Enhancement of synaptic plasticity through chronically reduced Ca2+ flux during uncorrelated activity

The plasticity of synapses within neural circuits is regulated by activity, but the underlying mechanisms remain elusive. Using the dye FM1-43 to directly image presynaptic function, we found that large numbers of presynaptic terminals in hippocampal cultures have a low release probability. While these terminals were not readily modifiable, a transient but not permanent long-term reduction of network activity or Ca2+ influx could increase their modifiability. This modulation of plasticity was mediated by Ca2+ flux through NMDA and voltage-gated calcium channels and was lost within 48 hr. A more permanent enhancement of synaptic plasticity was achieved by selectively reducing the Ca2+ flux associated with uncorrelated activity via adjustment of the voltage-dependent Mg2+ block of the NMDAR. Upregulation of NR2B-containing NMDARs induced by this treatment is an important but not sole contributor to the enhancement of plasticity. Thus, quantity and quality of activity have differential effects on the intrinsic plasticity of neurons.     

The lost correlation between heat shock protein 70 (HSPA1A) and plasminogen activator inhibitor-1 in patients with type 2 diabetes and albuminuria

We aimed to study the relation between plasma levels of stress-induced heat shock protein 70 (HSPA1A) with plasminogen activator inhibitor-1 (PAI-1) and high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1), and HDL-C/Apo-A1 ratio. In a matched case-control study on patients with diabetes (40 patients with albuminuria and 40 without albuminuria matched for age, sex, and body mass index), we observed that plasma levels of HSPA1A and PAI-1 are increased in patients with albuminuria (0.55 ± 0.02 vs. 0.77 ± 0.04 ng/ml, p value <0.001 for HSPA1A; 25.9 ± 2 vs. 31.8 ± 2.4 ng/ml, p value <0.05 for PAI-1). There was a significant correlation between HSPA1A and PAI-1 in diabetic patients without albuminuria (r = 0.28; p value = 0.04), but not in those with albuminuria (r = 0.07; p value = 0.63). No association was found between HSPA1A and HDL-C, between HSPA1A and Apo-A1, or between HSPA1A and HDL-C/Apo-A1 ratio. We concluded that there is a direct correlation between plasma HSPA1A and PAI-1 levels in patients with diabetes, which is lost when they develop albuminuria.     

The 2008 Anatomy Ceremony: Voices, Letter, Poems

Yale University medical and PA students express their gratitude in a compilation of reflections on learning human anatomy.     

Targeted co-delivery of paclitaxel and anti P-gp shRNA by low molecular weight PEI decorated with L-3,4-dihydroxyphenylalanine

Co-delivery of small chemotherapeutic molecules and nucleic acid materials via targeted carriers has attracted great attention for treatment of resistant tumors and reducing adverse effects. In this study, a targeted carrier for co-delivery was prepared based on low-molecular weight polyethylenimine (LMW PEI). Paclitaxel (PTX) was covalently conjugated onto PEI via a succinate linker. The PEI conjugate was decorated with L-DOPA in order to target large neutral amino acid transporter-1 (LAT-1) that is over-expressed on various cancer cells. This PEI conjugate was complexed with human ABCB1 shRNA plasmid to down-regulate the expression of P-glycoprotein, as one of the major efflux pumps inducing resistance against chemotherapeutics. The formation of PEI conjugate enhanced the solubility of PTX and resulted in the condensation and protection of plasmid DNA in nanosized polyplexes. The results of targeted delivery into the cells demonstrated that PEI conjugate transferred the payloads to the cells over-expressing LAT-1 transporter, while the biological effects on the cells lacking the transporter was negligible. Also, shRNA-mediated down-regulation of P-gp led to the increase of toxic effects on the cells over-expressing P-gp. This study suggests a promising approach for co-delivery of small molecules and nucleic acid materials in a targeted manner for cancer therapy.     

Predictors of postoperative atrial fibrillation after coronary artery bypass graft surgery

Objectives

The present study was aimed to identify the preoperative, intraoperative, and postoperative predictors of AF in a pure cohort of the patients with coronary artery disease who underwent CABG surgery.

Methods

Between November 2005 and May 2006, 302 consecutive patients were included in this prospective study. All the relevant clinical, electrocardiographic, echocardiographic, and laboratory data were gathered in the included patients and they were also monitored for development of post-CABG AF.

Results

Postoperative AF occurred in 46 (15%) of patients. By univariate analysis, older age, P-wave abnormality in ECG, presence of mitral regurgitation, larger left atrium (LA), left main coronary artery involvement, failure to graft right coronary artery (RCA), and adrenergic use in ICU were significantly associated with occurrence of post-CABG AF (all P< 0.05). However, in the logistic regression model, age (OR: 1.067, 95%CI: 1.02-1.116, P=0.005), LA dimension (OR: 1.102, 95%CI: 1.017-1.1936, P=0.017), P-wave morphology (OR: 12.07, 95%CI: 3.35-48.22, P=0.0001), failure to graft RCA (OR: 3.57, 95%CI: 1.20-10.64, P=0.022), and postoperative adrenergic use (OR: 0.35, 95%CI: 0.13-0.93, P=0.036) remained independently predictive of postoperative AF.

Conclusion

The present study suggested that age, P-wave morphology, LA dimension, failure to graft right coronary artery, and postoperative adrenergic use were independent predictors of post-CABG AF. Therefore, clinical data, ECG and echocardiography may be useful in preoperative risk stratification of the surgical patients for the occurrence of post-CABG AF.     

A close call: the role of screening mammography in the fight against breast cancer: health and medicine for women: a multidisciplinary, evidence-based review of mid-life health concerns

A multidisciplinary panel debated the role of screening mammography in fighting breast cancer during the Health and Medicine for Women continuing medical education (CME) conference at Yale Medical School in September 2010. Different guidelines from professional societies have presented conflicting recommendations for patients regarding both the benefits of mammography and the appropriate age and frequency of screening. In addition, a recent longitudinal study argues that screening mammography may only offer a modest benefit in terms of reducing cancer mortality. In light of these considerations, the panel debated whether mammography should be an informed decision that must be discussed and individualized for each patient based on the context of risk factors such as family history, age, and genetic dispositions.     

Novel stereoselective synthesis and chromatographic evaluation of E-guggulsterone

A new stereoselective synthesis of E-guggulsterone is described starting from androsten-3,17-dione. Protection of the ring A enonic system, followed by regioselective Wittig reaction and C-16 oxidation, affords E-guggulsterone in good yields and high stereoselectivity, making this approach easily accessible and scalable. Moreover, an original normal-phase HPLC method enabling the fast quantitation of the guggulsterone isomeric purity, combined with the suitability for sampling procedures, is detailed. The relying upon the cellulose-based Chiralpak IB column and the chloroform as the "non-standard" component of the eluent mixture, allows to get profitably high chromatographic performances.