Aortic Intramural Hematoma in a Female Patient During Sexual Intercourse.

BACKGROUND Acute aortic syndrome (AAS) is a spectrum of severe life-threatening disease processes that are often initially encountered in the emergency department (ED) setting and require prompt recognition and treatment to prevent significant complications, including death. We describe an atypical presentation of aortic intramural hematoma in a female patient during sexual intercourse, a situation not previously described in the literature. CASE REPORT The patient was a 45-year-old woman who presented to the ED with a chief concern of chest pain. Just prior to the onset of her symptoms, the patient was having sexual intercourse with her husband, and during her orgasm she felt a "pop" in her chest with radiation to her back. The patient was diaphoretic and hypertensive on arrival, with a blood pressure of 220/140 mmHg. Computed tomography angiography of the chest was performed and showed an intramural hematoma (or thrombosed dissection) of the distal aortic arch and descending thoracic aorta. In the ED, the patient was started on intravenous antihypertensives, which were eventually switched to oral agents. Cardio-thoracic surgery staff was consulted and recommended medical management. As oral doses were increased, the intravenous antihypertensives were weaned, and the patient was eventually discharged home with scheduled outpatient follow-up. CONCLUSIONS Intramural aortic hematoma is a form of AAS with independent pathogenesis but similar progression, complications, and treatment as aortic dissection and thus demands efficient diagnosis and treatment. A high degree of suspicion, even in atypical situations, is paramount, as efficient recognition and treatment can be lifesaving.

Acrolein-mediated neuronal cell death and alpha-synuclein aggregation: Implications for Parkinson's disease.

Growing evidence suggests that oxidative stress plays a critical role in neuronal destruction characteristic of Parkinson's disease (PD). However, the molecular mechanisms of oxidative stress-mediated dopaminergic cell death are far from clear. In the current investigation, we tested the hypothesis that acrolein, an oxidative stress and lipid peroxidation (LPO) product, is a key factor in the pathogenesis of PD. Using a combination of in vitro, in vivo, and cell free models, coupled with anatomical, functional, and behavioral examination, we found that acrolein was elevated in 6-OHDA-injected rats, and behavioral deficits associated with 6-OHDA could be mitigated by the application of the acrolein scavenger hydralazine, and mimicked by injection of acrolein in healthy rats. Furthermore, hydralazine alleviated neuronal cell death elicited by 6-OHDA and another PD-related toxin, rotenone, in vitro. We also show that acrolein can promote the aggregation of alpha-synuclein, suggesting that alpha-synuclein self-assembly, a key pathological phenomenon in human PD, could play a role in neurotoxic effects of acrolein in PD models. These studies suggest that acrolein is involved in the pathogenesis of PD, and the administration of anti-acrolein scavengers such as hydralazine could represent a novel strategy to alleviate tissue damage and motor deficits associated with this disease.

Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo.

The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates.

Perceptual Assessment of Velopharyngeal Dysfunction by Otolaryngology Residents.

OBJECTIVE: To assess the ability of otolaryngology residents to rate the hypernasal resonance of patients with velopharyngeal dysfunction. We hypothesize that experience (postgraduate year [PGY] level) and training will result in improved ratings of speech samples. STUDY DESIGN: Prospective cohort study. SETTING: Otolaryngology training programs at 2 academic medical centers. SUBJECTS AND METHODS: Thirty otolaryngology residents (PGY 1-5) were enrolled in the study. All residents rated 30 speech samples at 2 separate times. Half the residents completed a training module between the rating exercises, with the other half serving as a control group. Percentage agreement with the expert rating of each speech sample and intrarater reliability were calculated for each resident. Analysis of covariance was used to model accuracy at session 2. RESULTS: The median percentage agreement at session 1 was 53.3% for all residents. At the second session, the median scores were 53.3% for the control group and 60% for the training group, but this difference was not statistically significant. Intrarater reliability was moderate for both groups. Residents were more accurate in their ratings of normal and severely hypernasal speech. There was no correlation between rating accuracy and PGY level. Score at session 1 positively correlated with score at session 2. CONCLUSION: Perceptual training of otolaryngology residents has the potential to improve their ratings of hypernasal speech. Length of time in residency may not be best predictor of perceptual skill. Training modalities incorporating practice with hypernasal speech samples could improve rater skills and should be studied more extensively.

Adverse Event Reporting for Proton Pump Inhibitor Therapy: An Overview of Systematic Reviews.

OBJECTIVE: To assist clinicians in counseling patients regarding the risk of adverse events from proton pump inhibitors (PPIs), by synthesizing evidence from published systematic reviews of antireflux therapy. DATA SOURCES: Cochrane Library, CINAHL, PubMed, Web of Knowledge. REVIEW METHODS: Overview based on PRISMA reporting standards (preferred reporting items for systematic reviews and meta-analyses) of English-language meta-analyses and systematic reviews of PPI therapy for reflux disease through December 2014. Two independent investigators assessed study eligibility, rated the review quality with AMSTAR criteria (assessing the methodological quality of systematic reviews), and abstracted data for adverse events. RESULTS: Thirty-three systematic reviews met inclusion criteria. The most commonly reported adverse events were community-acquired pneumonia (odds ratios, 1.04-1.92), with a greater association noted with shorter duration of therapy and higher doses. Hip fractures were also associated with PPI use (odds ratios, 1.16-1.50), especially with long-term therapy. Last, enteric infection with Clostridium difficile was more common with PPI therapy (odds ratios, 1.69-1.33). Other less commonly reported adverse events included electrolyte and vitamin deficiency. Risk factors for adverse events are reported in the text. CONCLUSION: Our overview shows that PPI therapy is associated with significant and potentially serious adverse events that should be discussed with patients. The effect sizes and risk factors provided should facilitate this discussion and promote shared decision making.

ABC transporters and neuroblastoma.

Neuroblastoma is the most common cancer of infancy and accounts for 15% of all pediatric oncology deaths. Survival rates of high-risk neuroblastoma remain less than 50%, with amplification of the MYCN oncogene the most important aberration associated with poor outcome. Direct transcriptional targets of MYCN include a number of ATP-binding cassette (ABC) transporters, of which ABCC1 (MRP1), ABCC3 (MRP3), and ABCC4 (MRP4) are the best characterized. These three transporter genes have been shown to be strongly prognostic of neuroblastoma outcome in primary untreated neuroblastoma. In addition to their ability to efflux a number of chemotherapeutic drugs, evidence suggests that these transporters also contribute to neuroblastoma outcome independent of any role in cytotoxic drug efflux. Endogenous substrates of ABCC1 and ABCC4 that may be potential candidates affecting neuroblastoma biology include molecules such as prostaglandins and leukotrienes. These bioactive lipid mediators have the ability to influence biological processes contributing to cancer initiation and progression, such as angiogenesis, cell signaling, inflammation, proliferation, and migration and invasion. ABCC1 and ABCC4 are thus potential targets for therapeutic suppression in high-risk neuroblastoma, and recently developed small-molecule inhibitors may be an effective strategy in treating aggressive forms of this cancer, as well as other cancers that express high levels of these transporters.

Membrane voltage fluctuations reduce spike frequency adaptation and preserve output gain in CA1 pyramidal neurons in a high-conductance state.

Modulating the gain of the input-output function of neurons is critical for processing of stimuli and network dynamics. Previous gain control mechanisms have suggested that voltage fluctuations play a key role in determining neuronal gain in vivo. Here we show that, under increased membrane conductance, voltage fluctuations restore Na(+) current and reduce spike frequency adaptation in rat hippocampal CA1 pyramidal neurons in vitro. As a consequence, membrane voltage fluctuations produce a leftward shift in the frequency-current relationship without a change in gain, relative to an increase in conductance alone. Furthermore, we show that these changes have important implications for the integration of inhibitory inputs. Due to the ability to restore Na(+) current, hyperpolarizing membrane voltage fluctuations mediated by GABA(A)-like inputs can increase firing rate in a high-conductance state. Finally, our data show that the effects on gain and synaptic integration are mediated by voltage fluctuations within a physiologically relevant range of frequencies (10-40 Hz).