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Purpose: The purpose of this article is to describe current tracheal suctioning practices of physiotherapists in the province of Ontario and to determine what factors influence these practices. Method: A cross-sectional online survey was conducted. An online survey link and quick response code were mailed to Ontario physiotherapists who were actively providing patient care and were authorized to perform tracheal suctioning as identified by the College of Physiotherapists of Ontario. Results: Ninety physiotherapists participated in the survey (23% response rate). Most (66%) suctioned in an intensive care setting, and many (41%) reported frequently using a closed endotracheal suctioning system. Hyperoxygenation was frequently performed before suctioning by 48% of participants, and only 18% frequently hyperoxygenated after suctioning. Most participants reported infrequently performing saline instillation (52%) and infrequently hyperinflating before suctioning (79%). Clean gloves were reported as the personal protective equipment most frequently worn across all suctioning approaches, and goggles and sterile gloves were least often worn while suctioning. Previous suctioning experience had the most influence on suctioning practices, and limited access to equipment had the least influence. Conclusions: Some of the tracheal suctioning practices of physiotherapists in Ontario vary from evidence-based clinical guidelines.

RATIONALE: Given that airway suctioning is a higher-risk treatment technique, it is important to assess the competence of health care professional that perform it.OBJECTIVES: The objectives of this...

Ehlers-Danlos syndrome (EDS) describes a group of heritable disorders of connective tissue comprising mutations in the genes involved in the structure and/or biosynthesis of collagen. Thirteen EDS subtypes are recognized, with a wide degree of symptom overlap among subtypes and with other connective tissue disorders. The clinical hallmarks of EDS are tissue fragility, joint hypermobility, and skin hyperextensibility. Appropriate diagnosis of EDS is important for correct multidisciplinary management and is associated with better clinical outcomes for patients.

Purpose: Although health care professional education programmes around the world are increasingly using sophisticated simulation technology, the scope of simulation use in Canadian physiotherapy programmes is currently undefined. The current study explores the definitions of simulation, its current use, and the perceived benefits and barriers in Canadian entry-to-practice physiotherapy programmes. Method: Using a qualitative, descriptive study approach, we contacted Canadian physiotherapy programmes to identify faculty members with simulation experience. Using a semi-structured interview format, we asked participants to discuss their perspectives of simulation in their physiotherapy programmes. Interviews were audio recorded, transcribed, and analyzed for themes. Results: Of 13 eligible Canadian physiotherapy programmes, participants from 8 were interviewed. The interviews revealed three major themes: (1) variability in the definition of fidelity in simulation, (2) variability in simulation use, and (3) the benefits of and barriers to the use of simulation. Conclusions: Variability in the definition of fidelity in simulation among Canadian physiotherapy programmes is consistent with the current literature, highlighting a spectrum of complexity from low fidelity to high fidelity. Physiotherapy programmes are using a variety of simulations, with the aim of creating a bridge from theoretical knowledge to clinical practice. This study describes the starting point for characterizing simulation implementation in Canadian physiotherapy programmes and reflects the diversity that exists across the country.

Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD). Experimental Design: A breast tissue matched case–control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells). Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+ cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4–23.1) for subsequent breast cancer risk. Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945–52. ©2017 AACR.

Computer models have proven to be useful tools in studying epidemic disease in human populations. Such models are being used by a broader base of researchers, and it has become more important to ensure that descriptions of model construction and data analyses are clear and communicate important features of model structure. Papers describing computer models of infectious disease often lack a clear description of how the data are aggregated and whether or not non-epidemic runs are excluded from analyses. Given that there is no concrete quantitative definition of what constitutes an epidemic within the public health literature, each modeler must decide on a strategy for identifying epidemics during simulation runs. Here, an SEIR model was used to test the effects of how varying the cutoff for considering a run an epidemic changes potential interpretations of simulation outcomes. Varying the cutoff from 0% to 15% of the model population ever infected with the illness generated significant differences in numbers of dead and timing variables. These results are important for those who use models to form public health policy, in which questions of timing or implementation of interventions might be answered using findings from computer simulation models.

Testosterone has been shown to have dose-dependent effects on spatial memory in males, but the effects of aging upon this relationship remain unclear. Additionally, the mechanism by which testosterone regulates memory is unknown, but may involve changes in brain-derived neurotrophic factor (BDNF) within specific brain regions. We tested the effects of age and testosterone on spatial memory among male rats using two spatial memory tasks: an object-location memory task (OLMT) and the radial-arm maze (RAM). Castration had minimal effect on performance on the RAM, but young rats (2 months) performed significantly fewer working memory errors than aged rats (20 months), and aged rats performed significantly fewer reference memory errors. Both age and castration impaired performance on the OLMT, with only the young rats with intact gonads successfully performing the task. Subsequent experiments involved daily injections of either drug vehicle or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.00 mg/rat) given to castrated aged males. On the RAM, a low physiological dose (0.125 mg) and high doses (0.500-1.000 mg) of testosterone improved working memory, while an intermediate dose (0.250 mg) did not. On the OLMT, only the 0.250 mg T group showed a significant increase in exploration ratios from the exposure trials to the testing trials, indicating that this group remembered the position of the objects. Brain tissue (prefrontal cortex, hippocampus, and striatum) was collected from all subjects to assay BDNF. We found no evidence that testosterone influenced BDNF, indicating that it is unlikely that testosterone regulates spatial memory through changes in BDNF levels.

Previous research on activational effects of testosterone on spatial memory has produced mixed results, possibly because the effects of testosterone on memory are dose-dependent effects. We tested a wide range of testosterone doses using two spatial memory tasks: a working-reference memory version of the radial-arm maze (RAM) and an object location memory task (OLMT). Adult male Sprague-Dawley rats were castrated or sham-castrated and given daily injections of drug vehicle (Oil Sham and Oil GDX) or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.000 mg T) beginning seven days before the first day of behavioral tests and continuing throughout testing. For the RAM, four arms of the maze were consistently baited on each day of testing. Testosterone had a significant effect on working memory on the RAM, with the Oil Sham, 0.125 mg T, and 0.500 mg T groups performing better than the Oil GDX group. In contrast, there was no significant effect of testosterone on spatial reference memory on the RAM. For the OLMT, we tested long-term memory using a 2 h inter-trial interval between first exposure to two identical objects and re-exposure after one object had been moved. Only the 0.125 and 0.500 mg T groups showed a significant increase in exploration of the moved object during the testing trials, indicating better memory than all other groups. Testosterone replacement restored spatial memory among castrated male rats on both behavioral tasks, but there was a complex dose-response relationship; therefore, the therapeutic value of testosterone is likely sensitive to dose.

// Christine Mehner 1 , Alexandra Hockla 1 , Erin Miller 1 , Sophia Ran 2 , Derek C. Radisky 1,* and Evette S. Radisky 1,* 1 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 2 Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL Correspondence: Evette S. Radisky, email: // Derek C. Radisky, email: // Keywords : triple negative breast cancer, basal-like breast cancer, matrix metalloproteinases, invasion, metastasis, mouse orthotopic tumor models, bioluminescence imaging Received : March 3, 2014 Accepted : April 30, 2014 Published : May 1, 2014 Abstract Matrix metalloproteinases (MMPs) have been implicated in diverse roles in breast cancer development and progression. While many of the different MMPs expressed in breast cancer are produced by stromal cells MMP-9 is produced mainly by the tumor cells themselves. To date, the functional role of tumor cell-produced MMP-9 has remained unclear. Here, we show that human breast cancer cell-produced MMP-9 is specifically required for invasion in cell culture and for pulmonary metastasis in a mouse orthotopic model of basal-like breast cancer. We also find that tumor cell-produced MMP-9 promotes tumor vascularization with only modest impact on primary tumor growth, and that silencing of MMP-9 expression in tumor cells leads to an altered transcriptional program consistent with reversion to a less malignant phenotype. MMP-9 is most highly expressed in human basal-like and triple negative tumors, where our data suggest that it contributes to metastatic progression. Our results suggest that MMP9 may offer a target for anti-metastatic therapies for basal-like triple negative breast cancers, a poor prognosis subtype with few available molecularly targeted therapeutic options.

Background Optimal breastfeeding has benefits for the mother-infant dyads. This study investigated the prevalence and determinants of cessation of exclusive breastfeeding (EBF) in the early postnatal period in a culturally and linguistically diverse population in Sydney, New South Wales, Australia. Methods The study used routinely collected perinatal data on all live births in 2014 (N = 17,564) in public health facilities in two Local Health Districts in Sydney, Australia. The prevalence of mother’s breastfeeding intention, skin-to-skin contact, EBF at birth, discharge and early postnatal period (1–4 weeks postnatal) were estimated. Multivariate logistic regression models that adjusted for confounders were conducted to determine association between cessation of EBF in the early postnatal period and socio-demographic, psychosocial and health service factors. Results Most mothers intended to breastfeed (92%), practiced skin-to-skin contact (81%), exclusively breastfed at delivery (90%) and discharge (89%). However, the prevalence of EBF declined (by 27%) at the early postnatal period (62%). Younger mothers (

Basal subtype breast cancers have a particularly poor prognosis, with high invasiveness and resistance to most targeted therapies. TGFβ and MYC drive central features of basal breast cancer: TGFβ is an autocrine and paracrine signaling factor that drives cell invasion and metastasis, and MYC is a central regulator of cellular proliferation that is upregulated in many cancer types. We show here that genetic or pharmacologic inhibition of MYC in MCF10A basal breast cells results in increased sensitivity to TGFβ-stimulated invasion and metastasis and also show that this signaling loop is dependent on activation of SRC. Analysis of human breast cancer datasets and additional experiments with breast cancer cell lines further suggest the relevance of this signaling loop in basal, but not luminal, breast cancers. Our results imply precaution should be taken when utilizing therapeutic inhibitors of MYC with basal breast cancer patients as this could lead to increased metastasis; however, simultaneous pharmacologic inhibition of SRC and MYC for these patients could facilitate the antiproliferative effects of MYC inhibition while blocking the consequent promotion of metastasis. Cancer Res; 76(12); 3520–30. ©2016 AACR.

Breast, lung, and pancreatic cancers collectively represent one third of all diagnosed tumors and are responsible for almost 40% of overall cancer mortality. Despite improvements in current treatments, efforts to develop more specific therapeutic options are warranted. Here we identify matrix metalloproteinase 3 (MMP3) as a potential target within all three of these tumor types. MMP3 has previously been shown to induce expression of Rac1b, a tumorigenic splice isoform of Rac1. In this study we find that MMP3 and Rac1b proteins are both strongly expressed by the tumor cells of all three tumor types and that expression of MMP3 protein is prognostic of poor survival in pancreatic cancer patients. We also find that MMP3 gene expression can serve as a prognostic marker for patient survival in breast and lung cancer. These results suggest an oncogenic MMP3-Rac1b signaling axis as a driver of tumor progression in three common poor prognosis tumor types, further suggesting that new therapies to target these pathways could have substantial therapeutic benefit.

Objective:To investigate the mechanism of propranolol on regression of infantile hemangiomas.Background:Propranolol has been found to be effective in treatment of severe hemangiomas of infancy. However, its mechanism of action is as yet unknown.Methods:Cultured proliferating and involuting hemangiom

The Healthy Homes and Neighbourhoods (HHAN) Program provides long term care coordination to families with complex health and social needs, in the Sydney Local Health District (SLHD). Referral during the antenatal period is the preferred pathway, aiming to ensure complex families have support for themselves and their child, commencing in the period prior to birth. Previous geospatial mapping has identified two areas of clustered disadvantage within SLHD. Following identification of reduced attendance at one of two SLHD antenatal clinics, a HHAN care coordinator established communications with two hospitals in adjoining health districts to discover patterns of attendance for “out of area” pregnant women. Reasons for attendance at these “out of area” antenatal clinics is uncertain at this stage, but Local Government has identified gaps in public transport to the secondary SLHD hospital. Further research into cross boundary hospital attendance will be undertaken. By attending the adjacent Local Health District’s psychosocial meetings, HHAN aims to identify and engage with vulnerable women and their families, living with SLHD, but attending “out of area” health services. Engagement with adjoining health districts helps to integrate health and social care services beyond our local health district borders, which is vital for families living within previously identified areas of disadvantage. This initiative targeted pregnant women, and their families, with complex health and social needs residing in SLHD who were utilising antenatal health services outside SLHD boundaries. Engagement with health and social care providers across local health district boundaries is essential as HHAN aims to ensure vulnerable women and their families are not “falling through the cracks”. This presentation will focus on the initial collaboration between nurses/midwives and social workers, based in bordering health districts with the common aim of providing client focused support. Attendance at adjacent health district psychosocial meeting commenced in July 2017, following a period of discussion between health districts to acknowledge the identified gap in SLHD antenatal attendance and recognition of cross boundary health utilisation. Ongoing collaboration is planned to allow for seamless referral into the HHAN program and other health and social care services. Inter-Health District Care Coordination is a developing area within Australian public health. This Sydney-based, high-risk, antenatal pathway demonstrates to health care providers and their consumers that flexible support is possible across health boundaries. Interdisciplinary, cross health district collaboration is an essential current and future pathway to improve outcomes in the most vulnerable members of our population. The development of a trusting relationship between HHAN care coordinators, service providers and their clients has been an integral component of the success of the Healthy Homes and Neighbourhoods Program. This inter-health district liaison is enhancing communication and planning across health borders. Challenging and supporting health and social care partners to think and act outside their geographical boundaries is essential for ongoing change in these sectors, as we put the consumer and their complex lives at the forefront of our care. Whilst change is challenging, collaboration between health service providers is one step towards providing timely, integrated supportive care for vulnerable families.

True ossification within benign brain tumors is rare, and the molecular mechanism for this process is poorly understood. The authors report a case of ossified choroid plexus papilloma (CPP) and analyze it to help elucidate the underlying molecular basis of osteogenesis in benign brain tumors. A 21-year-old man presented with headache and depression that progressed over years. Computed tomography, MRI, and angiography demonstrated a large heavily calcified fourth ventricular tumor with a vascular blush and no hydrocephalus. The tumor was resected and was found to be an ossified CPP. Immunohistochemical staining for VEGF, Sox2, BMP-2, osterix, osteopontin, and osteocalcin was performed in an attempt to elucidate the mechanism of bone formation. The tumor was extensively ossified with mature bone trabeculae. Immunostaining for VEGF was positive. Additional staining showed the presence of osteocalcin in this ossified tumor but not in samples of nonossified CPPs collected from other patients. Staining for osterix and osteopontin was equivocally positive in the ossified CPP but also in the nonossified CPPs examined. The presence of osteocalcin in the ossified CPP demonstrates that there is true bone formation rather than simple calcification. Its appearance within cells around the trabeculae suggests the presence of osteoblasts. The presence of osterix suggests that a pluripotent cell, or one that is already partially differentiated, may be differentiated into an osteoblast through this pathway. This represents the first systematic immunohistochemical analysis of osteogenesis within choroid plexus tumors.

BACKGROUND The aim of this study was to compare the incidence of neuroma formation and neuropathic pain following different techniques of nerve ablation in a rat sural nerve model. METHODS Rat sural nerve was subjected to four different techniques of ablation with standardized creation of a 1-cm gap (n = 15 in each group). These included nerve avulsion, transection and burying in muscle, transection and folding of nerve, and transection alone. Animals were killed after 3 months. Explanted nerves were sectioned and stained with Masson trichrome and S-100 stain against neural tissue. The maximal neural cross-sectional area and neural-to-connective tissue ratio was quantified. Quantitative reverse-transcriptase polymerase chain reaction (n = 5) was used to analyze relative mRNA expression of ciliary neurotrophic factor and calcitonin gene-related peptide. RESULTS Neural cross-sectional area was statistically increased (p < 0.05) compared with controls in folded, muscle buried, and transected specimens but decreased in avulsed specimens. The neural-to-connective tissue ratio was statistically decreased in the avulsed group. Relative mRNA expression of ciliary neurotrophic factor was lowest in muscle buried (4 percent of control) (p < 0.05) and avulsed specimens (15 percent of control) (p < 0.05) and higher in folded (52 percent of control) and transected specimens (75 percent of control). Relative mRNA expression of calcitonin gene-related peptide was highest in folded specimens (302 percent of control) (p < 0.05). CONCLUSIONS Folding and transection lead to increased histologic evidence of neuroma formation, whereas folding leads to neuropathic pain, assayed by calcitonin gene-related peptide expression. Avulsion and muscle burying are preferable techniques for nerve ablation and inhibit nerve regeneration, evidenced by decreased ciliary neurotrophic factor expression. Avulsion offers an alternative to muscle burying when there is no muscle in the vicinity to bury the transected nerve.

Introduction: CD4+ and CD8+ T cells are important effector cells in the adaptive immune response against cancers. In premalignant proliferative breast tissues, the role of the immune system remains relatively undefined. In this study, we sought to investigate and quantify the presence of CD4 and CD8 expressing immune cells in benign breast tissues and their association with breast cancer risk. Method: Archived breast tissue samples from women with benign breast disease (BBD) or no clinical breast disease [Komen Tissue Bank (KTB)] were obtained for this age-matched case-control study. BBD samples included BBD cases (subsequently developed breast cancer) and BBD controls). Tissue sections were characterized for non-proliferative or proliferative disease and degree of lobular involution. CD4+ and CD8+ cell densities (cells/mm2) were obtained by digital image quantitation for up to 10 individual lobules per sample and a per-sample estimate of cell density was calculated as the median cell density across lobules within a sample. Statistical analysis was performed using Wilcoxon signed-rank and Kruskal-Wallis tests. Results: Among 267 women (median age 52, range 35-75) comprising 89 age-matched triplets, 2417 lobules were evaluated [783 KTB, 804 BBD case, 830 BBD control]. 1372 (57%) lobules were normal and 1045 (43%) were fibrocystic. CD4+ cells were present in 1903 (79%) lobules while CD8+ cells were present in 2214 (92%) lobules. CD4 and CD8 densities showed a moderate positive correlation (r = 0.39) with each other, but overall, lobules showed a lower density of CD4+ than CD8+ cells (mean difference -54 cells/mm2, 95% CI: -68 to -39 cells/mm2). At the per sample level (see Table), BBD controls showed significantly higher levels of both CD4+ (p=0.009) and CD8+ cells (p=0.0001) compared to KTB samples. In contrast, the BBD cases only showed elevated CD8 (p=0.007) and not CD4 (p=0.21) cell infiltrates compared to KTB samples. Comparing BBD cases to BBD controls, BBD cases showed significantly lower CD8 cell density as compared to BBD controls (p=0.002) and cases had lower CD4 cell density but the difference was not significant (p=0.07). Despite these differences in the cell densities, the ratio of CD4:CD8+ cells did not differ significantly across groups (p=0.83). The CD4:CD8+ ratio also did not differ significantly by histologic impression (p=0.74), degree of involution (p=0.27), or age (p=0.32). KTBBBD ControlsBBD CasesMedian (IQR)(n=89)(n=89)(n=89)CD4+ cells/mm240 (17-95)60 (25-124)49 (21-92)CD8+ cells/mm285 (49-131)157 (84-225)134 (80-168)Ratio (CD4:CD8)*0.45 (0.14-0.96)0.41 (0.15-0.81)0.40 (0.19-0.70)*Ratio is missing for n=7 samples (3 KTB, 2 BBD control, 2 BBD case) with undefined ratio due to zero CD8+ cells for all lobules in the sample. Conclusion: Our findings suggest that BBD is associated with increased infiltration of T cells into the breast tissue. Furthermore, these immune responses appear more robust in BBD patients at lower risk of developing breast cancer. Citation Format: Pena Jimenez A, Hoskin TL, Arshad MA, Visscher DW, Brahmbhatt RD, Miller EE, Stallings Mann ML, Carter JM, Murphy LM, Winham SJ, Radisky DC, Denison LA, Knutson KA, Degnim AC. CD4 and CD8 T cell densities are increased in benign breast disease compared to normal breast tissue. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-04-09.

Lung cancer is more deadly than colon, breast, and prostate cancers combined, and treatment improvements have failed to improve prognosis significantly. Here, we identify a critical mediator of lung cancer progression, Rac1b, a tumor-associated protein with cell-transforming properties that are linked to the matrix metalloproteinase (MMP)-induced epithelial-mesenchymal transition (EMT) in lung epithelial cells. We show that expression of mouse Rac1b in lung epithelial cells of transgenic mice stimulated EMT and spontaneous tumor development and that activation of EMT by MMP-induced expression of Rac1b gave rise to lung adenocarcinoma in the transgenic mice through bypassing oncogene-induced senescence. Rac1b is expressed abundantly in stages 1 and 2 of human lung adenocarcinomas and, hence, is an attractive molecular target for the development of new therapies that prevent progression to later-stage lung cancers.

Scores from the Alcohol Use Disorders Identification Test (AUDIT) and the Center for Epidemiological Studies Depression Scale (CES-D) administered to both antiretroviral therapy (ART)-experienced and -naive adults in HIV care in Nigeria were evaluated for association with participant characteristics and ART adherence measured by pharmacy records. Participants included 222 ART-experienced and 177 ART-naive adults, of whom 47 (12%) had AUDIT >/=8, 29 (7%) an AUDIT >/=10, 52 (13%) a CES-D >/=16, and 25 (6%) a CES-D >/=21. An elevated AUDIT score was more frequent among ART-naive and men, while disclosure of HIV status to others was associated with lower scores. An elevated CES-D score was more frequent among ART-naive and those with lower educational level, while disclosure of HIV status and choosing to be interviewed in English rather than Hausa was associated with lower scores. An elevated CES-D score was associated with poor adherence.

Purpose: To identify current practice for elderly individuals who have sustained a fall-related injury and subsequently presented to the emergency department (ED) of a community-based hospital in Toronto, Ontario. Methods: A retrospective longitudinal chart review was conducted for 300 persons, 65 years of age and older, who presented to the ED of a community-based teaching hospital with a fall from June 2004 through May 2005. Data were collected using a tool created by the investigators (based on information gathered through a literature review) to capture information related to risk factors for falling. Results: Our study sample was demographically similar to elderly individuals in other fall-related studies. Most patients discharged directly from the ED did not receive multidisciplinary care. In the ED, all patients saw a nurse or physician, while only 1.3% (n = 4) saw a physical therapist, 3.0% (n = 9) saw an occupational therapist, and 5.3% (n = 16) saw a social worker. At discharge, 62% (n = 152) had no documented referral for follow-up care. Abilities related to falls in elderly individuals were not consistently assessed in the ED. Frequency of assessment for these abilities was as follows: (1) gait, 10.2%; (2) balance, 4.1%; (3) lower-extremity range of motion, 4.9%; (4) lower-extremity strength, 2.0%; (5) cognition, 26.1%; (6) vision, 2.0%; (7) ability to perform activities of daily living, 7.3%. In the 6 months following the index fall, 8.3% of patients returned to the ED of the same hospital because of a subsequent fall. Conclusions: In the ED, fall-related risk factors were not consistently assessed or documented, and few patients received multidisciplinary management. Since elderly individuals who fall commonly present to the ED, the implementation of evidence-based strategies aimed at preventing repeat falls should be considered.

The aim of the paper is to determine the prevalence of thyroid peroxidase antibodies (TPOAb) and assess its effect on the thyroid-stimulating hormone (TSH) reference range during pregnancy in a primarily Latina population. Serum samples were collected from healthy pregnant women and non-pregnant controls. TSH reference ranges were calculated when TPOAb-positive patients were either included or excluded. A total of 134 pregnant women and 107 non-pregnant controls were recruited. Positive TPOAb titres were found in 23 (17.2%) of the 134 pregnant women, and in 14 (13.1%) of the 107 non-pregnant controls. When the TPOAb-positive women were included in the TSH analysis, the upper reference limit using two different methods was consistently higher: 0–2.2 fold in the non-pregnant women, 2.01–2.78 fold in the first trimester, 3.18–4.7 fold in the second and 1.05–1.42 fold in the third. The lower TSH reference limit was not affected by the inclusion of TPOAb-positive subjects. In conclusion, inclusion of TPOAb-positive patients results in higher upper reference limits during pregnancy.

A 32-month-old boy with hypotonia, developmental delay, and multiple craniofacial abnormalities including craniosynostosis presented with numerous nonspecific, flesh-colored papules on his right flank. Upon biopsy, these lesions were diagnosed as elastomas. Similar skin lesions were found in the patient's younger brother. The patient's father and brother had osteopoikilotic lesions on radiography, but the patient did not have these findings. None of the reported cases to date have included craniosynostosis in association with Buschke-Ollendorff syndrome. In addition to the case findings, the report also provides a short and current review of the syndrome.

Introduction: The role of macrophages in the tumor microenvironment is of increasing interest for tumor progression and invasion. Here we investigated the difference in CD68+ cell density in tissue samples from women with Benign Breast Disease (BBD) and women with no clinical breast disease from the Komen Tissue Bank (KTB) at Indiana University. Method: Archived breast tissue samples from women with BBD and no clinical breast disease were obtained for this age-matched case-control study. BBD samples included cases [later got Breast Cancer (BC)] and controls (did not get BC). Samples were characterized via H&E stain for epithelial proliferation [normal (N), fibrocystic non-proliferative (NP), proliferative (P), or atypia (A)]. CD68+ cell density was obtained by digital image quantitation on a per lobule basis (Total CD68+ cells/mm2). Statistical analysis was performed with mixed effects regression. Results: Among 276 women (median age 53, range 35-79) comprising 92 age-matched triplets, 2508 lobules were evaluated [789 KTB, 839 BBD case, 880 BBD control]. 1407 (56%) lobules were normal and 1101 (44%) were fibrocystic {NP [613 (56%)], P [448 (41%)] and A [40 (4%)]}. Out of 2508 lobules analyzed, 2362 (94%) had CD68+ cells, while 146 (6%) showed zero CD68+ cells [19 (2%) BBD cases, 20 (2%) BBD controls, 107 (14%) KTB, p Conclusion: CD68+ cells are more frequent in breast lobules from women with BBD compared to normal donors. This finding in premalignant breast tissues is consistent with inflammation as a driver of tumorigenesis. BBD case (n = 92 patients)BBD control (n = 92 patients)KTB(n = 92 patients)n lobulesMedian (IQR)n lobulesMedian (IQR)n lobulesMedian (IQR)Overall839313 (165 - 538)880299 (164 - 527)789136 (55 - 272)By Lobule TypeNormal344310 (177 - 557)434331 (177 - 567)629128 (55 - 255)All non-normal/fibrocystic lobules combined495314 (157 - 527)446274 (152 - 478)160159 (58 - 393)Fibrocystic non-proliferative231319 (153 - 543)263274 (140 - 496)119163 (71 - 359)Fibrocystic proliferative246295 (153 - 496)169277 (153 - 478)33128 (30 - 385)Atypia18484 (313 - 739)14260 (223 - 375)8216 (0 - 493)IQR - Interquartile range (25th percentile - 75th percentile) Citation Format: Muhammad A. Arshad, Daniel W. Visscher, Tanya L. Hoskin, Rushin D. Brahmbhatt, Alvaro Pena Jimenez, Melody L. Stallings Mann, Erin E. Miller, Linda M. Murphy, Jodi M. Carter, Stacey J. Winham, Keith L. Knutson, Derek C. Radisky, Amy C. Degnim. CD68+ immune cells show different infiltration patterns in tissue samples from women with no clinical breast disease and those who have benign breast disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2364. doi:10.1158/1538-7445.AM2015-2364

e22115 Background: There is a growing interest in the role of inflammatory modulators within the tumor microenvironment in breast carcinogenesis. Here we quantitated the density of dendritic cells ...

Introduction: Histologic characteristics of nonmalignant breast tissues (epithelial proliferation and involution) are associated with future breast cancer (BC) risk. We evaluated immune infiltration (lobulitis) in benign breast lobules and its association with features of BC risk. Methods: We analyzed archived nonmalignant breast tissue samples from 81 women in age-matched groups of varying cancer risk: 27 with benign breast disease (BBD) who later developed BC (cases), 27 with BBD without subsequent BC (controls), and 27 normal women without clinical breast disease from the Komen Tissue Bank at Indiana University (KTB). Up to 10 lobules in each sample were characterized by H&E for lobulitis, involution (none, partial, complete), and fibrocystic (FC) status (normal, nonproliferative, proliferative). Lobulitis was defined by H&E staining as lymphocyte nuclei in the intralobular stroma at low magnification and between adjacent acini at high magnification. Data was analyzed by mixed effects logistic regression. Results: Median age was 57 years (range 37-70). Among 81 breast tissue samples, 750 lobules were evaluated: 249 in BBD Cases, 265 in BBD Controls, and 236 in KTB donors. 56% of lobules were normal and 44% were FC, with 87% of FC lobules occurring in BBD samples. Lobulitis was present in 44% of lobules and varied according to subject age and individual lobule features. Younger women were more likely to have lobulitis (p=0.002); among women Conclusion: Lobulitis is common in normal and benign breast tissue lobules but varies with age, involution status, and epithelial abnormality. Further work is needed to understand the role of immune infiltrates in breast cancer risk. Citation Format: Rushin D. Brahmbhatt, Daniel W. Visscher, Tanya L. Hoskin, Derek C. Radisky, Linda M. Murphy, Melody L. Stallings Mann, Erin Miller, Vernon S. Pankratz, Lynn C. Hartmann, Marlene H. Frost, Amy C. Degnim. Immune infiltration of normal and benign breast lobules varies in breast tissues based on cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1652. doi:10.1158/1538-7445.AM2014-1652

Most breast cancer deaths are the consequence of metastasis from the primary site. In order to metastasize, tumor cells must escape the physical barriers that contain the growing primary tumor, enter the vascular system, exit the vascular system at a distant point, and colonize a distant organ. An important mediator of metastasis is matrix metalloproteinase-9, a member of the MMP family that has been found to be upregulated both in breast cancer cells and in the surrounding tumor stroma. Studies using animal models have sometimes produced apparently contradictory findings, due in part to methodology in which MMP-9 expression is suppressed throughout the host organism and throughout the course of tumor initiation and progression. To define the specific role of tumor cell-produced MMP-9 in metastasis of human breast cancer, we implemented a bioluminescent imaging animal model of metastasis in which luciferase-expressing MDA-MB-231 cells, infected either with control nontarget lentivirus (MDA-MB-231-NT) or with shRNA lentivirus targeting MMP-9 (MDA-MB-231-MMP9-KD), were orthotopically implanted into the mammary fat pads of immunocompromised mice. Tumor growth and development of lung metastases were assessed over 10 weeks using an IVIS imager. At 11 weeks mice were sacrificed, and tumor progression was assessed by ex vivo lung imaging and by immunohistochemical processing of the tumors and the lungs. Imaging studies revealed that primary tumors developing from MMP-9 knockdown cells grew more slowly throughout the course of the study (ranging from 25% to 50%), and that while the majority of the control group developed lung metastases, none of the mice injected with MDA-MB-231-MMP9-KD cells showed metastatic progression. After sacrifice, the measured tumor weight showed a median of 99 mg for the MDA-MB-231-MMP9-KD and 158 mg for the MDA-MB-231-NT tumors, showing that knockdown of MMP-9 inhibited tumor growth. Ex vivo imaging of the lungs confirmed the in vivo studies: no metastases were detected from MDA-MB-231-MMP9-KD cells, while all lungs of the MDA-MB-231-NT injected mice had detectable metastases (p=0.0079). Similarly, a single level immunohistochemical correlate found no metastases in the MDA-MB-231-MMP9-KD mice, while 3 of 4 mice with the non-target control cells showed large metastases (median 7×103 μm2). Our results demonstrate that expression of MMP-9 by human breast cancer cells plays a significant role in the progression of tumor growth and metastasis and provide insight into the potential of MMP-9 as a target for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1497. doi:10.1158/1538-7445.AM2011-1497

For the past three decades, plasma-derived factor VIII concentrates have been the mainstay of treatment for patients with hemophilia A and for those with severe or moderately severe von Willebrand disease (vWD). However, for persons with classic (Type I) vWD or mild and moderate hemophilia A (characterized by FVIII coagulant activity (F VIII: C) levels of 0.06-0.30U/dl and 0.01-0.05U/dl respectively, desmopressin (1-desamino-8-d-arginine vasopressin; DDAVP) is considered the treatment of choice. When given intravenously (IV) or subcutaneously, DDAVP effects a short-term rise in all components of the F VIII system as well as in plasminogen activator (PA).1-4 The major advantage of DDAVP is that it is a synthetic agent which makes it possible to avoid the risk of transfusion-transmitted viral diseases such as hepatitis B, C, HIV/AIDS and parvovirus B19.

During development, epithelial cells acquire mesenchymal characteristics through a process known as epithelial-mesenchymal transition (EMT). Substantial evidence now exists that EMT-related processes play a major role in tumor progression. EMT is a focus of interest in lung cancer as loss of E-cadherin expression confers increased resistance to several types of chemotherapy. In previous studies, we found that matrix metalloproteinase-3 (MMP3) induced EMT in mouse mammary epithelial cells through induction of Rac1b, an alternatively spliced isoform of Rac1. We now show that exposure to MMPs stimulates Rac1b and induction of EMT markers in human lung cancer cell lines, and that knockdown of Rac1b blocks MMP induced EMT. We also show that Rac1b expression levels in human lung tumor biopsies is predictive of patient outcome, and that Rac1b and MMP expression levels are correlated in these samples, suggesting a direct relationship. We also describe the generation of new transgenic mouse models for which MMP3 or Rac1b is inducibly expressed in lung epithelial cells; activation of kRAS in these mice reveals that expression of MMP3 or Rac1b promotes increased tumor number, size, and progression to adenocarcinoma as well as increased expression of EMT markers vimentin, sm-actin, col1a1, and Snail. We also show that expression of Rac1b in lung epithelial cells leads to spontaneous adenocarcinoma formation. These results demonstrate a direct linkage between induction of EMT and tumor progression, implicate Rac1b as a key mediator of these processes, and demonstrate that MMPs can directly stimulate all of these events. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2318.

Although developed as an epidemiological tool, the Kawasaki Disease (KD) case definition has become a clinical tool used to detect and treat children with KD. Based on our experience treating 103 cases at Children's Hospital, San Diego from January 1998 through December 2000, we found that the Center for Disease Control (CDC) KD case definition results in failure to detect children with coronary artery abnormalities (CAA). Using published nomograms for coronary artery diameters based on body surface area, we determined the prevalence of CAA in all children receiving IVIG treatment for Kawasaki disease at Children's Hospital, San Diego. There were 102 patients with one recurrence. 86/103 cases met the Center for Disease Control case definition (typical KD) and 17/103 did not (atypical KD). CAA occurred in 42/86(49%) typical KD cases and 10/17 atypical KD cases (59%). These data demonstrate that 50%(52/103) of KD patients have detectable CAA. Five patients developed coronary aneurysms- 2 in the atypical group (12%) and 3 in the typical group (3.5%). The sensitivity of the KD case definition for detecting children with CAA was only 0.81(42/42+10). With this level of sensitivity for CAA detection, reliance on the CDC case definition as the sole clinical tool for diagnosis results in physician failure to detect children with CAA. Because there is an effective treatment, clinicians need a case definition that is highly sensitive. As the treatment is relatively safe, specificity of the case definition is less important. Efforts to revise the clinical case definition in order to improve its sensitivity for CAA are warranted. New criteria may include clinical laboratory findings such as leukocyte count or ESR. Revisions may eliminate current criteria such as cervical lymphadenopathy. Candidate clinical case definitions should undergo prospective testing with CAA detection as the primary outcome.