Incident and recurrent major depressive disorder and coronary artery disease severity in acute coronary syndrome patients

There is recent evidence that acute coronary syndrome (ACS) patients with first time incident major depressive disorder (MDD) and those with recurrent MDD represent different subtypes among individuals with ACS and comorbid depression. However, few studies have examined whether or not these subtypes differ in coronary artery disease (CAD) severity. We assessed whether those with incident MDD (in-hospital MDD and negative for history of MDD) or recurrent MDD (in-hospital MDD and a positive history of MDD) differ in angiographically documented CAD severity. Within 1 week of admission for ACS, 88 patients completed a clinical interview to assess current and past diagnosis of MDD. CAD severity was assessed in all patients by coronary angiography. A hierarchical regression analysis showed that neither in-hospital MDD status, nor history of MDD were significant predictors of CAD severity, but the interaction term between in-hospital MDD status and history of MDD was a significant predictor of CAD severity, after controlling for age, sex and ethnicity. Follow-up analyses showed that patients with first time, incident MDD had significantly more severe CAD compared to patients with recurrent MDD (p=0.043). To conclude, our study adds to the growing evidence that patients with incident MDD should be considered as a clinically distinct subtype from those with recurrent MDD. Possible mechanisms for differing CAD severity by angiogram between these two subtypes are proposed and implications for prognosis and treatment are discussed.     

RAGE mediates podocyte injury in adriamycin-induced glomerulosclerosis

In the kidney, the receptor for advanced glycation end products (RAGE) is principally expressed in the podocyte at low levels, but is upregulated in both human and mouse glomerular diseases. Because podocyte injury is central to proteinuric states, such as the nephrotic syndrome, the murine adriamycin nephrosis model was used to explore the role of RAGE in podocyte damage. In this model, administration of the anthracycline antibiotic adriamycin provokes severe podocyte stress and glomerulosclerosis. In contrast to wild-type animals, adriamycin-treated RAGE-null mice were significantly protected from effacement of the podocyte foot processes, albuminuria, and glomerulosclerosis. Administration of adriamycin induced rapid generation of RAGE ligands, and treatment with soluble RAGE protected against podocyte injury and glomerulosclerosis. In vitro, incubation of RAGE-expressing murine podocytes with adriamycin stimulated AGE formation, and treatment with RAGE ligands rapidly activated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, via p44/p42 MAP kinase signaling, and upregulated pro-fibrotic growth factors. These data suggest that RAGE may contribute to the pathogenesis of podocyte injury in sclerosing glomerulopathies such as focal segmental glomerulosclerosis.     

Binding 3-D object perception in the human visual cortex

How do visual luminance, shape, motion, and depth bind together in the brain to represent the coherent percept of a 3-D object within hundreds of milliseconds (msec)? We provide evidence from simultaneous magnetoencephalographic (MEG) and electroencephalographic (EEG) data that perception of 3-D objects defined by luminance or motion elicits sequential activity in human visual cortices within 500 msec. Following activation of the primary visual cortex around 100 msec, 3-D objects elicited sequential activity with only little overlap (dynamic 3-D shapes: MT-LO-Temp; stationary 3-D shapes: LO-Temp). A delay of 80 msec, both in MEG/EEG responses and in reaction times (RTs), was found when additional motion information was processed. We also found significant positive correlations between RT, and MEG and EEG responses in the right temporal location. After about 400 msec, long-lasting activity was observed in the parietal cortex and concurrently in previously activated regions. Novel time-frequency analyses indicate that the activity in the lateral occipital (LO) complex is associated with an increase of induced power in the gamma band, a hallmark of binding. The close correspondence of an induced gamma response with concurrent sources located in the LO in both experimental conditions at different points in time ( approximately 200 msec for luminance and approximately 300 msec for dynamic cues) strongly suggests that the LO is the key region for the assembly of object features. The assembly is fed forward to achieve coherent perception of a 3-D object within 500 msec.     

Survey of treatment recommendations for anaplastic oligodendroglioma

Anaplastic oligodendroglioma is a malignant brain tumor uniquely sensitive to treatment with both chemotherapy and radiotherapy. There are few prospective clinical trials for newly diagnosed patients and multiple approaches to the treatment of these patients. This study explored the recommended treatment offered by experts in neuro-oncology. A Web-based survey was developed and distributed to 800 members of the Society of Neuro-Oncology (SNO) who had an e-mail address listed with SNO. Questions addressed use of molecular genetic information and treatment recommendations. A total of 99 clinical SNO members (20%) responded. The majority reported practicing at an academic center in the United States. Two-thirds of respondents see more than five patients with newly diagnosed anaplastic oligodendroglioma annually. Molecular genetic testing was requested for more than 75% of patients, and the results significantly influenced treatment recommendations (p = 0.000003). Regardless of molecular genetic status, the most commonly recommended treatment was the use of concurrent temozolomide and radiotherapy followed by adjuvant temozolomide (18%-34%). The current survey demonstrates that although neuro-oncologists have embraced the use of molecular genetic studies in newly diagnosed anaplastic oligodendroglioma, treatment recommendations vary widely and are often independent of the molecular data.     

Choleretic effects of the Mongolian medicinal plant Saussurea amara in the isolated perfused rat liver

Saussurea amara is used in traditional Mongolian medicine for the treatment of hepato-biliary disorders. To determine the plant's effect on the bile-salt independent bile flow (hydrocholeresis) as a measure of liver exocrine functions, different extracts were investigated in the isolated rat liver perfusion system. The methanolic extract (3) exerted a dose-dependent increase in bile flow (16%, 37%, 53%, 61%) in concentrations of 50 mg/L, 100 mg/L, 250 mg/L and 500 mg/L. The aqueous crude extract (1) and the ethyl acetate extract (2) also showed a dose-dependent increase, whereas at the highest concentrations (1000 mg/L and 100 mg/L, respectively) a continuous decrease in bile flow could be observed. Cynaropicrin also provoked a dose-dependent increase in bile flow, but caused liver damage at the highest dose tested (20 mg/L). Apigenin 7- O-glucoside, present in extracts 2 and 3, induced a dose-dependent increase of 20%, 30% and 40% (5 mg/L, 10 mg/L, 20 mg/L) and showed a significantly higher effect than the reference substance cynarin. The total flavonoid content was determined by spectrophotometry. To quantify the absolute amount of cynaropicrin in the crude drug and in the tested extracts, an HLPC system was established with santonin as internal standard.     

Lysophosphatidylcholine hydrolases of human erythrocytes, lymphocytes, and brain: sensitive targets of conserved specificity for organophosphorus delayed neurotoxicants

Brain neuropathy target esterase (NTE), associated with organophosphorus (OP)-induced delayed neuropathy, has the same OP inhibitor sensitivity and specificity profiles assayed in the classical way (paraoxon-resistant, mipafox-sensitive hydrolysis of phenyl valerate) or with lysophosphatidylcholine (LysoPC) as the substrate. Extending our earlier observation with mice, we now examine human erythrocyte, lymphocyte, and brain LysoPC hydrolases as possible sensitive targets for OP delayed neurotoxicants and insecticides. Inhibitor profiling of human erythrocytes and lymphocytes gave the surprising result of essentially the same pattern as with brain. Human erythrocyte LysoPC hydrolases are highly sensitive to OP delayed neurotoxicants, with in vitro IC50 values of 0.13-85 nM for longer alkyl analogs, and poorly sensitive to the current OP insecticides. In agricultural workers, erythrocyte LysoPC hydrolyzing activities are similar for newborn children and their mothers and do not vary with paraoxonase status but have high intersample variation that limits their use as a biomarker. Mouse erythrocyte LysoPC hydrolase activity is also of low sensitivity in vitro and in vivo to the OP insecticides whereas the delayed neurotoxicant ethyl n-octylphosphonyl fluoride inhibits activity in vivo at 1-3 mg/kg. Overall, inhibition of blood LysoPC hydrolases is as good as inhibition of brain NTE as a predictor of OP inducers of delayed neuropathy. NTE and lysophospholipases (LysoPLAs) both hydrolyze LysoPC, yet they are in distinct enzyme families with no sequence homology and very different catalytic sites. The relative contributions of NTE and LysoPLAs to LysoPC hydrolysis and clearance from erythrocytes, lymphocytes, and brain remain to be defined.     

Effects of nitrated-polycyclic aromatic hydrocarbons and diesel exhaust particle extracts on cell signalling related to apoptosis: possible implications for their mutagenic and carcinogenic effects

Nitrated-polycyclic aromatic hydrocarbons (nitro-PAHs) and diesel exhaust particle extracts (DEPE) induced apoptosis in Hepa1c1c7 cells with the following potency: 1,3-dinitropyrene (1,3-DNP)>1-nitropyrene (1-NP) > DEPE > 1,8-dinitropyrene (1,8-DNP). The compounds induced cyp1a1, and activated various intracellular signalling pathways related to apoptosis. The CYP inhibitor alpha-naphthoflavone strongly reduced 1,3-DNP-induced cell death, whereas cell death induced by 1-NP was rather increased. Toxic 1,3-DNP and 1-NP were found to induce a concentration-dependent lipid peroxidation. 1,3-DNP caused pro-apoptotic events, including increased phosphorylation and accumulation of p53 in the nucleus, cleavage of bid and of caspases 8 and 3, down-regulation of bcl-x(L) and phosphorylation of p38 and JNK MAPK. Furthermore, 1,3-DNP increased the activation of survival signals including phosphorylation of Akt and inactivation (phosphorylation) of pro-apoptotic bad. Although less potent, rather similar effects were observed following exposure to DEPE, compared to 1-NP. The most important finding was that the most mutagenic and carcinogenic compound tested, 1,8-DNP, induced little (if any) cell death, despite the fact that this compound seemed to give the most DNA damage as judged by DNA adduct formation, increased phosphorylation of p53 and accumulation of cells in S-phase. Immunocytochemical studies revealed that the p53 protein did not accumulate into the nucleus suggesting that 1,8-DNP inactivated the pro-apoptotic function of the p53 protein by a non-mutagenic event. These results suggest that after exposure to 1,8-DNP more cells may survive with DNA damage, thereby increasing its mutagenic and carcinogenic potential.