26 research outputs found
Visual short-term memory deficits associated with GBA mutation and Parkinson's disease.
Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson's disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar's orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional 'filtering' condition tested patients' ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson's disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson's disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson's disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson's disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson's disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short-term memory associated with GBA mutation and with Parkinson's disease. Identification of the specific pattern of cognitive impairment in GBA mutation versus Parkinson's disease is potentially important as it might help to identify individuals at risk of developing Parkinson's disease
Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials
Background Patients with chronic obstructive pulmonary disease (COPD) have few options for treatment. The efficacy and safety of the phosphodiesterase-4 inhibitor roflumilast have been investigated in studies of patients with moderate-to-severe COPD, but not in those concomitantly treated with longacting inhaled bronchodilators. The effect of roflumilast on lung function in patients with COPD that is moderate to severe who are already being treated with salmeterol or tiotropium was investigated. Methods In two double-blind, multicentre studies done in an outpatient setting, after a 4-week run-in, patients older than 40 years with moderate-to-severe COPD were randomly assigned to oral roflumilast 500 mu g or placebo once a day for 24 weeks, in addition to salmeterol (M2-127 study) or tiotropium (M2-128 study). The primary endpoint was change in prebronchodilator forced expiratory volume in 1s (FEV(1)). Analysis was by intention to treat. The studies are registered with ClinicalTrials.gov, number NCT00313209 for M2-127, and NCT00424268 for M2-128. Findings In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV(1) by 49 mL (p<0.0001) in patients treated with salmeterol, and 80 mL (p<0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV(1) was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal. Interpretation Roflumilast improves lung function in patients with COPD treated with salmeterol or tiotropium, and could become an important treatment for these patients
Synthesis, Characterization, and Evaluation of Castor Oil-Based Acylated Derivatives as Potential Lubricant Base Stocks
Synthesis,
characterization, and evaluation of a series of novel
acylated derivatives of castor oil as biolubricant base stocks are
described. The acylated derivatives of castor oil, castor oil fatty
acid methyl and 2-ethylhexyl esters were synthesized using different
anhydrides (C<sub>1</sub>âC<sub>6</sub>) in about 90â95%
yield. All the products were structurally characterized using NMR
and IR spectral data. The acylated products were evaluated for their
physicochemical and lubricant properties. Although these products
belong to group V, based on viscosity index (130â156), acylated
derivatives of castor fatty acid alkyl esters belong to group III,
the category of base fluids as per API classification. The acylated
products exhibited excellent pour point (â21 to â39
°C) and flash point (174â280 °C). The hexanoylated
and butanoylated esters of castor oil exhibited excellent flash points
of 280 and 272 °C, respectively. The air release value was found
to be excellent in the range of 0.38â0.99 min, and NOACK volatilities
in the range of 3.25â3.92%. The other lubrication properties
such as load carrying capacity, and emulsion stability were found
to be good. Therefore, these derivatives will have utility in hydraulic
and metal working fluids and other industrial fluids with their wide
range of properties
Design, Synthesis and Biological Evaluation of Quinazolinamine Derivatives as Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors with Improved Metabolic Stability
A series of twenty-two quinazolinamine derivatives showing potent inhibitory activities on breast cancer resistance protein (BCRP) and p-glycoprotein (P-gp) were synthesized. A cyclopropyl-containing quinazolinamine 22 was identified as a dual BCRP and P-gp inhibitor, while azide-containing quinazolinamine 33 showed BCRP inhibitory activity. These lead compounds were further investigated in a battery of mechanistic experiments. Compound 22 changed the localization of BCRP and P-gp in cells, thus inhibiting the efflux of anticancer drugs by the two ATP-binding cassette (ABC) transporters. In addition, both 22 and 33 significantly stimulated the ATP hydrolysis of the BCRP transporter, indicating that they can be competitive substrates of the BCRP transporter, and thereby increase the accumulation of mitoxantrone in BCRP-overexpressing H460/MX20 cells. Azide derivative 33, exhibited a greater inhibitory effect on BCRP after UV activation and can serve as a valuable probe for investigating the interactions of quinazolinamine derivatives with BCRP. Notably, the dual BCRP and P-gp inhibitors 4â5, 22â24, 27, and BCRP inhibitor 33 showed improved metabolic stability compared to Ko143
Synthesis and evaluation of anti-oxidant and cytotoxic activities of novel 10-undecenoic acid methyl ester based lipoconjugates of phenolic acids
The synthesis of five novel methyl 10-undecenoate-based lipoconjugates of phenolic acids from undecenoic acid was carried out. Undecenoic acid was methylated to methyl 10-undecenoate which was subjected to a thiolâene reaction with cysteamine hydrochloride. Further amidation of the amine was carried out with different phenolic acids such as caffeic, ferulic, sinapic, coumaric and cinnamic acid. All synthesized compounds were fully characterized and their structures were conïŹrmed by spectral data. The anti-oxidant activity of the synthesized lipoconjugates of phenolic acids was studied by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and also by the inhibition of linoleic acid oxidation in micellar medium by differential scanning calorimetry (DSC). The prepared compounds were also screened for their cytotoxic activity against five cell lines. It was observed that the lipoconjugates of caffeic acid, sinapic acid, ferulic acid, and coumaric acid displayed anticancer and anti-oxidant properties. The anticancer properties of these derivatives have been assessed by their IC50 inhibitory values in the proliferation of MDA-MB231, SKOV3, MCF7, DU 145 and HepG2 cancer cell lines
Preparation and Properties of Lubricant Base Stocks from Epoxidized Karanja Oil and Its Alkyl Esters
Lubricant base stocks
of epoxidized oil and its alkyl esters namely
epoxidized karanja fatty acid methyl, butyl, 2-methyl-1-propyl, and
2-ethylhexyl esters were synthesized from renewable nonedible source
karanja oil (<i>Pongamia glabra</i>). The reaction was carried
out using peroxy formic acid (HCOOH) generated <i>in situ,</i> 30 wt % aqueous hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) by
monitoring oxirane oxygen value. The optimized conditions to obtain
epoxidized products were oil/ester: HCOOH: H<sub>2</sub>O<sub>2</sub> (1:2:8/1:1.5:3 mol/mol/mol). The epoxidized products were obtained
in 90â97% conversion by GC analysis. All the products were
characterized by GC, GC-MS, IR, <sup>1</sup>H NMR spectral studies.
The synthesized products were evaluated for physicochemical and lubricant
properties. Based on viscosity index all the products belong to group
III, category of base fluids as per API classification. Expecting
pour point values that are on higher side, other lubrication properties
such as viscosity, VI, flash point, Cu corrosion value, and air release
value were found to be good