Positron emission tomography assessments of phosphodiesterase 10A in patients with schizophrenia

[Background and hypothesis] Phosphodiesterase 10A (PDE10A) is a highly expressed enzyme in the basal ganglia, where cortical glutamatergic and midbrain dopaminergic inputs are integrated. Therapeutic PDE10A inhibition effects on schizophrenia have been reported previously, but the status of this molecule in the living patients with schizophrenia remains elusive. Therefore, this study aimed to investigate the central PDE10A status in patients with schizophrenia and examine its relationship with psychopathology, cognition, and corticostriatal glutamate levels. [Study design] This study included 27 patients with schizophrenia, with 5 antipsychotic-free cases, and 27 healthy controls. Positron emission tomography with [18F]MNI-659, a specific PDE10A radioligand, was employed to quantify PDE10A availability by measuring non-displaceable binding potential (BPND) of the ligand in the limbic, executive, and sensorimotor striatal functional subregions, and in the pallidum. BPND estimates were compared between patients and controls while controlling for age and gender. BPND correlations were examined with behavioral and clinical measures, along with regional glutamate levels quantified by the magnetic resonance spectroscopy. [Study results] Multivariate analysis of covariance demonstrated a significant main effect of diagnosis on BPND (p = .03). A posthoc test showed a trend-level higher sensorimotor striatal BPND in patients, although it did not survive multiple comparison corrections. BPND in controls in this subregion was significantly and negatively correlated with the Tower of London scores, a cognitive subtest. Striatal or dorsolateral prefrontal glutamate levels did not correlate significantly with BPND in either group. [Conclusions] The results suggest altered striatal PDE10A availability and associated local neural dysfunctions in patients with schizophrenia

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Primary adenosquamous carcinoma of the maxillary sinus: A unique example showing diverse morphology and differentiation

Adenosquamous carcinoma of the sinonasal tract is extremely rare. We report a case of such tumor in a 66-year-old Japanese male who presented with a 3.0-cm tumor in the maxillary sinus. The tumor mass filled the maxillary sinus, and part of the maxillary sinus floor was destroyed. Histological analysis showed that tumor cells with a marked atypia and pleomorphism with a high nuclear-cytoplasm ratio infiltrated beneath the mucosa. The tumor formed invasive nests and cribriform structures, and these structures were partially accompanied by marked necrosis. Additionally, tendency toward keratinization and peripheral palisading were present in the nests, and neoplastic cells showed varying cellular morphology including clear cells, where immunohistochemically positive staining for p63, p40 and CK5/6 was observed. While, immunoreactivity for these markers was absent in some of cribriform structures and solid nests, as well as areas showing fine nesting and cells surrounding glandular lumina. p16 was negative throughout the tumor, while p53 positive staining was detected throughout the tumor. CDX2 expression was observed in some solid nests. The tumor could be termed adenosquamous carcinoma, and also simultaneously considered to be essentially an adenocarcinoma derived from the ciliated epithelium of the maxillary sinus mucosa gradually increasing nuclear atypia with partial squamous metaplasia. The morphological transition was more clearly recognized in the p53 immunostaining. The patient died of disease two years after the primary surgery. This tumor is considered a histological type that can be fatal, and clinical attention is especially required when such a tumor encountered

Symptom changes in patients with pre-existing psychiatric disorders in the initial phase of the COVID-19 pandemic: Vulnerability of female patients and patients with mood disorders

How patients with pre-existing psychiatric disorders are responding to the COVID-19 pandemic remains unclear, and no comprehensive studies have yet been performed. To elucidate (1) which psychiatric disorders were exacerbated during the initial phase of the COVID-19 pandemic and (2) the contributing factors, we prospectively assessed psychiatric symptoms of 1592 psychiatric outpatients in a single-center study using the Global Assessment of Functioning (GAF) before the state of emergency was declared in Japan and during two months under the state of emergency (study period: April 8 to June 7, 2020). We conducted a chi-squared test for the relationship between psychiatric diagnostic category (ICD-10) and exacerbation. To control for confounders, we conducted a logistic regression analysis using sex, age, diagnostic category, and pre-pandemic GAF score as independent variables. Exacerbation rates of patients with mood disorders (F3) and neurotic disorders (F4) were 4.32% and 5.37%, respectively, and were significantly higher than those for patients with organic disorders (F0) and schizophrenic disorders (F2) (X2 (9, N = 1592) = 27.8, p < .01). Logistic regression analysis revealed that patients with F3 and female patients were significantly more affected than patients with other disorders or male patients, respectively (odds ratio (95% confidence interval) = 2.4 (1.2–4.6), p < .01 for F3; 3.1 (1.5–6.6), p < .01 for females). These findings suggest a need for careful management of patients with mood disorders and female psychiatric patients during a pandemic

Relationship between Regional Gray Matter Volumes and Dopamine D2 Receptor and Transporter in Living Human Brains

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders.Here, we aimed to investigate associations of striatal dopamine transporter(DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthyhumans. Positron emission tomography images of D2 receptor (n = 34) and DAT(n = 17) captured with the specific radioligands [11C]raclopride and [18F]FE-PE2I, respectively, were acquired along with T1-weighted magnetic resonance imaging data in our previous studies, and were re-analyzed in this work. We quantified the binding potentials (BPND) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BPND and regional GM volume were then examined by voxel-based morphometry. In line with the functional and anatomical connectivity, [11C]raclopride BPND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BPND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BPND in the sensorimotorstriatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18F]FE-PE2I BPND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT