Uncommon and Miscellaneous Inflammatory Disorders of the Brain and Spine.

Inflammatory disorders of the brain and spine have a highly variable MRI appearance, often demonstrating significant overlap in imaging features. The resulting diagnostic dilemma is particularly challenging when considering the more uncommon neuroinflammatory entities. Diligent examination of the salient clinical presentation and signal alteration on imaging examination is necessary when considering neuroinflammation as a diagnostic possibility and may aid in raising suspicion for a particular neuroinflammatory entity.

Comparison of image quality and diagnostic efficacy of routine clinical lumbar spine imaging at 0.55T and 1.5/3T.

Purpose: To compare image quality, assess inter-reader variability, and evaluate the diagnostic efficacy of routine clinical lumbar spine sequences at 0.55T compared with those collected at 1.5/3T to assess common spine pathology.

A Role for Dystonia-Associated Genes in Spinal GABAergic Interneuron Circuitry.

Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions.

Myofibroblastoma of the male breast: a rare entity with radiologic-pathologic correlation.

A 73-year old man with a history of multiple genitourinary malignancies was found to have a left retroareolar soft tissue mass on CT assessment of disease, and dedicated breast imaging was recommended. Diagnostic mammography and ultrasonography confirmed a solid mass, for which biopsy was recommended. Pathologic analysis demonstrated a spindle cell neoplasm with an immunoreactivity pattern consistent with myofibroblastoma.

Sensory and spinal inhibitory dorsal midline crossing is independent of Robo3.

Commissural neurons project across the midline at all levels of the central nervous system (CNS), providing bilateral communication critical for the coordination of motor activity and sensory perception. Midline crossing at the spinal ventral midline has been extensively studied and has revealed that multiple developmental lineages contribute to this commissural neuron population. Ventral midline crossing occurs in a manner dependent on Robo3 regulation of Robo/Slit signaling and the ventral commissure is absent in the spinal cord and hindbrain of Robo3 mutants.

Small-Scale Assays for Studying Dissolution of Pharmaceutical Cocrystals for Oral Administration.

The purpose of this study was to better understand the dissolution properties and precipitation behavior of pharmaceutical cocrystals of poorly soluble drugs for the potential for oral administration based on a small-scale dissolution assay. Carbamazepine and indomethacin cocrystals with saccharin and nicotinamide as coformers were prepared with the sonic slurry method. Dissolution of the poorly soluble drugs indomethacin and carbamazepine and their cocrystals was studied with a small-scale dissolution assay installed on a SiriusT3 instrument.

Neuronal Ig/Caspr recognition promotes the formation of axoaxonic synapses in mouse spinal cord.

Inhibitory microcircuits are wired with a precision that underlies their complex regulatory roles in neural information processing. In the spinal cord, one specialized class of GABAergic interneurons (GABApre) mediates presynaptic inhibitory control of sensory-motor synapses. The synaptic targeting of these GABAergic neurons exhibits an absolute dependence on proprioceptive sensory terminals, yet the molecular underpinnings of this specialized axoaxonic organization remain unclear.

Corticospinal tract insult alters GABAergic circuitry in the mammalian spinal cord.

During perinatal development, corticospinal tract (CST) projections into the spinal cord help refine spinal circuitry. Although the normal developmental processes that are controlled by the arrival of corticospinal input are becoming clear, little is known about how perinatal cortical damage impacts specific aspects of spinal circuit development, particularly the inhibitory microcircuitry that regulates spinal reflex circuits. In this study, we sought to determine how ischemic cortical damage impacts the synaptic attributes of a well-characterized population of inhibitory, GABAergic interneurons, called GABApre neurons, which modulates the efficiency of proprioceptive sensory terminals in the sensorimotor reflex circuit.

The " dissolution" method: a low volume, apparatus for assessing the dissolution/precipitation behaviour of an active pharmaceutical ingredient under biorelevant conditions.

This paper describes a low volume, in vitro apparatus for investigating the dissolution and precipitation behaviour of active pharmaceutical ingredients (APIs) under a wide range of experimental conditions and dissolution media. The apparatus has automated and dynamic pH control, allowing the simulated passage of drugs through the gastrointestinal tract (GIT). Experiments can be performed in the presence of biorelevant media and excipients, providing information related to the predicted behaviour of APIs under physiological conditions.

The role of tribal experiences in shaping Native American health.

The relatively poor health and healthcare of Native Americans is well documented. However, the existing research does not adequately consider unique tribal experiences in shaping Native American health. Consequently, the purpose of this paper is to assess the role of tribes in explaining measures of healthcare and the perceptions of health-related problems.

ADMET--Fifth Annual SMi Conference.

SMi's fifth annual ADMET Conference, held in London, included topics covering new developments in the field of ADMET. This conference report highlights selected presentations on ADME optimization in drug discovery; targeting drugs to the brain; predicting bonds that might be attacked during metabolism; treating Caco-2 membranes with vinblastine to enhance P-glycoprotein interactions; predictive ADMET in hit-to-lead optimization; structure-based studies of ADMET targets; an accelerated process for integrated drug development; building hypotheses in lead selection and optimization; supersaturation effects; the prediction of drug-drug interactions; developing a mechanism-based pharmacokinetic/pharmacodynamic model; drug transporter assays in drug discovery; time-dependent inhibition screens in early drug discovery; the system-dependent inhibition of CYP enzymes; the integrating predictive toxicology framework OpenTox; high-content analysis for predictive cytotoxicity testing; and emerging in vitro toxicity assays.

Study of pH-dependent solubility of organic bases. Revisit of Henderson-Hasselbalch relationship.

In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equilibrium solubility values were determined using the saturation shake-flask and the Chasing Equilibrium Solubility (CheqSol) methods. Results obtained by the two methods are in good agreement.

New ideas about the solubility of drugs.

Methods are described for detecting precipitation of ionisable drugs under conditions of changing pH, estimating kinetic solubility from the onset of precipitation, and measuring solubility by chasing equilibrium. Definitions are presented for kinetic, equilibrium, and intrinsic solubility of ionisable drugs, supersaturation and subsaturation, and for chasers and non-chasers, which are two classes of ionisable drug with significantly different solubility properties. The use of Bjerrum Curves and Neutral-Species Concentration Profiles to depict solubility properties are described and illustrated with case studies showing super-dissolving behaviour, conversion between crystalline forms and enhancement of solubility through supersaturation, and the use of additives and simulated gastrointestinal fluids.

Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound.

The experimental conditions that affect equilibrium solubility values measured by the classical saturation shake-flask method have been examined, using hydrochlorothiazide as a model compound. Modifications in temperature, sedimentation time, composition of aqueous buffer and the technique of separation of solid and liquid phases were all found to influence the equilibrium solubility results strongly. However, variations in the amount of solid excess and stirring time were found to have less influence.

Potentiometric and spectrophotometric pKa determination of water-insoluble compounds: validation study in a new cosolvent system.

In this paper the validation of pKa determination in MDM-water mixtures is presented. The MDM-water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly water-soluble compounds. The cosolvent dissociation constants (p(s)Ka) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15-56 wt% MDM-water mixtures by potentiometric or spectrophotometric titration and the aqueous pKa values obtained by extrapolation.

Presentation of a structurally diverse and commercially available drug data set for correlation and benchmarking studies.

A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small, physicochemically diverse set of 24 drug compounds. Factors such as structural diversity, commercial availability, price, and a suitable analytical technique for quantification were considered in the selection. Lipophilicity, pKa, solubility, and permeability across human Caco-2 cell monolayers were measured for the compiled data set.

Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution--a validation study.

A novel potentiometric procedure has recently been described for rapid measurement of equilibrium aqueous solubility values of organic acids, bases, and ampholytes that form supersaturated solutions. In this procedure, the equilibrium solubility is actively sought by changing the concentration of the neutral form by adding HCl or KOH titrants and monitoring the rate of change of pH due to precipitation or dissolution in a process called Chasing Equilibrium. In this article, we seek to validate the procedure against a shake-flask protocol for solubility determination.

Permeability through DOPC/dodecane membranes: measurement and LFER modelling.

The permeabilities of 43 ionisable compounds through membranes consisting of 2% dioleylphosphatidylcholine (DOPC) in dodecane at pH values between 3 and 10 have been measured. The observed values are corrected for the effects of ionisation and diffusion through the unstirred water layer in order to obtain estimates of intrinsic permeability. The intrinsic permeabilities are modelled using Abraham's linear free energy relation method.

High-throughput measurement of pKa values in a mixed-buffer linear pH gradient system.

A procedure is described for measuring pKa values in a short time, e.g., 4 min/assay.

Application of hydrogen bonding calculations in property based drug design.

A drug can be characterized by "descriptors" that include size (volume) and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g.