Estimating the effect of vehicle speeds on bicycle and pedestrian safety on the Georgia arterial roadway network.

Cyclists and pedestrians account for a disproportionate amount of the world's 1.3 million road deaths every year. This is a growing problem in the United Sates where bicyclist and pedestrian fatalities have increased steadily since 2009. A large body of research suggests vehicle speeds are a key contributing factor for crashes. However, few studies of bicycle or pedestrian crash probability incorporate detailed vehicle speed data. This study uses probe vehicle speed data to examine the impact of vehicle speeds on bicycle and pedestrian crashes on the state of Georgia's network of major arterial roadways. The analysis examines 7000 road segments throughout the state in 2017. A Negative Binomial model relates annual crash and speed data on each segment. Models using speed percentiles (85th, 50th and 15th) are contrasted with models using speed differences (85th-50th and 50th-15th percentile). A small set of covariates are included: segment length, number of lanes, Average Annual Daily Traffic, and urbanicity. Results indicate that larger differences in high-end speed percentiles are positively associated with bicycle and pedestrian crash frequency on Georgia arterials. Furthermore, the coefficients on the high end of the speed distribution, measured by the difference in 85th and 50th percentile speeds, have greater magnitude and statistical significance than the low end of the distribution. This research shows a negative relationship between speed and crashes may be flawed, as it does not account for the distributions of speed. The findings in this study suggest that planners and engineers should identify areas with large speed distributions, especially at the high vehicle speeds, and work to reduce the fastest speeds on these roadways. To do so, differences in speed percentiles measured using probe vehicle speeds can be used to determine where high risk areas are located.

EXPRESSION OF SEROTONIN RECEPTOR SUBTYPE 3A (5HT3A) ON RAT TRIGEMINAL SENSORY NEURONS.

Serotonin (5-hydroxytryptamine, 5HT) is a neurotransmitter and proinflammatory mediator found largely in the peripheral nervous system where it can initiate pain signaling. 5HT binds a variety of 5HT receptors on sensory nerve endings specialized in detecting noxious stimuli, termed nociceptors. A subset of sensory neurons involved in pain signaling express the transient receptor potential vanilloid 1 ion channel (TRPV1), a pain generator. 5HT can both directly activate sensory neurons and sensitize TRPV1 leading to enhanced nociceptor sensitivity (peripheral sensitization). Previous studies in male rats reported that the 5HT receptor subtype 3A (5HT3A) and TRPV1 are co-expressed on sensory neurons, but it is unknown if 5HT3A and TRPV1 are co-expressed on female sensory neurons. Given that craniofacial pain disorders occur at a 2-3x greater prevalence in women, examining pain mechanisms in female trigeminal sensory neurons that innervate the craniofacial region is critical to advancing craniofacial pain management in women. Here we examined whether (1) 5HT acting via the 5HT3A receptor produces sexually dimorphic orofacial pain behaviors in rats and (2) whether 5HT3A receptor mRNA is expressed in trigeminal sensory neurons, including the TRPV1-expressing subpopulation, and increase pain signaling. We report that 5HT evokes pain behaviors in male and female rats, which was not significantly reduced by antagonism of 5HT3A. We performed in situ hybridization to label 5HT3A and TRPV1 mRNA in trigeminal sensory neurons and found distinct cell populations with either 5HT3A mRNA or TRPV1 mRNA in males and females. Further, 5HT3A antagonism failed to reduce pain signaling in cultured trigeminal sensory neurons. These data suggest that the 5HT3A subtype on trigeminal sensory neurons innervating the orofacial soft tissues does not play a significant role in sexually dimorphic craniofacial pain disorders. As previous studies have reported that granisetron reduces masseter muscle pain, 5HT3 may play a role in sex differences in myofascial pain disorders but not in other craniofacial pain disorders.

Cytomegalovirus pneumonitis-induced secondary hemophagocytic lymphohistiocytosis and SIADH in an immunocompetent elderly male literature review.

Hemophagocytic lymphohistiocytosis (HLH) is also known as hemophagocytic syndrome. It is a lethal hematologic condition due to a dysregulated immune response which results in inappropriately activated macrophages damaging host tissues. Based on the etiology, HLH can be primary (genetic) or secondary (acquired). The most common cause of a secondary HLH is an infection. Viral infections are the most common cause of secondary HLH. Among the viral causes of secondary HLH, Epstein-Barr virus is the most common etiologic agent. Cytomegalovirus (CMV) is a common causative pathogen in the immunocompromised host but is rare in an immunocompetent adult. In infection- associated secondary HLH, treatment includes antimicrobial therapy. HLH carries a high mortality and morbidity rate as it is an underdiagnosed clinical condition. Successful early diagnosis allows for adequate time for curative therapy. Treatment for HLH includes chemotherapy, immunomodulators, and a hematopoietic stem-cell transplant. The 2004 diagnostic criteria set by the Histiocyte Society serves as a guide to make an earlier clinical diagnosis. A review of PubMed literature revealed only five reported cases of CMV-induced HLH. We describe the sixth case of CMV pneumonitis-induced HLH and syndrome of inappropriate antidiuretic hormone secretion in a 72-year-old White male. He was treated successfully with oral valganciclovir and corticosteroids.

The prevalence of gastroesophageal reflux disease in an adult, South African black population, and the association with obesity.

BACKGROUND: The aim of the study was to determine the prevalence of gastroesophageal reflux disease (GERD) in a black population in South Africa and to determine if there was any association with obesity. METHODS: A sample of 312 black subjects was randomly selected and interviewed with a structured questionnaire (GerdQ) consisting of six questions translated into English and two of the most commonly used African languages (Zulu and Xhosa). This question-based symptom score for the diagnosis of GERD has been validated previously. Additional information about age, gender, smoking and alcohol was also obtained. All participants underwent anthropometric measurements. RESULTS: The prevalence of GERD was more common in black females (22.9%) than black males (4.1%; P<0.0005) and in females there was no association of GERD with waist circumference, age, smoking or alcohol intake. However, the prevalence of GERD was higher in the second compared to the first quartile of Body Mass Index (BMI) (31.4% versus 11.45; P<0.05) but fell in quartiles 3 (28.6%) and 4 (20.1%). CONCLUSIONS: GERD is more common in black females than males and in the former group its prevalence rose with increasing BMI and then decreases at BMIs exceeding 33.1. The reason for the gender differences and the inverted 'U' shaped relationship between GERD and BMI are not known and require further investigation.

Can post encroachment time substitute intersection characteristics in crash prediction models?

INTRODUCTION: Transportation safety analyses have traditionally relied on crash data. The limitations of these crash data in terms of timeliness and efficiency are well understood and many studies have explored the feasibility of using alternative surrogate measures for evaluation of road safety. Surrogate safety measures have the potential to estimate crash frequency, while requiring reduced data collection efforts relative to crash data based measures. Traditional crash prediction models use factors such as traffic volume, sight distance, and grade to make risk and exposure estimates that are combined with observed crashes, generally using an Empirical Bayes method, to obtain a final crash estimate. Many surrogate measures have the notable advantage of not directly requiring historical crash data from a site to estimate safety. Post Encroachment Time (PET) is one such measure and represents the time difference between a vehicle leaving the area of encroachment and a conflicting vehicle entering the same area. The exact relationship between surrogate measures, such as PET, and crashes in an ongoing research area. METHOD: This paper studies the use of PET to estimate crashes between left-turning vehicles and opposing through vehicles for its ability to predict opposing left-turn crashes. By definition, a PET value of 0 implies the occurrence of a crash and the closer the value of PET is to 0, the higher the conflict risk. RESULTS: This study shows that a model combining PET and traffic volume characteristic (AADT or conflicting volume) has better predictive power than PET alone. Further, it was found that PET may be capturing the impact of certain other intersection characteristics on safety as inclusion of other intersection characteristics such as sight distance, grade, and other parameters result in only marginal impacts on predictive capacity that do not justify the increased model complexity.

Emerging roles for intersectin (ITSN) in regulating signaling and disease pathways.

Intersectins (ITSNs) represent a family of multi-domain adaptor proteins that regulate endocytosis and cell signaling. ITSN genes are highly conserved and present in all metazoan genomes examined thus far. Lower eukaryotes have only one ITSN gene, whereas higher eukaryotes have two ITSN genes. ITSN was first identified as an endocytic scaffold protein, and numerous studies reveal a conserved role for ITSN in endocytosis. Subsequently, ITSNs were found to regulate multiple signaling pathways including receptor tyrosine kinases (RTKs), GTPases, and phosphatidylinositol 3-kinase Class 2beta (PI3KC2ß). ITSN has also been implicated in diseases such as Down Syndrome (DS), Alzheimer Disease (AD), and other neurodegenerative disorders. This review summarizes the evolutionary conservation of ITSN, the latest research on the role of ITSN in endocytosis, the emerging roles of ITSN in regulating cell signaling pathways, and the involvement of ITSN in human diseases such as DS, AD, and cancer.

Intersectin 1 contributes to phenotypes in vivo: implications for Down's syndrome.

Intersectin 1 (ITSN1) is a human chromosome 21 (HSA21) gene product encoding a multidomain scaffold protein that functions in endocytosis, signal transduction, and is implicated in Down's syndrome, Alzheimer's Disease, and potentially other neurodegenerative diseases through activation of c-Jun N-terminal kinase. We report for the first time that ITSN1 proteins are elevated in individuals with Down's syndrome of varying ages. However, ITSN1 levels decreased in aged cases with Down's syndrome with Alzheimer's disease-like neuropathology. Analysis of a novel ITSN1 transgenic mouse reveals that ITSN1 overexpression results in a sex-dependent decrease in locomotor activity. This study reveals a link between overexpression of specific ITSN1 isoforms and behavioral phenotypes and has implications for human neurodegenerative diseases such as Down's syndrome and Alzheimer's disease.

Pak1 regulates branching morphogenesis in 3D MDCK cell culture by a PIX and beta1-integrin-dependent mechanism.

Branching morphogenesis is a fundamental process in the development of the kidney. This process gives rise to a network of ducts, which form the collecting system. Defective branching can lead to a multitude of kidney disorders including agenesis and reduced nephron number. The formation of branching tubules involves changes in cell shape, cell motility, and reorganization of the cytoskeleton. However, the exact intracellular mechanisms involved are far from understood. We have used the three-dimensional (3D) Madin-Darby canine kidney (MDCK) cell culture system to study how p21-activated kinase 1 (Pak1), which is an important regulator of the cytoskeleton, modulates branching. Our data reveal that Pak1 plays a crucial role in regulating branching morphogenesis. Expression of a dominant-negative Pak1 mutant (DN-Pak1) in MDCK cysts resulted in the spontaneous formation of extensions and branching tubules. Cellular contractility and levels of phosphorylated myosin light chain (pMLC) were increased in DN-Pak1 cells in collagen. Expression of a DN-Pak1 mutant that does not bind to PIX (DN-Pak1-DeltaPIX) failed to form extensions in collagen and did not have increased contractility. This shows that the DN-Pak1 mutant requires PIX binding to generate extensions and increased contractility in 3D culture. Furthermore, a beta1-integrin function-blocking antibody (AIIB2) inhibited the formation of branches and blocked the increased contractility in DN-Pak1 cysts. Taken together, our work shows that DN-Pak1-induced branching morphogenesis requires PIX binding and beta1-integrin signaling.

The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis.

Hhex is required for early development of the liver. A null mutation of Hhex results in a failure to form the liver bud and embryonic lethality. Therefore, Hhex null mice are not informative as to whether this gene is required during later stages of hepatobiliary morphogenesis. To address this question, we derived Hhex conditional null mice using the Cre-loxP system and two different Cre transgenics (Foxa3-Cre and Alfp-Cre). Deletion of Hhex in the hepatic diverticulum (Foxa3-Cre;Hhex(d2,3/-)) led to embryonic lethality and resulted in a small and cystic liver with loss of Hnf4alpha and Hnf6 expression in early hepatoblasts. In addition, the gall bladder was absent and the extrahepatic bile duct could not be identified. Loss of Hhex in the embryonic liver (Alfp-Cre;Hhex(d2,3/-)) caused irregular development of intrahepatic bile ducts and an absence of Hnf1beta in many (cystic) biliary epithelial cells, which resulted in a slow, progressive form of polycystic liver disease in adult mice. Thus, we have shown that Hhex is required during multiple stages of hepatobiliary development. The altered expression of Hnf4alpha, Hnf6 and Hnf1beta in Hhex conditional null mice suggests that Hhex is an essential component of the genetic networks regulating hepatoblast differentiation and intrahepatic bile duct morphogenesis.

Hhex is a direct repressor of endothelial cell-specific molecule 1 (ESM-1).

Hhex encodes a homeodomain-containing protein that functions as both a transcriptional repressor and activator, and is necessary for normal embryonic development. We previously reported that a null mutation of Hhex leads to abnormalities in vasculogenesis and have focused on identifying the transcriptional targets of Hhex necessary for vascular development. Here we report that the expression of ESM-1, a cysteine-rich protein expressed in the endothelium, is increased in Hhex(-/-) embryos. Overexpression of Hhex in endothelial cells down-regulates ESM-1. The results from transient cotransfection assay, electrophoretic-mobility shift assay, site-directed mutagenesis, and chromatin immunoprecipitation assay demonstrate that Hhex can directly bind to and repress ESM-1 via an evolutionarily conserved Hhex response element (HRE) 1. These findings indicate that ESM-1 is a direct target of Hhex and that Hhex functions as a transcriptional repressor of ESM-1. We speculate that Hhex-mediated repression of ESM-1 is critical for the normal function of the vascular endothelium and for tumor vasculogenesis.

Zebrafish gcm2 is required for gill filament budding from pharyngeal ectoderm.

The pharyngeal arches give rise to multiple organs critical for diverse processes, including the thymus, thyroid and parathyroids. Several molecular regulators of thymus and thyroid organogenesis are strikingly conserved between mammals and zebrafish. However, land animals have parathyroids whereas fish have gills. The murine transcription factor Glial cells missing 2 (Gcm2) is expressed specifically in the parathyroid primordium in the endodermal epithelium of the third pharyngeal pouch, and in both mice and humans is required for normal development of parathyroid glands. The molecular regulation of fish gill organogenesis remains to be described. We report the expression of gcm2 in the zebrafish pharyngeal epithelium and a requirement for Hox group 3 paralogs for gcm2 expression. Strikingly, zebrafish gcm2 is expressed in the ectodermal portion of the pharyngeal epithelium and is required for the development of the gill filament buds, precursors of fish-specific gill filaments. This study identifies yet another role for a GCM gene in embryonic development and indicates a role for gcm2 during the evolution of divergent pharyngeal morphologies.

Zebrafish hox paralogue group 2 genes function redundantly as selector genes to pattern the second pharyngeal arch.

The pharyngeal arches are one of the defining features of the vertebrates, with the first arch forming the mandibles of the jaw and the second forming jaw support structures. The cartilaginous elements of each arch are formed from separate migratory neural crest cell streams, which derive from the dorsal aspect of the neural tube. The second and more posterior crest streams are characterized by specific Hox gene expression. The zebrafish has a larger overall number of Hox genes than the tetrapod vertebrates, as the result of a duplication event in its lineage. However, in both zebrafish and mouse, there are just two members of Hox paralogue group 2 (PG2): Hoxa2 and Hoxb2. Here, we show that morpholino-mediated "knock-down" of both zebrafish Hox PG2 genes results in major defects in second pharyngeal arch cartilages, involving replacement of ventral elements with a mirror-image duplication of first arch structures, and accompanying changes to pharyngeal musculature. In the mouse, null mutants of Hoxa2 have revealed that this single Hox gene is required for normal second arch patterning. By contrast, loss-of-function of either zebrafish Hox PG2 gene individually has no phenotypic consequence, showing that these two genes function redundantly to confer proper pattern to the second pharyngeal arch. We have also used hoxb1a mis-expression to induce localized ectopic expression of zebrafish Hox PG2 genes in the first arch; using this strategy, we find that ectopic expression of either Hox PG2 gene can confer second arch identity onto first arch structures, suggesting that the zebrafish Hox PG2 genes act as "selector genes."