Heart of the Matter: Syncope as a Rare Presentation of Lung Cancer Invading the Heart.

Syncope is common, affecting approximately 1 million Americans every year. Although multiple pathophysiological mechanisms regarding its etiology have been documented, neurocardiogenic or vasovagal syncope is the most common cause of these episodes. Other less appreciated etiologies include various cardiac abnormalities in which a structural, electrical, or obstructive disturbance leads to a temporary reduction in blood flow to the brain, resulting in transient loss of consciousness. Cardiac malignancies, while rare, can present with syncope by either disrupting the cardiac conduction apparatus or simply obstructing blood flow through the cardiac chambers. Electrocardiograms and echocardiography are often very helpful in identifying these abnormalities. Here, we report a rare case of late-stage invasive squamous cell carcinoma of the lung presenting with recurrent syncopal events. The cancer invaded the cardiac right atrium causing various dysrhythmias, leading to a very rare cause of cardiogenic syncope. We also discuss how lung cancer can present in a subclinical manner and at times without obvious respiratory symptoms, dramatic physical examination abnormalities, and/or thoracic imaging abnormalities on chest radiograph.

Regional Anesthesia to the Rescue: Phrenic Nerve Block to Prevent Wound Dehiscence From Intractable Hiccups-A Case Report.

Increased intra-abdominal pressure (IAP) following large abdominal surgeries can lead to postoperative complications, including wound dehiscence and surgical reoperation. Numerous factors can contribute to increased postoperative IAP, and intractable hiccups have been implicated as a culprit. Different treatment modalities have been widely used with variable success in addressing intractable hiccups. Here, we present a case in which postoperative hiccups leading to wound dehiscence and reoperation were successfully treated with an indwelling phrenic nerve catheter. Following placement, a significant reduction in hiccup severity and frequency was noted, improving the patient's quality of postoperative course and preventing further surgical intervention.

An Unresponsive Patient in Postanesthesia Care Unit: A Case Report of an Unusual Diagnosis for a Common Problem.

An unresponsive patient in the postoperative period is a serious complication that can be caused by anesthetics. However, nonanesthetic causes should also be considered. In this case report, we present an unresponsive postoperative patient diagnosed with possible psychosomatic catatonia. We further describe a systematic approach to the unresponsive patient in the postanesthesia care unit (PACU). While not an uncommon occurrence, catatonia is a complex psychomotor syndrome that can be difficult to diagnose; however, catatonia should be considered in unresponsive postoperative patients.

Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, α-actinin2 and filamin A.

KEY POINTS: Ion channels are transmembrane proteins that are synthesized within the cells but need to be trafficked to the cell membrane for the channels to function. Small-conductance, Ca2+ -activated K+ channels (SK, KCa 2) are unique subclasses of K+ channels that are regulated by Ca2+ inside the cells; they are expressed in human atrial myocytes and responsible for shaping atrial action potentials. We have previously shown that interacting proteins of SK2 channels are important for channel trafficking to the membrane. Using total internal reflection fluorescence (TIRF) and confocal microscopy, we studied the mechanisms by which the surface membrane localization of SK2 (KCa 2.2) channels is regulated by their interacting proteins. Understanding the mechanisms of SK channel trafficking may provide new insights into the regulation controlling the repolarization of atrial myocytes. ABSTRACT: The normal function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane. Small-conductance, Ca2+ -activated K+ channels (SK, KCa 2) are expressed in human atrial myocytes and are responsible for shaping atrial action potentials. Understanding the mechanisms of SK channel trafficking may provide new insights into the regulation controlling the repolarization of atrial myocytes. We have previously demonstrated that the C- and N-termini of SK2 channels interact with the actin-binding proteins α-actinin2 and filamin A, respectively. However, the roles of the interacting proteins on SK2 channel trafficking remain incompletely understood. Using total internal reflection fluorescence (TIRF) microscopy, we studied the mechanisms of surface membrane localization of SK2 (KCa 2.2) channels. When SK2 channels were co-expressed with filamin A or α-actinin2, the membrane fluorescence intensity of SK2 channels increased significantly. We next tested the effects of primaquine and dynasore on SK2 channels expression. Treatment with primaquine significantly reduced the membrane expression of SK2 channels. In contrast, treatment with dynasore failed to alter the surface membrane expression of SK2 channels. Further investigations using constitutively active or dominant-negative forms of Rab GTPases provided additional insights into the distinct roles of the two cytoskeletal proteins on the recycling processes of SK2 channels from endosomes. α-Actinin2 facilitated recycling of SK2 channels from both early and recycling endosomes while filamin A probably aids the recycling of SK2 channels from recycling endosomes.

Vocal Hoarseness and a Subglottic Mass: An Uncommon Diagnosis for a Common Complaint.

We report a patient with tracheopathia osteoplastica (TPO), a rare or perhaps underrecognized disorder, detected in approximately 1 in every 2000 to 5000 patients who undergo bronchoscopy. TPO is marked by proliferation of bony and cartilaginous spurs leading to airway stenosis. Multiple submucosal cartilaginous and osseous nodules can develop in the respiratory tract and may involve the entire trachea and mainstem bronchi. Symptoms may range from a completely silent condition to life-threatening respiratory failure and diagnosis is made based on radiological and bronchoscopic findings. Although the etiology has not been established, TPO can be familial and is sometimes associated with chronic inflammation, such as seen with rheumatic diseases. This case highlights the need for understanding TPO so that it can be differentiated from potentially serious conditions such as necrotizing granulomatous diseases, invasive infections, and cancer.

In vivo vocal fold cover layer replacement.

OBJECTIVES/HYPOTHESIS: An animal vocal fold replacement model is needed to investigate treatments for vocal fold scarring. We developed a rabbit surgical model, hypothesizing that orthotopic vocal fold cover implants would attach and survive. We further hypothesized that superficial scarring would be limited, allowing unimpeded vibration. STUDY DESIGN: Translational research: animal surgical study. METHODS: Rabbit vocal fold covers were excised and immediately reimplanted. After 4 weeks, rabbits were phonated and vibration was recorded with high-speed videography. Larynges were then excised, elastic moduli measured by indentation, and covers sectioned for histology. RESULTS: Five of six rabbits survived. Phonation was achieved in all, with mucosal waves evident. Elastic modulus did not differ significantly from contralateral uninjured control vocal folds. Histology demonstrated epithelial integrity, partial preservation of elastic fibers, and variable degrees of collagen deposition. CONCLUSIONS: Vocal fold cover implantation in rabbits is feasible, and grafts survived. Attachment onto the thyroarytenoid muscle prevented excessive scarring, maintained tissue mechanics, and preserved mucosal vibration. LEVEL OF EVIDENCE: NA.

Functional interaction with filamin A and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel.

For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca(2+)-activated K(+) channels (KCa2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca(2+)-dependent. Further, the Ca(2+) dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.

Young's modulus of canine vocal fold cover layers.

OBJECTIVES: The objective of this study was to measure the elastic modulus (Young's modulus) of canine vocal fold cover layers. STUDY DESIGN: Basic science study. METHODS: Cover layers from vocal folds of eight canine larynges were dissected. Cover layer samples from the mid-membranous, medial vocal fold surface area were used to measure material stiffness using a previously validated indentation method. Cover layers from two human larynges were also measured as control references. Superior and inferior medial cover layers were measured separately. A total of 15 superior medial surface and 17 inferior medial surface specimens from the canine and two and four specimens, respectively, from the human were tested. RESULTS: In the canine larynges, the mean Young's modulus of the superior medial surface was 4.2 kPa (range, 3.0-5.4 kPa; standard deviation [SD], 0.6 kPa) and of the inferior medial surface was 6.8 kPa (range, 5.4-8.5 kPa; SD, 0.8 kPa). Measurements on human cover samples were 5.0 kPa (range, 4.7-5.4 kPa; SD, 0.5 kPa) and 7.0 kPa (range, 6.7-7.3 kPa; SD, 0.3 kPa) for the superior medial and inferior medial surface, respectively. Human measurements were similar to the previously validated measurements. There was no difference between the stiffness measurements in the human and canine cover layer samples (P>0.05). CONCLUSIONS: The elastic stiffness (Young's modulus) of the canine and human vocal fold cover layers is similar. Findings support the use of canine larynx as an externally valid model to study voice production.

Comparison of dental health of patients with head and neck cancer receiving IMRT vs conventional radiation.

OBJECTIVE: To analyze the dental health of patients with head and neck cancer who received comprehensive dental care after intensity-modulated radiation therapy (IMRT) compared with radiation therapy (RT). STUDY DESIGN: Historical cohort study. SETTING: Veteran Affairs (VA) hospital. SUBJECTS AND METHODS: In total, 158 patients at a single VA hospital who were treated with RT or IMRT between 2003 and 2011 were identified. A complete dental evaluation was performed prior to radiation treatment, including periodontal probing, tooth profile, cavity check, and mobility. The dental treatment plan was formulated to eliminate current and potential dental disease. The rates of dental extractions, infections, caries, mucositis, xerostomia, and osteoradionecrosis (ORN) were analyzed, and a comparison was made between patients treated with IMRT and those treated with RT. RESULTS: Of the 158 patients, 99 were treated with RT and 59 were treated with IMRT. Compared with those treated with IMRT, significantly more patients treated with RT exhibited xerostomia (46.5% vs 16.9%; P < .001; odds ratio [OR], 0.24; 95% confidence interval [CI], 0.11-0.52), mucositis (46.5% vs 16.9%; P < .001; OR, 0.24; 95% CI, 0.11-0.52), and ORN (10.1% vs 0%; P = .014; OR, 0.07; 95% CI, 0.00-1.21). However, significantly more patients treated with IMRT were edentulous by the conclusion of radiation treatment (32.2% vs 11.1%; P = .002; OR, 3.8; 95% CI, 1.65-8.73). CONCLUSION: Patients who were treated with IMRT had fewer instances of dental disease, more salivary flow, and fewer requisite posttreatment extractions compared with those treated with RT. The number of posttreatment extractions has been reduced with the advent of IMRT and more so with a complete dental evaluation prior to treatment.

Slc26a6 functions as an electrogenic Cl-/HCO3- exchanger in cardiac myocytes.

AIMS: Alterations in cardiac acid-base balance can produce profound impact on excitation-contraction coupling and precipitate cardiac dysfunction and arrhythmias. A member of the solute carrier (SLC) family, Slc26a6, has been shown to be a chloride-hydroxyl exchanger and the predominant chloride-bicarbonate exchanger in the mouse heart. However, the exact isoforms and functional characteristics of cardiac Slc26a6 remain unknown. The objective of the present study is to determine the molecular identity of cardiac Slc26a6 isoforms, to examine their cellular expressions in the heart, and to test the function of Slc26a6 in cardiomyocytes. METHODS AND RESULTS: We examined the expression and function of slc26a6 in mouse cardiomyocytes using RT-PCR, immunofluorescence confocal microscopy, and patch-clamp technique coupled with the fast solution exchange system. We identified four cardiac Slc26a6 isoforms, denoted C-a, C-b, C-c, and C-d, and detected significant expression of Slc26a6 in the plasma membrane of both atrial and ventricular myocytes. Isoforms C-a and C-b share the same sequence with the previously reported murine Slc26a6a and Slc26a6b, respectively. Isoform C-c lacks an alternate in-frame exon 12, whereas C-d is a C-terminal truncated form resulting from 102 bp exon insertion between exons 15 and 16 compared with C-b. Patch-clamp recordings demonstrated electrogenic Cl(-)/oxalate and electrogenic Cl(-)/HCO3(-) exchange activities in cardiomyocytes. CONCLUSION: We demonstrate that cardiac myocytes express different isoforms of Slc26a6, which encode electrogenic Cl(-)/HCO3(-) and Cl(-)/oxalate exchangers. The electrogenic nature of the Cl(-)/HCO3(-) exchange of cardiac Slc26a6 suggests important roles in regulating acid-base balance in the heart.

Pantothenate kinase-associated neurodegeneration causing paradoxical vocal fold motion.

We report a patient with paradoxical vocal fold motion (PVFM) due to pantothenate kinase-associated neurodegeneration, a rare neurodegenerative disease and a subclass of neurodegeneration with brain iron accumulation disorders. PVFM is marked by normal vocal fold anatomy and physiology with intermittent adduction during the respiratory cycle. Many etiologies have been reported and include laryngeal hypersensitivity such as asthma and gastroesophageal reflux, functional disorders, and neurologic disorders such as focal respiratory dystonia. This case highlights the occasional association of PVFM with underlying neurologic disorders, especially those that disrupt autonomic functioning.

Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels.

RATIONALE: Ca(2+)-activated K(+) channels are present in a wide variety of cells. We have previously reported the presence of small conductance Ca(2+)-activated K(+) (SK or K(Ca)) channels in human and mouse cardiac myocytes that contribute functionally toward the shape and duration of cardiac action potentials. Three isoforms of SK channel subunits (SK1, SK2, and SK3) are found to be expressed. Moreover, there is differential expression with more abundant SK channels in the atria and pacemaking tissues compared with the ventricles. SK channels are proposed to be assembled as tetramers similar to other K(+) channels, but the molecular determinants driving their subunit interaction and assembly are not defined in cardiac tissues. OBJECTIVE: To investigate the heteromultimeric formation and the domain necessary for the assembly of 3 SK channel subunits (SK1, SK2, and SK3) into complexes in human and mouse hearts. METHODS AND RESULTS: Here, we provide evidence to support the formation of heteromultimeric complexes among different SK channel subunits in native cardiac tissues. SK1, SK2, and SK3 subunits contain coiled-coil domains (CCDs) in the C termini. In vitro interaction assay supports the direct interaction between CCDs of the channel subunits. Moreover, specific inhibitory peptides derived from CCDs block the Ca(2+)-activated K(+) current in atrial myocytes, which is important for cardiac repolarization. CONCLUSIONS: The data provide evidence for the formation of heteromultimeric complexes among different SK channel subunits in atrial myocytes. Because SK channels are predominantly expressed in atrial myocytes, specific ligands of the different isoforms of SK channel subunits may offer a unique therapeutic opportunity to directly modify atrial cells without interfering with ventricular myocytes.

Alpha-actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+ channel (SK2 channel).

The importance of proper ion channel trafficking is underpinned by a number of channel-linked genetic diseases whose defect is associated with failure to reach the cell surface. Conceptually, it is reasonable to suggest that the function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane, which is determined jointly by the secretory and endocytic pathways. Yet the precise mechanisms of the entire ion channel trafficking pathway remain unknown. Here, we directly demonstrate that proper membrane localization of a small-conductance Ca(2+)-activated K(+) channel (SK2 or K(Ca)2.2) is dependent on its interacting protein, alpha-actinin2, a major F-actin crosslinking protein. SK2 channel localization on the cell-surface membrane is dynamically regulated, and one of the critical steps includes the process of cytoskeletal anchoring of SK2 channel by its interacting protein, alpha-actinin2, as well as endocytic recycling via early endosome back to the cell membrane. Consequently, alteration of these components of SK2 channel recycling results in profound changes in channel surface expression. The importance of our findings may transcend the area of K(+) channels, given that similar cytoskeletal interaction and anchoring may be critical for the membrane localization of other ion channels in neurons and other excitable cells.