2,257 research outputs found
Simple, efficient protocols for the Pd-catalyzed cross-coupling reaction of aryl chlorides and dimethylamine
Simple and efficient procedures for the Pd-catalyzed cross-coupling reaction of aryl chlorides and dimethylamine are described. At room temperature with a strong base, t-BuXPhos is employed as the supporting ligand; at 110 °C with a weak base, XPhos is employed as the supporting ligand. In each of these cases, commercially available solutions constitute the source of the dimethylamine, and recently disclosed precatalysts constitute the source of the ligand and Pd. This work further expands the utility of these precatalysts in reactions that benefit from an easily activated source of L[subscript 1]Pd(0).National Institutes of Health (U.S.) (GM-058160)National Institutes of Health (U.S.) (Postdoctoral Fellowship GM-F32-75685)Amgen Inc.Merck & Co., Inc.Boehringer Ingelheim PharmaceuticalsMassachusetts Institute of Technology. Undergraduate Research Opportunities Program (Summer Fellowship
Impact of Low-Dose Dronabinol Therapy on Cognitive Function in Cancer Patients Receiving Palliative Care: A Case-Series Intervention Study
BACKGROUND: Cannabis may offer therapeutic benefits to patients with advanced cancer not responding adequately to conventional palliative treatment. However, tolerability is a major concern. Cognitive function is a potential adverse reaction to tetrahydrocannabinol containing regimens. The aim of this study was to test cognitive function in patients being prescribed dronabinol as an adjuvant palliative therapy.METHODS: Adult patients with advanced cancer and severe related pain refractory to conventional palliative treatment were included in this case-series study. Patients were examined at baseline in conjunction with initiation of dronabinol therapy and at a two-week follow-up using three selected Wechsler's adult intelligence scale III neurocognitive tests: Processing Speed Index (PSI), Perceptual Organization Index (POI), and Working Memory Index (WMI). Patients were also assessed using pain visual analog scale, Major Depression Inventory, and Brief Fatigue Inventory.RESULTS: Eight patients consented to take part in the study. Two patients discontinued dronabinol therapy, one due to a complaint of dizziness and another critical progression of cancer disease, respectively. The remaining six patients were successfully treated with a daily dosage of 12.5 mg dronabinol (p = 0.039). PSI (p = 0.020), POI (p = 0.034.), and WMI (p = 0.039).CONCLUSIONS: Cognitive function improved in this group of patients with advanced cancer in conjunction with low-dose dronabinol therapy. The cause is likely multifactorial including reported relief of cancer-associated symptoms. Further clinical investigation is required.</p
Absence of a consistent classical equation of motion for a mass-renormalized point charge
The restrictions of analyticity, relativistic (Born) rigidity, and negligible
O(a) terms involved in the evaluation of the self electromagnetic force on an
extended charged sphere of radius "a" are explicitly revealed and taken into
account in order to obtain a classical equation of motion of the extended
charge that is both causal and conserves momentum-energy. Because the
power-series expansion used in the evaluation of the self force becomes invalid
during transition time intervals immediately following the application and
termination of an otherwise analytic externally applied force, transition
forces must be included during these transition time intervals to remove the
noncausal pre-acceleration and pre-deceleration from the solutions to the
equation of motion without the transition forces. For the extended charged
sphere, the transition forces can be chosen to maintain conservation of
momentum-energy in the causal solutions to the equation of motion within the
restrictions of relativistic rigidity and negligible O(a) terms under which the
equation of motion is derived. However, it is shown that renormalization of the
electrostatic mass to a finite value as the radius of the charge approaches
zero introduces a violation of momentum-energy conservation into the causal
solutions to the equation of motion of the point charge if the magnitude of the
external force becomes too large. That is, the causal classical equation of
motion of a point charge with renormalized mass experiences a high acceleration
catastrophe.Comment: 13 pages, No figure
Imaging of arrhythmia: Real-time cardiac magnetic resonance imaging in atrial fibrillation
Objectives Quantitative evaluations of function, volume and mass are fundamental in the diagnostic workup of different cardiovascular diseases and can be exactly determined by CMRI in sinus rhythm. This does not hold true in arrhythmia as CMR is hampered by reconstruction artifacts caused by inconsistent data from multiple heartbeats. Real-time (RT) MRI at high temporal resolution might reduce these problems. Methods Consecutive patients with atrial fibrillation were prospectively included and underwent RT and conventional CINE CMR in randomized order. 29 patients were studied at 1.5 T and 30 patients at 3 T. At 3 T a group of 20 subjects in sinus rhythm served as controls. RT and CINE image quality was evaluated in different planes and for different wall sections using a Likert scale (from zero to four). Volumetric analysis was performed using two types of software and differences between RT and CINE CMR were evaluated. Results In patients with atrial fibrillation RT CMR short axis (SA) resulted in a significantly higher image quality compared to CINE imaging both at 1.5 T and 3 T (1.5 T: mid SA: 3.55 ± 0.5 RT vs 2.6 ± 0.9 CINE, p = 0.0001; 3 T: mid SA: 3.15 ± 0.9 RT vs 2.6 ±1.0 CINE, p = 0.03); This qualitative difference was more marked and significant for the long axis views (2CV and 4CV) at 1.5 T (1.5 T: 2CV: 3.2 ± 0.6 RT vs 2.65 ± 1.1 CINE; p = 0.011; 4CV: 2.9 ± 0.69 RT vs 2.4 ± 0.9 CINE; p = 0.0044). During sinus rhythm CINE images were superior concerning diagnostic quality (3 T mid SA: 3.35 ± 0.45 RT vs 3.8 ± 0.5 CINE, p = 0.008). Quantitative analysis was successful with both software packages and the results showed a good correlation (Pearson correlation between 0.679 and 0.921 for patients). RT CMR resulted in slightly lower functional volumes than CINE CMR (3 T: patients: EDVI 86 ± 29 ml/m2 RT vs 93 29 ml/m2± 29 CINE, Pearson r = 0.902) but similar ejection fractions (3 T: patients: EF 47 ± 16% RT vs 45 ± 13% CINE, Pearson r = 0679; controls: EF 63 ± 6 RT vs 63 ± 3 CINE, Pearson r = 0.695). Conclusion RT CMR improves image quality in arrhythmic patients and renders studies more comfortable. Volumetric analysis is feasible with slightly lower values relative to CINE CMR, while ejection fractions are comparable
The paranasal sinuses are focus for colonisation and chronic biofilm lung infection in CF patients
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Virtual screening for inhibitors of the human TSLP:TSLPR interaction
The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Ra), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP: TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP: alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP: TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation
Reconstruction of the gastric passage by a side-to-side gastrogastrostomy after failed vertical-banded gastroplasty: a case report
INTRODUCTION: Vertical-banded gastroplasty, a technique that is commonly performed in the treatment of morbid obesity, represents a nonadjustable restrictive procedure which reduces the volume of the upper stomach by a vertical stapler line. In addition, a textile or silicone band restricts food passage through the stomach. CASE PRESENTATION: A 71-year-old woman presented with a severe gastric stenosis 11 years after vertical gastroplasty. We describe a side-to-side gastrogastrostomy as a safe surgical procedure to restore the physiological gastric passage after failed vertical-banded gastroplasty. CONCLUSION: Occasionally, restrictive procedures for morbid obesity cannot be converted into an alternative bariatric procedure to maintain weight control. This report demonstrates that a side-to-side gastrogastrostomy is a feasible and safe procedure
In-Depth Assessment of the Palladium-Catalyzed Fluorination of Five-Membered Heteroaryl Bromides
A thorough investigation of the challenging Pd-catalyzed fluorination of five-membered heteroaryl bromides is presented. Crystallographic studies and density functional theory (DFT) calculations suggest that the challenging step of this transformation is C–F reductive elimination of five-membered heteroaryl fluorides from Pd(II) complexes. On the basis of these studies, we have found that various heteroaryl bromides bearing phenyl groups in the ortho position can be effectively fluorinated under catalytic conditions. Highly activated 2-bromoazoles, such as 8-bromocaffeine, are also viable substrates for this reaction.National Institutes of Health (U.S.) (GM46059)National Science Foundation (U.S.) (Predoctoral Fellowship 2010094243)Amgen Inc
Neuromuscular synaptic function in mice lacking major subsets of gangliosides
Gangliosides are a family of sialylated glycosphingolipids enriched in the outer leaflet of neuronal membranes, in particular at synapses. Therefore, they have been hypothesized to play a functional role in synaptic transmission. We have measured in detail the electrophysiological parameters of synaptic transmission at the neuromuscular junction (NMJ) ex vivo of a GD3-synthase knockout mouse, expressing only the O- and a-series gangliosides, as well as of a GM2/GD2-synthase*GD3-synthase double-knockout (dKO) mouse, lacking all gangliosides except GM3. No major synaptic deficits were found in either null-mutant. However, some extra degree of rundown of acetylcholine release at high intensity use was present at the dKO NMJ and a temperature-specific increase in acetylcholine release at 35 °C was observed in GD3-synthase knockout NMJs, compared with wild-type. These results indicate that synaptic transmission at the NMJ is not crucially dependent on the particular presence of most ganglioside family members and remains largely intact in the sole presence of GM3 ganglioside. Rather, presynaptic gangliosides appear to play a modulating role in temperature- and use-dependent fine-tuning of transmitter output
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