The Na/K-ATPase is the specific receptor for cardiotonic steroids (CTS) such as ouabain and digoxin. At pharmacological concentrations used in the treatment of cardiac conditions, CTS inhibit the ion-pumping function of Na/K-ATPase. At much lower concentrations, in the range of those reported for endogenous CTS in the blood, they stimulate hypertrophic growth of cultured cardiac myocytes through initiation of a Na/K-ATPase-mediated and reactive oxygen species (ROS)-dependent signaling. To examine a possible effect of endogenous concentrations of CTS on cardiac structure and function in vivo, we compared mice expressing the naturally resistant Na/K-ATPase α1 and age-matched mice genetically engineered to express a mutated Na/K-ATPase α1 with high affinity for CTS. In this model, total cardiac Na/K-ATPase activity, α1, α2, and β1 protein content remained unchanged, and the cardiac Na/K-ATPase dose–response curve to ouabain shifted to the left as expected. In males aged 3–6 months, increased α1 sensitivity to CTS resulted in a significant increase in cardiac carbonylated protein content, suggesting that ROS production was elevated. A moderate but significant increase of about 15% of the heart-weight-to-tibia-length ratio accompanied by an increase in the myocyte cross-sectional area was detected. Echocardiographic analyses did not reveal any change in cardiac function, and there was no fibrosis or re-expression of the fetal gene program. RNA sequencing analysis indicated that pathways related to energy metabolism were upregulated, while those related to extracellular matrix organization were downregulated. Consistent with a functional role of the latter, an angiotensin-II challenge that triggered fibrosis in the α1^r/rα2^s/s mouse failed to do so in the α1^s/sα2^s/s. Taken together, these results are indicative of a link between circulating CTS, Na/K-ATPase α1, ROS, and physiological cardiac hypertrophy in mice under baseline laboratory conditions.

Leiomyosarcomas (LMS) are malignant tumors originating from smooth muscle and rarely found in the scrotum. LMS has an insidious presentation that is often misdiagnosed as a benign lesion. This report outlines an innocuous case of paratesticular leiomyosarcoma while focusing on the diagnosis and treatment paratesticular LMS. We report the case of an 84-year-old male who presented with a painless left scrotal swelling of 5 days’ duration. Imaging and tumor markers suggested a paratesticular mass suspicious for malignancy. Surgical excision revealed a Fédération Nationale des Centres de Lutte Contre le Cancer Grade 2 leiomyosarcoma arising from the scrotal soft tissue, confirmed by positive smooth muscle markers on immunohistochemistry. Postoperative imaging demonstrated no recurrence at 8 months. This case highlights the diagnostic challenge of paratesticular leiomyosarcoma and the importance of surgical resection and careful follow-up for optimal patient outcomes.

Gastrointestinal bleeding (GIB) is a common cause of urgent hospitalization in patients with cirrhosis. However, limited studies have examined the prevalence and risk of these complications based on etiology. This study aims to compare the occurrence and risk of cirrhosis complications on inpatient mortality between alcoholic cirrhosis (ALC) and other etiology-induced cirrhosis (NALC). This retrospective analysis included 7,159,694 patients. ALC was diagnosed based on ICD-10, while NALC included primary and secondary biliary cirrhosis, nonalcoholic steatohepatitis (NASH), and unspecified cirrhosis of the liver. GIB included bleeding from esophageal and gastric varices. Bivariate analyses using appropriate statistical tests were performed to compare the two groups. ALC patients had a significantly higher incidence of GIB compared with NALC patients (10.8% vs. 6.4%, p < 0.01), with an associated 60% higher risk of GIB than NALC patients (p < 0.01). ALC was associated with a higher prevalence of ascites (45.6% vs. 27.9%, p < 0.01) and hepatic encephalopathy (HE) (45.5% vs. 27.2%, p < 0.01) compared with NALC patients. The risk of ascites and HE was 2.2 times and 2.3 times higher, respectively, in ALC patients compared with NALC patients (p < 0.01). Furthermore, ALC patients had higher hospital mortality rates compared with NALC patients, with a 47% higher risk of hospital mortality after adjustment (p < 0.01). ALC patients also had prolonged hospital stays, higher charges, more emergency room (ER) visits, and more frequent esophagogastroduodenoscopy (EGD) requirements compared with those of NALC patients (p < 0.01). ALC patients have a significantly higher risk of developing GIB, ascites, and HE compared with NALC patients, leading to increased mortality and greater medical burden on hospitals.

Cardiac Na/K-ATPase (NKA) inhibition by cardiotonic steroids (CTS) modulates intracellular Na⁺ and Ca²⁺, leading to increased force of contraction. In contrast, hypertrophy of cardiomyocytes (CM) is triggered by CTS through stimulation of reactive oxygen species (ROS) and fetal gene re-expression independently of changes in intracellular Na⁺ or Ca²⁺. Based on recent evidence that NKAα1 serves an isoform-specific function in the regulation of oxidative metabolism and ROS generation, we used a genetic approach in the mouse and in human cardiac cells (AC16) to test the hypothesis that NKAα1 is required for cardiac hypertrophy. Cardio α1^-/- mice, a conditional KO of NKAα1 in the heart, were viable without overt abnormality of cardiac structure or function. NKAα1 was undetectable in heart lysates or isolated CM of adult cardio α1^-/- mice. Despite a compensatory upregulation of NKAα2, Na/K-ATPase activity in crude heart homogenates and NKA currents in CM were reduced by about 60%. Decreased ROS (assessed by total protein carbonylation) and reduced fatty acid oxidation (FAO) and oxidative phosphorylation pathways (revealed by RNA-seq analysis) were noted at baseline. RT-qPCR revealed downregulated genes involved with FAO and the electron transport chain (such as, Acadl and Ndufa9, about 20% decrease, n=6) in cardio α1^-/- hearts. The activity of the electron transport chain complex I was decreased in cardio α1^-/- hearts (0.3354 vs 0.2732 mOD/min/mg of protein, p<0.05). When 3-month-old male mice were challenged with angiotensin II (1.5 mg.kg^-1.day^-1 for 1 week, n=6-15), cardio α1^-/- mice did not develop cardiac hypertrophy, as assessed by heart weight to tibia length ratio, but displayed exacerbated cardiac fibrosis, revealed by Trichrome staining, consistent with the postulated role of CM NKAα1 isoform-specific function in cardiac hypertrophy in vivo. In vitro, CRISPR-Cas9-mediated KO of NKAα1 in AC16 cells led to a drastic downregulation of NKAα1 compared to WT AC16 cells. In contrast to WT AC16 cells, NKAα1 KO cells did not respond to the α-adrenergic agonist phenylephrine (50 μM for 24h) with the expected increase in cell area (2243 vs 3520 μm² for WT, p0.05). These data suggest that NKAα1 isoform-specific function is required for cardiac hypertrophy. Mechanistically, our data support an isoform-specific regulatory function of NKAα1 in normal FAO, electron transport chain activity, and ROS generation, which are critical for CM hypertrophy. Supported by NIH Grant R15 HL145666 and American Heart Association Grant 22POST917776 (Marco T. Pessoa) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this Physiology was not involved in the peer review process.

Penile squamous cell carcinoma (PSCC) is a rare presentation in the United States and Europe, accounting for only 1% of male malignancies. Most commonly due to human papilloma virus (HPV), PSCC has an insidious onset, often ignored by patients until functional impairments are present. This report outlines an interesting presentation of penile squamous cell carcinoma while focusing on current developments in the prognosis and treatment of PSCC. We present the case of a 68-year-old male who presented with a 5 cm fungating mass of the glans penis after emergent care following a stroke. Visual inspection revealed a large mass of the glans penis which had completely obliterated the urethral meatus. A partial penectomy and urethrostomy were performed. Surgical excision revealed a unifocal moderately differentiated (G2) squamous cell carcinoma, with immunohistochemical staining demonstrating p16 positivity, consistent with HPV-associated etiology. This case highlights the importance of individualized treatment regimens and prognostic determination for optimal patient outcomes.