Venous thromboembolic disease presenting as inferior vena cava thrombus extending into the right atrium

With increasing use of echocardiography, especially transesophageal echocardiography, the diagnosis of intracardiac masses has surged. Masses that are most commonly seen in the atrial chambers include thrombi due to atrial fibrillation, cardiac myxomas often located in the atria, and valvular vegetations of infective endocarditis. In this report we present a case of a patient who developed thrombus in the inferior vena cava that extended up to the right atrium and presented as an apparent intracardiac mass. This mass embolized to the right pulmonary artery shortly after diagnosis resulting in pulmonary embolism, which the patient fortunately survived.     

IQGAP1 and IQGAP2 are Reciprocally Altered in Hepatocellular Carcinoma

Background  

IQGAP1 and IQGAP2 are homologous members of the IQGAP family of scaffold proteins. Accumulating evidence implicates IQGAPs in tumorigenesis. We recently reported that IQGAP2 deficiency leads to the development of hepatocellular carcinoma (HCC) in mice. In the current study we extend these findings, and investigate IQGAP1 and IQGAP2 expression in human HCC.     

Targeting SVCT for enhanced drug absorption: synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

In order to improve oral absorption, a novel prodrug of saquinavir (Saq), ascorbyl-succinic-saquinavir (AA-Su-Saq) targeting sodium dependent vitamin C transporter (SVCT) was synthesized and evaluated. Aqueous solubility, stability and cytotoxicity were determined. Affinity of AA-Su-Saq towards efflux pump P-glycoprotein (P-gp) and recognition of AA-Su-Saq by SVCT were studied. Transepithelial permeability across polarized MDCK-MDR1 and Caco-2 cells were determined. Metabolic stability of AA-Su-Saq in rat liver microsomes was investigated. AA-Su-Saq appears to be fairly stable in both DPBS and Caco-2 cells with half lives of 9.65 and 5.73 h, respectively. Uptake of [(3)H]Saquinavir accelerated by 2.7 and 1.9 fold in the presence of 50 μM Saq and AA-Su-Saq in MDCK-MDR1 cells. Cellular accumulation of [(14)C]AA diminished by about 50-70% relative to control in the presence of 200 μM AA-Su-Saq in MDCK-MDR1 and Caco-2 cells. Uptake of AA-Su-Saq was lowered by 27% and 34% in the presence of 5mM AA in MDCK-MDR1 and Caco-2 cells, respectively. Absorptive permeability of AA-Su-Saq was elevated about 4-5 fold and efflux index reduced by about 13-15 fold across the polarized MDCK-MDR1 and Caco-2 cells. Absorptive permeability of AA-Su-Saq decreased 44% in the presence of 5mM AA across MDCK-MDR1 cells. AA-Su-Saq was devoid of cytotoxicity over the concentration range studied. AA-Su-Saq significantly enhanced the metabolic stability but lowered the affinity towards CYP3A4. In conclusion, prodrug modification of Saq through conjugation to AA via a linker significantly raised the absorptive permeability and metabolic stability. Such modification also caused significant evading of P-gp mediated efflux and CYP3A4 mediated metabolism. SVCT targeted prodrug approach can be an attractive strategy to enhance the oral absorption and systemic bioavailability of anti-HIV protease inhibitors.     

Protective role of curcumin on colchicine-induced cognitive dysfunction and oxidative stress in rats

Dementia is a syndrome of progressive nature, affects wide range of cognitive abilities like memory, language, calculation and so on, neuropsychiatric and social deficits to impair the routine social functions. The present study was designed to assess the effect of curcumin against colchicine-induced cognitive dysfunction and oxidative stress in rats and compare it with rivastigmine. Colchicine (15 μg/5μl) was administered to male Wistar rats intracerebroventricularly (i.c.v.) by stereotaxic apparatus to induce cognitive dysfunction. Administration of colchicine caused poor retention of memory in elevated plus maze, passive avoidance apparatus and Morris water maze paradigms. Chronic treatment with curcumin (100, 200 and 400 mg/kg, p.o.) twice daily and rivastigmine (2.5 mg/kg, p.o.) daily for a period of 28 days beginning 7 days prior to colchicine injection significantly improved colchicine-induced cognitive impairment. Biochemical assessment revealed that i.c.v. colchicine injection significantly increased lipid peroxidation, depleted reduced glutathione levels and decreased acetyl cholinesterase (AChE) activity in rat brains. Chronic administration of curcumin significantly reduced the elevated lipid peroxidation, restored the reduced glutathione levels and AChE activity; however, rivastigmine failed to prevent oxidative stress. The results of the current study indicate that curcumin (100, 200 and 400 mg/kg, p.o.) twice daily has a protective role against colchicine-induced cognitive impairment and associated oxidative stress.     

Hexamethyldisiloxane-based nanoprobes for (1) H MRI oximetry

Quantitative in vivo oximetry has been reported using ¹⁹F MRI in conjunction with reporter molecules, such as perfluorocarbons, for tissue oxygenation (pO₂). Recently, hexamethyldisiloxane (HMDSO) has been proposed as a promising alternative reporter molecule for ¹H MRI‐based measurement of pO₂. To aid biocompatibility for potential systemic administration, we prepared various nanoemulsion formulations using a wide range of HMDSO volume fractions and HMDSO to surfactant ratios. Calibration curves (R₁ versus pO₂) for all emulsion formulations were found to be linear and similar to neat HMDSO for low surfactant concentrations (< 10% v/v). A small temperature dependence in the calibration curves was observed, similar to previous reports on neat HMDSO, and was characterized to be approximately 1 Torr/ °C under hypoxic conditions. To demonstrate application in vivo, 100 µL of this nanoemulsion was administered to healthy rat thigh muscle (Fisher 344, n = 6). Dynamic changes in mean thigh tissue pO₂ were measured using the PISTOL (proton imaging of siloxanes to map tissue oxygenation levels) technique in response to oxygen challenge. Changing the inhaled gas to oxygen for 30 min increased the mean pO₂ significantly (p < 0.001) from 39 ± 7 to 275 ± 27 Torr. When the breathing gas was switched back to air, the tissue pO₂ decreased to a mean value of 45 ± 6 Torr, not significantly different from baseline (p > 0.05), in 25 min. A first‐order exponential fit to this part of the pO₂ data (i.e. after oxygen challenge) yielded an oxygen consumption‐related kinetic parameter k = 0.21 ± 0.04 min^?1. These results demonstrate the feasibility of using HMDSO nanoemulsions as nanoprobes of pO₂ and their utility to assess oxygen dynamics in vivo, further developing quantitative ¹H MRI oximetry. Copyright © 2011 John Wiley & Sons, Ltd.     

Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy

The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-β superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg(-1) body weight. After 12 weeks of treatment, the 10.0 mg/kg(-1) dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg(-1)), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.