MRs, and whether and how Gli3 regulates these mechanisms. We found a 5.5 to 10.7-fold lower cell proliferation rate in wt MRs compared to their adjacent surface ectoderm, indicating that MRs do not emerge or grow via locally enhanced cell proliferation. Cell-tracing experiments showed that surface ectodermal cells are recruited toward the positions where MRs emerge, and contribute to MR growth during at least two days. During the second day of MR development, peripheral cells within the MRs undergo hypertrophy, which also contributes to MR growth. Limited apoptotic cell death counterbalances MR growth. The relative contribution of each of these processes varies among the five MRs. Furthermore, each of these processes is impaired in the absence of Gli3, but to different extents in each MR. This differential involvement of Gli3 explains the variation in phenotype among Gli3(Xt-J/Xt-J) MRs, and may help to understand the variation in numbers and positions of mammary glands among mammals.

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A zebrafish heart can fully regenerate after amputation of up to 20% of its ventricle. During this process, newly formed coronary blood vessels revascularize the regenerating tissue. The formation of coronary blood vessels during zebrafish heart regeneration likely recapitulates embryonic coronary vessel development, which involves the activation and proliferation of the epicardium, followed by an epithelial-to-mesenchymal transition. The molecular and cellular mechanisms underlying these processes are not well understood. We examined the role of PDGF signaling in explant-derived primary cultured epicardial cells in vitro and in regenerating zebrafish hearts in vivo. We observed that mural and mesenchymal cell markers, including pdgfrß, are up-regulated in the regenerating hearts. Using a primary culture of epicardial cells derived from heart explants, we found that PDGF signaling is essential for epicardial cell proliferation. PDGF also induces stress fibers and loss of cell-cell contacts of epicardial cells in explant culture. This effect is mediated by Rho-associated protein kinase. Inhibition of PDGF signaling in vivo impairs epicardial cell proliferation, expression of mesenchymal and mural cell markers, and coronary blood vessel formation. Our data suggest that PDGF signaling plays important roles in epicardial function and coronary vessel formation during heart regeneration in zebrafish.

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Shrimp Sicyonia ingentis were either injected with Vibrio parahaemolyticus (10(4) CFU) or V. harveyi (10(6) CFU) or immersed in ASW containing either species at 10(5) CFU ml(-1). These densities were shown in preliminary experiments to kill approximately half the population by 7 d. On Day 7, surviving shrimp were classified as either diseased or apparently healthy, and their midgut trunks (MGT) were examined by light and electron microscopy. All shrimp immersed in ASW containing either species of Vibrio showed detachment of the epithelium in the MGT. In shrimp injected with either species of Vibrio, epithelial detachment was common in diseased shrimp but not in apparently healthy animals. Experiments with live shrimp were supported by in vitro experiments where MGTs were removed, tied off at both ends, and injected with either pathogenic bacteria (V. parahaemolyticus or V. harveyi), non-pathogenic bacteria (Bacillus subtilis or Escherichia coli), or ASW. After 2 h incubations in ASW at 15 degrees C, the MGTs were processed and examined. The epithelium consistently detached from isolated MGTs injected with either species of Vibrio, but not from MGTs injected with non-pathogenic bacteria or ASW. Because the MGT epithelium secretes the peritrophic membrane, loss of the epithelium eliminates 2 layers that may restrict penetration of ingested pathogens into the shrimp body and may disrupt the osmoregulatory function of the MGT. A second finding was that fixed, large-granule hemocytes associated with the basal lamina degranulated in the presence of the 2 species of Vibrio, but not with the non-pathogenic bacteria or ASW. These blood cells may help fight specific bacteria penetrating the MGT.

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