Citations

Chest wall strapping has been used to assess mechanisms of dyspnea with restrictive lung disease. This study examined the hypothesis that dyspnea with restriction depends principally on the degree of reflex ventilatory stimulation. We compared dyspnea at the same (iso)ventilation when added dead space provided a component of the ventilatory stimulus during exercise. Eleven healthy men undertook a randomized controlled crossover trial that compared four constant work exercise conditions: 1) control (CTRL): unrestricted breathing at 90% gas exchange threshold (GET); 2) CTRL+dead space (DS): unrestricted breathing with 0.6-l dead space, at isoventilation to CTRL due to reduced exercise intensity; 3) CWS: chest wall strapping at 90% GET; and 4) CWS+DS: chest strapping with 0.6-l dead space, at isoventilation to CWS with reduced exercise intensity. Chest strapping reduced forced vital capacity by 30.4 ± 2.2% (mean ± SE). Dyspnea at isoventilation was unchanged with CTRL+DS compared with CTRL (1.93 ± 0.49 and 2.17 ± 0.43, 0–10 numeric rating scale, respectively; P = 0.244). Dyspnea was lower with CWS+DS compared with CWS (3.40 ± 0.52 and 4.51 ± 0.53, respectively; P = 0.003). Perceived leg fatigue was reduced with CTRL+DS compared with CTRL (2.36 ± 0.48 and 2.86 ± 0.59, respectively; P = 0.049) and lower with CWS+DS compared with CWS (1.86 ± 0.30 and 4.00 ± 0.79, respectively; P = 0.006). With unrestricted breathing, dead space did not change dyspnea at isoventilation, suggesting that dyspnea does not depend on the mode of reflex ventilatory stimulation in healthy individuals. With chest strapping, dead space presented a less potent stimulus to dyspnea, raising the possibility that leg muscle work contributes to dyspnea perception independent of the ventilatory stimulus. NEW & NOTEWORTHY Chest wall strapping was applied to healthy humans to simulate restrictive lung disease. With chest wall strapping, dyspnea was reduced when dead space substituted for part of a constant exercise stimulus to ventilation. Dyspnea associated with chest wall strapping depended on the contribution of leg muscle work to ventilatory stimulation. Chest wall strapping might not be a clinically relevant model to determine whether an alternative reflex ventilatory stimulus mimics the intensity of exertional dyspnea.

We describe a case of human infection with Gongylonema pulchrum acquired in southeast Georgia. The patient presented with intermittent yet persistent nausea and vomiting for months. This case describes the need for extraction of worms on two occasions each followed by courses of albendazole treatment. Gongylonema pulchrum infections with high worm burden may relapse after extraction of the worm and a 3-day short course of albendazole therapy. Longer courses of albendazole may be indicated in selected circumstances.

The clinical nature of laryngeal amyloidosis has not been well established, and the natural history of the disease remains a controversial matter. To address these issues, we reviewed the clinicopathologic and immunohistochemical features of 22 cases (11 men and 11 women; mean age, 56 years) of laryngeal amyloidosis. Hoarseness was the most common symptom, and the most frequent site affected was the false vocal cords. Six patients had concomitant tracheal amyloidosis. Paraffin blocks were available for immunostaining in 20 cases. Nineteen cases were positive for amyloid P component. λ‐Light chains were detected in 12 cases and κ‐light chains in 5; three cases did not show definite light‐chain staining. Ten patients underwent repeated operations for persistent or recurrent respiratory tract disease. One patient died of progressive tracheobronchial amyloidosis, but systemic amyloidosis did not develop in any of the patients. Laryngeal amyloidosis is a form of localized amyloidosis characterized by monoclonal light‐chain deposition. Recurrent respiratory tract disease is not uncommon, but the usual clinical course is relatively benign.

ABSTRACTPurpose of the studyTo reduce the number of unnecessary laboratory tests ordered through a measurement of effects of education and cost awareness on laboratory ordering behaviour by internal medicine residents for common tests, including complete blood cell count (CBC) and renal profile (RP), and to evaluate effects of cost awareness on hospitalisation, 30-day readmission rate and mortality rate.Study design567 patients admitted during February, March and April 2014 were reviewed as the control group. Total CBC, CBC with differential and RP tests were counted, along with readmission and mortality rates. Interventions were education and visual cost reminders. The same tests were reassessed for 629 patients treated during 12 months after intervention in 2015.ResultsData showed a significant increase in CBCs ordered after the intervention (mean number per hospitalisation changed from 1.7 to 2.3 (p<0.001)), a decrease in CBCs with differential (mean number changed from 1.7 to 1.2 (p<0.001)) and no change in RPs ordered (mean number, 3.7 both before and after intervention (p=0.23)). No change was found in mortality rate, but the decrease in the readmission rate was significant (p=0.008).ConclusionsEducation in the form of cost reminders did not significantly reduce the overall ordering of the most common daily laboratory testing in our academic teaching service. We believe further research is needed to fully evaluate the effectiveness of other education forms on the redundant ordering of tests in the hospital setting.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTOR in PDAC cells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Cancer Res; 77(2); 320–9. ©2017 AACR.

Objective Genome‐wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger‐onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age‐at‐onset informed GWAS meta‐analysis, including a large younger‐onset SVS population, to identify novel associations with stroke. Methods We used a three‐stage age‐at‐onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10–1.22]; p = 3.2 × 10 −9 ). The lead single‐nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05–1.16]; p = 5.3 × 10 −5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84–1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues ( p = 9.4 × 10 −7 ) and DNA methylation at probe cg16596957 in whole blood ( p = 5.3 × 10 −6 ). Interpretation 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383–394