Search

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F-isotopologue validated our liver-targeting approach.

Aim The aim of this study was to investigate the influences of menopause on brain morphological changes in schizophrenia using magnetic resonance imaging (MRI). Methods Forty female schizophrenia patients, 20 premenopausal and 20 postmenopausal, and 50 female controls underwent cerebral MRI. Optimized voxel-based morphometry was performed with Statistical Parametric Mapping version 5. Results Compared with controls, regional gray matter reductions in schizophrenia patients were observed in the insula, superior temporal gyrus, anterior cingulate, parahippocampal gyrus, and thalamus. Direct comparison between the patient groups showed that the gray matter of postmenopausal patients was significantly smaller when compared with premenopausal patients in the left middle frontal gyrus, and no region had significantly lower gray matter volume in premenopausal patients relative to postmenopausal patients. Significant negative correlation between gray matter volume and the interval after menopause was found in the right superior frontal gyrus in the postmenopause patient group. Conclusion Differential morphological alterations between postmenopausal and premenopausal schizophrenia patients were observed, suggesting that the female hormone plays a protective role against schizophrenia.

Aim: Somatoform pain disorder is characterized by persistent and chronic pain at one or more sites without an associated general medical condition and in which psychological factors are thought to play a role. This study aimed to investigate the pathological features of somatoform pain disorder localized to the oral region by single photon emission computed tomography (SPECT). Methods: Ten patients (nine females and one male; average age 55.0 ± 14.4 years) having somatoform pain disorder with oral symptoms participated. SPECT was performed using N-isopropyl-4-[123I] iodoamphetamine intravenous injections, and regional cerebral blood flow (rCBF) was assessed by three-dimensional stereotactic surface projections. We also selected 12 healthy individuals (seven females and five males; average age 61.8 ± 13.2 years) to act as controls. Results: Both the patient and control groups showed no atrophy or infarction on CT or magnetic resonance imaging. The patient group showed higher rCBF in the subcortical area, especially in the thalamus and cingulate gyri, than the control group. In contrast, the patient group showed lower rCBF in the bilateral frontal and occipital lobes as well as in the left temporal lobe. Conclusions: These results suggest that the biological process involved in somatoform pain disorder of the oral region is characterized by changes in limbic and cortical functions. The finding that somatoform pain disorder with oral symptoms is associated with brain functional changes will help to develop treatment regimes for this disorder and clarify the underlying pathology.