BackgroundCurrent methods for diagnosing primary aldosteronism (PA) are limited by their invasiveness and diagnostic accuracy. This study aimed to develop nuclear medicine imaging tracers targeting CYP11B2, which is overexpressed in patients with PA.ResultsWe successfully synthesized iodinated and fluoroethoxynated pyridinyldihydroquinolinone (PDHQ) derivatives, among which PDHQ-1 exhibited the highest selectivity for CYP11B2. Furthermore, [125I]PDHQ-1 accumulated in the adrenal gland soon after administration, reaching its highest saturation compared to that in other organs 5 min after administration; however, its radioactivity decreased over time. Autoradiographic analysis revealed that [125I]PDHQ-1 displayed a 4.4-fold higher accumulation in the CYP11B2 region of adrenal sections from human patients with aldosterone-producing adenomas than in the CYP11B1 region. In contrast, [125I]IMTO, which is a highly specific radiotracer for imaging adrenocortical tissue, displayed similar accumulation in the CYP11B2 and CYP11B1 regions.ConclusionsCollectively, our results suggest that [125I]PDHQ-1, featuring a pyridinyldihydroquinolinone scaffold, shows potential as an imaging tracer for PA.

The remnant stomach after distal gastrectomy (DG) which receives its blood supply mainly from the splenic artery (SPA), is at high risk for gastric ischemia following distal pancreatectomy (DP). We investigated the risk factors for ischemic necrosis of the remnant stomach (INS) during or after DP in DG patients. We collected 414 patients who underwent DP after DG between July 2009 and December 2019 by distributing questionnaires to members of the Japanese Society of Pancreatic Surgery (JSPS) in 2020, and the risk factors for INS were analyzed in 364 eligible patients. INS developed in 17 (4.7%) patients. A multivariate logistic regression analysis revealed that dissection of the left inferior phrenic artery (LIPA) during DP (odds ratio [OR] 51.9, p < 0.001), current DP for pancreatic cancer (OR 6.19, p = 0.017), and previous DG for gastric cancer (OR 6.12, p = 0.017) were independent risk factors for INS. Preservation of the LIPA is necessary to avoid INS when DP is performed in DG patients. Additionally, careful surgical management is required in patients undergoing DP for pancreatic cancer and who have undergone DG for gastric cancer because they are candidates for INS after DP.

To identify factors associated with prehospital intravenous access (IVA) in non-minor emergencies and compare the outcomes of emergency medical service (EMS)-witnessed out-of-hospital cardiac arrest (OHCA) occurring before and after IVA was established. IVA performance varied significantly among prefectures; high performance was associated with a high sensitivity of IVA for subsequent EMS-witnessed OHCA. Cases with a high likelihood of IVA before OHCA included lethal cases, those transported to tertiary emergency hospitals, and medical emergency cases. Among EMS-witnessed OHCA cases, the proportion of hospital transports outside the jurisdiction, physician presence in ambulances, and shockable initial rhythms were higher in patients who received IVA before OHCA than in those who received it afterward. Conversely, incidences of advanced airway management and adrenaline administration were lower. In a multivariate logistic regression model with an interaction test, the neurologically favourable 1-month survival rate was higher in patients who received IVA before OHCA than in those who received it afterward. The impact of IVA before OHCA was more pronounced in OHCA with presumed cardiac aetiology and was negated in cases where prehospital adrenaline was administered. Compared with IVA administered after EMS-witnessed OHCA, IVA performed before OHCA is likely associated with better outcomes.

The sigma-1 receptor (Sig-1R) plays diverse roles in regulating Endoplasmic Reticulum (ER) stress, calcium handling, and ion channel activity under pathological conditions, offering cardioprotective effects in pressure overload-induced dysfunction. However, its role in post-myocardial ischemia damage remains unclear. This study evaluated the cardioprotective effects of Sig-1R activation by fluvoxamine following myocardial ischemia in rats. Wistar rats underwent 20min of coronary artery occlusion followed by reperfusion. Rats received either saline (control) or fluvoxamine for two weeks. ECG-gated SPECT with 99mTc-MIBI was performed on days 1, 14, and 28 post-reperfusion to measure the end-diastolic volume (EDV), end-systolic volume (ESV), left ventricular ejection fraction (LVEF), and summed rest score (SRS). Autoradiography and histological analyses were performed on day 29. Fluvoxamine significantly improved LVEF after two weeks (D14-D1: 6 ± 7, p = 0.03), with the improvement persisting to the 28th day (8 ± 5, p < 0.01). Autoradiography revealed a smaller non-salvaged area (0.15 ± 0.19 vs. 0.42 ± 0.32, p < 0.05) and more salvaged myocardium (0.33 ± 0.13 vs. 0.14 ± 0.14, p < 0.05) in the fluvoxamine group. Histology showed less fibrosis (0.06 ± 0.05 vs. 0.11 ± 0.08, p < 0.05) and reduced macrophage infiltration (0.08 ± 0.05 vs. 0.16 ± 0.08, p < 0.001) with fluvoxamine. Sig-1R stimulation by fluvoxamine suppresses LV remodelling and enhances LVEF recovery post-ischemia, suggesting its potential as a novel cardioprotective strategy.

BackgroundThe patient characteristics and preoperative factors that affect the Knee Injury and Osteoarthritis Outcome Score (KOOS) quality of life (QOL) after total knee arthroplasty (TKA) remain unclear. Therefore, we aimed to determine patient characteristics and preoperative risk factors associated with the lack of the minimal clinically important difference (MCID) in the KOOS QOL subscales 1 year after TKA.MethodsThis single-center cohort study included 149 patients with knee osteoarthritis who underwent primary TKA using the subvastus approach. Patients were divided into two groups based on whether they achieved or failed to achieve the 1-year postoperative MCID in KOOS, in reference to the preoperative baseline score.ResultsFifty-four patients did not achieve the MCID in the KOOS QOL scales 1 year after TKA. Significant predictors included in univariate analysis included the preoperative prevalence period, knee flexion range of motion (ROM), and KOOS pain, activities of daily living (ADL), and function in sports and recreation (Sport/Rec). Multivariate logistic regression analysis identified knee flexion ROM as the most significant factor (odds ratio: 1.080; 95% confidence interval: 1.048–1.112; P = 0.001). According to the receiver operating characteristic curve, a preoperative knee flexion ROM of 120° was the threshold for predicting achieved MCID in the KOOS QOL 1 year postoperatively (sensitivity: 0.61; specificity: 0.86); the area under the curve was 0.81.ConclusionsPatients with longer preoperative prevalence periods and higher preoperative KOOS pain, ADL, and Sport/Rec scores were more likely not to achieve the MCID in the QOL. Furthermore, limited preoperative knee flexion ROM may affect the risk of not achieving the MCID.

Leucine-rich glioma-inactivated 1 protein (LGI1) is a secreted neuronal protein consisting of the N-terminal leucine-rich repeat (LRR) and C-terminal epitempin-repeat (EPTP) domains. LGI1 is linked to epilepsy, a neurological disorder that can be caused by genetic mutations of genes regulating neuronal excitability (e.g. voltage- or ligand-gated ion channels). ADAM22 is a membrane receptor that binds to LGI1 extracellularly and interacts with AMPA-type glutamate receptors via PSD-95 intracellularly to maintain normal synaptic signal transmission. Structural analysis of the LGI1–ADAM22 complex is important for understanding the molecular mechanism of epileptogenesis and developing new therapies against epilepsy. We previously reported the crystal structure of a 2:2 complex consisting of two molecules of LGI1 and two molecules of the ADAM22 ectodomain (ECD), which is suggested to bridge neurons across the synaptic cleft. On the other hand, multiangle light scattering, small-angle X-ray scattering, and cryo-electron microscopy (cryo-EM) analyses have suggested the existence of a 3:3 complex consisting of three molecules of LGI1 and three molecules of ADAM22. In the previous cryo-EM analysis, many observed particles were in a dissociated state, making it difficult to determine the three-dimensional (3D) structure of the 3:3 complex. In this study, we stabilized the 3:3 LGI1–ADAM22ECD complex using chemical cross-linking and determined the cryo-EM structures of the LGI1LRR–LGI1EPTP–ADAM22ECD and 3:3 LGI1–ADAM22ECD complexes at 2.78 Å and 3.79 Å resolutions, respectively. Furthermore, high-speed atomic force microscopy (HS-AFM) visualized the structural features and flexibility of the 3:3 LGI1–ADAM22ECD complex in solution. We discuss new insights into the interaction modes of the LGI1–ADAM22 higher-order complex and the structural properties of the 3:3 LGI1–ADAM22 complex.

Chemotherapeutic drugs induce DNA damage, including double-strand breaks (DSBs), interstrand cross-links (ICLs), and DNA-protein cross-links (DPCs), to inhibit cancer cell proliferation. Understanding the relative contributions of these damages is essential for optimizing therapeutic strategies. To achieve physiologically relevant conditions, we determined the LD20 for four classes of chemotherapeutic agents and treated HeLa cells accordingly. Topoisomerase inhibitors (CPT, ETO) primarily induced DSBs and DPCs, whereas platinum-based agents (CisPt, OXA) predominantly caused DPCs and ICLs. The DNMT inhibitor AzadC was strongly associated with DPC formation. Although both L-PAM and MMC are bifunctional alkylating agents, their cytotoxic mechanisms differed; L-PAM induced DSBs, DPCs, and ICLs, while MMC primarily caused ICLs. DPCs were consistently detected across all drug treatments except MMC, with a half-life of 4.7 to 8.4 h, suggesting their prolonged impact on cytotoxicity. To assess apoptosis induction, we performed Annexin-V assays, which revealed significant apoptotic responses in all treated cells. CPT exhibited the highest proportion of early apoptotic cells (~ 80%) at 24 h, with all drug treatments shifting from early to late apoptosis over time. By 48 h, late apoptotic fractions exceeded 60% in CPT-, ETO-, and AzadC-treated cells. These findings highlight the critical role of DPCs in chemotherapeutic cytotoxicity and suggest that targeting apoptotic pathways could enhance cancer treatment efficacy.

BackgroundThe heart-to-contralateral lung (H/CL) ratio, derived from planar imaging, is a standard quantitative metric in 99mTc-pyrophosphate (99mTc-PYP) studies. However, cardiac-dedicated cadmium-zinc-telluride cameras, which primarily generate single-photon emission computed tomography (SPECT) images, cannot produce planar images. We propose the myocardium-to-cavity (M/C) ratio, derived from simultaneous dual-isotope 99mTc-PYP/201Tl SPECT imaging, as an alternative quantitative measure. This study evaluates the clinical utility of the M/C ratio by comparing it to the H/CL ratio.Methods/resultsWe retrospectively analyzed 121 consecutive patients with suspected cardiac amyloidosis who underwent dual-isotope 99mTc-PYP/201Tl imaging. Anterior planar images were acquired using an Anger camera at 1 h after 99mTc-PYP injection. Dual-isotope D-SPECT 99mTc-PYP/201Tl images were acquired from 10 min after 201Tl injection at 1 and/or 3 h after 99mTc-PYP injection. For M/C ratio calculation, circular regions of interest of equal diameter were set on the myocardium and left ventricular cavity using 201Tl images, then superimposed on 99mTc-PYP images. The optimal cut-off values were 1.5 for H/CL and 1.0 for M/C ratios to distinguish 99mTc-PYP positive and negative uptake. Of 121 patients, 19 (16%) were classified as 99mTc-PYP positive with planar and SPECT imaging, following the stepwise diagnostic flow recommended by the Japanese Society of Nuclear Cardiology (adapted for D-SPECT). Both H/CL and M/C ratios were significantly higher in patients with 99mTc-PYP-positive than in negative cases. Notably, five false-positive cases with H/CL ratios > 1.5 had M/C ratio < 1.0, correctly distinguishing them from 99mTc-PYP-positive patients. The M/C ratio demonstrated 100% sensitivity, specificity, and predictive values, irrespective of imaging time. In contrast, the H/CL ratios showed 100% sensitivity, 95% specificity, 79% positive predictive value, and 100% negative predictive value. The inter- and intra-observer reproducibility of the M/C ratio was excellent with correlation coefficients exceeding 0.99. Additionally, 13 of the 19 (68%) 99mTc-PYP positive patients exhibited a mismatch pattern with decreased 201Tl uptake corresponding to high 99mTc-PYP uptake.ConclusionsThe M/C ratio demonstrated superior diagnostic accuracy compared to the H/CL ratio, particularly in eliminating false positive cases. Its simplicity and reproducibility make it a promising alternative for routine clinical practice, potentially replacing the H/CL ratio in dual-isotope imaging.