Safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121: An overview of phase I randomized trials in healthy volunteers.

Background: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available.

Aims: Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug-drug interactions.

Methods: Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males.

Tissue distribution of renadirsen sodium, a dystrophin exon-skipping antisense oligonucleotide, in heart and diaphragm after subcutaneous administration to cynomolgus monkeys.

The pharmacokinetics and tissue distribution of renadirsen sodium, a dystrophin exon-skipping phosphorothioate-modified antisense oligonucleotide with 2'-,4'--ethylene-bridged nucleic acid (ENA), after subcutaneous or intravenous administration to cynomolgus monkeys were investigated. The plasma concentration of renadirsen after subcutaneous administration at 1, 3, and 10 mg/kg increased with the dose. The absolute bioavailability at 3 mg/kg after subcutaneous administration was calculated as 88.

Downsloping TP Segment in the Precordial Leads on a Standard 12-lead Electrocardiogram: Suspected Cardiac Impulse-tapping Artifact.

We herein report an 80-year-old man showing a downsloping TP segment together with an increase in the height of the T wave in the precordial leads on a standard 12-lead electrocardiogram (ECG). Separately, an 87-year-old woman showed only a downsloping TP segment in the precordial leads on a standard 12-lead ECG. Neither patient reported chest pain or dyspnea when ECGs was obtained.

Pharmacokinetics of monoclonal antibodies locally-applied into the middle ear of guinea pigs.

Countless therapeutic antibodies are currently available for the treatment of a broad range of diseases. Some target molecules of therapeutic antibodies are involved in the pathogenesis of sensorineural hearing loss (SNHL), suggesting that SNHL may be a novel target for monoclonal antibody (mAb) therapy. When considering mAb therapy for SNHL, understanding of the pharmacokinetics of mAbs after local application into the middle ear is crucial.

Iatrogenic intramuscular hematoma of the oblique muscles as a complication of technetium-99m-labeled pyrophosphate imaging-based computed tomography-guided core-needle biopsy in a patient with wild-type transthyretin cardiac amyloidosis.

Technetium-99m-labeled pyrophosphate imaging-based computed tomography-guided core-needle biopsy of the internal oblique muscle with tracer uptake is a safe and sensitive extracardiac screening biopsy. It can provide histopathological confirmation of the deposition of amyloid transthyretin in patients with wild-type transthyretin cardiac amyloidosis. This case report presents the case of a 73-year-old man receiving triple anti-thrombotic therapy for atrial flutter and coronary stenting who underwent this biopsy to confirm the diagnosis of transthyretin cardiac amyloidosis.

A Gluteus Medius Muscle Biopsy to Confirm Amyloid Transthyretin Deposition in Wild-type Transthyretin Cardiac Amyloidosis: A Report of Two Cases.

In patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), the uptake of the tracer on technetium-99m-labeled pyrophosphate (Tc-PYP) scintigraphy, which indicates amyloid transthyretin (ATTR) per se, is often observed in skeletal muscles, such as the abdominal oblique and gluteal muscles. Among extracardiac biopsies for confirming ATTR deposition in ATTRwt-CA, a Tc-PYP imaging-based computed tomography (CT)-guided core needle biopsy of the internal oblique muscle has relatively high sensitivity. In some patients, the Tc-PYP uptake is more pronounced in the gluteal muscles than in oblique muscles.

Survey of medications for myelomeningocele patients over their lifetime in Japan.

Background: This study aimed to investigate medication prescriptions for patients with myelomeningocele (MMC) across different age groups, particularly in adulthood and after middle age.

Methods: The Japan Medical Data Center (JMDC) database, based on medical claims data, was utilized for this analysis. Patients were divided into 10-year age groups, and prescriptions for analgesics, anticonvulsants, psychotropic drugs, lifestyle disease-related drugs, drugs for urinary incontinence, and laxatives were examined.

Technetium-99m-pyrophosphate imaging-based computed tomography-guided core-needle biopsy of internal oblique muscle in wild-type transthyretin cardiac amyloidosis.

Background: Technetium-99m-pyrophosphate (Tc-PYP) uptake in the internal oblique muscle (IOM), which is often observed in patients with wild-type transthyretin cardiac amyloidosis (ATTR-CA), indicates amyloid transthyretin (ATTR) deposition.

Objective: This study aimed to assess the safety and efficacy of Tc-PYP imaging-based computed tomography (CT)-guided core-needle biopsy of the IOM as a new extracardiac screening biopsy for confirming the presence of ATTR deposits.

Methods: Patients with suspected ATTR-CA in whom myocardial tracer uptake was detected on chest- and abdomen-centered images of Tc-PYP scintigraphy underwent CT-guided core-needle biopsy at the site with the highest tracer uptake in the IOM between September 2021 and November 2022.

Big insulin-like growth factor 2-producing multiple solitary fibrous tumors treated with debulking surgery: A case report.

Background: Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome caused by a tumor-producing high molecular weight form of insulin-like growth factor 2 (IGF2) known as big IGF2. The only curative treatment for this condition is surgical resection of the responsible tumors. However, this may not be feasible in cases with multiple metastases at diagnosis of NICTH, and no standard treatment strategy for multiple tumors has been established.

Renal tubular transporter-mediated interactions between mirogabalin and cimetidine in rats.

Cimetidine at a clinical dosage decreased the renal clearance (CLr) of mirogabalin in humans by inhibition of renal secretion. Mirogabalin is a substrate of human OAT1/3, OCT2, MATE1 and/or MATE2-K. To clarify the mechanism behind the above interaction, it was investigated whether cimetidine inhibits the process of mirogabalin uptake at the basolateral side or the process of its efflux at the apical side in rat kidney .

99mTc-Pyrophosphate Scintigraphy Can Image Tracer Uptake in Skeletal Trunk Muscles of Transthyretin Cardiac Amyloidosis.

Purpose: 99mTc-pyrophosphate (99mTc-PYP) uptake in the skeletal muscles is minimal in patients with transthyretin cardiac amyloidosis (ATTR-CA) when assessed qualitatively and quantitatively. We previously demonstrated moderate- to high-grade 99mTc-PYP uptake in the subcutaneous abdominal fat of some patients with ATTR-CA and showed that this abnormal finding could reflect the regional amyloid burden of this tissue. We aimed to investigate the frequency of 99mTc-PYP uptake in skeletal trunk muscles of patients with ATTR-CA.

Detecting inattentiveness caused by mind-wandering during a driving task: A behavioral study.

This study aims to investigate whether behavioral variability and participants' self-ratings can be used to detect mind-wandering while driving and to examine their effects on braking performance during a driving task. We created a novel driving task and added a sustained attention response task (SART). We examined the effects of mind-wandering on braking performance and whether mind-wandering could be detected from SART response variability.

Mirogabalin, a novel αδ ligand, is not a substrate of LAT1, but of PEPT1, PEPT2, OAT1, OAT3, OCT2, MATE1 and MATE2-K.

Mirogabalin is a αδ ligand as well as pregabalin. The aim of this study was to clarify whether mirogabalin is a substrate of human LAT1, which involved in absorption and disposition of pregabalin, and to investigate transporters involved in renal secretion and absorption of mirogabalin using transporter-expressing cells and fresh human kidney slices.We employed uptake assay of [H]mirogabalin by HEK293T or HEK293 cells transiently overexpress human OAT1, OAT3, OCT2, LAT1/4F2hc, LAT2/4F2hc, PEPT1, and PEPT2 proteins.

Epigenome editing reveals core DNA methylation for imprinting control in the Dlk1-Dio3 imprinted domain.

The Dlk1-Dio3 imprinted domain is controlled by an imprinting control region (ICR) called IG-DMR that is hypomethylated on the maternal allele and hypermethylated on the paternal allele. Although several genetic mutation experiments have shown that IG-DMR is essential for imprinting control of the domain, how DNA methylation itself functions has not been elucidated. Here, we performed both gain and loss of DNA methylation experiments targeting IG-DMR by transiently introducing CRISPR/Cas9 based-targeted DNA methylation editing tools along with one guide RNA into mouse ES cells.

Pharmacokinetics and metabolism of mirogabalin, a novel αδ ligand, in rats and monkeys.

The purpose of this study was to investigate the pharmacokinetic behaviour of mirogabalin in rats and monkeys.Pharmacokinetic parameters of mirogabalin after its oral and intravenous administration were determined. Distribution study, mass balance study, and metabolite identification were also conducted after the oral administration of [C]mirogabalin.

[Changes in long-term care certification rate and related factors in municipalities affected by the heavy rain disaster in July 2018].

Objectives　The purpose of this study was to determine the change in the certification rate for long-term care (LTC) in the municipalities affected by the heavy rain disaster in July 2018, and to clarify the relationships between the change in the LTC certification rate and the damage situation and regional characteristics.Methods　The subjects were 108 municipalities to which the Disaster Relief Act was applied. Interrupted time series analyses were conducted of the monthly LTC certification rate for a total of 37 months from July 2016 to July 2019, and the changes in the LTC, mild LTC (requiring support 1 and 2), moderate LTC (requiring long-term care 1 to 3), and severe LTC (requiring long-term care 4 and 5) certification rates after the disaster were determined.

Amyloid deposit corresponds to technetium-99m-pyrophosphate accumulation in abdominal fat of patients with transthyretin cardiac amyloidosis.

Background: Radionuclide imaging using bone-avid tracers plays a critical role in diagnosing transthyretin cardiac amyloidosis (ATTR-CA), but technetium-99m-pyrophosphate (PYP) rarely allows the detection of extracardiac amyloid infiltration. We retrospectively investigated the frequency of PYP uptake in the subcutaneous abdominal fat of patients with ATTR-CA and its relevance to the results of fine-needle aspiration biopsy (FNAB) of this tissue.

Methods: Chest-centered images of PYP scintigraphy were obtained 2 h after the intravenous injection of the tracer (20 mCi), and the frequency of PYP uptake in the subcutaneous abdominal fat was evaluated.

CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective Na1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate.

Predicting human disproportionate metabolites is difficult, especially when drugs undergo species-specific metabolism mediated by cytochrome P450s (P450s) and/or non-P450 enzymes. This study assessed human metabolites of DS-1971a, a potent Na1.7-selective blocker, by performing human mass balance studies and characterizing DS-1971a metabolites, in accordance with the Metabolites in Safety Testing guidance.

Biomechanical Gain in Joint Excursion from the Curvature of the Achilles Tendon: Role of the Geometrical Arrangement of Inflection Point, Center of Rotation, and Calcaneus.

The dorsal movement of the Achilles tendon during ankle rotation is restricted by anatomical obstructions. Previously, we demonstrated that the anatomical obstruction provides a gain (gain) in the proximal displacement of the calcaneus compared to the change in the Achilles tendon length. Here, we empirically validate and extend our previous modeling study by investigating the effects of a broad range of obstruction locations on gain.