Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)

Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis (MS). EAE is a complex condition in which the interaction between a variety of immunopathological and neuropathological mechanisms leads to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss and gliosis. The counter-regulatory mechanisms of resolution of inflammation and remyelination also occur in EAE, which, therefore can also serve as a model for these processes. Moreover, EAE is often used as a model of cell-mediated organ-specific autoimmune conditions in general. EAE has a complex neuropharmacology, and many of the drugs that are in current or imminent use in MS have been developed, tested or validated on the basis of EAE studies. There is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions, many of which are reviewed here. This makes EAE a very versatile system to use in translational neuro- and immunopharmacology, but the model needs to be tailored to the scientific question being asked. While creating difficulties and underscoring the inherent weaknesses of this model of MS in straightforward translation from EAE to the human disease, this variability also creates an opportunity to explore multiple facets of the immune and neural mechanisms of immune-mediated neuroinflammation and demyelination as well as intrinsic protective mechanisms. This allows the eventual development and preclinical testing of a wide range of potential therapeutic interventions.     

Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3

CONTEXT: Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported. Research DESIGN AND METHODS: We now report a third proband, a 6-yr-old boy, offspring of a consanguineous union of parents of North African origin, who was homozygous for a novel missense mutation Ser307Leu. We characterized the functional properties of the mutant PC1/3 and characterized the clinical phenotype of the patient. RESULTS: In vitro this mutation markedly impairs the catalytic activity of the convertase. However, in contrast to other previously described naturally occurring mutations, intracellular trafficking of this mutant enzyme appeared normal. The Ser307Leu mutant retained some autocatalytic activity, even though it was completely inactive on other substrates. As with the previous two patients, this child had obesity and persistent diarrhea, however, there was no history of reactive hypoglycemia. The patient showed markedly increased food intake at an ad libitum test meal, confirming that hyperphagia makes a major contribution to the obesity seen in this syndrome. CONCLUSION: This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency.     

Intrarenal post-traumatic pseudoaneurysm-USG colour Doppler diagnosis: a case report with review of literature

Renal artery pseudoaneurysm, although a well-known complication in patients after penetrating trauma or iatrogenic injury, has rarely been described after blunt torso trauma. A 22-year-old man suffered an accident while on a motorcycle. Upon arrival in the Emergency Room, the patient was unconscious, hypotensive and had hematuria. Initial investigations revealed a fractured shaft of the right femur, multiple rib fractures with hemothorax, extradural haematoma on the right side and a laceration in the right kidney. After the evacuation of intracranial bleed, the patient was managed conservatively. The patient recovered well and was discharged on the 15th post-trauma day. The patient was again present in the emergency room after 6 weeks with 1-week history of gross hematuria. Ultrasonography revealed an anechoic lesion in the right kidney with pulsatile flow on colour Doppler. Further investigation with computed tomography renal angiography was done, which confirmed the pseudoaneurysm of a branch of renal artery. The patient was referred to a higher centre where he was successfully managed with selective arterial coil embolisation.     

The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals

BACKGROUND: Previous studies have suggested that a variant in the melanocortin-4 receptor (MC4R) gene is important in protecting against common obesity. Larger studies are needed, however, to confirm this relation. METHODS: We assessed the association between the V103I polymorphism in the MC4R gene and obesity in three UK population based cohort studies, totalling 8304 individuals. We also did a meta-analysis of relevant studies, involving 10 975 cases and 18 588 controls, to place our findings in context. FINDING: In an analysis of all studies, individuals carrying the isoleucine allele had an 18% (95% confidence interval 4-30%, P=0.015) lower risk of obesity compared with non-carriers. There was no heterogeneity among studies and no apparent publication bias. INTERPRETATION: This study confirms that the V103I polymorphism protects against human obesity at a population level. As such it provides proof of principle that specific gene variants may, at least in part, explain susceptibility and resistance to common forms of human obesity. A better understanding of the mechanisms underlying this association will help determine whether changes in MC4R activity have therapeutic potential.     

A Theoretical Study on the Structure of Cyclohexylaminoglutethimide: A Potent Aromatase Inhibitor. Comparison of the Three Configurations of the Cyclohexyl Moiety

This paper reports on studies of the theoretical geometrical structure of the three configurations forms of cyclohexylamino-glutethimide, chemically known as 3-cyclohexyl-3-(4-aminophenyl)-2,6-piperidinedione. The semi-empirical method AM1 was used to optimize the structures. In the minimum energy state the geometries of non cyclohexyl portion of the three molecules are quite similar. Dipole moments, charge density distributions, and electrostatic potential distributions are not important in this set of molecules. The torsion angles point to the significance of the geometries and their respective stability for these three forms namely the chair, boat, and twisted configuration of the cyclohexyl moiety.     

Endovascular stent implantation to relieve extrinsic right pulmonary artery compression due to an enlarged neoaorta

This case report describes extrinsic compression of the right pulmonary artery, following aortic reconstructive surgery, to create a neo-ascending aorta in a 5-year-old boy with aortic atresia, coarctation of the aorta, and a ventricular septal defect, in an effort to achieve a biventricular circulation (Yasui operation). The obstruction was successfully relieved by transcatheter implantation of a balloon-expandable stent. Cathet. Cardiovasc. Intervent. 46:430–433, 1999. © 1999 Wiley-Liss, Inc.