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In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.

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Hepatic metabolic stability is a key pharmacokinetic parameter in drug discovery. Metabolic stability is usually assessed in microsomal fractions and only the best compounds progress in the drug discovery process. A high-throughput single time point substrate depletion assay in rat liver microsomes (RLM) is employed at the National Center for Advancing Translational Sciences. Between 2012 and 2020, RLM stability data was generated for ~ 24,000 compounds from more than 250 projects that cover a wide range of pharmacological targets and cellular pathways. Although a crucial endpoint, little or no data exists in the public domain. In this study, computational models were developed for predicting RLM stability using different machine learning methods. In addition, a retrospective time-split validation was performed, and local models were built for projects that performed poorly with global models. Further analysis revealed inherent medicinal chemistry knowledge potentially useful to chemists in the pursuit of synthesizing metabolically stable compounds. In addition, we deposited experimental data for ~ 2500 compounds in the PubChem bioassay database (AID: 1508591). The global prediction models are made publicly accessible (https://opendata.ncats.nih.gov/adme). This is to the best of our knowledge, the first publicly available RLM prediction model built using high-quality data generated at a single laboratory.

Fractionated stereotactic radiotherapy (FSR) for acoustic neuromas offers both higher tumor dose and potential sparing of the facial and auditory cranial nerve functions. Eighty consecutive patients (45 males and 35 females; age 56.8 ± 1.7 years) received FSR for acoustic neuromas and had a median follow-up of 2.9 years (range 2.3–6.5 years). For FSR, 70 patients had 5 daily fractions of 5 Gy (25 Gy total) and 10 patients had 10 daily fractions of 3 Gy (30 Gy total). Volume decreased by an average of 18%. No tumor increased in size, no patient developed facial weakness, and hearing was preserved.

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delta 1-Pyrroline-5-carboxylic acid, an intermediate in the interconversions of proline, ornithine, and glutamate, is a potent stimulator of glucose oxidation through the hexosemonophosphate-pentose pathway. The effect is observed in cultured human fibroblasts, Chinese hamster ovary cells (CHO-K1), and rabbit kidney cells (LLC-RK1). In human fibroblasts, the magnitude of the stimulation of the hexosemonophosphate-pentose pathway is dependent on the concentration of added pyrroline-5-carboxylate and the effect is observed over a wide range of glucose concentrations. The mechanism of the effect is related to the generation of oxidizing potential in the form of NADP+ by pyrroline-5-carboxylate reductase concomitant with the conversion of pyrroline-5-carboxylate to proline. In LLC-RK1 cells, a cell line unique in having proline oxidase activity, proline also stimulated hexosemonophosphate-pentose pathway activity. Although pyrroline-5-carboxylate markedly stimulated the hexosemonophosphate-pentose pathway, it has no effect on glucose metabolism in the Embden-Meyerhof pathway or the tricarboxylic acid cycle. Since the hexosemonophosphate-pentose pathway is a source of ribose-5-phosphate, the precursor of phosphoribosyl pyrophosphate, the effect of pyrroline-5-carboxylate on the hexosemonophosphate-pentose pathway may link amino acid and nucleic acid metabolism.

Background The presence of frailty or prefrailty in older adults is a risk factor for postsurgical complications. The frailty phenotype can be improved through long-term resistance and aerobic training. It is unknown whether short-term preoperative interventions targeting frailty will help to mitigate surgical risk. The purpose of this study was to determine the proportion of frail and prefrail patients presenting to a thoracic surgical clinic who could benefit from a frailty reduction intervention. Methods A prospective cohort study was performed at a single-site thoracic surgical clinic. Starting October 1, 2014, surgical candidates 60 years of age or older who consented to be screened were included. Patients were screened using an adapted version of Fried’s phenotypic frailty criteria: weakness (grip strength), slow gait (15-foot walk), unintentional weight loss, self-reported exhaustion, and low self-reported physical activity (Physical Activity Scale for the Elderly). Prefrailty was identified when participants demonstrated one to two frailty characteristics; frailty was identified when participants demonstrated three to five frailty characteristics. Results Of 180 eligible patients, 126 consented, and 125 completed screening. Thirty-nine participants (31%) were not frail, 71 (57%) were prefrail, and 15 (12%) were frail. Exhaustion was the most common frailty symptom (34%). Frailty prevalence did not significantly differ among men and women (men: 10%, women: 14%; p = 0.75). Conclusions We found a high proportion of prefrail and frail patients among patients deemed candidates for thoracic surgical procedures. This finding indicates that frailty may be underrecognized. Substantial numbers of patients may be considered for a presurgical frailty reduction intervention.