Parahydrogen‐induced polarization of carboxylic acids: a pilot study of valproic acid and related structures

Parahydrogen‐induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non‐Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. ¹³C), thus improving the signal‐to‐noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the ¹H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized ¹³C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP‐based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. Copyright © 2014 John Wiley & Sons, Ltd.     

Review of biologics in allergic contact dermatitis

The resistant and recalcitrant nature of severe allergic contact dermatitis (ACD) makes its management challenging. With advances in the understanding of the cellular and molecular pathogenesis of ACD, newer therapeutic targets are becoming apparent. In particular, the use of biologics has gained momentum, given the specificity of their action. This article aims to review the presently available data on the use of biologics in ACD. English-language–based literature available on the use of biological therapy was thoroughly probed in the following databases as on October 14, 2019: PubMed, Google Scholar, The Cochrane library, Embase, Scopus, and EBSCO. The following keywords were used: “contact dermatitis”, “allergens”, “delayed-type hypersensitivity reaction”, “biologics”, “biological therapy”, “monoclonal antibodies”, “patch testing”, “TNF-α inhibitors”, “infliximab”, “adalimumab”, “etanercept”, “dupilumab”, “omalizumab”, “secukinumab”, “ustekinumab”, “rituximab”.     

Genotype-phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non-missense, including 20 stop-gain, 11 affecting splicing, five large deletions, four in-frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non-missense, and 17 for two non-missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty-five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non-missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non-missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.     

Early detection of schizophrenia

An initial prodromal condition was shown for about 75% of first-episode psychosis patients, lasting five years on average, possessing pathological significance and leading to psychosocial disruptions. Whereas most symptoms of the initial prodromal condition appear to be rather un-specific and hard to distinguish from other psychiatric conditions especially depressive ones, some syndromes seem to enable an early detection and thus an indicated prevention. These are constituted by attenuated and/or transient psychotic symptoms on the one hand and certain cognitive-perceptive basic symptoms on the other. Whereas the former are thought to delineate an advanced prodromal state, the latter can occur early in course and even at the beginning of the transition sequence to first-rank symptoms. This review will outline the current state of the art of a phase specific early detection and intervention based on these syndromes.