Neuraxial TNF and IFN-beta co-modulate persistent allodynia in arthritic mice.

In rheumatoid arthritis, joint pain can persist despite resolution of swelling. Similarly, in the murine K/BxN serum transfer model, a persistent tactile allodynia is observed after the resolution of joint inflammation (post-inflammatory pain) in male mice. Here, we found female wild type (WT) mice show inflammatory, but reduced post-inflammatory tactile allodynia. The transition to the post-inflammatory phenotype is dependent on TLR4 signaling. At the spinal level, we found differences in TNF and IFNß mRNA expression in WT and TLR4 deficient males. In wild type male and female mice, there is differential temporal spinal expression of TNF and IFNß. In WT males, blockade of TNF or administration of IFNß was insufficient to affect the persistent allodynia. However, co-administration of intrathecal (IT) IFNß and anti-TNF antibodies in male WT mice permanently reversed tactile allodynia. IT IFNß treatment induces expression of anti-inflammatory proteins, contributing to the beneficial effect. Together, these experiments illustrated differences in the transition to chronic tactile allodynia in male and female animals and the complexities of effective pharmacologic interventions.

Determination of molecular vibrational state energies using the ab initio semiclassical initial value representation: application to formaldehyde.

We have demonstrated the use of ab initio molecular dynamics (AIMD) trajectories to compute the vibrational energy levels of molecular systems in the context of the semiclassical initial value representation (SC-IVR). A relatively low level of electronic structure theory (HF/3-21G) was used in this proof-of-principle study. Formaldehyde was used as a test case for the determination of accurate excited vibrational states. The AIMD-SC-IVR vibrational energies have been compared to those from curvilinear and rectilinear vibrational self-consistent field/vibrational configuration interaction with perturbation selected interactions-second-order perturbation theory (VSCF/VCIPSI-PT2) and correlation-corrected vibrational self-consistent field (cc-VSCF) methods. The survival amplitudes were obtained from selecting different reference wavefunctions using only a single set of molecular dynamics trajectories. We conclude that our approach is a further step in making the SC-IVR method a practical tool for first-principles quantum dynamics simulations.

Dose-by-dose virological and hematological responses to intravenous immunoglobulin in an immunocompromised patient with persistent parvovirus B19 infection.

A 42-year-old male with stage IV mantle cell lymphoma received chemotherapy and autologous peripheral blood stem cell transplantation. He developed pancytopaenia, and bone marrow examination indicated a parvovirus B19 (PVB 19)-induced red cell aplasia, confirmed by virological tests. Multiple doses of intravenous immunoglobulin (IVIG) were given over the following months, with blood samples being taken after each dose for quantitative PVB 19 DNA and hematological testing to assess the response. Each dose of IVIG produced a 1-3 log(10) drop in PVB 19 DNA levels. Eventually, after the fifth dose of IVIG, the PVB 19 DNA was reduced to <10 copies/ml serum, with a gradual improvement in his hematological parameters. This report demonstrates how close monitoring of the virological and hematological response to IVIG therapy for persistent PVB 19 infection in an immunocompromised patient can optimize the usage of this relatively expensive, and sometimes scarce intervention.

Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system.

This paper presents the synthesis of combinatorial libraries performed on a single-channel glass micro reactor under hydrodynamic flow control. The experiments were carried out in a non-well based micro chip and consisted of the preparation of libraries of pyrazoles by means of a Knorr reaction of 1,3-dicarbonyl compounds with hydrazines. The aim of this work is to investigate the capabilities of an automated micro reactor based system to synthesise sequentially multiple analogue reactions. Small slugs of reactants were introduced automatically by an autosampler in a serpentine-etched glass chip. The mobility of the reagents and products was achieved using hydrodynamic driven flow. Reaction slug dilution and UV slug detection took place at the outlet. A sample of the slug was analysed by using an on-line LC-UV-MS system. The degree of conversion was quantified using the UV signal and comparing with standards of starting materials and final products. After the LC-UV-MS analysis, the automated system proceeds to inject the slugs to carry out the next reaction programmed. The results suggest that the micro reactor system is capable of repeating the process of injection, mixing and reaction in an automated manner as many times as required.

Synthesis of a three-member array of cycloadducts in a glass microchip under pressure driven flow.

The synthesis of a series of cycloadduct products carried out in a glass microchip under pressure driven flow is presented. Initially, four different compounds were synthesized individually with conversions similar to those obtained in the corresponding batch macroscale reactions. Using identical experimental conditions for all four compounds, the results were highly predictable and reproducible, without the need for individual optimization. A multi-reaction experiment was then carried out in a single chip achieving the synthesis of a three-member array in a single run.

A Hantzsch synthesis of 2-aminothiazoles performed in a heated microreactor system.

This paper presents the first example known to the authors of a heated organic reaction performed on a glass microreactor under electro-osmotic flow control. The experiments consisted of the preparation of a series of 2-aminothiazoles by means of a Hantzsch reaction of ring-substituted 2-bromoacetophenones and 1-substituted-2-thioureas carried out in microchannels, with the aim of investigating the generic utility of the reactor in carrying out analogue reactions. The reactions were performed on T-design microchips etched into a thin borosilicate glass plate and sealed over with a thick borosilicate top plate containing reservoirs. The mobility of the reagents and products was achieved using electro-osmotic flow (EOF), with the driving voltages being generated by a computer-controlled power supply. During the experiments the T-shaped chip was heated at 70 C using a Peltier heater, aligned with the channels and the heat generated by this device was applied to the lower plate. The degree of conversion was quantified by LC-MS using UV detection by comparison with standard calibration curves for starting materials and final products. In all cases, conversions were found to be similar or greater than those found for equivalent macro scale batch syntheses, thus illustrating the potential of this heated microreactor system to generate a series of compounds which contain biologically active molecules.