Immunogenicity of SARS-CoV-2 vaccination in adolescents with cardiac disease.

BACKGROUND: Although widely reported to affect older adults more, coronavirus disease 2019 (COVID-19) also affects adolescents, especially those with co-morbidities, including heart diseases. The safety and efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines has been established in healthy adolescents, yet there are few data for humoral and cellular immunogenicity in adolescents with cardiac diseases. METHODS: We evaluated anti-spike antibodies, neutralizing activities, and interferon-gamma production prior to and after SARS-CoV-2 vaccination in adolescents with cardiac diseases and healthy controls. RESULTS: Five healthy adolescents and 26 patients with cardiac diseases, including congenital heart disease (CHD, n = 10), dilated cardiomyopathy (DCM, n = 4), idiopathic pulmonary arterial hypertension (IPAH, n = 4), and those post-heart transplantation (post-HTx, n = 8) were enrolled. No severe adverse events, including myocarditis and pericarditis, were noted, even in patients with severe heart failure. Febrile events were noted after 21 of 62 injections (34%). All the healthy adolescents and 21 of the 26 patients (81%) showed sufficient elevation of neutralizing antibodies after the second dose of vaccination. Neutralizing antibodies and cellular immunity were absent in four of the eight post-HTx patients and one with single ventricle CHD. There was no correlation between the anti-spike and neutralizing antibody titers and interferon-gamma levels. When comparing the clinical characteristics of the patients post-HTx who did or did not acquire antibodies, there was no significant difference in the immunosuppressant types and trough levels. CONCLUSIONS: SARS-CoV-2 mRNA vaccine has efficient immunogenicity for adolescents with CHD, IPAH, and DCM. Half of post-HTx patients could not acquire sufficient humoral immunity.

Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease.

PURPOSE: Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated. METHODS: CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated. RESULTS: When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered. CONCLUSION: Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

Identification of Adenovirus-Derived Cell-Penetrating Peptide.

Cell-penetrating peptides (CPPs) have been highly anticipated as an efficient delivery system due to their ability to cross biological membranes and transport various cargoes into cells. In the present study, we have identified adenovirus-derived CPPs using various capsid-mutant adenovirus (Ad) vectors. First, we examined the endocytosis-inducing ability of these vectors. A fiber-shaft substituted Ad vector, Ad type 5 vector with the fiber shaft domain replaced by that derived from Ad type 35, induced the highest fluorescein isothiocyanate (FITC)-dextran uptake into a human liver cell line, HepG2 cells. In contrast, the FITC-dextran uptake in HepG2 cells was not significantly different between coxsackievirus and adenovirus receptor (CAR)-binding-ablated Ad vector, integrin-binding-ablated Ad vector or conventional Ad vector. Next, we produced a recombinant Ad type 35 shaft protein using the Escherichia coli recombinant system. The recombinant Ad type 35 shaft protein retained the ability for FITC-dextran uptake and efficient gene delivery by plasmid transfection reagent. Furthermore, we identified 26 C-terminal amino acids in the Ad type 35 shaft protein as the cell membrane binding domain. The 26 amino-acid peptides also have the potential to be internalized into cultured cells. The internalization ability of the peptide was dependent on degree and was inhibited by an actin polymerization inhibitor (Latrunculin B) and by a lipid raft formation inhibitor (methyl-ß-cyclodextrin). The results of the present study indicate that Ad type 35-derived peptides induce endocytosis in cultured cells and have the ability to cross biological membranes. This report is the first paper to identify Ad-derived CPPs.

Seroevidence for a High Prevalence of Subclinical Infection With Avian Influenza A(H5N1) Virus Among Workers in a Live-Poultry Market in Indonesia.

BACKGROUND: In Indonesia, highly pathogenic avian influenza A(H5N1) virus has become endemic in poultry and has caused sporadic deadly infections in human. Since 2012, we have conducted fixed-point surveillance of avian influenza viruses at a live-poultry market in East Java, Indonesia. In this study, we examined the seroprevalence of avian influenza A(H5N1) virus infection among market workers. METHODS: Sera were collected from 101 workers in early 2014 and examined for antibody activity against avian A(H5N1) Eurasian lineage virus by a hemagglutination-inhibition (HI) assay. RESULTS: By the HI assay, 84% of the sera tested positive for antibody activity against the avian virus. Further analysis revealed that the average HI titer in 2014 was 2.9-fold higher than in 2012 and that seroconversion occurred in 44% of paired sera (11 of 25) between 2012 and 2014. A medical history survey was performed in 2016; responses to questionnaires indicated that none of workers had had severe acute respiratory illness during 2013. CONCLUSIONS: This study provides evidence of a high prevalence of avian A(H5N1) virus infection in 2013 among workers at a live-poultry market. However, because no instances of hospitalizations were reported, we can conclude the virus did not manifest any clinical symptoms in workers.

Comprehensive analysis of serum cytokines/chemokines in febrile children with primary human herpes virus-6B infection.

Cytokines and chemokines induced by primary human herpes virus (HHV)-6B infection may play a critical role in the clinical manifestations of infection. In this study, we analyzed 40 cytokines/chemokines in febrile children with primary HHV-6B infection. Blood samples from 233 febrile and 36 afebrile patients 0-3 years of age were used for this study. In febrile patients, primary HHV-6B infection was determined by detection of HHV-6B DNA without anti-HHV-6 immunoglobulin G in the blood (HHV-6B group). Infection by other pathogens was assumed when HHV-6B DNA was not detected in the blood (non-HHV-6B group). Of the 233 febrile patients, 30 patients (13%) were diagnosed with primary HHV-6B infection. To analyze serum cytokines/chemokines, patients were randomly chosen from the HHV-6B (n = 25) and non-HHV-6B groups (n = 8). Sera from 25 afebrile patients were used as a control. When comparing the levels of 40 cytokines/chemokines between the HHV-6B and control groups, we found that four chemokines (chemokine [C-X-C motif] ligand [CXCL] 11, CXCL10, CXCL16, and chemokine [C-C motif] ligand [CCL] 2) were significantly upregulated in the HHV-6B group compared with those in the control. Of these, only CXCL11 levels were significantly higher in the HHV-6B group than in the non-HHV-6B group. Because the induction of CCL2 was already reported in an early study, we found, for the first time, the induction of three new chemokines, i.e., CXCL11, CXCL10, and CXCL16 in patients with primary HHV-6B infection. Importantly, we demonstrated that serum CXCL11 levels increased specifically in patients with HHV-6B infection.

Efficient Adenovirus Gene Transfer Methods in Human Colonic Caco-2 Epithelial Cells Using Capric Acid.

Adenovirus (Ad) vectors are widely used in gene therapy and in vitro/in vivo gene transfer. However, Ad-mediated gene transfer in epithelial cells shows low efficiency, because Ad fiber cannot bind to the primary receptor, the coxsackievirus and adenovirus receptor (CAR), present in tight junctions. Caco-2 monolayer cells cultured on Transwell-chamber plates for approximately 2 weeks are widely used for drug membrane permeation studies, but Ad-mediated gene transfer is difficult in Caco-2 monolayer cells. First, we examined the efficiency of gene transfer into Caco-2 monolayer cells. Luciferase production in cultured Caco-2 cells transduced with Ad vectors was 20-fold lower on day 12 than on day 1. In contrast, the expression of CAR protein in Caco-2 cells gradually increased along with the duration of culture. For efficient gene transfer into Caco-2 monolayer cells, the binding ability of Ad vectors with CAR was found to be important. Capric acid (C10), a medium-chain fatty acid is a tight-junction modulator used as a pharmaceutical agent. We found that a novel gene transfer method using transduction with Ad vectors in the presence of C10 led more efficiently to LacZ expression in Caco-2 monolayer cells than Ad vectors alone. The results of the present study indicate that C10 could be very useful for Ad-mediated gene transfer in human colonic Caco-2 epithelial cells.

Physiologically based pharmacokinetic model analysis of the inhibitory effect of vonoprazan on the metabolic activation of proguanil.

We previously reported that repeated oral administration of vonoprazan (VPZ) followed by oral administration of proguanil (PG) in healthy adults increased blood concentration of PG and decreased blood concentration of its metabolite cycloguanil (CG) compared with administration of PG alone. In this study, we investigated whether this interaction can be quantitatively explained by VPZ inhibition of PG metabolism. In an in vitro study using human liver microsomes, VPZ inhibited CG formation from PG in a concentration-dependent manner, and the inhibition was enhanced depending on preincubation time. Then, a physiologically based pharmacokinetic (PBPK) model analysis was performed incorporating the obtained inhibition parameters. By fitting the blood concentration profiles of VPZ and PG/CG after VPZ and PG were orally administered alone to our PBPK model, parameters were obtained which can reproduce their concentration profiles. In contrast, when the VPZ inhibition parameters for CG formation from the in vitro study were incorporated, the predicted blood PG and CG concentrations were unchanged; the apparent dissociation constant had to be set to about 1/23 of the obtained in vitro value to reproduce the observed interaction. Further comprehensive evaluation is required, including the possibility that mechanisms other than metabolic inhibition may be involved.

Nosocomial outbreak of multidrug-resistant Pseudomonas aeruginosa caused by damaged transesophageal echocardiogram probe used in cardiovascular surgical operations.

Multidrug-resistant Pseudomonas aeruginosa (MDRP) is a major problem among hospital-acquired infections. We had a one-month outbreak of this strain at a university hospital in Osaka, Japan, from May to June 2004. To determine the cause of the outbreak, we collected and analyzed epidemiological information about the patients from whom MDRP was isolated, and performed microbiological investigations. MDRP was detected in respiratory specimens from eight patients in the intensive care unit. One of these patients developed severe lethal pneumonia accompanied by septicemia, and two contracted less severe non-lethal pneumonia. All the MDRP patients had been monitored with a contaminated transesophageal echocardiography (TOE) probe during their cardiac surgery. The TOE probe proved to have a defect 5 mm in diameter at the surface near the transducer, and the MDRP strain was traced to this defect. Pulsed-field gel electrophoresis showed that the strain isolated from the patients and from the TOE probe were genetically indistinguishable. After use of the damaged TOE probe was terminated, MDRP was not isolated from any patients who underwent cardiac surgery in the subsequent 8 years. In conclusion, TOE is routinely used during cardiac surgery and has been shown to have a significant clinical effect. Prevention of similar post-operative pneumonia outbreaks will require thorough infection control of TOE probes used for monitoring during cardiovascular surgery.

Adenovirus vector-mediated assay system for hepatitis C virus replication.

The efficient delivery of the hepatitis C virus (HCV) RNA subgenomic replicon into cells is useful for basic and pharmaceutical studies. The adenovirus (Ad) vector is a convenient and efficient tool for the transduction of foreign genes into cells in vitro and in vivo. However, an Ad vector expressing the HCV replicon has never been developed. In the present study, we developed Ad vector containing an RNA polymerase (pol) I-dependent expression cassette and a tetracycline-controllable RNA pol I-dependent expression system. We prepared a hybrid promoter from the tetracycline-responsive element and the RNA pol I promoter. Ad vector particles coding the hybrid promoter-driven HCV replicon could be amplified, and interferon, an inhibitor of HCV replication, reduced HCV replication in cells transduced with the Ad vector coding HCV replicon. This is the first report of the development of an Ad vector-mediated HCV replicon system.

Methicillin-resistant Staphylococcus aureus bacteremia at a university hospital in Japan.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading cause of infections in hospitals, and mortality from MRSA bacteremia is high. In this study, we assessed the clinical characteristics and optimum management of 115 patients with MRSA bacteremia who were admitted to Osaka University Hospital between January 2006 and December 2010. Sixty-nine of the patients survived and 46 died of heart failure or renal failure. The nonsurvivors had reduced levels of platelets and albumin, and increased aspartate aminotransferase, total bilirubin, blood urea nitrogen, and creatinine levels. Other causes of death included sepsis, septic shock plus respiratory failure, disseminated intravascular coagulation, and unknown causes. However, a significant number of those whose infections were catheter-derived survived. Nonsurvivors were more often administered catecholamines and consultation with an infection-control team (ICT) was significantly associated with improved survival. Patients about whom the ICT were consulted were administered significantly more additional anti-MRSA drugs, for example trimethoprim-sulfamethoxazole, clindamycin, and gentamycin, than patients who were not the subject of consultation, although trough values for vancomycin did not differ between the two groups. Catheter removal was significantly higher for surviving patients with severe or complicated infections. These results suggest the status of patients with MRSA bacteremia who did not survive was worse than those who did survive, but that ICT consultation might significantly affect survival by recommendation of appropriate care and anti-MRSA drug use.

Safety evaluation of MA-T after ingestion in mice.

MA-T (Matching Transformation System®) is a proprietary chemical mixture for on-demand production of aqueous chlorine dioxide that is used for the treatment of oral malodor. MA-T is also an effective disinfectant against at least 39 pathological microorganisms, including severe acute respiratory syndrome coronavirus 2, and therefore may be useful as a disinfectant mouthwash to prevent the spread of infection. Accidental ingestion is the putative worst hazard scenario associated with mouthwash use; therefore, here we investigated the safety of MA-T ingestion in mice. Mice were provided drinking water containing 0-3000 µg/ml MA-T for 7 days followed by non-spiked drinking water for an additional 14 days. At day 7, mice ingesting 1000 or 3000 µg/ml MA-T showed significantly decreased body weight and significantly increased liver, kidney, and heart tissue injury biomarkers compared with control. However, at 14 days after stopping MA-T ingestion, body weight and tissue injury biomarkers had returned to normal. Histological analysis revealed that MA-T-induced injuries in liver, kidney, spleen, stomach, duodenum, colon, and rectum had also recovered at 14 days after stopping MA-T ingestion; however, mild vascular endothelial injuries remained in heart, jejunum, and ileum in the worst-case scenario. Taken together, MA-T may be potentially safety for further development as a disinfectant mouthwash by risk management, such as placing a caution of the label and adding a distinctive flavor.

Gastroprotective Effect of Enteral Nutrition Formula in Mice Injected Subcutaneously with Indomethacin.

We have previously shown that two enteral nutrition formulas suppressed gastric lesions induced by the oral administration of indomethacin (IND) in mice. However, the mechanism of their protective effect is unknown. In this study, the effect of the two enteral nutrition formulas on gastric lesions induced by subcutaneous IND injection was investigated, with the objective of exploring the possibility that they may interact directly with IND in the gastrointestinal tract. Ten-week-old, male, ICR mice were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition formula (25 mL/kg). IND was injected subcutaneously at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of mice given enteral nutrition formula was reduced to 56-89% and 34-61%, respectively, compared with the mice given purified water. The time courses of plasma IND concentrations were comparable among the three groups. These results suggested that the effect of these enteral nutrition formulas on gastric lesions did not originate from their direct interaction with IND in the gastrointestinal tract or their effect on the disposition of IND.

Combining machine learning and nanopore construction creates an artificial intelligence nanopore for coronavirus detection.

High-throughput, high-accuracy detection of emerging viruses allows for the control of disease outbreaks. Currently, reverse transcription-polymerase chain reaction (RT-PCR) is currently the most-widely used technology to diagnose the presence of SARS-CoV-2. However, RT-PCR requires the extraction of viral RNA from clinical specimens to obtain high sensitivity. Here, we report a method for detecting novel coronaviruses with high sensitivity by using nanopores together with artificial intelligence, a relatively simple procedure that does not require RNA extraction. Our final platform, which we call the artificially intelligent nanopore, consists of machine learning software on a server, a portable high-speed and high-precision current measuring instrument, and scalable, cost-effective semiconducting nanopore modules. We show that artificially intelligent nanopores are successful in accurately identifying four types of coronaviruses similar in size, HCoV-229E, SARS-CoV, MERS-CoV, and SARS-CoV-2. Detection of SARS-CoV-2 in saliva specimen is achieved with a sensitivity of 90% and specificity of 96% with a 5-minute measurement.

Varicella-zoster virus glycoprotein M homolog is glycosylated, is expressed on the viral envelope, and functions in virus cell-to-cell spread.

Although envelope glycoprotein M (gM) is highly conserved among herpesviruses, the varicella-zoster virus (VZV) gM homolog has never been investigated. Here we characterized the VZV gM homolog and analyzed its function in VZV-infected cells. The VZV gM homolog was expressed on virions as a glycoprotein modified with a complex N-linked oligosaccharide and localized mainly to the Golgi apparatus and the trans-Golgi network in infected cells. To analyze its function, a gM deletion mutant was generated using the bacterial artificial chromosome system in Escherichia coli, and the virus was reconstituted in MRC-5 cells. VZV is highly cell associated, and infection proceeds mostly by cell-to-cell spread. Compared with wild-type VZV, the gM deletion mutant showed a 90% reduction in plaque size and 50% of the cell-to-cell spread in MRC-5 cells. The analysis of infected cells by electron microscopy revealed numerous aberrant vacuoles containing electron-dense materials in cells infected with the deletion mutant virus but not in those infected with wild-type virus. However, enveloped immature particles termed L particles were found at the same level on the surfaces of cells infected with either type of virus, indicating that envelopment without a capsid might not be impaired. These results showed that VZV gM is important for efficient cell-to-cell virus spread in cell culture, although it is not essential for virus growth.

Septic arthritis and acute hematogenous osteomyelitis in childhood at a tertiary hospital in Japan.

BACKGROUND: The aim of the present study was to describe the clinical features of septic arthritis (SA) and acute hematogenous osteomyelitis (AHO) in children and to assess the impact of health-care-associated infections and antimicrobial resistance. METHODS: A retrospective review of medical records of children presenting to Osaka City General Hospital with SA and AHO was undertaken during an 85 month period. The following data were assessed: location at onset, age and gender, risk factors, involved joints and/or bones, symptoms and time of presentation, causative agents and sensitivity to antibiotics, treatments and late complications. RESULTS: There were four health-care-associated (HCAI) and 20 community-acquired infections (CAI). The latency period from initial presentation to diagnosis was relatively longer in HCAI than CAI. The most common pathogen was methicillin-resistant Staphylococcus aureus (MRSA). Twenty percent of CAI patients and half of the HCAI patients were treated empirically for MRSA. All patients with complications had MRSA infection. CONCLUSION: Many pediatric patients with SA were not treated initially with optimal antibiotics. Although surgical intervention was almost inevitably required, selection and administration of effective antibiotics was necessary not only to cure the current infection but also to prevent metastatic infection. In Japan, empiric treatment of SA and AHO should include first-line antibiotics against MRSA.

Identification of CD4 and H-2Kd-restricted cytotoxic T lymphocyte epitopes on the human herpesvirus 6B glycoprotein Q1 protein.

The identification of Human herpesvirus 6B (HHV-6B) epitopes that are recognized by T-cells could contribute to the development of potential vaccines and immunotherapies. Here, we identified CD4+ and H-2Kd-restricted CD8+ T-cell epitopes on the glycoprotein Q1 of HHV-6B (BgQ1), which is a unique glycoprotein and essential for HHV-6B viral entry, by using in vivo electroporation with a plasmid DNA encoding BgQ1, overlapping peptides spanning the BgQ1 sequence, ELISPOT assay for quantification of gamma interferon (IFN-γ), and computer-based T-cell epitope prediction programs. The CD4+ and CD8+ T-cell epitopes identified in BALB/c mice in this study could be a good animal model system for use in the development of T-cell responses, inducing HHV-6B vaccines or immunotherapies.

Study of the Inhibitory Effects of Enteral Nutrition Formula on Indomethacin-Induced Gastric Lesions in Mice.

We investigated the effects of enteral nutrition formula on non-steroidal anti-inflammatory drug (NSAID)-induced gastric lesions in mice. Male ICR mice aged 7-9 weeks old were fasted, then orally given either purified water, Mermed® One, or 2-fold diluted Terumeal® 2.0α as enteral nutrition (25 or 50 mL/kg each). Indomethacin (IND) was orally administered at 20 mg/kg after 30 min, and the stomach was removed 6 h later and fixed in formalin. The number and area of lesions in the stomachs of the mice given enteral nutrition showed a significant, dose-dependent decrease compared to the purified water-treated group, and no significant difference was seen between the two enteral nutrition-treated groups. Comparable time courses of plasma IND concentrations suggest that enteral nutrition does not inhibit gastrointestinal absorption of IND. Our findings indicate that administering enteral nutrition could inhibit the onset of NSAID-induced gastric ulcers.

Identification of claudin-4 binder that attenuates tight junction barrier function by TR-FRET-based screening assay.

Claudins are key functional and structural components of tight junctions (TJs) in epithelial cell sheets. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds to claudin-4 and reversibly modulates intestinal TJ seals, thereby enhancing paracellular transport of solutes. However, the use of C-CPE as an absorption enhancer is limited by the molecule's immunogenicity and manufacturing cost. Here, we developed a high-throughput screening system based on the Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method to identify claudin-4 binders in a library collection of 32,560 compounds. Thiostrepton, identified from the screen, decreased transepithelial electrical resistance and increased flux of 4-kDa fluorescein isothiocyanate-labelled dextran (FD-4) in Caco-2 cell monolayers, a model of intestinal epithelium. Thiostrepton changed the expression, but not the localisation, of TJ components. Treatment of rat jejunum with thiostrepton increased the absorption of FD-4 without tissue toxicity, indicating that thiostrepton is a novel claudin-4 binder that enhances intestinal permeability. The screening system may therefore be a useful tool for identifying claudin-4 binders to enhance drug absorption in mucosa.

Exposure of drugs for hypertension, diabetes, and autoimmune disease during pregnancy and perinatal outcomes: an investigation of the regulator in Japan.

Assessment of perinatal effects of drug exposure during pregnancy after approval is an important issue for regulatory agencies. The study aimed to explore associations between perinatal outcomes and maternal exposure to drugs for chronic diseases, including hypertension, diabetes, and autoimmune disease.We reviewed 521 cases of adverse reactions due to drug exposure during pregnancy who were reported to the Pharmaceuticals and Medical Devices Agency, a regulatory authority in Japan. The primary outcomes were fetal and neonatal death and malformation of infants. Associations between perinatal outcomes and exposure to each drug category for hypertension, diabetes, and autoimmune disease were evaluated using logistic regression analysis.Of the 521 cases (maternal age: 15-47 years; mean 32.3 ±â€Š5.5), fetal and neonatal deaths were reported in 159 cases (130 miscarriage; 12 stillbirth; 4, neonatal death; and 13 abortion due to medical reasons), and malformations of infants were observed in 124 cases. In contrast to the trend of association between diabetes with or without medication and fetal and neonatal death (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.17-1.36), exposure to oral antidiabetics tended to be associated with fetal and neonatal death (OR, 4.86; 95% CI, 0.81-29.2). Malformation tended to be correlated with exposure to angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (OR, 2.98; 95% CI, 0.76-11.7). This association showed trends opposite to that of the association with hypertension itself (OR, 0.42; 95% CI, 0.18-1.02) or overall antihypertensives (OR, 0.42; 95% CI, 0.15-1.13). Occurrence of multiple malformations was associated with exposure to biologics (OR, 8.46; 95% CI, 1.40-51.1), whereas there was no significant association between multiple malformations and autoimmune disease with or without medication (OR 1.07; 95% CI, 0.37-3.06).These findings suggest that drugs of different categories may have undesirable effects when used during pregnancy. However, the regulatory database was not originally designed to evaluate the causal associations between drug exposure and adverse drug reactions. The limitations of spontaneous reporting systems should be carefully taken into account. Further studies are needed to elucidate the effects of individual drugs in each category on perinatal outcomes.

Acute and chronic nephrotoxicity of platinum nanoparticles in mice.

Platinum nanoparticles are being utilized in various industrial applications, including in catalysis, cosmetics, and dietary supplements. Although reducing the size of the nanoparticles improves the physicochemical properties and provides useful performance characteristics, the safety of the material remains a major concern. The aim of the present study was to evaluate the biological effects of platinum particles less than 1 nm in size (snPt1). In mice administered with a single intravenous dose of snPt1, histological analysis revealed necrosis of tubular epithelial cells and urinary casts in the kidney, without obvious toxic effects in the lung, spleen, and heart. These mice exhibited dose-dependent elevation of blood urea nitrogen, an indicator of kidney damage. Direct application of snPt1 to in vitro cultures of renal cells induced significant cytotoxicity. In mice administered for 4 weeks with twice-weekly intraperitoneal snPt1, histological analysis of the kidney revealed urinary casts, tubular atrophy, and inflammatory cell accumulation. Notably, these toxic effects were not observed in mice injected with 8-nm platinum particles, either by single- or multiple-dose administration. Our findings suggest that exposure to platinum particles of less than 1 nm in size may induce nephrotoxicity and disrupt some kidney functions. However, this toxicity may be reduced by increasing the nanoparticle size.