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Case Presentation: A 57-year-old man with history of stage IIIB right-sided malignant pleural mesothelioma was admitted from his oncologist's office for progressive dyspnea of two weeks duration. He had associated dyspnea at rest and a new dry cough. He denied sputum production, hemoptysis, or fevers, but he did endorse chills, fatigue, and weight loss. The patient was a veteran of the Navy and had extensive international travel in his 20s. He had never been incarcerated and denied any sick contacts or recent travels. He had received a diagnosis of mesothelioma 11 months earlier after presenting to his physician's office with complaints of shortness of breath on exertion. Initial imaging revealed a large right-sided pleural effusion with irregular pleural thickening. He underwent right-sided thoracoscopy, and the pleural biopsy result was consistent with epithelioid mesothelioma. Because of invasion of his seventh rib, he was not a candidate for surgery and underwent palliative radiation and chemotherapy with cisplatin, pemetrexed, and bevacizumab. He was undergoing his eighth cycle of chemotherapy at the time of presentation., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: There is emerging reliance on clinical imaging for the diagnosis, prognosis, and treatment evaluation of early stage non-small cell lung cancer (NSCLC) in patients deemed too high risk for biopsy. We report our experience of clinically diagnosed NSCLC treated empirically with stereotactic body radiotherapy (SBRT) to validate the imaging parameters used for management in this high-risk population., Methods: We reviewed 101 empiric lung SBRT cases and profiled imaging specifics of computed tomography and positron emission tomography for diagnosis and follow-up. Secondarily, we identified potential correlates of disease progression with Cox regression multivariate analysis., Results: Fifty-seven men and 43 women aged 45-94 (median 76) were treated with a median dose of 48 Gy in four fractions. The median nodule diameter was 1.6 cm (0.6-4.5 cm) and most were spiculated (n = 58), right-sided (n = 63), and in the upper lobe (n = 68). Median follow-up and survival rates were 14 and 28 months, respectively. Local control at three years was 94%. Freedom from any progression at one and three years was 85% and 69%, respectively. Toxicity ≥ grade 3 included two grade 3 dyspneas. A pre-treatment standard uptake value > 4.1 was the only significant predictor of disease progression., Conclusion: This study illustrates the instrumental role of modern clinical imaging for the effective management of presumed early stage NSCLC treated with empiric lung SBRT. As lung SBRT without tissue confirmation becomes more common, hopefully these assertions can be prospectively validated., (© 2018 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: There are limited data comparing the clinical presentations, comorbidities, and outcomes of patients with infections due to seasonal influenza with patients with infections due to pandemic (H1N1) 2009 influenza., Objective: To compare the epidemiological characteristics and outcomes of pandemic (H1N1) 2009 influenza with those of seasonal influenza., Methods: A cross-sectional study was conducted among patients who received diagnoses during emergency department and inpatient encounters at 2 affiliated academic medical centers in Philadelphia, Pennsylvania. Cases of seasonal influenza during the period November 1, 2005, through June 1, 2008, and cases of pandemic influenza during the period from May 1, 2009, through August 7, 2009, were identified retrospectively., Results: Forty-nine cases of pandemic influenza and 503 cases of seasonal influenza were identified. Patients with pandemic H1N1 were younger (median age, 29 years) than patients with seasonal influenza (median age, 59 years) (P<.001). More patients with pandemic H1N1 (35 [71%] of 49) were African American, compared with patients with seasonal influenza (267 [53%] of 503; P=.02). Several symptoms were more common among patients with pandemic influenza infections than among patients with seasonal influenza infections: cough (98% vs 83%; P=.007), myalgias (71% vs 46%; P=.001), and pleuritic chest pain (45% vs 15%; P<.001). Pregnancy was the only comorbidity that occurred significantly more often in the pandemic influenza group than in the seasonal influenza group (16% vs 1%; P<.001). There were no significant differences in frequencies of deaths of hospitalized patients, intensive care unit admission, or length of hospitalization between groups., Conclusion: Other than pregnancy, there were few clinically important differences between infections due to seasonal influenza and those due to pandemic influenza. The greater rate of lower respiratory tract symptoms in pandemic cases might serve to differentiate pandemic influenza from seasonal influenza.

In CA1 pyramidal neurons of the hippocampus, calcium-dependent spikes occur in vivo during specific behavioral states and may be enhanced during epileptiform activity. However, the mechanisms that control calcium spike initiation and repolarization are poorly understood. Using dendritic and somatic patch-pipette recordings, we show that calcium spikes are initiated in the apical dendrites of CA1 pyramidal neurons and drive bursts of sodium-dependent action potentials at the soma. Initiation of calcium spikes at the soma was suppressed in part by potassium channels activated by sodium-dependent action potentials. Low-threshold, putative D-type potassium channels [blocked by 100 microM 4-aminopyridine (4-AP) and 0.5-1 microM alpha-dendrotoxin (alpha-DTX)] played a prominent role in setting a high threshold for somatic calcium spikes, thus restricting initiation to the dendrites. DTX- and 4-AP-sensitive channels were activated during sodium-dependent action potentials and mediated a large component of their afterhyperpolarization. Once initiated, repetitive firing of calcium spikes was limited by activation of putative BK-type calcium-activated potassium channels (blocked by 250 microM tetraethylammonium chloride, 70 nM charybdotoxin, or 100 nM iberiotoxin). Thus, the concerted action of calcium- and voltage-activated potassium channels serves to focus spatially and temporally the membrane depolarization and calcium influx generated by calcium spikes during strong, synchronous network excitation.

Sodium channels in the somata and dendrites of hippocampal CA1 pyramidal neurons undergo a form of long-lasting, cumulative inactivation that is involved in regulating back-propagating action potential amplitude and can influence dendritic excitation. Using cell-attached patch-pipette recordings in the somata and apical dendrites of CA1 pyramidal neurons, we determined the properties of slow inactivation on response to trains of brief depolarizations. We find that the amount of slow inactivation gradually increases as a function of distance from the soma. Slow inactivation is also frequency and voltage dependent. Higher frequency depolarizations increase both the amount of slow inactivation and its rate of recovery. Hyperpolarized resting potentials and larger command potentials accelerate recovery from slow inactivation. We compare this form of slow inactivation to that reported in other cell types, using longer depolarizations, and construct a simplified biophysical model to examine the possible gating mechanisms underlying slow inactivation. Our results suggest that sodium channels can enter slow inactivation rapidly from the open state during brief depolarizations or slowly from a fast inactivation state during longer depolarizations. Because of these properties of slow inactivation, sodium channels will modulate neuronal excitability in a way that depends in a complicated manner on the resting potential and previous history of action potential firing.

During low-frequency firing, action potentials actively invade the dendrites of CA1 pyramidal neurons. At higher firing rates, however, activity-dependent processes result in the attenuation of back-propagating action potentials, and propagation failures occur at some dendritic branch points. We tested two major hypotheses related to this activity-dependent attenuation of back-propagating action potentials: (1) that it is mediated by a prolonged form of sodium channel inactivation and (2) that it is mediated by a persistent dendritic shunt activated by back-propagating action potentials. We found no evidence for a persistent shunt, but we did find that cumulative, prolonged inactivation of sodium channels develops during repetitive action potential firing. This inactivation is significant after a single action potential and continues to develop during several action potentials thereafter, until a steady-state sodium current is established. Recovery from this form of inactivation is much slower than its induction, but recovery can be accelerated by hyperpolarization. The similarity of these properties to the time and voltage dependence of attenuation and recovery of dendritic action potentials suggests that dendritic sodium channel inactivation contributes to the activity dependence of action potential back-propagation in CA1 neurons. Hence, the biophysical properties of dendritic sodium channels will be important determinants of action potential-mediated effects on synaptic integration and plasticity in hippocampal neurons.