Vitamin D supplementation blocks pulmonary structural and functional changes in a rat model of perinatal vitamin D deficiency.

Whereas epidemiological data strongly link vitamin D (VD) deficiency to childhood asthma, the underlying molecular mechanisms remain unknown. Although VD is known to stimulate alveolar epithelial-mesenchymal interactions, promoting perinatal lung maturation, whether VD supplementation during this period protects against childhood asthma has not been demonstrated experimentally. Using an in vivo rat model, we determined the effects of perinatal VD deficiency on overall pulmonary function and the tracheal contraction as a functional marker of airway contractility. One month before pregnancy, rat dams were put on either a no cholecalciferol-added or a 250, 500, or 1,000 IU/kg cholecalciferol-added diet, which was continued throughout pregnancy and lactation. At postnatal day 21, offspring plasma 25(OH)D levels and pulmonary function (whole body plethysmography and tracheal contraction response to acetylcholine) were determined. 25(OH)D levels were lowest in the no cholecalciferol-supplemented group, increasing incrementally in response to cholecalciferol supplementation. Compared with the 250 and 500 IU/kg VD-supplemented groups, the no cholecalciferol-supplemented group demonstrated a significant increase in airway resistance following methacholine challenge. However, the cholecalciferol deficiency-mediated increase in tracheal contractility in the cholecalciferol-depleted group was only blocked by supplementation with 500 IU/kg cholecalciferol. Therefore, in addition to altering alveolar epithelial-mesenchymal signaling, perinatal VD deficiency also alters airway contractility, providing novel insights to asthma pathogenesis in perinatally VD-deficient offspring. Perinatal VD supplementation at 500 IU/kg appears to effectively block these effects of perinatal VD deficiency in the rat model used, providing a strong clinical rationale for effective perinatal VD supplementation for preventing childhood asthma.

Rho-ROCK-myosin signaling mediates membrane type 1 matrix metalloproteinase-induced cellular aggregation of keratinocytes.

Membrane type 1-matrix metalloproteinase (MT1-MMP, MMP14), which is associated with extracellular matrix (ECM) breakdown in squamous cell carcinoma (SCC), promotes tumor formation and epithelial-mesenchymal transition. However, in this report we demonstrate that MT1-MMP, by cleaving the underlying ECM, causes cellular aggregation of keratinocytes and SCC cells. Treatment with an MMP inhibitor abrogated MT1-MMP-induced phenotypic changes, but decreasing E-cadherin expression did not affect MT1-MMP-induced cellular aggregation. As ROCK1/2 can regulate cell-cell and cell-ECM interaction, we examined its role in mediating MT1-MMP-induced phenotypic changes. Blocking ROCK1/2 expression or activity abrogated the cellular aggregation resulting from MT1-MMP expression. Additionally, blocking Rho and non-muscle myosin attenuated MT1-MMP-induced phenotypic changes. Moreover, SCC cells expressing only the catalytically active MT1-MMP protein demonstrated increased cellular aggregation and increased myosin II activity in vivo when injected subcutaneously into nude mice. Together, these results demonstrate that expression of MT1-MMP may be anti-tumorigenic in keratinocytes by promoting cellular aggregation.

Ethanol differentially regulates snail family of transcription factors and invasion of premalignant and malignant pancreatic ductal cells.

Pancreatic cancer is one of the deadliest of cancers with a dismal 5-year survival rate. Epidemiological studies have identified chronic pancreatitis as a risk factor for pancreatic cancer. Pancreatic cancer cells also demonstrate increased expression of the transcription factor Snail, a key regulator of epithelial-mesenchymal transition. As ethanol is one of the major causes of pancreatitis, we examined the effect of ethanol on Snail family members in immortalized human pancreatic ductal epithelial (HPDE) cells and in pancreatic cancer cells. Ethanol induced Snail mRNA levels 2.5-fold in HPDE cells, with only 1.5-fold mRNA induction of the Snail-related protein slug. In contrast, ethanol increased Slug mRNA levels 1.5- to 2-fold in pancreatic cancer cells, with minimal effect on Snail. Because Snail increases invasion of cancer cells, we examined the effect of ethanol on invasion of HPDE and pancreatic cancer cells. Surprisingly, ethanol decreased invasion of HPDE cells, but had no effect on invasion of pancreatic cancer cells. Mechanistically, ethanol increased adhesion of HPDE cells to collagen and increased expression of the collagen binding α2- and ß1-integrins. In contrast, ethanol did not affect collagen adhesion or integrin expression in pancreatic cancer cells. Also in contrast to HPDE cells, ethanol did not attenuate ERK1/2 phosphorylation in pancreatic cancer cells; however, inhibiting ERK1/2 decreased pancreatic cancer cell invasion. Overall, our results identify the differential effects of ethanol on premalignant and malignant pancreatic cells, and demonstrate the pleiotropic effects of ethanol on pancreatic cancer progression.

Adrenal hemorrhage and hemorrhagic masses; diagnostic workup and imaging findings.

Adrenal hemorrhage (AH) is a rare condition. It can be traumatic or non-traumatic. Most common causes are septicemia, coagulopathy or bleeding diathesis, and underlying neoplasms. Other reported less common causes of AH are COVID-19 and neonatal stress. Clinical diagnosis of AH is challenging due to its non-specific presentation and occurrence in the setting of acute medical illness. Therefore, most cases are diagnosed incidentally on imaging. Having high clinical suspicion in the proper clinical setting for AH is crucial to avoid life-threatening adrenal insufficiency that occurs in 16-50% of patients with bilateral AH. We discuss the clinical situations that predispose to AH, review the imaging features on different imaging modalities, highlight a variety of clinical cases, imaging features that should be concerning for an underlying neoplasm, and outline the potential role of interventional radiology in management of AH.

Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by jugular venous occlusion: case report.

OBJECTIVE: The cause of perimesencephalic nonaneurysmal subarachnoid hemorrhage remains unknown. We describe a patient in whom jugular venous occlusion preceded the occurrence of perimesencephalic nonaneurysmal subarachnoid hemorrhage. This finding supports the theory that the source of the hemorrhage is venous in origin. CLINICAL PRESENTATION: A 25-year-old man presented with sudden onset of headache after his head was held in a headlock during a playful fight 48 hours before the ictus. His computed tomographic (CT) scan on admission demonstrated a perimesencephalic pattern of subarachnoid hemorrhage. CT angiography excluded the presence of an underlying aneurysm or vascular malformation but showed bilateral jugular venous obstruction with hematoma surrounding the right internal jugular vein. Magnetic resonance imaging and a 4-vessel cerebral angiogram confirmed the CT angiographic findings. INTERVENTION: The patient was observed as an inpatient and had no complication of his hemorrhage. Follow-up at 5 months with CT angiography showed resolution of his neck hematoma and reopening of his internal jugular veins. CONCLUSION: The presence of acute jugular venous occlusion as a cause of perimesencephalic nonaneurysmal subarachnoid hemorrhage supports a venous origin of hemorrhage.