Prion-Like Propagation of Post-Translationally Modified Tau in Alzheimer’s Disease: A Hypothesis

The microtubule-associated protein Tau plays a key role in the neuropathology of Alzheimer’s disease by forming intracellular neurofibrillary tangles. Tau in the normal physiological condition helps stabilize microtubules and transport. Tau aggregates due to various gene mutations, intracellular insults and abnormal post-translational modifications, phosphorylation being the most important one. Other modifications which alter the function of Tau protein are glycation, nitration, acetylation, methylation, oxidation, etc. In addition to forming intracellular aggregates, Tau pathology might spread in a prion-like manner as revealed by several in vitro and in vivo studies. The possible mechanism of Tau spread can be via bulk endocytosis of misfolded Tau species. The recent studies elucidating this mechanism have mainly focussed on the aggregation and spread of repeat domain of Tau in the cell culture models. Further studies are needed to elucidate the prion-like propagation property of full-length Tau and its aggregates in a more intense manner in vitro as well as in vivo conditions. Varied post-translational modifications can have discrete effects on aggregation propensity of Tau as well as its propagation. Here, we review the prion-like properties of Tau and hypothesize the role of glycation in prion-like properties of Tau. This post-translationally modified Tau might have an enhanced propagation property due to differential properties conferred by the modifications.     

Desipramine treatment for cocaine dependence in buprenorphine- or methadone-treated patients: baseline urine results as predictor of response

The prognostic importance of baseline urines for cocaine was examined in a randomized, placebo-controlled, twelve-week clinical trial in 165 opioid- and cocaine-dependent patients who were treated with desipramine (DMI) in combination with buprenorphine (BUP) or methadone (Meth). Patients with a cocaine-positive urine at baseline (CU+) had significantly fewer cocaine-free urines than those with a negative urine at baseline (CU-neg). The CU+ patients showed a treatment effect of DMI. This DMI effect was significant in patients maintained on BUP but not on Meth.     

Concentration‐independent MRI of pH with a dendrimer‐based pH‐responsive nanoprobe

The measurement of extracellular pH (pH_e) has significant clinical value for pathological diagnoses and for monitoring the effects of pH‐altering therapies. One of the major problems of measuring pH_e with a relaxation‐based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH‐unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation‐based dendritic MRI contrast agent in a concentration‐independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA‐4AmP)₄₄‐G5, a G5–PAMAM dendrimer‐based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r₁) increased from 7.91 to 9.65 mM^?1 s^?1 (on a per Gd³⁺ basis) on changing pH from 8.84 to 6.35. At 7 T, r₁ relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r₂) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA‐4AmP)₄₄‐G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R₂/R₁ also showed a linear relationship in a pH‐responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA‐4AmP)₄₄‐G5 agent. Importantly, the nanoprobe (GdDOTA‐4AmP)₄₄‐G5 shows pH response in the range commonly found in the microenvironment of solid tumors. Copyright © 2015 John Wiley & Sons, Ltd.     

Pearl Millet Mapping Population Parents: Performance and Selection Under Salt Stress Across Environments Varying in Evaporative Demand

It is vital to screen the germplasm of crop plants for salt stress tolerance so as to utilize them in breeding programs. Accordingly, in the present study, twenty diverse inbred lines, parents of mapping populations of pearl millet were chosen to determine the phenotypic contrasts for seed yield, which can open the way for developing salt tolerance QTLs. Parents were grown in two summer seasons (late and early) with VPD ≥ 2 kPa, and one rainy season with VPD < 2 kPa, during flowering and grain filling under saline (150 and 200 mM) and non-saline (0 mM) conditions. Salinity delayed flowering time by a fortnight in the summer seasons but only 5–6 days in the low VPD rainy season. Salinity decreased grain yield by 86% in late-summer and 80% in early-summer, but less than 70% in rainy season. GY penalty was higher than vegetative biomass under saline conditions especially in summer season when the evaporative demand was very high. It appears that reproduction and grain filling are sensitive to high temperature that can compound the effect of salinity and high VPD. GY of inbreds under salinity was not better in comparison with non-saline conditions. DOF and grain density (thousand grain weight) were found as important correlated traits under salinity. Also, GY was affected significantly if VPD increased during flowering time.

     

Cryoablation versus radiofrequency ablation for treatment of pediatric atrioventricular nodal reentrant tachycardia: Initial experience with 4-mm cryocatheter

BACKGROUND: Initial reports have shown cryoablation to be safe and efficacious for treatment of atrioventricular nodal reentrant tachycardia (AVNRT). No direct comparisons of cryoablation vs radiofrequency (RF) catheter ablation in pediatric patients have been made. OBJECTIVES: The purpose of this study was to compare the outcomes of cryothermal vs RF catheter ablation for treatment of AVNRT in pediatric patients. METHODS: We retrospectively reviewed consecutive ablation procedures for treatment of AVNRT at a single arrhythmia center. The RF group consisted of patients who underwent RF ablation from 2002 until cryothermy became available. The cryoablation group consisted of patients who underwent cryothermal ablation from 2004 to 2005. The groups were compared for procedural and electrophysiologic outcomes. RESULTS: RF (n = 60, age 14 +/- 4 years) and cryoablation (n = 57, age 14 +/- 4 years) groups had similar demographic and baseline parameters. Procedural times were shorter in the RF group (RF ablation 112 +/- 31 minutes vs cryoablation 148 +/- 46 minutes, P < .001). Fluoroscopy times were comparable (RF ablation 21 +/- 15 minutes vs cryoablation 20 +/- 13 minutes, P = .77). In an intention-to-treat analysis, success of the procedure was 100% for RF ablation and 95% for cryoablation (P = .11). No permanent AV block occurred in either group. Recurrence rates were higher for the cryoablation group, but this did not reach statistical significance (RF ablation 2% vs cryoablation 8%, P = .19). CONCLUSION: Cryoablation appears to be similar to RF for ablation of AVNRT with respect to short-term efficacy and safety of the procedure in a pediatric population. Recurrence rates are higher with cryoablation.     

Comparison of myocardial tissue velocities measured by two-dimensional speckle tracking and tissue Doppler imaging

Myocardial velocities have prognostic implications, and transmitral E wave to mitral annular early diastolic tissue velocity ratio (E/Em) is utilized to estimate left ventricular (LV) end-diastolic pressure (EDP). There are no reference values for 2-dimensional (2D) speckle tracking myocardial velocities (S(2D), E(2D), A(2D)), and it is unknown if they are comparable with color tissue Doppler imaging (TDI). Predictors of E/E(2D) ratios are unknown and E/E(2D) has not been validated with LVEDP. The myocardial velocities of 142 subjects were measured by TDI and 2D speckle tracking. Mean E/Em and E/E(2D) were calculated as transmitral E wave to mean 6 basal early diastolic myocardial velocities using TDI and 2D speckle tracking respectively, and compared with LVEDP during catheterizations (n = 20). Mean E(2D) was lower but mean S(2D) and A(2D) were higher than TDI (all p <0.001). When TDI sample volume was tracked throughout the cardiac cycle, this directional difference was no longer apparent with S(2D), E(2D), and A(2D) higher than TDI (all p <0.05). Age, systolic blood pressure, LV ejection fraction, and mean S(2D) were independent correlates of E/E(2D). Receiver-operator characteristic analysis showed E/E(2D) (p = 0.03), not E/Em, identified elevated LVEDP (>/=12 mm Hg). E/E(2D) of 11.6 had 83% sensitivity and 70% specificity to predict elevated LVEDP. In conclusion, TDI and 2D speckle tracking myocardial velocities are not comparable due to angle independency and ability for tissue tracking with the latter. LV systolic function, age, and afterload are independent correlates of E/E(2D). Only E/E(2D) identifies elevated LVEDP, and an E/E(2D) of 11.6 has the optimal sensitivity and specificity.     

Comorbid major depressive disorder as a prognostic factor in cocaine-abusing buprenorphine-maintained patients treated with desipramine and contingency management

Depression is common among patients who abuse both opiates and cocaine, and its treatment has had mixed success. This study compares buprenorphine-maintained patients with lifetime major depressive disorder (MDD, N = 53) with those never depressed (ND, N = 96) on cocaine and opiate-free urines during a 12-week outpatient double-blind, placebo-controlled, randomized clinical trial. The 149 subjects were assigned to four groups: 1) desipramine (DMI) + contingency management (CM); 2) DMI + noncontingency management (NCM); 3) placebo + CM; and 4) placebo + NCM. Depression assessments included Hamilton Depression Rating Scale, Center for Epidemiological Studies Depression Inventory, and Structured Clinical Interview for DSM-IV interview for diagnosis of lifetime MDD. Urine toxicologies were performed thrice weekly and the CES-D was performed monthly. The MDD group had a larger proportion of females (45% vs 21%, P = 0.02) and were more likely to be married (13.2% vs 7.3%, P = 0.02) than the ND group. Treatment retention did not vary by depression status. Hierarchical Linear Modeling found that depressive symptoms decreased comparably across the four treatment groups. Although participation in CM improved drug-free urines more for patients with MDD than for the ND group (Z = 2.44, P = 0.01), treatment with DMI was significantly more efficacious for the ND group than for the MDD group (Z = -2.89, P = 0.003). These results suggest that patients with MDD may respond better to behavioral treatments such as CM than to desipramine plus buprenorphine. The ND cocaine-abusing, opiate-dependent patients may be more responsive to the anticraving effects of DMI.     

Influence of tissue factor polymorphisms (603A>G and 5466A>G) on plasma tissue factor levels and their impact on deep vein thrombosis risk in young Indian population

Deep vein thrombosis (DVT) is multifactorial disorder and well known to cause substantial morbidity and mortality. There is sparse data in the Asian population, particularly India regarding association of tissue factor (TF) gene single nucleotide polymorphisms (SNPs) with plasma TF levels in DVT. So, we analyzed the distribution of SNPs (603A>G and 5466A>G) in India, to evaluate their effect on TF levels in DVT patients. Plasma level and SNPs (603A>G and 5466A>G) of TF gene were screened in subjects (100 DVT patients and 100 controls). Patients had significantly higher TF levels than controls (patients: 84.95?±?17.16 pg/ml, controls: 70.55?±?15.87 pg/ml, p?G polymorphism was significantly higher in patients than controls (patients: 40.5% controls: 27.5%, p?=?0.004). Subjects with AG and GG genotype had significantly higher TF levels than AA genotype (p?=?0.001). After multiple logistic regression analysis, risk of DVT was increased 1.398 fold (95% CI 0.738–2.651) and 4.41 fold (95% CI 1.404–13.884) with AG and GG genotype respectively. Allelic and genotypic frequencies of 5466A>G polymorphism was neither associated with TF levels nor with DVT. We found high TF level in patients with TF 603A>G polymorphism, which is an important predisposing factor in increasing risk of DVT in young Indians. Furthermore, GG genotype of 603A>G polymorphism augments the risk of thrombosis by 4.4 fold, thus highlighting the significance of this polymorphism in the development of DVT. So, we suggest that inclusion of 603A>G polymorphism in prothrombotic work-up may be helpful in making the treatment strategy in DVT patients.