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Left ventricular outflow track obstruction and mitral valve regurgitation in a patient with takotsubo cardiomyopathy. - Journal of community hospital internal medicine perspectives
Takotsubo cardiomyopathy (TCM) can be complicated by left ventricular outflow tract (LVOT) obstruction and severe acute mitral regurgitation (MR), leading to hemodynamic instability in an otherwise benign disorder. Despite the severity of these complications, there is a paucity of literature on the matter. Because up to 20-25% of TCM patients develop LVOT obstruction and/or MR, it is important to recognize the clinical manifestations of these complications and to adhere to specific management in order to reduce patient morbidity and mortality. We report the clinical history, imaging, treatment strategy, and clinical outcome of a patient with TCM that was complicated with severe MR and LVOT obstruction. We then discuss the pathophysiology, characteristic imaging, key clinical features, and current treatment strategy for this unique patient population.A postmenopausal woman with no clear risk factor for coronary artery disease (CAD) presented to the emergency department with chest pain after an episode of mental/physical stress. Physical examination revealed MR, mild hypotension, and pulmonary vascular congestion. Her troponins were mildly elevated. Cardiac catheterization excluded obstructive CAD, but revealed severe apical hypokinesia and ballooning. Notably, multiple diagnostic tests revealed the presence of severe acute MR and LVOT obstruction. The patient was diagnosed with TCM complicated by underlying MR and LVOT obstruction, and mild hemodynamic instability. The mechanism of her LVOT and MR was attributed to systolic anterior motion of the mitral valve (SAM), which the transesophageal echocardiogram clearly showed during workup. She was treated with beta-blocker, aspirin, and ACE-I with good outcome. Nitroglycerin and inotropes were discontinued and further avoided.Our case illustrated LVOT obstruction and MR associated with underlying SAM in a patient with TCM. LVOT obstruction and MR are severe complications of TCM and may result in heart failure and/or pulmonary edema. Timely and accurate identification of these complications is critical to achieve optimal clinical outcomes in patients with TCM.
Cholesterol affects flow-stimulated cyclooxygenase-2 expression and prostanoid secretion in the cortical collecting duct. - American journal of physiology. Renal physiology
Essential hypertension (eHTN) is associated with hypercholesterolemia, but how cholesterol contributes to eHTN is unknown. Recent evidence demonstrates that short-term dietary cholesterol ingestion induces epithelial Na channel (ENaC)-dependent Na absorption with a subsequent rise in blood pressure (BP), implicating cholesterol in salt-sensitive HTN. Prostaglandin E2 (PGE2), an autocrine/paracrine molecule, is induced by flow in endothelia to vasodilate the vasculature and inhibit ENaC-dependent Na absorption in the renal collecting duct (CD), which reduce BP. We hypothesize that cholesterol suppresses flow-mediated cyclooxygenase-2 (COX-2) expression and PGE2 release in the CD, which, in turn, affects Na absorption. Cortical CDs (CCDs) were microperfused at 0, 1, and 5 nlÂ·min(-1)Â·mm(-1), and PGE2 release was measured. Secreted PGE2 was similar between no- and low-flow (151 Â± 28 vs. 121 Â± 48 pgÂ·ml(-1)Â·mm(-1)) CCDs, but PGE2 was greatest from high-flow (578 Â± 146 pgÂ·ml(-1)Â·mm(-1); P < 0.05) CCDs. Next, mice were fed either a 0 or 1% cholesterol diet, injected with saline to generate high urine flow rates, and CCDs were microdissected for PGE2 secretion. CCDs isolated from cholesterol-fed mice secreted less PGE2 and had a lower PGE2-generating capacity than CCDs isolated from control mice, implying cholesterol repressed flow-induced PGE2 synthesis. Next, cholesterol extraction in a CD cell line induced COX-2 expression and PGE2 release while cholesterol incorporation, conversely, suppressed their expression. Moreover, fluid shear stress (FSS) and cholesterol extraction induced COX-2 protein abundance via p38-dependent activation. Thus cellular cholesterol composition affects biomechanical signaling, which, in turn, affects FSS-mediated COX-2 expression and PGE2 release via a p38-dependent mechanism.
Flow regulation of endothelin-1 production in the inner medullary collecting duct. - American journal of physiology. Renal physiology
Collecting duct-derived endothelin (ET)-1 is an autocrine inhibitor of Na(+) and water reabsorption; its deficiency causes hypertension and water retention. Extracellular fluid volume expansion increases collecting duct ET-1, thereby promoting natriuresis and diuresis; however, how this coupling between volume expansion and collecting duct ET-1 occurs is incompletely understood. One possibility is that volume expansion increases tubular fluid flow. To investigate this, cultured IMCD3 cells were subjected to static or flow conditions. Exposure to a shear stress of 2 dyn/cm(2) for 2 h increased ET-1 mRNA content by âˆ¼2.3-fold. Absence of perfusate Ca(2+), chelation of intracellular Ca(2+), or inhibition of Ca(2+) signaling (calmodulin, Ca(2+)/calmodulin-dependent kinase, calcineurin, PKC, or phospholipase C) prevented the flow response. Evaluation of possible flow-activated Ca(2+) entry pathways revealed no role for transient receptor potential (TRP)C3, TRPC6, and TRPV4; however, cells with TRPP2 (polycystin-2) knockdown had no ET-1 flow response. Flow increased intracellular Ca(2+) was blunted in TRPP2 knockdown cells. Nonspecific blockade of P2 receptors, as well as specific inhibition of P2X7 and P2Y2 receptors, prevented the ET-1 flow response. The ET-1 flow response was not affected by inhibition of either epithelial Na(+) channels or the mitochondrial Na(+)/Ca(2+) exchanger. Taken together, these findings provide evidence that in IMCD3 cells, flow, via polycystin-2 and P2 receptors, engages Ca(2+)-dependent signaling pathways that stimulate ET-1 synthesis.
Angiotensin II type 2 receptor regulates ROMK-like Kâº channel activity in the renal cortical collecting duct during high dietary Kâº adaptation. - American journal of physiology. Renal physiology
The kidney adjusts Kâº excretion to match intake in part by regulation of the activity of apical Kâº secretory channels, including renal outer medullary Kâº (ROMK)-like Kâº channels, in the cortical collecting duct (CCD). ANG II inhibits ROMK channels via the ANG II type 1 receptor (AT1R) during dietary Kâº restriction. Because AT1Rs and ANG II type 2 receptors (AT2Rs) generally function in an antagonistic manner, we sought to characterize the regulation of ROMK channels by the AT2R. Patch-clamp experiments revealed that ANG II increased ROMK channel activity in CCDs isolated from high-Kâº (HK)-fed but not normal Kâº (NK)-fed rats. This response was blocked by PD-123319, an AT2R antagonist, but not by losartan, an AT1R antagonist, and was mimicked by the AT2R agonist CGP-42112. Nitric oxide (NO) synthase is present in CCD cells that express ROMK channels. Blockade of NO synthase with N-nitro-l-arginine methyl ester and free NO with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt completely abolished ANG II-stimulated ROMK channel activity. NO enhances the synthesis of cGMP, which inhibits phosphodiesterases (PDEs) that normally degrade cAMP; cAMP increases ROMK channel activity. Pretreatment of CCDs with IBMX, a broad-spectrum PDE inhibitor, or cilostamide, a PDE3 inhibitor, abolished the stimulatory effect of ANG II on ROMK channels. Furthermore, PKA inhibitor peptide, but not an activator of the exchange protein directly activated by cAMP (Epac), also prevented the stimulatory effect of ANG II. We conclude that ANG II acts at the AT2R to stimulate ROMK channel activity in CCDs from HK-fed rats, a response opposite to that mediated by the AT1R in dietary Kâº-restricted animals, via a NO/cGMP pathway linked to a cAMP-PKA pathway.
Effects of biomechanical forces on signaling in the cortical collecting duct (CCD). - American journal of physiology. Renal physiology
An increase in tubular fluid flow rate (TFF) stimulates Na reabsorption and K secretion in the cortical collecting duct (CCD) and subjects cells therein to biomechanical forces including fluid shear stress (FSS) and circumferential stretch (CS). Intracellular MAPK and extracellular autocrine/paracrine PGE2 signaling regulate cation transport in the CCD and, at least in other systems, are affected by biomechanical forces. We hypothesized that FSS and CS differentially affect MAPK signaling and PGE2 release to modulate cation transport in the CCD. To validate that CS is a physiological force in vivo, we applied the intravital microscopic approach to rodent kidneys in vivo to show that saline or furosemide injection led to a 46.5 Â± 2.0 or 170 Â± 32% increase, respectively, in distal tubular diameter. Next, murine CCD (mpkCCD) cells were grown on glass or silicone coated with collagen type IV and subjected to 0 or 0.4 dyne/cm(2) of FSS or 10% CS, respectively, forces chosen based on prior biomechanical modeling of ex vivo microperfused CCDs. Cells exposed to FSS expressed an approximately twofold greater abundance of phospho(p)-ERK and p-p38 vs. static cells, while CS did not alter p-p38 and p-ERK expression compared with unstretched controls. FSS induced whereas CS reduced PGE2 release by âˆ¼40%. In conclusion, FSS and CS differentially affect ERK and p38 activation and PGE2 release in a cell culture model of the CD. We speculate that TFF differentially regulates biomechanical signaling and, in turn, cation transport in the CCD.Copyright Â© 2014 the American Physiological Society.
Biomechanical regulation of cyclooxygenase-2 in the renal collecting duct. - American journal of physiology. Renal physiology
High-dietary sodium (Na), a feature of the Western diet, requires the kidney to excrete ample Na to maintain homeostasis and prevent hypertension. High urinary flow rate, presumably, leads to an increase in fluid shear stress (FSS) and FSS-mediated release of prostaglandin E2 (PGE2) by the cortical collecting duct (CCD) that enhances renal Na excretion. The pathways by which tubular flow biomechanically regulates PGE2 release and cyclooxygenase-2 (COX-2) expression are limited. We hypothesized that FSS, through stimulation of neutral-sphingomyelinase (N-SM) activity, enhances COX-2 expression to boost Na excretion. To test this, inner medullary CD3 cells were exposed to FSS in vitro and mice were injected with isotonic saline in vivo to induce high tubular flow. In vitro, FSS induced N-SM activity and COX-2 protein expression in cells while inhibition of N-SM activity repressed FSS-induced COX-2 protein abundance. Moreover, the murine CCD expresses N-SM protein and, when mice are injected with isotonic saline to induce high tubular flow, renal immunodetectable COX-2 is induced. Urinary PGE2 (445 Â± 91 vs. 205 Â± 14 pg/ml; P < 0.05) and microdissected CCDs (135.8 Â± 21.7 vs. 65.8 Â± 11.0 pgÂ·ml(-1)Â·mm(-1) CCD; P < 0.05) from saline-injected mice generate more PGE2 than sham-injected controls, respectively. Incubation of CCDs with arachidonic acid and subsequent measurement of secreted PGE2 are a reflection of the PGE2 generating potential of the epithelia. CCDs isolated from polyuric mice doubled their PGE2 generating potential and this was due to induction of COX-2 activity/protein. Thus, high tubular flow and FSS induce COX-2 protein/activity to enhance PGE2 release and, presumably, effectuate Na excretion.
Prostaglandin E(2) mediates proliferation and chloride secretion in ADPKD cystic renal epithelia. - American journal of physiology. Renal physiology
Prostaglandin E(2) (PGE(2)) contributes to cystogenesis in genetically nonorthologous models of autosomal dominant polycystic kidney disease (ADPKD). However, it remains unknown whether PGE(2) induces the classic features of cystic epithelia in genetically orthologous models of ADPKD. We hypothesized that, in ADPKD epithelia, PGE(2) induces proliferation and chloride (Cl(-)) secretion, two archetypal phenotypic features of ADPKD. To test this hypothesis, proliferation and Cl(-) secretion were measured in renal epithelial cells deficient in polycystin-1 (PC-1). PC-1-deficient cells increased in cell number (proliferated) faster than PC-1-replete cells, and this proliferative advantage was abrogated by cyclooxygenase inhibition, indicating a role for PGE(2) in cell proliferation. Exogenous administration of PGE(2) increased proliferation of PC-1-deficient cells by 38.8 Â± 5.2% (P < 0.05) but inhibited the growth of PC-1-replete control cells by 49.4 Â± 1.9% (P < 0.05). Next, we tested whether PGE(2)-specific E prostanoid (EP) receptor agonists induce intracellular cAMP and downstream Î²-catenin activation. PGE(2) and EP4 receptor agonism (TCS 2510) increased intracellular cAMP concentration and the abundance of active Î²-catenin in PC-1-deficient cells, suggesting a mechanism for PGE(2)-mediated proliferation. Consistent with this hypothesis, antagonizing EP4 receptors reverted the growth advantage of PC-1-deficient cells, implicating a central role for the EP4 receptor in proliferation. To test whether PGE(2)-dependent Cl(-) secretion is also enhanced in PC-1-deficient cells, we used an Ussing chamber to measure short-circuit current (I(sc)). Addition of PGE(2) induced a fivefold higher increase in I(sc) in PC-1-deficient cells compared with PC-1-replete cells. This PGE(2)-induced increase in I(sc) in PC-1-deficient cells was blocked by CFTR-172 and flufenamic acid, indicating that PGE(2) activates CFTR and calcium-activated Cl(-) channels. In conclusion, PGE(2) activates aberrant signaling pathways in PC-1-deficient epithelia that contribute to the proliferative and secretory phenotype characteristic of ADPKD and suggests a therapeutic role for PGE(2) inhibition and EP4 receptor antagonism.
Flow-induced prostaglandin E2 release regulates Na and K transport in the collecting duct. - American journal of physiology. Renal physiology
Fluid shear stress (FSS) is a critical regulator of cation transport in the collecting duct (CD). High-dietary sodium (Na) consumption increases urine flow, Na excretion, and prostaglandin E(2) (PGE(2)) excretion. We hypothesize that increases in FSS elicited by increasing tubular flow rate induce the release of PGE(2) from renal epithelial cells into the extracellular compartment and regulate ion transport. Media retrieved from CD cells exposed to physiologic levels of FSS reveal several fold higher concentration of PGE(2) compared with static controls. Treatment of CD cells with either cyclooxygenase-1 (COX-1) or COX-2 inhibitors during exposure to FSS limited the increase in PGE(2) concentration to an equal extent, suggesting COX-1 and COX-2 contribute equally to FSS-induced PGE(2) release. Cytosolic phospholipase A2 (cPLA2), the principal enzyme that generates the COX substrate arachidonic acid, is regulated by mitogen-activated protein-kinase-dependent phosphorylation and intracellular Ca(2+) concentration ([Ca(2+)](i)), both signaling processes, of which, are activated by FSS. Inhibition of the ERK and p38 pathways reduced PGE(2) release by 53.3 Â± 8.4 and 32.6 Â± 11.3%, respectively, while antagonizing the JNK pathway had no effect. In addition, chelation of [Ca(2+)](i) limited the FSS-mediated increase in PGE(2) concentration by 47.5 Â± 7.5% of that observed in untreated sheared cells. Sheared cells expressed greater phospho-cPLA2 protein abundance than static cells; however, COX-2 protein expression was unaffected (P = 0.064) by FSS. In microperfused CDs, COX inhibition enhanced flow-stimulated Na reabsorption and abolished flow-stimulated potassium (K) secretion, but did not affect ion transport at a slow flow rate, implicating that high tubular flow activates autocrine/paracrine PGE(2) release and, in turn, regulates flow-stimulated cation transport. In conclusion, FSS activates cPLA2 to generate PGE(2) that regulates flow-mediated Na and K transport in the native CD. We speculate that dietary sodium intake modulates tubular flow rate to regulate paracrine PGE(2) release and cation transport in the CD.
OCRL1 modulates cilia length in renal epithelial cells. - Traffic (Copenhagen, Denmark)
Lowe syndrome is an X-linked disorder characterized by cataracts at birth, mental retardation and progressive renal malfunction that results from loss of function of the OCRL1 (oculocerebrorenal syndrome of Lowe) protein. OCRL1 is a lipid phosphatase that converts phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 4-phosphate. The renal pathogenesis of Lowe syndrome patients has been suggested to result from alterations in membrane trafficking, but this cannot fully explain the disease progression. We found that knockdown of OCRL1 in zebrafish caused developmental defects consistent with disruption of ciliary function, including body axis curvature, pericardial edema, hydrocephaly and impaired renal clearance. In addition, cilia in the proximal tubule of the zebrafish pronephric kidney were longer in ocrl morphant embryos. We also found that knockdown of OCRL1 in polarized renal epithelial cells caused elongation of the primary cilium and disrupted formation of cysts in three-dimensional cultures. Calcium release in response to ATP was blunted in OCRL1 knockdown cells, suggesting changes in signaling that could lead to altered cell function. Our results suggest a new role for OCRL1 in renal epithelial cell function that could contribute to the pathogenesis of Lowe syndrome.Â© 2012 John Wiley & Sons A/S.
Fluid shear stress induces renal epithelial gene expression through polycystin-2-dependent trafficking of extracellular regulated kinase. - Nephron. Physiology
The cilium and cilial proteins have emerged as principal mechanosensors of renal epithelial cells responsible for translating mechanical forces into intracellular signals. Polycystin-2 (PC-2), a cilial protein, regulates flow/shear-induced changes in intracellular Ca(2+) ([Ca(2+)](i)) and recently has been implicated in the regulation of mitogen-activated protein (MAP) kinases. We hypothesize that fluid shear stress (FSS) activates PC-2 which regulates MAP kinase and, in turn, induces MAP kinase-dependent gene expression, specifically, monocyte chemoattractant protein-1 (MCP-1).To test this, PC-2 expression was constitutively reduced in a murine inner medullary collecting duct (IMCD3) cell line, and the expression of FSS-induced MCP-1 expression and MAP kinase signaling compared between the parental (PC-2-expressing) and PC-2-deficient IMCD3 cells.FSS induces MAP kinase signaling and downstream MCP-1 mRNA expression in wild-type IMCD3 cells, while inhibitors of MAP kinase prevented the FSS-induced MCP-1 mRNA response. In contradistinction, FSS did not induce MCP-1 mRNA expression in PC-2-deficient cells, but did increase activation of the upstream MAP kinases. Wild-type cells exposed to FSS augmented the nuclear abundance of activated MAP kinase while PC-2-deficient cells did not.PC-2 regulates FSS-induced MAP kinase trafficking into the nucleus of CD cells.Copyright Â© 2010 S. Karger AG, Basel.
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