Does Acetaldehyde Mediate Ethanol Action in the Central Nervous System?

BACKGROUND: Some of the effects of ethanol in the central nervous system are due to changes in function of ligand-gated ion channels. Production of detectable amounts of acetaldehyde, a primary metabolite of ethanol, has been demonstrated in brain homogenates. The aim of this study was to determine whether central actions that are often attributed to ethanol may actually be mediated by acetaldehyde. METHODS: The effects of acetaldehyde (1-1000 microM) were tested by two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes expressing 10 different ligand-gated ion channel receptors [alpha1 glycine; alpha1beta2gamma2Sgamma-aminobutyric acid (GABA)A; rho1 GABAc; 5-hydroxytryptamine-3A; NR1a/NR2A NMDA; GluR1/GluR2 AMPA; GluR6/KA2 kainate; and alpha4beta2, alpha4beta4, and alpha2beta4 nicotinic-acetylcholine] and the G-protein-coupled inward rectifying potassium channel GIRK2. We also investigated the effect of acetaldehyde on the dopamine transporter (DAT), performing dopamine uptake assays in oocytes expressing DAT. RESULTS: Acetaldehyde (1 and 10 microM) significantly enhanced alpha1 glycine receptor-mediated currents. Acetaldehyde did not affect the function of any of the other receptors tested or the potassium currents measured in GIRK2 channels. Moreover, acetaldehyde did not alter the DAT-mediated dopamine uptake. CONCLUSIONS: Our results suggest a potential minor role for acetaldehyde in the glycine receptor-mediated effects of ethanol. Otherwise, acetaldehyde does not modulate function of the neuronal receptors tested in this study, in GIRK channels or DAT, when expressed recombinantly in Xenopus laevis oocytes.     

Chylous Ascites Secondary to Pancreatitis: Management of an Uncommon Entity Using Parenteral Nutrition and Octreotide

Malignancy, surgical trauma, cirrhosis and tuberculosis account for more than 95% of causes for chylous ascites. We report a case of persistent chylous ascites following acute pancreatitis that responded to parenteral nutrition and octreotide. A 50 year-old male was diagnosed with acute alcoholic pancreatitis after presenting with typical abdominal pain, and elevated amylase and lipase. The acute symptoms resolved within one week. Four weeks later he started developing increased abdominal girth. Examination revealed the presence of shifting dullness and paracentesis confirmed diagnosis of chylous ascites. Investigations for the common causes of chylous ascites were negative. Laparoscopy confirmed the presence of fat necrosis within mesenteric lymph nodes linking the chylous ascites to the episode of pancreatitis. The Chylous ascites was resistant to the usual medical therapy, but responded only to the combination of octreotide and total parenteral nutrition with complete resolution of ascites in 8 weeks. This case of chylous ascites secondary to pancreatitis represents an uncommon presentation with effective management resulting in a dramatic response.     

Doppler echocardiography in normally functioning replacement aortic valves: a review of 129 studies

Echocardiography is the technique of choice for the assessment of replacement aortic valves. Hemodynamic function depends on the design and size of the valve. This review summarizes the published information available to the end of 2005. The most obstructive valve was the caged-ball, followed by the stented porcine and single tilting-disc valves. The stented bovine pericardial valves were slightly less obstructive than these, and similar to the intra-annular bileaflet mechanical valves. Stentless valves appeared slightly less obstructive still, and similar to reduced-cuff mechanical bileaflet valves. Homografts were the least obstructive. Approximate guide thresholds suggesting obstruction were derived.     

Etoposide loaded solid lipid nanoparticles for curtailing B16F10 melanoma colonization in lung

Poor solubility of etoposide and associated poor bioavailability of the drug was circumvented by developing solid lipid nanocarrier system. The objective of the research work was to prepare etoposide loaded solid lipid nanoparticles (SLN) for improved efficacy and therapy of metastasized cancers. Entrapment of drug into nanoparticulate system modifies the pharmacokinetic and biodistribution profile of the drug with improved therapeutic efficacy. Solid lipid nanoparticles of various triglycerides were prepared using hot homogenization technique. Further, the process and formulation parameters viz. homogenization cycle and pressure, type of lipid were optimized. Developed nanoparticles were characterised for particle size, in vitro dissolution studies, DSC thermogram, surface morphology and cytotoxicity assay. Pharmacokinetic and biodistribution study were performed to assess the distribution of the drug in vivo. Modulation of the therapeutic activity of the drug was studied by performing antimetastatic activity on a B16F10 melanoma mouse model. The obtained results exhibited suitability of trimysristin for fabrication of nanoparticles. Characterisation of nanoparticles depicted formation of homogenous, spherical particles entrapping approximately 50% of the drug. The results for the performed MTT assay suggested that the developed nanoparticles exhibited cytotoxicity in a time- and concentration-dependent fashion. These findings concord with the results of the in vitro dissolution profile. Pharmacokinetic parameters demonstrated increase in area under curve (AUC), t_1/2 and mean residence time (MRT) for drug in plasma. Further there is enhancement in the ratio of the drug that reaches to the highly perfused organs (upon encapsulation into solid lipid nanoparticles). Generally, cancer cells metastasized through the blood or lymphatic system. Accumulation of the drug in the highly perfused organ suggests suitability of the developed nanoparticles for targeting metastasized tumors. This was proved by the findings of the in vivo B16F10 mouse melanoma model. Improvement in the tumoricidal activity and survival rate of the animals substantiates the application of nanoparticles for improved therapeutic activity of etoposide.     

Flow mediated dilatation and cardiac function in type 1 diabetes mellitus

The present study sought to examine the occurrence of subclinical markers of cardiovascular risk and cardiac dysfunction with increasing disease duration in type 1 diabetes mellitus (DM). There are few data on subclinical cardiovascular abnormalities in type 1 DM. The study included 100 patients without any cardiovascular complaints (mean age 46.6 years, range 22 to 63), with a history of type 1 DM ranging from 2 to 36 years, and 75 age-matched controls. Standard 2-dimensional and Doppler echocardiography and pulse-wave tissue Doppler (tD) mapping of systolic (Sm) and diastolic (Em, Am) velocities (12 left ventricular [LV] segments and right-sided cardiac) were performed. An Em/Am ratio of <1 was considered to represent abnormal segmental diastolic function. Flow-mediated dilation (FMD) of the brachial artery, carotid intima media thickness (IMT) measurement, and extensive laboratory analysis were performed. The FMD was reduced, and IMT increased in patients (p < 0.01). Regional tD-derived diastolic and systolic functional abnormalities were observed within the first decade of the disease. Significant correlations were found between FMD and LV segments with tD-derived dysfunction, the duration of DM, and fibrinogen (p < 0.0001 for all). Stepwise regression analysis showed that FMD was the strongest predictor of abnormal segmental function (p < 0.0001). Data further presented as an analysis of tertiles by DM duration show an increasing occurrence of subclinical cardiac dysfunction and cardiovascular risk markers compared with age-matched controls. In conclusion, FMD is associated with abnormal segmental cardiac function in type 1 DM.     

Cervical lymph node metastasis in squamous cell carcinoma of the buccal mucosa: a retrospective study on pattern of involvement and clinical analysis

Background The study was performed with an aim to map the pattern of metastasis of squamous cell carcinomas of buccal mucosa to various cervical lymph node levels and analyze its correlation with primary tumor size and histo-pathological grading. Material and Methods 254 patients with squamous cell carcinoma of the buccal mucosa treated with surgery first approach were analyzed retrospectively. The tumor size was noted from pre-operative CT Scans and were divided into early and advanced tumors. The resected specimen was studied to note the histo-pathological grading of the squamous cell carcinoma and the metastatic deposits at various lymph node levels. Results Out of 254 patients (149 females, 105 males), 145 patients showed histo-pathologically proven metastatic deposits in one or more lymph nodes out of which there were 56 patients showing occult metastasis. 78/145 patients showed metastatic involvement of level IB and/or IA lymph nodes, 31 showed involvement of level II and/or I lymph nodes, 27 showed involvement of level III with or without involvement of level I and II and 9 showed metastasis to level IV and V lymph nodes with or without level I, II or III lymph nodes. Cervical lymph node metastasis had statistically significant association with tumor size with advanced tumors showing worse pattern of metastatic spread beyond level I and II lymph nodes. As the degree of differentiation of squamous cell carcinoma reduced, they were more prone for cervical metastasis with moderately and poorly differentiated squamous cell carcinoma showing higher involvement of level III, IV and V lymph nodes. Conclusions The majority of buccal mucosa cases showed metastasis to level I, II and III lymph nodes out of which level IB and/or IA was most frequently involved. Metastasis to level IV and V lymph nodes was rare and was seen especially in patients with advanced primary tumor and poor histo-pathologic differentiation. Key words:Oral squamous cell carcinoma (OSCC), cervical lymph node metastasis, histologic differentiation, locally advanced disease.     

Massive right atrial myxoma

Right atrial myxomas are uncommon and are often detected incidentally in asymptomatic individuals. We describe a case of a massive right atrial myxoma that was suspected following an abnormal right heart border on a chest X-ray and an abnormal 12 lead electrocardiogram.     

Chronic lymphocytic leukemia cells receive RAF-dependent survival signals in response to CXCL12 that are sensitive to inhibition by sorafenib

The chemokine CXCL12, via its receptor CXCR4, promotes increased survival of chronic lymphocytic leukemia (CLL) B cells that express high levels of ζ-chain-associated protein (ZAP-70), a receptor tyrosine kinase associated with aggressive disease. In this study, we investigated the underlying molecular mechanisms governing this effect. Although significant differences in the expression or turnover of CXCR4 were not observed between ZAP-70(+) and ZAP-70(-) cell samples, CXCL12 induced greater intracellular Ca(2+) flux and stronger and more prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase/ERK kinase (MEK) in the ZAP-70(+) CLL cells. The CXCL12-induced phosphorylation of ERK and MEK in ZAP-70(+) CLL cells was blocked by sorafenib, a small molecule inhibitor of RAF. Furthermore, ZAP-70(+) CLL cells were more sensitive than ZAP-70(-) CLL cells to the cytotoxic effects of sorafenib in vitro at concentrations that can readily be achieved in vivo. The data suggest that ZAP-70(+) CLL cells may be more responsive to survival factors, like CXCL12, that are elaborated by the leukemia microenvironment, and this sensitivity could be exploited for the development of new treatments for patients with this disease. Moreover, sorafenib may have clinical activity for patients with CLL, particularly those with ZAP-70(+) CLL.