Characterizing vascular parameters in hypoxic regions: a combined magnetic resonance and optical imaging study of a human prostate cancer model

The integration of imaging technologies with the capabilities of genetic engineering has created novel opportunities for understanding and imaging cancer. Here, we have combined vascular magnetic resonance imaging (MRI) and optical imaging to understand the relationship between hypoxia and vascularization in a human prostate cancer model engineered to express enhanced green fluorescent protein (EGFP) under hypoxia. Characterization and validation of EGFP expression under hypoxic conditions was done in culture and in solid tumors in vivo. MRI measurements showed that vascular volume was significantly lower in fluorescing regions. These regions also frequently exhibited high permeability. These data were further supported by the detection of low vessel density in EGFP-positive regions, as determined by the distribution of intravascularly administered, fluorescence-labeled Lycopersicon esculentum lectin in frozen tumor sections. These observations are consistent with the possibility that regions of low vascular volumes are hypoxic, which induces increased expression of functionally active vascular endothelial growth factor, a potent vascular permeability factor.     

Split therapy: planned neck dissection followed by definitive radiotherapy for a T1, T2 pharyngolaryngeal primary cancer with operable N2, N3 nodal metastases--a prospective study

BACKGROUND: The management of patients with a small pharyngolaryngeal cancer (T1 and T2) with large nodal metastases is a subject of debate. We present data on the feasibility and outcome of treating these patients with surgery for the nodal metastases followed by definitive radiotherapy. METHODS: Prospective study of 59 patients of small pharyngolaryngeal primary squamous carcinomas with operable (N2/N3) nodal metastasis treated with neck dissection followed by radiotherapy. RESULTS: Complete nodal clearance was achieved in 54 (90%). The mean nodal size was 4 cm and extranodal extension was seen in 88% of patients in the study group. There were no significant postoperative complications. Median interval between surgery and radiotherapy was 23 days. Forty-nine patients (83%) started their RT within 6 weeks of surgery. With a median follow-up of 25 months, the disease free and overall survival was 54% and 60% (5 years). CONCLUSION: The management of patients with a radiocurable pharyngolaryngeal primary with large nodes by this approach is a feasible option with adequate control and survival.     

Supracardiac total anomalous pulmonary venous connection with a supramitral ring: a rare, surgically correctable anomaly

Total anomalous pulmonary venous connection is rarely associated with a supramitral ring. This condition should be suspected in any infant having total anomalous pulmonary venous connection with obstruction to the pulmonary venous return. Preoperative echocardiography is usually successful in detecting the lesion. The Shumaker and King repair for total anomalous pulmonary venous connection is most appropriate for such composite lesions as it enables the surgeon to identify the membrane and excise it easily and completely. We report one such case.     

CNS activity of Calotropis gigantea roots

Alcoholic extract of peeled roots of Calotropis gigantea R.Br. (Asclepiadaceae) was tested orally in albino rats at the dose level of 250 and 500 mg/kg bodyweight for CNS activity. Prominent analgesic activity was observed in Eddy's hot plate method and acetic acid induced writhings. The paw licking time was delayed and the numbers of writhings were greatly reduced. Significant anticonvulsant activity was seen as there was a delay in the onset of pentylenetetrazole induced convulsions as well as decrease in its severity. The extract treated rats spent more time in the open arm of EPM showing its antianxiety activity. There was a decrease in the locomotor activity. The fall off time (motor coordination) was also decreased. A potentiation in the pentobarbitone-induced sleep due to the sedative effect of the extract was observed. No mortality was seen upto the dose of 1 g/kg. These results show the analgesic, anticonvulsant, anxiolytic and sedative effect of the extract.     

Physicochemical characterization and dissolution enhancement of aceclofenac-hydroxypropyl beta-cyclodextrin binary systems

The aim of this study is to prepare and characterize binary systems of aceclofenac (AC) with hydroxypropyl beta-cyclodextrin (HPbetaCD) in equimolar ratio. Solid binary systems of aceclofenac with HPbetaCD were prepared using cogrinding, kneading, and coevaporating methods, and a physical mixture was prepared for comparison. The binary systems were characterized by differential scanning calorimetry, thermogravimetric analysis, mass spectroscopy, 1H nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy, and in vitro dissolution studies. 1H NMR studies showed that AC partially fits into the HPbetaCD torus cavity with a preferential inclusion of the phenyl ring of the drug. All the binary systems showed superior dissolution and lower dose:solubility ratio (D:S ratio) as compared to pure AC, but the kneaded product exhibited the best dissolution, with complete drug release within 10 min and a D:S ratio of 5 mL. Hence, it was suggested that complexation of aceclofenac with HPbetaCD may be used as an approach to change the drug from Biopharmaceutics Classification System BCS Class II to BCS Class I without changing its intrinsic permeability.     

Influence of cadmium on murine thymocytes: potentiation of apoptosis and oxidative stress

Cadmium (Cd) is a well-known environmental carcinogen and a potent immunotoxicant. It induces thymocyte apoptosis in vitro. However, the mode of action is unclear. In this study, we examined the effect of Cd (10, 25 and 50microM) on mitochondrial membrane potential and caspase-3 as well as oxidative stress markers in murine thymocytes. The cadmium induced apoptosis occurred in a concentration and time dependent manner. The early markers of apoptosis-loss in mitochondrial membrane potential and caspase-3 activation were evident as early as 1.5h by 50microM Cd. Enhanced reactive oxygen species (ROS) generation and glutathione (GSH) depletion were observed at 60min, prior to the lowering of mitochondrial membrane potential. The Cd induced DNA damage as depicted by internucleosomal fragmentation on agarose and histone associated mono- and oligonucleosomes detection by ELISA, corrobated with the apoptotic DNA (sub-G(1) population) and total apoptotic cells by Annexin V binding assay. The number of cells in sub-G(1) population increased to 66% at 50microM Cd concentration and the distribution of early and late apoptotic cells was 47% and 15%, respectively. Addition of N-acetylcysteine and pyrrolidine dithiocarbamate (thiol antioxidants) to the Cd treated cells, lowered the sub-G(1) population, inhibited the ROS generation and raised the GSH levels. Buthionine sulfoximine (GSH depletor) on the other hand, enhanced both the ROS production and the sub-G(1) fraction. These results clearly demonstrate the apoptogenic potential of Cd in murine thymocytes, following mitochondrial membrane depolarization, caspase activation and ROS and GSH acting as critical mediators.     

Cardiac effects of cytokines produced after rituximab infusion

Rituximab (Mabthera) is used in the treatment of refractory low-grade non-Hodgkin's lymphoma or in case of relapse after chemotherapy. Among the different adverse reactions with this drug, the most common is a constellation of symptoms (fever, rigors and chills) that occur more frequently during administration of the first dose of drug. These symptoms could be related to a cytokine-release syndrome. We report the case of a 46 year-old patient, presenting a familial cardiomyopathy, deceased a few minutes after having developed this syndrome, at the time of the 2nd infusion of rituximab. Several hypothesis have been suggested to explain this sudden death: a cardiac failure following deterioration of the systolic function, potentially related to the negative inotropic effects of TNFalpha, and/or an impairment of the diastolic function following the volemic overload. The impact of the reflex "administration of monoclonal antibody/cytokine-release syndrome" was only little investigated under physiologic or pathologic conditions. In spite of a risk of adverse reactions apparently moderated compared to the other drugs used in this context, this case report underlines the need for a special attention when using rituximab among patients with cardiac risk factors (reassessment of the benefit-risk ratio, specific monitoring, pre medication). More generally, it underlines the need for a systematic and continuous identification and reporting of adverse drug reactions to the French network of regional pharmacovigilance centres.     

Oxidative stress and cyclooxygenase activity in prostate carcinogenesis: targets for chemopreventive strategies

Over the last decade, epidemiological, experimental and clinical studies have implicated oxidative stress in the development and progression of prostate cancer. Oxidative stress may be linked to the effects of androgens, anti-oxidant systems and the pre-malignant condition, high-grade prostatic intraepithelial neoplasia. Cyclooxygenase-2 activity has been linked with prostate carcinogenesis. Evidence suggests that oxidative stress and cyclo-oxygenase-2 activity may be mechanistically linked. Agents such as anti-oxidants and cyclo-oxgenase-2 inhibitors may be of value in the chemoprevention of prostate cancer. The feasibility of intervention with such agents will depend on the development and validation of biomarkers for clinical trials, particularly markers of oxidative damage caused by reactive oxygen species (ROS). A greater understanding of the molecular events associated with oxidative stress will enhance the development of such biomarkers and should result in better strategies for the chemoprevention of prostate cancer.     

What Factors are Associated With 90-day Episode-of-care Payments for Younger Patients With Total Joint Arthroplasty?

Clinical Orthopaedics and Related Research® - Total joint arthroplasty (TJA) has been identified as a procedure with substantial variations in inpatient and postacute care payments. Most...