Postobstructive pulmonary edema in the setting of aspiration and air travel.

BACKGROUND: Postobstructive pulmonary edema (POPE)-also referred to as negative pressure pulmonary edema-occurs with deep inspiration against a closed glottis or obstructed airway. The result can be life threatening, however, most cases have a self-limited presentation and resolve with supportive care. OBJECTIVE: Our aim was to critically evaluate a previously unreported mechanism in the exacerbation of POPE. CASE REPORT: This is a report of a 50-year-old woman who experienced an acute episode of hypoxia and altered mental status aboard a transcontinental flight. Her presentation was suggestive of pulmonary embolus. However, a detailed history yielded an episode of preflight choking relieved by the Heimlich maneuver. After 2 days of supportive care she was discharged with a complete return to baseline. CONCLUSIONS: Subclinical cases of POPE can be exacerbated by the low atmospheric pressure experienced on commercial airlines. With early recognition and supportive treatment, the patient returned to baseline before her discharge 2 days later. Making the diagnoses of POPE is not always straightforward for the practitioner and necessitates a broad differential. Initial supportive care focusing on maximizing respiratory support is critical.

Ultrasonography versus computed tomography for suspected nephrolithiasis.

BACKGROUND: There is a lack of consensus about whether the initial imaging method for patients with suspected nephrolithiasis should be computed tomography (CT) or ultrasonography. METHODS: In this multicenter, pragmatic, comparative effectiveness trial, we randomly assigned patients 18 to 76 years of age who presented to the emergency department with suspected nephrolithiasis to undergo initial diagnostic ultrasonography performed by an emergency physician (point-of-care ultrasonography), ultrasonography performed by a radiologist (radiology ultrasonography), or abdominal CT. Subsequent management, including additional imaging, was at the discretion of the physician. We compared the three groups with respect to the 30-day incidence of high-risk diagnoses with complications that could be related to missed or delayed diagnosis and the 6-month cumulative radiation exposure. Secondary outcomes were serious adverse events, related serious adverse events (deemed attributable to study participation), pain (assessed on an 11-point visual-analogue scale, with higher scores indicating more severe pain), return emergency department visits, hospitalizations, and diagnostic accuracy. RESULTS: A total of 2759 patients underwent randomization: 908 to point-of-care ultrasonography, 893 to radiology ultrasonography, and 958 to CT. The incidence of high-risk diagnoses with complications in the first 30 days was low (0.4%) and did not vary according to imaging method. The mean 6-month cumulative radiation exposure was significantly lower in the ultrasonography groups than in the CT group (P<0.001). Serious adverse events occurred in 12.4% of the patients assigned to point-of-care ultrasonography, 10.8% of those assigned to radiology ultrasonography, and 11.2% of those assigned to CT (P=0.50). Related adverse events were infrequent (incidence, 0.4%) and similar across groups. By 7 days, the average pain score was 2.0 in each group (P=0.84). Return emergency department visits, hospitalizations, and diagnostic accuracy did not differ significantly among the groups. CONCLUSIONS: Initial ultrasonography was associated with lower cumulative radiation exposure than initial CT, without significant differences in high-risk diagnoses with complications, serious adverse events, pain scores, return emergency department visits, or hospitalizations. (Funded by the Agency for Healthcare Research and Quality.).

Inactivation of the transcription factor GLI1 accelerates pancreatic cancer progression.

The role of GLI1 in pancreatic tumor initiation promoting the progression of preneoplastic lesions into tumors is well established. However, its function at later stages of pancreatic carcinogenesis remains poorly understood. To address this issue, we crossed the gli1 knock-out (GKO) animal with cre-dependent pancreatic activation of oncogenic kras concomitant with loss of the tumor suppressor tp53 (KPC). Interestingly, in this model, GLI1 played a tumor-protective function, where survival of GKO/KPC mice was reduced compared with KPC littermates. Both cohorts developed pancreatic cancer without significant histopathological differences in survival studies. However, analysis of mice using ultrasound-based imaging at earlier time points showed increased tumor burden in GKO/KPC mice. These animals have larger tumors, decreased body weight, increased lactate dehydrogenase production, and severe leukopenia. In vivo and in vitro expression studies identified FAS and FAS ligand (FASL) as potential mediators of this phenomenon. The FAS/FASL axis, an apoptotic inducer, plays a role in the progression of pancreatic cancer, where its expression is usually lost or significantly reduced in advanced stages of the disease. Chromatin immunoprecipitation and reporter assays identified FAS and FASL as direct targets of GLI1, whereas GKO/KPC mice showed lower levels of this ligand compared with KPC animals. Finally, decreased levels of apoptosis were detected in tumor tissue in the absence of GLI1 by TUNEL staining. Together, these findings define a novel pathway regulated by GLI1 controlling pancreatic tumor progression and provide a new theoretical framework to help with the design and analysis of trials targeting GLI1-related pathways.

Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration.

Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced ß-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and ß-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway.

Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation.

Although the biological role of KRAS is clearly established in carcinogenesis, the molecular mechanisms underlying this phenomenon are not completely understood. In this study, we provide evidence of a novel signaling network regulated by the transcription factor GLI1 mediating KRAS-induced carcinogenesis. Using pancreatic cancer (a disease with high prevalence of KRAS mutations) as a model, we show that loss of GLI1 blocks the progression of KRAS-induced pancreatic preneoplastic lesions in mice with pancreas-specific Cre-activated oncogenic mutant kras. Mice lacking GLI1 develop only low-grade lesions at low frequency, and in most cases, the pancreata are histologically normal. Further characterization of the phenotype showed a decrease in the activation of STAT3 in pancreatic preneoplastic lesions; STAT3 is a transcription factor required for the development of premalignant lesions and their progression into pancreatic cancer. Analysis of the mechanisms revealed a key role for GLI1 in maintaining the levels of activated STAT3 through the modulation of IL-6 signaling. GLI1 binds to the IL-6 mouse promoter and regulates the activity and expression of this cytokine. This newly identified GLI1/IL-6 axis is active in fibroblasts, a known source of IL-6 in the tumor microenvironment. Sonic hedgehog induces GLI1 binding to the IL-6 promoter and increases IL-6 expression in fibroblasts in a paracrine manner. Finally, we demonstrate that mutant KRAS initiates this cascade by inducing the expression of Sonic hedgehog in cancer cells. Collectively, these results define a novel role for GLI1 in carcinogenesis acting as a downstream effector of oncogenic KRAS in the tumor microenvironment.

A case of foreign accent syndrome.

BACKGROUND: Foreign accent syndrome is a rare but potentially devastating clinical condition associated with altered speech rhythm and prosody, often occurring after a cerebral vascular accident. Missing this diagnosis can lead to delayed stroke work-up and treatment. OBJECTIVE: We report a case of foreign accent syndrome in a 60-year-old woman who presented to the Emergency Department (ED) with 3 weeks of altered speech pattern, widened gait, bilateral leg heaviness, and mild headache. CASE REPORT: The patient had a history of Type 2 diabetes, malignant hypertension, toxic nodular goiter, and hyperlipidemia. She initially presented to the ED at the onset of symptoms, was thought to have had speech change secondary to a goiter impinging on the recurrent laryngeal nerve, and was discharged. She returned to the ED 3 weeks later when outpatient imaging revealed subacute infarction of the left hemi-pons and absent flow within the left vertebral artery. On examination, the patient was alert and conversational. She spoke fluently with an accent that had components of Jamaican and the accent of an Italian speaking English. Neurology was consulted and the patient was admitted. The patient was treated medically, and was discharged home with primary care follow-up. She developed a second, more significant stroke 1 month later, with unilateral weakness and slurred speech in the middle cerebral artery distribution. CONCLUSION: Clinicians should be aware that some stroke patients present with various atypical symptoms, and should suspect stroke in any patient with acute-onset neurological symptoms, including speech change.

Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells.

Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient-replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complexes with the histone acetyltransferase p300 to regulate promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity of VMP1 upstream of the GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy.

Post-traumatic stress disorder in an emergency department population one year after Hurricane Katrina.

BACKGROUND: Hurricane Katrina resulted in a significant amount of injury, death, and destruction. STUDY OBJECTIVES: To determine the prevalence of, and risk factors for, symptoms of post-traumatic stress disorder (PTSD) in an emergency department (ED) population, 1 year after hurricane Katrina. METHODS: Survey data including the Primary Care PTSD (PC-PTSD) screening instrument, demographic data, and questions regarding health care needs and personal loss were collected and analyzed. RESULTS: Seven hundred forty-seven subjects completed the survey. The PC-PTSD screen was positive in 38%. In the single variate analysis, there was a correlation with a positive PC-PTSD screen and the following: staying in New Orleans during the storm (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.28-2.34), having material losses (OR 1.64, 95% CI 1.03-2.60), experiencing the death of a loved one (OR 1.96, 95% CI 1.35-1.87), needing health care during the storm (OR 2.01, 95% CI 1.48-2.73), and not having health care needs met during the storm (OR 2.00, 95% CI 1.26-3.18) or after returning to New Orleans (OR 2.29, 95% CI 1.40-3.73). In the multivariate analysis, the death of a loved one (OR 1.87, 95% CI 1.26-2.78), being in New Orleans during the storm (OR 1.69, 95% CI 1.22-2.33), and seeking health care during the storm (OR 1.69, 95% CI 1.22-2.35) were associated with positive PC-PTSD screens. CONCLUSIONS: There was a high prevalence of PTSD in this ED population surveyed 1 year after hurricane Katrina. By targeting high-risk patients, disaster relief teams may be able to reduce the impact of PTSD in similar populations.

Pneumoscrotum after jejunal perforation: a case report.

BACKGROUND: Pneumoscrotum is a rare disease entity in which gas is present in the scrotum. It has been described after diagnostic and therapeutic procedures, as well as with disease states. The entity itself is a benign condition, but is associated with both incidental and life-threatening conditions. OBJECTIVES: We discuss the pathophysiology and associated conditions of pneumoscrotum. CASE REPORT: We report a case of pneumoscrotum after jejunum perforation. CONCLUSION: Even though pneumoscrotum is a benign, rare condition, its mere presence should signal the possibility of a severe, life-threatening disease process within the peritoneum or retroperitoneum.

Peritonsillar abscess with uvular hydrops.

The use of ultrasound by emergency physicians has improved the evaluation of pharyngeal infections. We present a unique case of concomitant peritonsillar abscess and uvular hydrops in which ultrasound provided accurate, timely information in the evaluation.

Sexual assault victims in the emergency department: analysis by demographic and event characteristics.

The objective of this study was to analyze demographic and event characteristics of patients presenting to the Emergency Department (ED) for evaluation after sexual assault, using a Sexual Assault Nurse Examiner standardized database. Data were prospectively collected as part of the Sexual Assault Nurse Examiner program at an urban teaching hospital. This study reviewed all ED patient records with a complaint of sexual assault between January 1, 2000 and December 31, 2004. Data were collected on 1172 patients; 92.6% were women, with a mean age of 27 years. The sample was 59.1% black, 38.6% white, and 2.3% "Other." Black victims of sexual assault were significantly more likely to be young (25 years or less) than Whites. Over half (54%) reported involvement of drugs or alcohol during the event. Fifty-three percent knew their assailant(s), and black and young patients were significantly more likely to know the perpetrator(s). Threats of force were common (72.4% of sample), and multiple assailants were uncommon (18.1% of sample). Physical evidence of trauma was present in more than half (51.7%), with increased rates among Whites and older persons. Multivariate analysis showed that race, age, threats, and substance use during the event were independent risk factors for evident trauma on physical examination. Survivors of sexual assault who present to the ED are overwhelmingly female, relatively young, often know the perpetrator of the event, and are likely to be threatened and show signs of physical trauma. Differences between patients according to demographic and event characteristics may have important implications for ED management and treatment plans.

Advanced glycation end products accumulate in vascular smooth muscle and modify vascular but not ventricular properties in elderly hypertensive canines.

BACKGROUND: Advanced glycation end products (AGEs) are believed to increase left ventricular (LV) and vascular stiffness, in part via cross-linking proteins. We determined whether and where AGEs were increased in elderly hypertensive nondiabetic dogs and whether an AGE cross-link breaker (ALT-711) improved vascular or ventricular function. METHODS AND RESULTS: Elderly dogs with experimental hypertension (old hypertensives [OH]) were randomized to receive ALT-711 (OH+ALT group; n=11; 1 mg/kg PO) or not (OH group; n=11) for 8 weeks. Conscious blood pressure measurements (weekly), echocardiography (week 8), and anesthetized study (week 8) with LV pressure-volume analysis and aortic pressure-dimension and pressure-flow assessment over a range of preloads and afterloads were performed. In LV and aorta from OH, OH+ALT, and young normal dogs, AGE content (immunohistochemistry and Western analysis for N(epsilon)-(carboxymethyl)lysine [CML]) was assessed. Aortic CML content was markedly increased in OH and OH+ALT dogs compared with young normal dogs. CML was localized to aortic and aortic vasa vasorum smooth muscle but not to collagen or elastin. CML was essentially undetectable in young normal, OH, or OH+ALT myocardium but was visible in large vessels in the LV. ALT-711 therapy was associated with lower blood pressure and pulse pressure, decreased systemic vascular resistance, increased aortic distensibility and arterial compliance, and, notably, significant aortic dilatation. Neither LV systolic nor diastolic function was different in OH+ALT versus OH dogs. CONCLUSIONS: In elderly hypertensive canines, AGE accumulation and AGE cross-link breaker effects were confined to the vasculature without evidence of myocardial accumulation or effects. The lack of AGE accumulation in collagen-rich areas suggests that the striking vascular effects may be mediated by mechanisms other than collagen cross-linking.

Spontaneous vulvar papillomas in a colony of mice used for pancreatic cancer research.

Mice in a colony used for pancreatic cancer research and maintained in a barrier animal facility presented with vulvar masses. A census and examination of all colony animals was conducted on 17 February 2006; line, gender, and mass location were recorded; a slide caliper was used to measure the width, length, and height of each mass; and the volume of each mass was calculated. Progeny female mice from crossbreeding of the B6.FVB-Tg(Ipf1-cre)1Tuv and B6;129-Kras2tm4Tyj (KRAS(G12D/+)) strains presented with external vulvar and periauricular papillomas. The papillomas were present in 41.2% of all female crossbred mice and ranged in size from 8 to 36 mm3. Age of mice and tumor size were not correlated. Compared with the B6.FVB-Tg(Ipf1-cre)1Tuv line, the crossbred female mice were more likely to have a vulvar mass, with an odds ratio of 29.3, 95% confidence interval (1.5, 563.9) and a positive predictive value of 42.9%. Diagnostic evaluation, including electron microscopy, light microscopy, serology, and bacteriology, did not reveal a viral or other infectious etiology. Therefore, we speculate that interaction between the genetic background of the mice and the introduced Kras oncogene may be responsible for these papillomas.

Systemic toxicity after an ocular exposure to xylazine hydrochloride.

There are limited reports of human overdose with the animal tranquilizer, xylazine hydrochloride. The reported effects include hypotension, bradycardia, and respiratory depression. Ocular exposures to xylazine have not been previously reported. A 38-year-old man arrived in the Emergency Department, reporting the accidental irrigation of both eyes with approximately 8 mL of xylazine (100 mg/mL) 30 min before arrival. The patient was asymptomatic. The eyes were copiously irrigated with isotonic crystalloid. Two hours after the exposure, the patient developed sinus bradycardia (40-50 beats/min), hypotension (90/60 mm Hg), and a decreased level of consciousness. The patient was admitted for observation, during which the bradycardia and hypotension were noted to persist. He remained otherwise asymptomatic. The symptoms resolved without intervention, other than i.v. fluids, approximately 25 h after the exposure. The patient was discharged home. This case demonstrates that ocular exposure to xylazine can cause systemic central nervous system and cardiovascular effects.

Association of clinical and laboratory variables with ultrasound findings in right upper quadrant abdominal pain.

BACKGROUND: The purpose of this study was to determine how laboratory values and physical examination findings correlate with ultrasound findings in the setting of right upper quadrant pain. METHODS: Patients undergoing emergent ultrasound for the evaluation of biliary disease between November 1999 and April 2000 were included. Physical examination findings, laboratory data, and ultrasound results were variables. Logistic regression was performed. Ultrasound diagnosis of acute cholecystitis, cholelithiasis, and normal biliary tract were end points. One hundred seventy-seven patients were enrolled. RESULTS: Forty-two percent were diagnosed with acute cholecystitis, 30.5% with cholelithiasis, and 27.1% with normal biliary tract. Alkaline phosphatase, Murphy sign, white blood cell count, and total bilirubin were statistically significant predictors of acute cholecystitis. A Murphy sign was defined as arrest of inspiration with pressure over the right upper quadrant. CONCLUSIONS: The findings from this study allow clinicians to apply objective significance to laboratory data and physical examination findings in patients with suspected gallstone disease. The data can be applied to create a predictive model.

Symptoms of post-traumatic stress disorder among emergency medicine residents.

There have been anecdotal reports of post-traumatic stress disorder (PTSD) in physicians responding to mass casualty events. No formal, prospective study has addressed the presence of PTSD symptoms as a result of the work of Emergency Medicine residents in non-mass casualty settings. The purpose of this study is to evaluate the presence of symptoms of PTSD among Emergency Medicine residents (EMR). The study was a survey of EMR, administered in an anonymous, voluntary format in late June 2001. The survey was conducted at an Emergency Medicine residency program that serves a large, urban, county hospital. Four groups, incoming interns and three EM resident classes were surveyed. PTSD symptoms were divided into three categories according to the DSM IV. The Jonckheere-Terpstra test for trends was applied to each of the three categories of symptoms. Sixty-three surveys were administered, with a 93.6% response rate. All respondents reported experience with patient death or dying. Seven residents reported sufficient symptoms to meet the DSM IV criteria for PTSD. Each of the three symptom categories showed a statistically significant increase in the proportion of positive responses as the resident time in training increased (p < 0.01). In conclusion, many EM residents reported symptoms of PTSD. Symptoms of PTSD significantly increased as resident level of training increased.

Iron bezoar retained in colon despite 3 days of whole bowel irrigation.

Concretion formation is a documented complication of large iron ingestions. The generally accepted treatment is supportive care, whole bowel irrigation, and intravenous deferoxamine for systemic toxicity. Laparotomy and gastrotomy have also been used in patients with a high iron burden and bezoar formation. Though experiments suggest that iron is poorly absorbed in the colon, there are no case reports of iron overdose without systemic toxicity, despite a retained colonic bezoar. We report the case of a 16-month-old who presented to an Emergency Department 19 h after an iron ingestion. Initial laboratory studies revealed an anion gap of 14 mEq/L, and a 20 h serum iron concentration of 429 mcg/dL. An abdominal radiograph revealed multiple pills throughout the stomach and small bowel; whole bowel irrigation was initiated. Deferoxamine was administered at 10 mg/kg/h and then stopped when the serum iron level reached 27 mcg/dL, 36 h later. At this time, the abdominal radiograph showed an iron bezoar remaining in the ascending colon despite a clear rectal effluent from whole bowel irrigation. Despite whole bowel irrigation over the next 36 h, the iron bezoar was not removed and actually migrated proximally in the colon. Treatment was stopped on the third day and a normal diet was instituted with prompt passage of the bezoar.