The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-beta signaling pathways.

BACKGROUND: Zinc (Zn) is an essential trace element and it is abundant in connective tissues, however biological roles of Zn and its transporters in those tissues and cells remain unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that mice deficient in Zn transporter Slc39a13/Zip13 show changes in bone, teeth and connective tissue reminiscent of the clinical spectrum of human Ehlers-Danlos syndrome (EDS). The Slc39a13 knockout (Slc39a13-KO) mice show defects in the maturation of osteoblasts, chondrocytes, odontoblasts, and fibroblasts. In the corresponding tissues and cells, impairment in bone morphogenic protein (BMP) and TGF-beta signaling were observed. Homozygosity for a SLC39A13 loss of function mutation was detected in sibs affected by a unique variant of EDS that recapitulates the phenotype observed in Slc39a13-KO mice. CONCLUSIONS/SIGNIFICANCE: Hence, our results reveal a crucial role of SLC39A13/ZIP13 in connective tissue development at least in part due to its involvement in the BMP/TGF-beta signaling pathways. The Slc39a13-KO mouse represents a novel animal model linking zinc metabolism, BMP/TGF-beta signaling and connective tissue dysfunction.

Persistent association of nailfold capillaroscopy changes and skin involvement over thirty-six months with duration of untreated disease in patients with juvenile dermatomyositis.

OBJECTIVE: To determine the association of changes on nailfold capillaroscopy with clinical findings and genotype in children with juvenile dermatomyositis (DM), in order to identify potential differences in disease course over 36 months. METHODS: At diagnosis of juvenile DM in 61 children prior to the initiation of treatment, tumor necrosis factor alpha (TNFalpha) -308 allele and DQA1*0501 status was determined, juvenile DM Disease Activity Scores (DAS) were obtained, and nailfold capillaroscopy was performed. The disease course was monitored for 36 months. Variations within and between patients were assessed by regression analysis. RESULTS: At diagnosis, shorter duration of untreated disease (P = 0.05) and a lower juvenile DM skin DAS (P = 0.035) were associated with a unicyclic disease course. Over 36 months, end-row loop (ERL) regeneration was associated with lower skin DAS (P < 0.001) but not muscle DAS (P = 0.98); ERL regeneration and decreased bushy loops were associated with a shorter duration of untreated disease (P = 0.04 for both). At 36 months, increased ERL regeneration (P = 0.007) and improvement of skin DAS (P < 0.001) and muscle DAS (P = 0.025) were associated with a unicyclic disease course. CONCLUSION: Early treatment of juvenile DM may lead to a unicyclic disease course. The non-unicyclic disease course usually involves continuing skin manifestations with persistent nailfold capillaroscopy changes. The correlation of nailfold capillaroscopy results with cutaneous but not with musculoskeletal signs of juvenile DM over a 36-month period suggests that the cutaneous and muscle vasculopathies have different pathophysiologic mechanisms. These findings indicate that efforts to identify the optimal treatment of cutaneous features in juvenile DM require greater attention.

Identification of ectodysplasin target genes reveals the involvement of chemokines in hair development.

Ectodysplasin (Eda), a member of the tumor necrosis factor (Tnf) family, regulates skin appendage morphogenesis via its receptor Edar and transcription factor NF-κB. In humans, inactivating mutations in the Eda pathway components lead to hypohidrotic ectodermal dysplasia (HED), a syndrome characterized by sparse hair, tooth abnormalities, and defects in several cutaneous glands. A corresponding phenotype is observed in Eda-null mice, where failure in the initiation of the first wave of hair follicle development is a hallmark of HED pathogenesis. In an attempt to discover immediate target genes of the Eda/NF-κB pathway, we performed microarray profiling of genes differentially expressed in embryonic skin explants after a short exposure to recombinant Fc-Eda protein. Upregulated genes included components of the Wnt, fibroblast growth factor, transforming growth factor-β, Tnf, and epidermal growth factor families, indicating that Eda modulates multiple signaling pathways implicated in skin appendage development. Surprisingly, we identified two ligands of the chemokine receptor cxcR3, cxcl10 and cxcl11, as new hair-specific transcriptional targets of Eda. Deficiency in cxcR3 resulted in decreased primary hair follicle density but otherwise normal hair development, indicating that chemokine signaling influences the patterning of primary hair placodes only.

Statewide Heavy-Truck Crash Assessment, 2014

In 2010, 16.5 percent of all fatal vehicle crashes in Iowa involved large trucks compared to the national average of 7.8 percent. Only about 16 percent of these fatalities involved the occupants of the heavy vehicles, meaning that a majority of the fatalities in fatal crashes involve non-heavy-truck occupants. These statistics demonstrate the severe nature of heavy-truck crashes and underscore the serious impact that these crashes can have on the traveling public. These statistics also indicate Iowa may have a disproportionately higher safety risk compared to the nation with respect to heavy-truck safety. Several national studies, and a few statewide studies, have investigated large-truck crashes; however, no rigorous analysis of heavy-truck crashes has been conducted for Iowa. The objective of this study was to investigate and identify the causes, locations, and other factors related to heavy-truck crashes in Iowa with the goal of reducing crashes and promoting safety. To achieve this objective, this study used the most current statewide data of heavy-truck crashes in Iowa. This study also attempted to assess crash experience with respect to length of commercial driver’s license (CDL) licensure using the most recent five years of CDL data linked to the before mentioned crash data. In addition, this study used inspection and citation data from the Iowa Department of Transportation (DOT) Motor Vehicle Division and Iowa State Patrol to investigate the relationship between enforcement activities and crash experience.

Early olfactory involvement in Alzheimer's disease.

BACKGROUND: In Alzheimer's disease (AD) the olfactory system, including the olfactory bulb, a limbic paleocortex is severely damaged. The occurrence of early olfactory deficits and the presence of senile plaques and neurofibrillary tangles in olfactory bulb were reported previously by a few authors. The goal of the present study was to analyze the occurrence of AD-type degenerative changes in the peripheral part of the olfactory system and to answer the question whether the frequency and severity of changes in the olfactory bulb and tract are associated with those of the cerebral cortex in AD. MATERIAL AND METHODS: In 110 autopsy cases several cortical areas and the olfactory bulb and tract were analyzed using histo- and immunohistochemical techniques. Based on a semiquantitative analysis of cortical senile plaques, neurofibrillary tangles and curly fibers, the 110 cases were divided into four groups: 19 cases with severe (definite AD), 14 cases with moderate, 58 cases with discrete and 19 control cases without AD-type cortical changes. RESULTS: The number of cases with olfactory involvement was very high, more than 84% in the three groups with cortical AD-type lesions. Degenerative olfactory changes were present in all 19 definite AD cases, and in two of the 19 controls. The statistical analysis showed a significant association between the peripheral olfactory and cortical degenerative changes with respect to their frequency and severity (P < 0.001). Neurofibrillary tangles and neuropil threads appear in the olfactory system as early as in entorhinal cortex. CONCLUSION: The results indicate a close relationship between the olfactory and cortical degenerative changes and indicate that the involvement of the olfactory bulb and tract is one of the earliest events in the degenerative process of the central nervous system in AD.

Calibration of Highway Safety Manual Work Zone Crash Modification Factors, TPF-5(081), 2014

The Highway Safety Manual is the national safety manual that provides quantitative methods for analyzing highway safety. The HSM presents crash modification factors related to work zone characteristics such as work zone duration and length. These crash modification factors were based on high-impact work zones in California. Therefore there was a need to use work zone and safety data from the Midwest to calibrate these crash modification factors for use in the Midwest. Almost 11,000 Missouri freeway work zones were analyzed to derive a representative and stratified sample of 162 work zones. The 162 work zones was more than four times the number of work zones used in the HSM. This dataset was used for modeling and testing crash modification factors applicable to the Midwest. The dataset contained work zones ranging from 0.76 mile to 9.24 miles and with durations from 16 days to 590 days. A combined fatal/injury/non-injury model produced a R2 fit of 0.9079 and a prediction slope of 0.963. The resulting crash modification factors of 1.01 for duration and 0.58 for length were smaller than the values in the HSM. Two practical application examples illustrate the use of the crash modification factors for comparing alternate work zone setups.

Food-dependent Cushing's syndrome: possible involvement of leptin in cortisol hypersecretion.

Stimulation ofcortisol secretion by food intake has been implicated in the pathogenesis of some cases of ACTH-independent Cushing's syndrome, via an aberrant response of the adrenal glands to gastric inhibitory polypeptide (GIP). We report here a novel case of food-dependent Cushing's syndrome in a patient with bilateral macronodular adrenal hyperplasia. In this patient we were able to confirm a paradoxical stimulation of cortisol secretion by GIP in vivo as well as in vitro on dispersed tumor adrenal cells obtained at surgery. In addition to GIP, in vitro stimulation of these cultured tumor adrenal cells with leptin, the secreted product of the adipocyte, induced cortisol secretion. By comparison, no such stimulation was observed in vitro in adrenal cells obtained from another patient with bilateral macronodular adrenal hyperplasia and Cushing's syndrome that did not depend on food intake, in tumor cells obtained from a solitary cortisol-secreting adrenal adenoma, and in normal human adrenocortical cells. These results demonstrate that as in previously described cases of food-dependent Cushing's syndrome, GIP stimulated cortisol secretion from the adrenals of the patient reported here. Therefore, they indicate that such a paradoxical response probably represents the hallmark of this rare condition. In addition, they suggest that leptin, which normally inhibits stimulated cortisol secretion in humans, participated in cortisol hypersecretion in this case. Further studies in other cases of food-dependent Cushing's syndrome, however, will be necessary to better ascertain the pathophysiological significance of this finding.

Cardiac involvement in a patient with clinical and serological evidence of African tick-bite fever.

BACKGROUND: Myocarditis and pericarditis are rare complications of rickettsiosis, usually associated with Rickettsia rickettsii and R. conorii. African tick-bite fever (ATBF) is generally considered as a benign disease and no cases of myocardial involvement due to Rickettsia africae, the agent of ATBF, have yet been described. CASE PRESENTATION: The patient, that travelled in an endemic area, presented typical inoculation eschars, and a seroconversion against R. africae, was admitted for chest pains and increased cardiac enzymes in the context of an acute myocarditis. CONCLUSION: Our findings suggest that ATBF, that usually presents a benign course, may be complicated by an acute myocarditis.

TraumaHawk: Improving Treatment for Crash Victims Using Photos and a Smartphone App

Photographic documentation of crashed vehicles at the scene can be used to improve triage of crash victims. A U.S. expert panel developed field triage rules to determine the likelihood of occupants sustaining serious injuries based on vehicle damage that would require transport to a trauma center (Sasser et al., 2011). The use of photographs for assessing vehicle damage and occupant compartment intrusion as it correlates to increased injury severity has been validated (Davidson et al., 2014). Providing trauma staff with crash scene photos remotely could assist them in predicting injuries. This would allow trauma care providers to assess the appropriate transport, as well as develop mental models of treatment options prior to patient arrival at the emergency department (ED). Crash-scene medical response has improved tremendously in the past 20-30 years. This is in part due to the increasing number of paramedics who now have advanced life support (ALS) training that allows independence in the field. However, while this advanced training provides a more streamlined field treatment protocol, it also means that paramedics focused on treating crash victims may not have time to communicate with trauma centers regarding crash injury mechanisms. As a result, trauma centers may not learn about severe trauma patients until just a few minutes before they arrive. The information transmitted by the TraumaHawk app allows interpretation of injury mechanisms from crash scene photos at the trauma center, providing clues about the type and severity of injury. With strategic crash scene photo documentation, trained trauma professionals can assess the severity and patterns of injury based on exterior crush and occupant intrusion. Intrusion increases the force experienced by vehicle occupants, which translates into a higher level of injury severity (Tencer et al., 2005; Assal et al., 2002; Mandell et al., 2010). First responders have the unique opportunity to assess the damaged vehicle at the crash scene, but often the mechanism of injury is limited or not even relayed to ED trauma staff. To integrate photographic and scene information, an app called TraumaHawk was created to capture images of crash vehicles and send them electronically to the trauma center. If efficiently implemented, it provides the potential advantage of increasing lead-time for preparation at the trauma center through the crash scene photos. Ideally, the result is better treatment outcomes for crash victims. The objective of this analysis was to examine if the extra lead-time granted by the TraumaHawk app could improve trauma team activation time over the current conventional communication method.

Remote Sensing (LIDAR) for Management of Highway Assets for Safety, 2003

The main objective of this study was to utilize light detection and ranging (LIDAR) technology to obtain highway safety-related information. The safety needs of older drivers in terms of prolonged reaction times were taken into consideration. The tasks undertaken in this study were (1) identification of crashes that older drivers are more likely to be involved in, (2) identification of highway geometric features that are important in such crashes, (3) utilization of LIDAR data for obtaining information on the identified highway geometric features, and (4) assessment of the feasibility of using LIDAR data for such applications. A review of previous research indicated that older drivers have difficulty negotiating intersections, and it was recognized that intersection sight triangles were critical to safe intersection negotiation. LIDAR data were utilized to obtain information on potential sight distance obstructions at six selected intersections located on the Iowa Highway 1 corridor by conducting in-office line-of-sight analysis. Crash frequency, older driver involvement, and data availability were considerations in the selection of the six intersections. Results of the in-office analysis were then validated by visiting the intersections in the field. Sixty-six potential sight distance obstructions were identified by the line-of-sight analysis, out of which 62 (89.8%) were confirmed while four (5.8%) were not confirmed by the video. At least three (4.4%) potential sight distance obstructions were discovered in the video that were not detected by the line-of-sight analysis. The intersection with the highest crash frequency involving older drivers was correctly found to have obstructions located within the intersection sight triangles. Based on research results, it is concluded that LIDAR data can be utilized for identifying potential sight distance obstructions at intersections. The safety of older drivers can be enhanced by locating and rectifying intersections with obstructions in sight triangles.

Pulmonary involvement in Fabry disease: Overview and perspectives.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A, which leads to storage of sphingolipids in virtually all human cells and consequently to organ dysfunction. Pulmonary involvement is still debated. But, obstructive lung disease is up to ten times more prevalent in patients with FD compared to general public. Also, an accelerated decline in forced expiratory volume in one second (FEV1) over time was observed in these patients. Lysosomal storage of glycosphingolipids is considered leading to small airway disease via hyperplasia of the bronchiolar smooth muscle cells. Larger airways may become involved with ongoing disease process. There is no evidence for involvement of the lung interstitium in FD. The effect of enzyme replacement therapy on respiratory involvement remains to be determined in large, prospective controlled trials.

Rural Expressway Intersection Synthesis of Practice and Crash Analysis, 2004

This report presents a national synthesis of rural expressway, two-way stop -controlled (TWSC) intersection safety strategies and intersection designs and an analysis of Iowa expressway TWSC intersection crash characteristics. A rural expressway is a multi-lane highway with a divided median and with mostly at -grade intersections, although some intersections may be grade separated. The synthesis of intersection strategies is conducted in two parts. The first is a literature review and the second part is a national survey of strategies currently being applied by state transportation agencies. The characterization of crash patterns at TWSC expressway intersections is examined through the analysis of 5 years of crash data at 644 intersections.