Positron emission tomography staging of pleural deposits following Monaldi's procedure: an accurate reflection or a false staging?

Positron emission tomography (PET) has become widely available in staging non-small cell lung cancer (NSCLC) and despite its high accuracy, false positive staging remains a problem. We report a rare case where such false positive staging caused a dilemma in optimal management.     

Cortical reorganization in NT3-treated experimental spinal cord injury: Functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) studies were performed for visualizing ongoing brain plasticity in Neurotrophin-3 (NT3)-treated experimental spinal cord injury (SCI). In response to the electrical stimulation of the forepaw, the NT3-treated animals showed extensive activation of brain structures that included contralateral cortex, thalamus, caudate putamen, hippocampus, and periaqueductal gray. Quantitative analysis of the fMRI data indicated significant changes both in the volume and center of activations in NT3-treated animals relative to saline-treated controls. A strong activation in both ipsi- and contralateral periaqueductal gray and thalamus was observed in NT3-treated animals. These studies indicate ongoing brain reorganization in the SCI animals. The fMRI results also suggest that NT3 may influence nociceptive pathways.     

Protective Effects of Pioglitazone Against Global Cerebral Ischemic-Reperfusion Injury in Gerbils

Despite of the huge socio-economic burden, stroke still represents an unmet therapeutic need. Researchers failed to reproduce preclinical efficacy in subsequent clinical development. To bridge this translation failure, the Stroke Therapy Academic Industry Round Table (STAIR) has suggested a rigorous, robust, and detailed preclinical evaluation in at least 2 species and multiple cerebral ischemia models to avoid the clinical failure. Considering these recommendations, in the present study, we have investigated the effects of pioglitazone in global model cerebral ischemic-reperfusion (IR) injury in gerbils. Global cerebral IR injury, produced by bilateral carotid artery occlusion for 5 min, was characterized by neurological deficits, hyperlocomotion, and neurodegeneration in the hippocampal CA1 region. Global ischemia was also associated with oxidative stress and DNA fragmentation as evident from increased malondialdehyde (MDA) levels and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells. Global cerebral IR injury associated neurological damage was significantly attenuated by pioglitazone pretreatment as evident from reduction in neurological symptoms, hyperlocomotion, and CA1 hippocampal neuronal damage in IR-challenged gerbils. Pioglitazone pretreatment also attenuated the oxidative stress and DNA fragmentation after cerebral IR injury. Pioglitazone post-treatment has also significantly reduced the CA1 hippocampal neuronal damage and DNA fragmentation after cerebral IR injury in IR-challenged gerbils. This study demonstrates the neuroprotective activity of pioglitazone in global cerebral IR injury and its neuroprotective effects may be attributed to reduction in oxidative stress and DNA fragmentation.     

Discovery of a novel class of AKT pleckstrin homology domain inhibitors

AKT, a phospholipid-binding serine/threonine kinase, is a key component of the phosphoinositide 3-kinase cell survival signaling pathway that is aberrantly activated in many human cancers. Many attempts have been made to inhibit AKT; however, selectivity remains to be achieved. We have developed a novel strategy to inhibit AKT by targeting the pleckstrin homology (PH) domain. Using in silico library screening and interactive molecular docking, we have identified a novel class of non-lipid-based compounds that bind selectively to the PH domain of AKT, with "in silico" calculated K(D) values ranging from 0.8 to 3.0 mumol/L. In order to determine the selectivity of these compounds for AKT, we used surface plasmon resonance to measure the binding characteristics of the compounds to the PH domains of AKT1, insulin receptor substrate-1, and 3-phosphoinositide-dependent protein kinase 1. There was excellent correlation between predicted in silico and measured in vitro K(D)s for binding to the PH domain of AKT, which were in the range 0.4 to 3.6 mumol/L. Some of the compounds exhibited PH domain-binding selectivity for AKT compared with insulin receptor substrate-1 and 3-phosphoinositide-dependent protein kinase 1. The compounds also inhibited AKT in cells, induced apoptosis, and inhibited cancer cell proliferation. In vivo, the lead compound failed to achieve the blood concentrations required to inhibit AKT in cells, most likely due to rapid metabolism and elimination, and did not show antitumor activity. These results show that these compounds are the first small molecules selectively targeting the PH domain of AKT. [Mol Cancer Ther 2008;7(9):2621-32].     

Giant ruptured sinus of Valsalva aneurysm: diagnosis on echocardiography

A giant ruptured sinus of Valsalva aneurysm was diagnosed ontransthoracic and subsequent transesophageal echocardiography,in a 45-year-old man who presented with gradual onset shortnessof breath. Although the initial presentation was insidious,he later rapidly deteriorated. We discuss the unusual clinicalcourse in a patient with such a large aneurysm and discuss thelikely reasons.     

Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats

Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral and brain bioavailabilities. The objective of this study is to investigate whether prodrug modification of SQV to dipeptide prodrugs Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal perfusion experiments in rat jejunum were performed to calculate the absorption rate constant and intestinal permeability of SQV, Val-Val-SQV and Gly-Val-SQV. Equimolar concentration (25 microM) of SQV, Val-Val-SQV and Gly-Val-SQV were employed in the perfusion studies. Perfusion experiments were also carried out in the presence of cyclosporine (10 microM) and glycyl-sarcosine (20 mM). Absorption rate constants in rat jejunum (ka) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be 14.1+/-3.4x10(-3), 65.8+/-4.3x10(-3), and 25.6+/-5.7x10(-3) min(-1), respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. Significant permeability enhancement of SQV across rat jejunum was observed in the presence of cyclosporine 10 microM (P-gp inhibitor). However, permeability of Val-Val-SQV was unchanged in the presence of cyclosporine suggesting lack of any interaction of the prodrug with efflux pump. Intestinal absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar indicating the involvement of peptide transporter in intestinal absorption. In conclusion, peptide transporter targeted prodrug modification of P-gp substrates could lead to shielding of these drug molecules from efflux pumps.     

Evaluation of the effect of SMA-pirarubicin micelles on colorectal cancer liver metastases and of hyperbaric oxygen in CBA mice

Tetrahydropyranyladriamycin (THP or pirarubicin) destroys tumors via several mechanisms; one of which involves the production of ROS that requires molecular oxygen for its generation. SMA forms stable self-assembled associated micelles with pirarubicin (SMA-pirarubicin), and confers macromolecular characteristics to pirarubicin. This micellar macromolecular drug is selectively delivered to solid tumors via the EPR effect and its preferential tumor accumulation suppresses the systemic toxicity whilst its prolonged high concentration at the site of tumor enhances its efficacy much higher compared to free pirarubicin. Administration of SMA-pirarubicin micelle under HBO can further enhance the delivery of molecular oxygen that facilitates tumor selective generation of ROS, thus augmenting its antitumor potency. In this study, we evaluated the efficacy of SMA-pirarubicin micelles either as single drug or in combination with HBO in a mouse metastatic colorectal cancer model. At or below the maximum tolerated dose, SMA-pirarubicin remarkably reduced metastatic tumor nodules and it was far more effective than free pirarubicin. The data also suggests a potential benefit of combined therapy of HBO with micellar anthracyclins.     

Effects of thalidomide on isoprenaline-induced acute myocardial injury: a haemodynamic, histopathological and ultrastructural study

In the present study, we investigated the cardioprotective effects of thalidomide in a rat model of acute myocardial injury, induced by subcutaneous injection of isoprenaline hemisulphate (85 mg/kg per day for 2 days). Thalidomide (75/150/300 mg/kg) or vehicle (dimethylsulphoxide) or saline (0.9% NaCl) was administered orally for 14 days and isoprenaline injection on the 12th and 13th days. Cardiovascular responses (arterial and left ventricular haemodynamic parameters and heart rate) were obtained in anaesthetized rats on the 14th day. Histopathological and electronmicroscopical analysis of myocardial injury was done. The results showed that thalidomide 300 mg/kg per day orally caused significant improvement in isoprenaline-induced reduction of cardiac function with increases in maximum rate of pressure development (+LVdP/dt, P < 0.001) and maximum rate of pressure decline (-LVdP/dt, P < 0.001) and decreases in left ventricular end-diastolic pressure (P < 0.01), systolic arterial pressure (P < 0.001), diastolic arterial pressure (P < 0.001), mean arterial pressure (P < 0.001) and heart rate (P < 0.001). The myocardial injury caused by isoprenaline was significantly reduced by thalidomide treatment as judged by the reduction of myocardial necrosis, ultrastructural changes such as mitochondria and myofibril damage, 300 mg/kg being the most effective dose. In conclusion, oral administration of thalidomide is able to ameliorate isoprenaline-induced myocardial injury and impaired myocardial function in spite of decreases in systolic arterial pressure, diastolic arterial pressure and mean arterial pressure, which may be due to its depressant effect on the sino-atrial node and sedative action.     

Outcome of Combined Liver and Kidney Transplantation in Hepatitis C: A Single-Center Long-Term Follow-up Experience

Introduction

Hepatitis C (HCV) cirrhosis is the prevalent liver disease requiring liver transplantation in the United States. Candidates who also have end-stage renal disease, chronic renal disease stage 4, or prolonged hepatorenal syndrome are considered for combined liver and kidney transplantation (CLKT).

Materials and methods

We performed a retrospective study of HCV(+) and HCV(−) CLKT patients with more than 12 months of follow-up and HCV(+) patients with isolated liver transplant (OLT) to compare the outcomes of various groups.

Results

Since 1988, 2983 OLTs were performed at our institution including 58 CLKTs. Of these, 23 were HCV(+) subjects who were significantly older than HCV(−) CLKT patients. Race, pretransplant dialysis time, renal indication for CLKT, Model for End-stage Liver Disease score, donor age, liver and kidney rejection as well as occurrence of posttransplant hypertension were similar among HCV(+) and HCV(−) CLKT patients. Posttransplant diabetes was observed in 80% of the HCV(+) group and 30% of the HCV(−) group (P = .01). Renal function seemed to be better in HCV(−) when compared with HCV(+) subjects at 5 years (P = .09). Overall patient survival for HCV(+) CLKT, HCV(−) CLKT, and HCV(+) OLT groups at 1, 2, and 5 years were not significantly different (P = .6).

Conclusion

HCV positivity should not exclude appropriate candidates for CLKT.