Deconstructing the Pharmacological Contribution of Sphingosine-1 Phosphate Receptors to Mouse Models of Multiple Sclerosis Using the Species Selectivity of Ozanimod, a Dual Modulator of Human Sphingosine 1-Phosphate Receptor Subtypes 1 and 5.

Ozanimod, a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P) and 5 (S1P), is approved for the treatment of relapsing multiple sclerosis (MS) in multiple countries. Ozanimod profiling revealed a species difference in its potency for S1P in mouse, rat, and canine compared with that for human and monkey. Site-directed mutagenesis identified amino acid alanine at position 120 to be responsible for loss of activity for mouse, rat, and canine S1P, and mutation back to threonine as in human/monkey S1P restored activity.

Development of national consensus statements on food labelling interpretation and protein allocation in a low phenylalanine diet for PKU.

Background: In the treatment of phenylketonuria (PKU), there was disparity between UK dietitians regarding interpretation of how different foods should be allocated in a low phenylalanine diet (allowed without measurement, not allowed, or allowed as part of phenylalanine exchanges). This led to variable advice being given to patients.

Methodology: In 2015, British Inherited Metabolic Disease Group (BIMDG) dietitians (n = 70) were sent a multiple-choice questionnaire on the interpretation of protein from food-labels and the allocation of different foods.

Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues.

Sirt1 is a NAD(+)-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice.

Comparison of oral and transdermal administration of rasagiline mesylate on human melanoma tumor growth in vivo.

Background/aims: Transdermal patch administration results in a locally high concentration of drug that induce local toxicity, including tumorogenicity. As a worst-case scenario for consequences of repeated application on neoplastic growth, the melanin-binding drug, rasagiline, was used in a transdermal formulation applied directly to a human-derived melanoma to determine the effects on tumor growth.

Materials And Methods: Rasagiline mesylate was administered either orally or transdermally to athymic mice implanted with human melanoma (SKMEL28) to determine the effects on tumor growth and survival.

Optimization of hCFTR lung expression in mice using DNA nanoparticles.

Efficient and prolonged human cystic fibrosis transmembrane conductance regulator (hCFTR) expression is a major goal for cystic fibrosis (CF) lung therapy. A hCFTR expression plasmid was optimized as a payload for compacted DNA nanoparticles formulated with polyethylene glycol (PEG)-substituted 30-mer lysine peptides. A codon-optimized and CpG-reduced hCFTR synthetic gene (CO-CFTR) was placed in a polyubiquitin C expression plasmid.

A simple method for fitting sphere-like surfaces.

In this paper we present a new and simple method for fitting a sphere-like surface to a set of data points in 3-space. In comparison to the standard method that involves using spherical harmonics, this method is conceptually simpler and computationally less complex and intensive, especially when used to address problems in which data is sparse or nonuniform.

Structure-activity relationships of novel, highly potent, selective, and orally active CCR1 antagonists.

Design and synthesis of a series of 3-amino-4-(2-(2-(4-benzylpiperazin-1-yl)-2-oxoethoxy)phenylamino)cyclobutenedione derivatives as novel CCR1 antagonists are described. Structure-activity relationship studies led to the identification of compound 22, which demonstrated potent binding activity, functional antagonism of CCR1 as well as good species cross-reactivity. In addition, compound 22 also showed desirable pharmacokinetic profiles and was selected for in vivo studies in the mouse collagen-induced arthritis model.

Modeling prostate anatomy from multiple view TRUS images for image-guided HIFU therapy.

Current planning methods for transrectal high-intensity focused ultrasound treatment of prostate cancer rely on manually defining treatment regions in 15-20 sector transrectal ultrasound (TRUS) images of the prostate. Although effective, it is desirable to reduce user interaction time by identifying functionally related anatomic structures (segmenting), then automatically laying out treatment sites using these structures as a guide. Accordingly, a method has been developed to effectively generate solid three-dimensional (3-D) models of the prostate, urethra, and rectal wall from boundary trace data.

Prosaposin gene expression and the efficacy of a prosaposin-derived peptide in preventing structural and functional disorders of peripheral nerve in diabetic rats.

We have recently demonstrated that prosaposin is a neurotrophic and myelinotrophic factor with the active trophic sequence located at the N-terminal region of the saposin C domain. There are also reports that prosaposin mRNA is increased distal to a physical nerve injury and that exogenous prosaposin treatment induces subsequent neuronal sprouting, suggesting involvement in repair processes. In the present study, we show that prosaposin mRNA is significantly (p < 0.

Effects of hindlimb temperature on sciatic nerve laser Doppler vascular conductance in control and streptozotocin-diabetic rats.

The effects of hindlimb temperature on sciatic nerve and skeletal muscle laser Doppler vascular conductance (LDVC) were assessed in anesthetized control and streptozotocin (STZ)-diabetic rats. With core temperature at 37 degrees C and exposed hindlimb temperature at 32 degrees C, nerve LDVC was significantly lower in rats after 8 weeks of STZ diabetes than in age-matched control rats. Subsequent warming of the exposed hindlimb of control rats from 32 degrees C to 37 degrees C significantly decreased nerve LDVC by 41% and increased muscle LDVC by 48%.

Mast cell-associated Renaut bodies in the peroneal nerve of a dog with a history of mastocytosis.

Multiple Renaut bodies were identified by light microscopy in the biopsied common peroneal nerve of a dog with generalized neuropathy, hypothyroidism and a history of cutaneous mastocytosis. In addition, numerous granulated cells were associated with most of the Renaut bodies. Electron microscopic examination confirmed these to be mast cells, both central and peripheral to Renaut bodies, a phenomenon never previously reported.

Nerve conduction velocity, laser Doppler flow, and axonal caliber in galactose and streptozotocin diabetes.

In an initial study, the effects of galactose intoxication on nerve laser Doppler blood flow (NLDF) and nerve conduction velocity (NCV) were assessed after 1-16 weeks of galactose feeding in pentobarbital-anesthetized rats. NLDF was not significantly changed at any time point. NCV was significantly reduced after 16, but not 1 or 4, weeks of galactose feeding.

NT-3 attenuates functional and structural disorders in sensory nerves of galactose-fed rats.

The present study investigated the effect of NT-3, a neurotrophin expressed in nerve and skeletal muscle, on myelinated fiber disorders of galactose-fed rats. Adult, female Sprague-Dawley rats were fed diets containing complete micronutrient supplements and either 0% D-galactose (control) or 40% D-galactose. Treated controls received 20 mg/kg NT-3 and treated galactose-fed rats received 1, 5, or 20 mg/kg NT-3 three times per week by subcutaneous injections.

Effects of the peptide HP228 on nerve disorders in diabetic rats.

Motor and sensory nerve conduction velocities (MNCV and SNCV) were reduced in the sciatic nerve of rats after 4 weeks of untreated streptozotocin-induced diabetes, and declined further during the following 4 weeks. Treating diabetic rats with the novel peptide HP228 had no effect on the decline of MNCV after the first 4 weeks of diabetes but attenuated the decline in SNCV. HP228 treatment also prevented any further decline in MNCV or SNCV between weeks 4 and 8 of diabetes.

Tactile hyperesthesia, altered epidermal innervation and plantar nerve injury in the hindfeet of rats housed on wire grates.

The effects of wire grates on nerve injury and recovery were examined in rats housed in cages with sawdust-covered solid flooring. For the first 3 weeks of the study, 20 rats were housed on sawdust alone and 20 rats were housed in cages with wire grates placed over the sawdust. For the remaining 9 weeks, 10 animals housed on sawdust had wire grates added to their cages, while grates were removed from the cages of 10 animals.

Mast cell interactions with the nervous system: relationship to mechanisms of disease.

In summary, mast cell interactions in the nervous system are relevant to both physiological processes (i.e. reproduction) and pathologic states (i.

Effects of body and hindlimb temperature on laser Doppler blood flow and vascular conductance in rat sciatic nerve and skeletal muscle.

The role of body and hindlimb temperature in the control of blood flow in nerve and muscle was assessed by laser Doppler flowmetry. Following surgical exposure of nerve, initial measurements were taken for 5 min at hindlimb temperatures of 30-31 degrees C. A second set of identical measurements was then made either with or without warming to 37 degrees C.

Effectiveness of natural oils as sources of gamma-linolenic acid to correct peripheral nerve conduction velocity abnormalities in diabetic rats: modulation by thromboxane A2 inhibition.

Reduced nerve conduction velocity (NCV) in experimental diabetes can be prevented by evening primrose oil (EP), which is rich in gamma-linolenic acid (GLA). This study examined the efficacy of natural GLA sources, blackcurrant (BC), borage (BO) and fungal (FU) oils, compared with EP, in correcting motor and sensory NCV deficits in streptozotocin-diabetic rats, and any potential contribution of thromboxane (TX) A2 synthesis using the TX antagonist, ZD1542, alone and jointly with GLA-rich oils. Sciatic motor NCV, 20% reduced by 8 weeks of diabetes, was partially (16%) corrected by 2 weeks ZD1542 treatment.

Reversal of defective peripheral nerve conduction velocity, nutritive endoneurial blood flow, and oxygenation by a novel aldose reductase inhibitor, WAY-121,509, in streptozotocin-induced diabetic rats.

The main aim was to investigate whether 1 month of aldose reductase inhibitor treatment could correct a deficit in sciatic nerve nutritive blood flow following 1 month of untreated streptozotocin-induced diabetes in rats. Treatment was with two doses of WAY-121,509, both of which completely blocked neuronal sorbitol accumulation. The high dose fully corrected a motor conduction velocity deficit, whereas the low dose caused 51.

Effects of natural free radical scavengers on peripheral nerve and neurovascular function in diabetic rats.

Increased generation of reactive oxygen species, coupled with impaired endogenous scavenging mechanisms, plays a prominent role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. We examined the efficacy of the natural anti-oxidants vitamins C, E and beta-carotene in preventing nerve conduction and nutritive blood flow deficits in streptozotocin-diabetic rats. One month of diabetes caused a 19.

Effects of acetyl- and proprionyl-L-carnitine on peripheral nerve function and vascular supply in experimental diabetes.

L-Carnitine metabolism is abnormal in diabetes mellitus, and treatment with acetyl-L-carnitine (ALC) improves the function of cardiac muscle, retina, and peripheral nerve in experimental models. The aim was to compare the effects of ALC and proprionyl-L-carnitine (PLC) on motor and sensory nerve conduction in streptozotocin-diabetic rats and to ascertain whether their action could be mediated by a vascular mechanism. ALC and PLC treatment for 2 months after diabetes induction attenuated the development of sciatic motor nerve conduction velocity (NCV) deficits by 59.

Comparison of the effects of evening primrose oil and triglycerides containing gamma-linolenic acid on nerve conduction and blood flow in diabetic rats.

The aim was to ascertain whether the ability of evening primrose oil (EPO) treatment to correct peripheral nerve dysfunction in streptozotocin-diabetic rats depends on a gamma-linolenic acid (GLA)-containing triglyceride constituent, di-linolein mono-gamma-linolenate (DLMG). A second objective was to investigate whether the triglyceride conformation of GLA affects efficacy, using tri-gamma-linolenate (TGLA), which is not present in EPO. Third, we examined the actions of these omega-6 essential fatty acid-containing oils on sciatic nerve blood flow to establish a common mechanism.

Experimental assessment by high frequency ultrasound of articular cartilage thickness and osteoarthritic changes.

Objective: Osteoarthritis (OA) is characterized by progressive loss of articular cartilage in the involved joint. Accurate, reproducible measurement of the thickness of the cartilage in vivo, however, is difficult. Because development of an ultrasonic imaging device for intraarticular use is feasible and would permit acquisition of information that could complement the assessment of articular cartilage made at arthroscopy, we evaluated the efficacy of high frequency ultrasound in assessing the thickness and subsurface characteristics of normal and OA cartilage.

The potential contribution of endothelin-1 to neurovascular abnormalities in streptozotocin-diabetic rats.

Abnormal vascular endothelium function may contribute to the reduced nerve perfusion implicated in the aetiology of neuropathy in diabetes mellitus. The aim was to test the hypothesis that a powerful vasoconstrictor, endothelin-1, could be involved in nerve dysfunction in streptozotocin-diabetic rats. After 6 weeks of untreated diabetes, rats were implanted with osmotic minipumps which continuously delivered the endothelin-1 antagonist, BQ-123, to the circulation via a jugular vein cannula.

Aldose reductase inhibition, nerve perfusion, oxygenation and function in streptozotocin-diabetic rats: dose-response considerations and independence from a myo-inositol mechanism.

We examined the effects of aldose reductase inhibition on nerve biochemistry and function, blood flow and endoneurial oxygenation in experimental diabetes mellitus. After 1 month untreated diabetes in rats, treatment with the novel sulphonylnitromethane aldose reductase inhibitor, ZENECA ZD5522, prevented a progressive increase in sciatic nerve resistance to hypoxic conduction failure (p < 0.05).