ABSTRACT
Viral hemorrhagic fevers caused by members of the order Bunyavirales comprise endemic and emerging human infections that are significant public health concerns. Despite the disease severity, there are few therapeutic options available, and therefore effective antiviral drugs are urgently needed to reduce disease burdens. Bunyaviruses, like influenza viruses (IFVs), possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We screened compounds from our CEN inhibitor (CENi) library and identified specific structural compounds that are 100 to 1,000 times more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. To investigate their inhibitory mechanism of action, drug-resistant viruses were selected in culture. Whole-genome sequencing revealed that amino acid substitutions in the CEN region of drug-resistant viruses were located in similar positions as those of the CEN α3-helix loop of IFVs derived under drug selection. Thus, our studies suggest that CENi compounds inhibit both bunyavirus and IFV replication in a mechanistically similar manner. Structural analysis revealed that the side chain of the carboxyl group at the seventh position of the main structure of the compound was essential for the high antiviral activity against bunyaviruses. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. These data suggest a potential broad-spectrum clinical utility of CENis for the treatment of both severe influenza and hemorrhagic diseases caused by bunyaviruses.
Subject(s)
Antiviral Agents , Endonucleases , Orthobunyavirus , Animals , Antiviral Agents/pharmacology , Drug Evaluation, Preclinical , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Endonucleases/antagonists & inhibitors , Humans , Mice , Orthobunyavirus/drug effects , Orthobunyavirus/genetics , Orthobunyavirus/metabolism , Virus Replication/drug effectsABSTRACT
Due to the manufacturability of highly well-defined structures and wide-range versatility in its microstructure, SiO2 is an attractive template for synthesizing graphene frameworks with the desired pore structure. However, its intrinsic inertness constrains the graphene formation via methane chemical vapor deposition. This work overcomes this challenge by successfully achieving uniform graphene coating on a trimethylsilyl-modified SiO2 (denote TMS-MPS). Remarkably, the onset temperature for graphene growth dropped to 720 °C for the TMS-MPS, as compared to the 885 °C of the pristine SiO2. This is found to be mainly from the Si radicals formed from the decomposition of the surface TMS groups. Both experimental and computational results suggest a strong catalytic effect of the Si radicals on the CH4 dissociation. The surface engineering of SiO2 templates facilitates the synthesis of high-quality graphene sheets. As a result, the graphene-coated SiO2 composite exhibits a high electrical conductivity of 0.25 S cm-1. Moreover, the removal of the TMP-MPS template has released a graphene framework that replicates the parental TMS-MPS template on both micro- and nano- scales. This study provides tremendous insights into graphene growth chemistries as well as establishes a promising methodology for synthesizing graphene-based materials with pre-designed microstructures and porosity.
ABSTRACT
In addition to the classical actions of hemodynamic regulation, natriuretic peptides (NPs) interact with various neurohumoral factors that are deeply involved in the pathophysiology of cardiovascular diseases. However, their effects on the hypothalamic-pituitary-adrenal (HPA) axis, which is activated under acute high-stress conditions in acute coronary syndrome (ACS), remain largely unknown. We investigated the impact of plasma B-type NP (BNP) on plasma adrenocorticotropic hormone (ACTH)-cortisol levels during the acute phase of ACS ischemic attacks. The study population included 436 consecutive patients with ACS for whom data were collected during emergency cardiac catheterization. Among them, biochemical data after acute-phase treatment were available in 320 cases, defined as the ACS-remission phase (ACS-rem). Multiple regression analyses revealed that plasma BNP levels were significantly negatively associated with plasma ACTH levels only during ACS attacks (P < 0.001), but not in ACS-rem, whereas plasma BNP levels were not significantly associated with plasma cortisol levels at any point. Accordingly, covariance structure analyses were performed to clarify the direct contribution of BNP to ACTH by excluding other confounding factors, confirming that BNP level was negatively correlated with ACTH level only during ACS attacks (ß = -0.152, P = 0.002), whereas BNP did not significantly affect ACTH in ACS-rem. In conclusion, despite the lack of a significant direct association with cortisol levels, BNP negatively regulated ACTH levels during the acute phase of an ACS attack in which the HPA axis ought to be activated. NP may alleviate the acute stress response induced by severe ischemic attacks in patients with ACS.NEW & NOTEWORTHY BNP negatively regulates ACTH during a severe ischemic attack of ACS in which hypothalamic-pituitary-adrenal axis ought to be activated, indicating an important role of natriuretic peptides as a mechanism of adaptation to acute critical stress conditions in humans.
Subject(s)
Acute Coronary Syndrome , Peptide Hormones , Humans , Adrenocorticotropic Hormone , Natriuretic Peptide, Brain , Hypothalamo-Hypophyseal System , Acute Coronary Syndrome/drug therapy , Hydrocortisone , Pituitary-Adrenal SystemABSTRACT
OBJECTIVES: This study evaluated the association between aortic valve calcification (AVC) and aortic stenosis (AS) by scoring the AVC to determine the threshold scores for significant AS on non-electrocardiographic (ECG)-gated computed tomography (CT). METHODS: We retrospectively analyzed the AVC scores of 5385 patients on non-contrast non-ECG-gated CT, who underwent transthoracic echocardiography (TTE) from March 1, 2013, to December 26, 2019, at our institution. Multivariable logistic regression models were used to identify potential risk factors for significant AS. The thresholds for significant AS were computed using receiver operator characteristic (ROC) curves, based on the AVC scores after propensity score matching. RESULTS: A significant association was found between AS and age (p < 0.001; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.06), female sex (p < 0.001; OR, 4.5; 95% CI, 2.75-7.36), bicuspid aortic valve (p < 0.001; OR, 23.2; 95% CI, 7.35-72.9), and AVC score (AVC score/100) (p < 0.001; OR, 1.82; 95% CI, 1.71-1.95). All sex-specific AVC thresholds for significant AS (moderate and over AS severity, moderate and over AS severity without discordance, discordant severe AS, and concordant severe AS) showed high sensitivity and specificity (AUC, 0.939-0.968; sensitivity, 84.6-96%; specificity, 84.2-97.1%). CONCLUSIONS: We determined the optimal AVC threshold scores for significant AS, which may aid in diagnosing significant asymptomatic AS on incidental detection of AVC through non-ECG-gated CT for non-cardiac indications. KEY POINTS: ⢠Increased frequency of non-electrocardiographic (ECG)-gated computed tomography (CT) for non-cardiac indications has led to the increased incidental identification of aortic valve calcification (AVC). ⢠It is important to identify patients with significant aortic stenosis (AS) who require additional echocardiographic assessment on incidental detection of AVC via non-ECG-gated CT. ⢠We determined the AVC thresholds with high sensitivity and specificity to identify significant AS on non-ECG-gated CT, which could lead to early diagnosis of asymptomatic significant AS and improved prognosis.
Subject(s)
Aortic Valve Stenosis , Aortic Valve , Male , Humans , Female , Aortic Valve/diagnostic imaging , Retrospective Studies , Multidetector Computed Tomography/methods , Aortic Valve Stenosis/diagnostic imaging , Severity of Illness IndexABSTRACT
Bunyaviruses, including the Lassa virus (LASV), are known to cause hemorrhagic fever and have a high fatality rate among hospitalized patients, as there are few effective treatments. We focused on the fact that bunyaviruses use cap-dependent endonuclease (CEN) for viral replication, which is similar to influenza viruses. This led us to screen carbamoyl pyridone bicycle (CAB) compounds, which compose a series of baloxavir acid (BXA) derivatives, against lymphocytic choriomeningitis virus (LCMV) and Junin virus (JUNV) among the bunyaviruses. This led to the discovery of 1c, which has potent anti-bunyaviral activities. In SAR studies, we found that a large lipophilic side chain is preferred for the 1-position of the CAB scaffold, similar to the influenza CEN inhibitor, and that a small alkyl group for the 3-position shows high activity. Moreover, the 7carboxyl group of the scaffold is essential for anti-bunyaviral activities, and the antiviral activity is reduced by conversion to various carboxylic acid bioisosteres. The SAR results are discussed using a binding model of 9d in the active center of the known LCMV CEN crystal structure. These compounds show promise as broad-spectrum anti-bunyavirus therapeutics, given their relatively favorable metabolic stability and PK profiles.
Subject(s)
Influenza, Human , Orthomyxoviridae , Humans , Structure-Activity Relationship , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Endonucleases/metabolismABSTRACT
Several studies have investigated the association between P2Y12 reaction unit (PRU) value and major adverse cardiovascular events (MACEs) in patients with ischemic heart disease, but there is no well-established consensus on the utility of PRU value. Furthermore, the optimal PRU cut-off value varied with studies. One reason may be that the endpoints and observation periods differed, depending on the study. This study aimed to investigate the optimal cut-off and predictive ability of the PRU value for predicting cardiovascular events, while considering different endpoints and observation periods. We surveyed a total of 338 patients receiving P2Y12 inhibitors and measured PRU during cardiac catheterization. Using time-dependent receiver operating characteristic analysis, we evaluated the cut-off and area under curve (AUC) of the PRU value for two MACEs (MACE â : composite of death, myocardial infarction, stent thrombosis, and cerebral infarction; MACE â¡: composite of MACE â and target vessel revascularization) at 6, 12, 24 and 36 months after cardiac catheterization. MACE â occurred in 18 cases and MACE â¡ in 32 cases. The PRU cut-off values at 6, 12, 24, and 36 months were 257, 238, 217, and 216, respectively, for MACE â and 250, 238, 209, and 204, respectively, for MACE â¡. The AUCs at 6, 12, 24, and 36 months were 0.753, 0.832, 0.718, and 0.717, respectively, for MACE â and 0.724, 0.722, 0.664, and 0.682, respectively, for MACE â¡. The optimal cut-off and predictive ability of PRU values for cardiovascular events varied depending on different endpoints and duration of the observation periods. A relatively high PRU value is effective for short-term event suppression, but a low value is required for long-term event suppression.
Subject(s)
Myocardial Infarction , Myocardial Ischemia , Humans , Platelet Aggregation Inhibitors/pharmacology , Blood Platelets , Prospective Studies , Myocardial Ischemia/complications , Myocardial Ischemia/diagnosis , Treatment OutcomeABSTRACT
OBJECTIVES: (1) To delineate whether cognitive flexibility and inhibitory ability are neurocognitive markers of passive suicidal ideation (PSI), an early stage of suicide risk in depression and (2) to determine whether PSI is associated with volumetric differences in regions of the prefrontal cortex (PFC) in middle-aged and older adults with depression. DESIGN: Cross-sectional study. SETTING: University medical school. PARTICIPANTS: Forty community-dwelling middle-aged and older adults with depression from a larger study of depression and anxiety (NIMH R01 MH091342-05 PI: O'Hara). MEASUREMENTS: Psychiatric measures were assessed for the presence of a DSM-5 depressive disorder and PSI. A neurocognitive battery assessed cognitive flexibility, inhibitory ability, as well as other neurocognitive domains. RESULTS: The PSI group (n = 18) performed significantly worse on cognitive flexibility and inhibitory ability, but not on other neurocognitive tasks, compared to the group without PSI (n = 22). The group with PSI had larger left mid-frontal gyri (MFG) than the no-PSI group. There was no association between cognitive flexibility/inhibitory ability and left MFG volume. CONCLUSIONS: Findings implicate a neurocognitive signature of PSI: poorer cognitive flexibility and poor inhibitory ability not better accounted for by other domains of cognitive dysfunction and not associated with volumetric differences in the left MFG. This suggests that there are two specific but independent risk factors of PSI in middle- and older-aged adults.
Subject(s)
Cognitive Dysfunction , Suicidal Ideation , Humans , Middle Aged , Aged , Adult , Depression/psychology , Cross-Sectional Studies , Cognition , Risk FactorsABSTRACT
BACKGROUND: The manual traditional anterior drawer test (ADT) is essential for deciding the treatment for chronic ankle instability, but it has been shown to have a comparatively low reproducibility and accuracy, especially in less experienced hands. To clarify the inter-examiner reproducibility, we compared the actual distance of anterior translation between junior and senior examiners in ADT. We also evaluated the diagnostic abilities of traditional ADT, and a novel modified ADT (supported ADT). METHODS: Thirty ankles were included in this study, and ankle instability was defined using stress radiography. All subjects underwent two methods of manual ADT by junior and senior examiners, and ankle instability was judged in a blinded fashion. The anterior drawer distance was calculated from the lengthening measured using a capacitance-type sensor device. RESULTS: The degree of anterior translation determined by the junior examiner was significantly lower than that determined by the senior examiner when traditional ADT was performed (3.3 vs. 4.5 mm, P = 0.016), but there was no significant difference in anterior translation between the two examiners when supported ADT was performed (4.6 vs. 4.1 mm, P = 0.168). The inter-examiner reliability of supported ADT was higher than that of traditional ADT. For the junior examiner, the diagnostic accuracy of supported ADT was higher than that of traditional ADT (sensitivity, 0.40 vs. 0.80; specificity, 0.75 vs. 0.80). CONCLUSION: Supported ADT may have the advantage of being a simple manual test of ankle instability with less error between examiners.
Subject(s)
Ankle , Joint Instability , Humans , Reproducibility of Results , Electric Capacitance , Hand , Joint Instability/diagnosisABSTRACT
BACKGROUND: Pulmonary vein (PV) stenosis after atrial fibrillation (AF) ablation is rare; however, it remains a serious complication. PV angioplasty is reportedly an effective therapy; however, a dedicated device for PV angioplasty has not been developed, and the detailed procedural methods remain undetermined. This study describes the symptoms, indications, treatment strategies, and long-term outcomes for PV stenosis after AF ablation.MethodsâandâResults: This study retrospectively analyzed 7 patients with PV stenosis after catheter ablation for AF and who had undergone PV angioplasty at our hospital during 2015-2021. PV stenosis occurred in the left superior (5 patients) and left inferior (2 patients) PV. Six patients had hemoptysis, chest pain, and dyspnea. Seven de novo lesions were treated using balloon angioplasty (BA) (3 patients), a bare metal stent (BMS) (3 patients), and a drug-coated balloon (DCB) (1 patient). The restenosis rate was 42.9% (n=3; 2 patients in the BA group and 1 patient in the DCB group). The repeat treatment rate was 28.6% (2 patients in the BA group). Stenting was performed as repeat treatment. One patient with subsequent repeat restenosis development underwent BA. Ten PV angioplasties were performed; there were no major complications. CONCLUSIONS: Regarding PV angioplasty after ablation therapy for AF, stenting showed superior long-term PV patency than BA alone; therefore, it should be considered as a standard first-line approach.
Subject(s)
Atrial Fibrillation , Catheter Ablation , Pulmonary Veins , Stenosis, Pulmonary Vein , Angioplasty/adverse effects , Angioplasty/methods , Atrial Fibrillation/diagnosis , Atrial Fibrillation/surgery , Catheter Ablation/adverse effects , Constriction, Pathologic/complications , Humans , Pulmonary Veins/surgery , Retrospective Studies , Stenosis, Pulmonary Vein/diagnostic imaging , Stenosis, Pulmonary Vein/etiology , Stenosis, Pulmonary Vein/therapy , Treatment OutcomeABSTRACT
In the transcatheter aortic valve implantation (TAVI) era, the indications for balloon aortic valvuloplasty (BAV) are increasing. Previously, the INOUE-BALLOON® (IB) was used only for antegrade BAV, but recently, it has also been used for retrograde BAV. However, the safety and feasibility of retrograde BAV using an IB are not fully understood. In this study, we investigated the safety and feasibility of retrograde BAV using an IB in elderly Japanese patients with severe aortic stenosis (AS). We compared 39 cases of retrograde BAV using an IB performed from June 2018 to September 2020 and 34 cases of antegrade BAV using an IB performed from August 2013 to May 2018. The total number of complications was lower in retrograde BAV than in antegrade BAV (p = 0.020). The procedure time was significantly shorter in retrograde BAV than in antegrade BAV (p < 0.001), and the maximum balloon size and number of balloon inflations were smaller in retrograde BAV than in antegrade BAV (p = 0.002 and p < 0.001, respectively). There was no significant difference in the degree of improvement in the aortic valve area or ejection fraction between retrograde and antegrade BAV. In conclusion, the present study showed the safety and feasibility of retrograde BAV using an IB in elderly Japanese patients with severe AS compared with antegrade BAV using an IB.
Subject(s)
Aortic Valve Stenosis , Balloon Valvuloplasty , Transcatheter Aortic Valve Replacement , Humans , Aged , Aortic Valve Stenosis/diagnosis , Aortic Valve Stenosis/surgery , Feasibility Studies , Balloon Valvuloplasty/adverse effects , Treatment Outcome , Aortic Valve/diagnostic imaging , Aortic Valve/surgery , Retrospective StudiesABSTRACT
BACKGROUND: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. OBJECTIVES: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. METHODS: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50â eqâ mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. RESULTS: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. CONCLUSIONS: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.
Subject(s)
Dibenzothiepins , Influenza A Virus, H1N1 Subtype , Influenza, Human , Animals , Antiviral Agents/therapeutic use , Dibenzothiepins/therapeutic use , Disease Models, Animal , Endonucleases , Humans , Influenza A Virus, H3N2 Subtype , Influenza, Human/drug therapy , Mice , Mice, Inbred BALB C , Morpholines/therapeutic use , Oxazines , Pyridones , TriazinesABSTRACT
BACKGROUND: In addition to various biological effects of natriuretic peptides (NP) on cardiovascular systems, we recently reported that NP raises intracellular temperature in cultured adipocytes. We herein examined the possible thermogenic action of NP in consideration of hemodynamic parameters and inflammatory reaction by proposing structural equation models. METHODS AND RESULTS: The study population consisted of 1985 consecutive patients who underwent cardiac catheterization. Covariance structure analyses were performed to clarify the direct contribution of plasma B-type NP (BNP) to body temperature (BT) by excluding other confounding factors. A hierarchical path model showed increase in BNP, increase in C-reactive protein and decrease in left ventricular ejection fraction were mutually associated. As expected, C-reactive protein was positively correlated with BT. Importantly, despite a negative correlation between BNP and left ventricular ejection fraction, a decrease in the left ventricular ejection fraction was associated with BT decrease, whereas elevation in BNP level was associated with BT increase independently of C-reactive protein level (Pâ¯=â¯.007). CONCLUSIONS: Patients with LV dysfunction tend to manifest a decrease in BT, whereas BNP elevation is associated with an increase in BT independently of inflammatory response. These findings suggest the adaptive heat-retaining property of NP (and/or NP-associated factors) when BT falls owing to unfavorable hemodynamic conditions in a state of impaired cardiac function.
Subject(s)
Cardiovascular Diseases , Heart Failure , Ventricular Dysfunction, Left , Biomarkers , Body Temperature , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Humans , Natriuretic Peptide, Brain , Stroke Volume , Temperature , Ventricular Function, LeftABSTRACT
BACKGROUND: The aim of this study was to clarify the clinical outcomes of patients with atrial functional mitral regurgitation (FMR) who underwent the MitraClip procedure compared with those with conventional FMR and sinus rhythm (SR).MethodsâandâResults:Of 303 patients with FMR who underwent the MitraClip procedure, 40 with "atrial-FMR" defined as FMR with permanent atrial fibrillation and normal left ventricular (LV) function/size and 115 with "sinus-FMR" defined as FMR with SR and LV dysfunction were reviewed. Transthoracic and 3D transesophageal echocardiography, and the cardiac complication rate (composite of all-cause death, heart failure admission, mitral valve (MV) surgery, and redo MitraClip procedure) during the 12-month follow-up were compared between the groups. After the MitraClip procedure, reductions in the mitral annular area and its anteroposterior dimension and in the leaflet closure area were observed in both groups. MV orifice area was smaller with greater transmitral pressure gradient (P<0.05) after the procedure in atrial-FMR patients than in those with sinus-FMR. The prevalence of residual MR was similar, but significant tricuspid regurgitation (TR) was more prevalent in the atrial-FMR group at follow-up. Cardiac complication rate was comparable between groups (20% vs. 25%, P=0.63). CONCLUSIONS: Reduction of MR occurred in atrial-FMR probably because of the increase in leaflet coaptation area. Significant TR was more common after the MitraClip procedure in patients with atrial-FMR than with sinus-FMR. However, mid-term outcomes were comparable between patients with atrial-FMR and sinus-FMR.
Subject(s)
Mitral Valve Insufficiency , Echocardiography, Three-Dimensional , Echocardiography, Transesophageal , Humans , Mitral Valve/diagnostic imaging , Mitral Valve/surgery , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/surgery , Treatment Outcome , Ventricular Function, LeftABSTRACT
This work describes a set of discovery research studies of an influenza cap-dependent endonuclease (CEN) inhibitor with a carbamoyl pyridone bicycle (CAB) scaffold. Using influenza CEN inhibitory activity, antiviral activity and pharmacokinetic (PK) parameters as indices, structure activity relationships (SAR) studies were performed at the N-1 and N-3 positions on the CAB scaffold, which is a unique template to bind two metals. The hydrophobic substituent at the N-1 position is extremely important for CEN inhibitory activity and antiviral activity, and dihydrodibenzothiepine is the most promising pharmacophore. The compound (S)-13i showed potent virus titer reduction over oseltamivir phosphate in an in vivo mouse model. The CAB compound described herein served as the lead compound of baloxavir marboxil with a tricyclic scaffold, which was approved in Japan and the USA in 2018.
Subject(s)
Antiviral Agents/pharmacology , Endonucleases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Orthomyxoviridae/drug effects , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Endonucleases/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Molecular Structure , Orthomyxoviridae/enzymology , Structure-Activity RelationshipABSTRACT
OBJECTIVES: The short form or s-allele variant of the serotonin transporter polymorphism (5-HTTLPR), as compared with the long-form or l-allele variant, has been associated with the presence of cognitive dysfunction, and particularly memory impairment in older adults. This body of cross-sectional work has culminated in the hypothesis that presence of the s-allele predicts greater memory decline in older adults. Yet, to date, there are no longitudinal studies that have investigated this issue. METHODS/DESIGN: Here, we examine 109 community-dwelling older adults (mean and SD of age = 70.7 ± 8.7 years) who underwent blood draw for genotyping, cognitive, and psychological testing at baseline, 12-, and 24-monthfollow-ups. RESULTS: Multilevel modeling found that s-allele carriers (ss or ls) performed worse than ll homozygotes at baseline on delayed verbal recall. Yet, s-allele carriers' memory performance was stable over the two-yearfollow-up period, while l-allele homozygotes experienced significant memory decline. l-allele homozygote status was associated with both increased cortisol and decreased memory over time, resulting in attenuated verbal memory performance differences compared to s-allele carriers with age. CONCLUSIONS: Overall, our findings do not support the hypothesis that presence of the 5-HTTLPRs-allele is a marker for memory decline in older adults. J Am Geriatr Soc 68:-, 2020.
Subject(s)
Hydrocortisone , Serotonin Plasma Membrane Transport Proteins , Aged , Alleles , Cross-Sectional Studies , Genotype , Humans , Serotonin Plasma Membrane Transport Proteins/geneticsABSTRACT
Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, nâ¯=â¯17; female, nâ¯=â¯25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11â¯years; female, 8â¯years). The slope of the left ventricular mass (LVM) increase was 3.02⯱â¯3.41â¯g/m2/year in males and 1.69⯱â¯2.73â¯g/m2/year in females. In a subgroup analysis, the slopes of males with and without LVH did not differ to a statistically significant extent; however, the slope in female patients without LVH was significantly smaller than that of female patients with LVH. We then compared our data to the natural historical data that have previously been reported. In comparison to the previously reported data, we found a significant reduction in the LVM changes (g/height2.7/year) of patients who received long-term ERT (male, 4.07⯱â¯1.03 to 1.25⯱â¯1.39; female, 2.31⯱â¯0.81 to 0.78⯱â¯1.23). Long-term ERT effectively prevents LVH in Fabry patients. This effect was also observed in the patients with LVH prior to the initiation of ERT.
Subject(s)
Enzyme Replacement Therapy , Fabry Disease/complications , Hypertrophy, Left Ventricular/therapy , alpha-Galactosidase/administration & dosage , Adult , Echocardiography , Fabry Disease/enzymology , Female , Humans , Hypertrophy, Left Ventricular/enzymology , Hypertrophy, Left Ventricular/etiology , Male , Prognosis , Retrospective Studies , alpha-Galactosidase/metabolismABSTRACT
Cell models to investigate intestinal absorption functions, such as those of transporters and metabolic enzymes, are essential for oral drug discovery and development. The purpose of this study was to generate intestinal epithelial cells from human induced pluripotent stem cells (hiPSC-IECs) and then clarify whether the functions of hydrolase and transporters in them reflect oral drug absorption in the small intestine. The hiPSC-IECs showed the transport activities of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and peptide transporter 1 (PEPT1), revealed by using their probe substrates ([3H]digoxin, sulfasalazine, and [14C]glycylsarcosine), and the metabolic activities of CYP3A4, CES2, and CES1, which were clarified using their probe substrates (midazolam, irinotecan, and temocapril). The intrinsic clearance by hydrolysis of six ester prodrugs into the active form in hiPSC-IECs was correlated with the plasma exposure (Cmax , AUC, and bioavailability) of the active form after oral administration of these prodrugs to rats. Also, the permeability coefficients of 14 drugs, containing two substrates of P-gp (doxorubicin and [3H]digoxin), one substrate of BCRP (sulfasalazine), and 11 nonsubstrates of transporters (ganciclovir, [14C]mannitol, famotidine, sulpiride, atenolol, furosemide, ranitidine, hydrochlorothiazide, acetaminophen, propranolol, and antipyrine) in hiPSC-IECs were correlated with their values of the fraction of intestinal absorption (Fa) in human clinical studies. These findings suggest that hiPSC-IECs would be a useful cell model to investigate the hydrolysis of ester prodrugs and to predict drug absorption in the small intestine.
Subject(s)
Cell Differentiation/physiology , Epithelial Cells/metabolism , Induced Pluripotent Stem Cells/physiology , Intestinal Absorption/physiology , Intestine, Small/metabolism , Pharmaceutical Preparations/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Administration, Oral , Animals , Biological Availability , Caco-2 Cells , Cell Line, Tumor , Cells, Cultured , Humans , Hydrolysis , Induced Pluripotent Stem Cells/metabolism , Intestine, Small/physiology , Male , Membrane Transport Proteins/metabolism , Permeability , Pharmaceutical Preparations/administration & dosage , Prodrugs/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
OBJECTIVE: To examine the relationship between subclinical anxiety and depressive symptoms and objective sleep architecture measures and subjective sleep reports in older adults. METHODS: Community-dwelling older adults (N = 167) self-rated their current severity of anxiety symptoms, depressive symptoms, daytime sleepiness, and global sleep quality. Participants received overnight ambulatory polysomnography to assess sleep architecture. Multivariate linear regression models examined associations between anxiety and depressive symptoms and objective and subjective sleep measures. RESULTS: Significant findings emerged for subjective sleep, with higher depression and anxiety scores associated with worse global sleep quality and greater anxiety scores associated with greater daytime sleepiness. No significant associations were observed between subclinical levels of anxiety or depressive symptoms with sleep architecture. CONCLUSION: Subclinical levels of late-life anxiety and depression have distinct associations with subjective sleep disturbance. Findings implicate subjective measures of sleep quality and daytime sleepiness as stronger trait markers for subthreshold psychiatric symptoms than objective sleep biomarkers.
Subject(s)
Anxiety/epidemiology , Depression/epidemiology , Prodromal Symptoms , Sleep Wake Disorders/epidemiology , Aged , Aged, 80 and over , California/epidemiology , Comorbidity , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Monitoring, Ambulatory , Polysomnography , Self ReportABSTRACT
We report the discovery of a novel series of influenza Cap-dependent EndoNuclease (CEN) inhibitors based on the 4-pyridone-carboxylic acid (PYXA) scaffold, which were found from our chelate library. Our SAR research revealed the lipophilic domain to be the key to CEN inhibition. In particular, the position between the chelate and the lipophilic domain in the derivatives was essential for enhancing the potency. Our study, based on virtual modeling, led to the identification of 2y as a potent CEN inhibitor with an IC50 of 5.12nM.