Analogues of acifran: agonists of the high and low affinity niacin receptors, GPR109a and GPR109b

Recently identified GPCRs, GPR109a and GPR109b, the high and low affinity receptors for niacin, may represent good targets for the development of HDL elevating drugs for the treatment of atherosclerosis. Acifran, an agonist of both receptors, has been tested in human subjects, yet until recently very few analogs had been reported. We describe a series of acifran analogs prepared using newly developed synthetic pathways and evaluated as agonists for GPR109a and GPR109b, resulting in identification of compounds with improved activity at these receptors.     

Focal β‐catenin mutation identified on formalin‐fixed and paraffin‐embedded inflammatory hepatocellular adenomas

The identification of hepatocellular adenoma (HCA) with mutation in exon 3 of the CTNNB1 gene encoding for β‐catenin is clinically relevant due to a higher risk of malignant transformation. Inflammatory HCA (IHCA) can exhibit β‐catenin activation (β‐IHCA). We report two cases with multiple IHCA in which focal β‐catenin activation has been found in one of the IHCA. In both cases, the diagnosis of IHCA was confirmed on the resected nodules by routine stains, immunohistochemical detection of C‐reactive protein (CRP) and molecular biology on frozen material. An additional molecular analysis was performed on formalin‐fixed paraffin‐embedded (FFPE) material that showed focal glutamine synthetase (GS) staining, the surrogate marker of β‐catenin activation. In case 1, it was a 1.8‐cm area within the 7.5 cm IHCA, and in case 2 a small 0.3‐cm area within a 1.8 cm resected IHCA located close to a larger IHCA, negative for GS. In both cases, nuclear β‐catenin expression and decreased reticulin network were observed in the GS expressing foci, together with cholestasis and diffuse CD34 expression in case 1. Molecular analysis by pyrosequencing on FFPE material using the GS‐stained slides as reference to select areas with/without positive staining revealed a CTNNB1 exon 3 mutation restricted to the areas exhibiting both positive GS and CRP expression, whereas wild‐type CTNNB1 was found in areas showing only CRP staining. These two cases illustrate focal β‐catenin activation that can occur within IHCAs. Additional data are needed to determine if β‐catenin mutation is a secondary event in IHCA.     

Development and characterization of 21 polymorphic microsatellite markers for the barren-ground shrew, Sorex ugyunak (Mammalia: Sorcidae), through next-generation sequencing, and cross-species amplification in the masked shrew, S. cinereus

We used next generation shotgun sequencing to develop 21 novel microsatellite markers for the barren-ground shrew (Sorex ugyunak), which were polymorphic among individuals from northern Alaska. The loci displayed moderate allelic diversity (averaging 6.81 alleles per locus) and heterozygosity (averaging 70 %). Two loci deviated from Hardy–Weinberg equilibrium (HWE) due to heterozygote deficiency. While the population did not deviate from HWE overall, it showed significant linkage disequilibrium suggesting this population is not in mutation-drift equilibrium. Nineteen of 21 loci were polymorphic in masked shrews (S. cinereus) from interior Alaska and exhibited linkage equilibrium and HWE overall. All loci yielded sufficient variability for use in population studies.     

Major Neurological Disease and Occupational Exposure to Organic Solvents

Five patients are described who presented with major organicbrain disease affecting one or more of pyramidal and extrapyramidaltracts, cerebellum, and higher cortical functions. All had ahistory of 10 years or more of regular occupational exposureto solvents in confined spaces, three in painting inside shipsand the others in weapons maintenance and printing. All hadbeen regularly exposed to high air vapour peaks as well as toskin contamination. Four showed some evidence of improvementafter the exposure ceased. None was initially suspected of havinga toxic encephalopathy by the consultant to whom he was referred.The spectrum of neurological disease presented by these menmirrors closely that described in solvent abusers. All wereforced by illness to retire from their work, a circumstancewhich might have in the past have led to such conditions beingmissed in cross-sectional studies, which in general have notshown evidence of major disease. We suggest that when such diseaseoccurs nowadays, its cause is usually not suspected. Furtherepidemiological study of the problem is necessary.     

Hemoglobin Woodville: alpha (2)6(A4) aspartic acid----tyrosine

Hemoglobin Woodville was detected in a Vietnamese woman during antenatal and cord blood screening programs for families of South East Asian origin. The variant constitutes 9% of total hemoglobin and structural analysis demonstrated the substitution alpha 6 Asp----Tyr. Hematological data on the proposita were normal. No apparent clinical or pathological findings were associated with this abnormal hemoglobin.