Efficacy of Nanoparticle Albumin-Bound Paclitaxel (nab-PTX) Monotherapy Can Be Improved after Treatment with Immune Checkpoint Inhibitor in Patients with Non-Small Cell Lung Cancer: Long-Term Follow-Up and Updated Analysis of Two Previous Prospective Clinical Studies.

INTRODUCTION: Recent studies have suggested enhanced therapeutic effects of subsequent chemotherapy after immune checkpoint inhibitor (ICI) treatment, highlighting the importance of subsequent treatment selection. Nanoparticle albumin-bound paclitaxel (nab-PTX) is commonly used in subsequent chemotherapies; however, its efficacy as a subsequent treatment after ICI treatment has not been reported. METHODS: We retrospectively evaluated the efficacy and safety of nab-PTX using two prospective studies that we previously reported. The first study evaluated the efficacy and safety of nab-PTX as a second-line treatment after the failure of the first-line cytotoxic chemotherapy, excluding ICI (study 1; n = 32), and the other as a subsequent treatment after failure of ICI treatment, regardless of treatment line (study 2; n = 29). RESULTS: The objective response rate was significantly higher in study 2 {55.2% (95% confidence interval [CI]: 28.1-79.6)} than in study 1 (28.1% [95% CI: 13.7-46.7]) (p = 0.04). Although the disease control rate was slightly higher in study 2 (86.2% [95% CI: 65.9-97.0]) than in study 1 (71.9% [95% CI: 53.3-86.3]), there was no significant difference (p = 0.2). The median progression-free survival was significantly longer in study 2 than in study 1 (3.9 months [95% CI: 2.0-5.5] in study 1 vs. 5.6 months [95% CI: 3.0-12.8] in study 2; hazard ratio [HR]: 0.46 [95% CI: 0.27-0.81], p = 0.006). The median overall survival was slightly longer in study 2 despite the greater number of patients who received nab-PTX in late treatment line, but there was no significant difference between study 1 and study 2 (10.9 months [95% CI: 5.1-16.8] in study 1 vs. 11.9 months [95% CI: 7.6-24.8] in study 2; HR: 0.77 [95% CI: 0.46-1.31], p = 0.34). Safety profiles did not differ between the patients in studies 1 and 2. CONCLUSION: Nab-PTX monotherapy may be an effective subsequent treatment option after ICI treatment.

Human T-cell Lymphotropic Virus Type-1-associated Bronchioloalveolar Disorder with Non-necrotizing Granulomas: A Case Report and Literature Review.

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated bronchioloalveolar disorder (HABA) is a pulmonary disorder characterized by lymphocytic infiltration of the peribronchiolar space and interstitium in HTLV-1 carriers and in adult T-cell leukemia/lymphoma (ATLL). We herein report an 85-year-old woman carrying HTLV-1 with HABA who presented with a miliary pattern of micronodules in both lungs on high-resolution computed tomography and a lymphocytic infiltrate with non-necrotizing granulomas on pathology. This rare case of HABA should be differentiated from sarcoidosis, hypersensitivity pneumonitis, or miliary tuberculosis.

Safety and utility of Endoscopic Ultrasound with Bronchoscope-guided Fine Needle Aspiration (EUS-B-FNA) in suspected lung cancer patients with poor respiratory or general conditions: a prospective three-center observational study.

BACKGROUND: Although transbronchial diagnostic procedures are sometimes difficult to perform because of the patient's respiratory or general conditions, endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA), a known transesophageal diagnostic procedure, might be useful for such cases. We conducted this prospective three-center observational study to evaluate the safety and efficacy of EUS-B-FNA in suspected lung cancer patients with poor respiratory or general conditions. METHODS: Patients with suspected lung cancer with respiratory failure, Eastern Cooperative Oncology Group performance status of 2 or higher, or severe respiratory symptoms, were enrolled. The primary endpoints were the diagnostic yield of lung cancer and its safety, and the secondary endpoints were the success rate of molecular and programmed death ligand 1 (PD-L1) analyses, and the 6-month survival rate in patients with lung cancer. RESULTS: We enrolled 30 patients, of which 29 were included in the analysis. Among them, 26 were eventually diagnosed with lung cancer. The diagnostic yield for lung cancer was 100% (26/26). There were no adverse events associated with EUS-B-FNA requiring procedure discontinuation. The success rates of molecular analysis for EGFR, ALK, ROS-1, and BRAF were 100% (14/14), 100% (11/11), 100% (9/9), and 75% (6/8), respectively. The success rate of the PD-L1 analysis was 100% (15/15). The 6-month survival rate in patients with lung cancer was 53.8% (95% confidence interval [CI]: 33.4-76.4), and the median overall survival (OS) was 196 days (95% CI: 142-446). CONCLUSIONS: EUS-B-FNA is a safe and effective diagnostic method, even in patients with suspected lung cancer with poor respiratory or general conditions. TRIAL REGISTRATION: This clinical trial was registered at https://www.umin.ac.jp/ctr/index.htm (UMIN000041235, approved on 28/07/2020).

Efficacy and safety of nanoparticle albumin-bound paclitaxel monotherapy after immune checkpoint inhibitor administration for advanced non-small cell lung cancer: A multicenter Phase 2 clinical trial.

BACKGROUND: Whether immunotherapy improves the efficacy or worsens adverse events of subsequent chemotherapy remains unclear. We performed a Phase 2 study to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as a treatment for advanced non-small cell lung cancer (NSCLC) after treatment with programmed cell death 1 or programmed death ligand 1 [PD-(L)1] inhibitor failure. METHODS: Nab-paclitaxel (100 mg/m2 ) was administered on Days 1, 8, and 15 of a 28-day cycle to patients with advanced NSCLC within 12 weeks after the failure of PD-(L)1 inhibitor treatment. The primary endpoint was objective response rate (ORR) in all patients; the secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Thirty cases were registered, and 29 cases were included in the analysis. The ORR was 55.2% (95% confidence interval [CI]: 28.1%-79.6%) and the DCR was 86.2% (95% CI: 65.9%-97.0%). The median PFS was 5.6 months (95% CI: 4.4-6.7 months), and PFS rates at 1- and 2-year timepoints were 34.5% and 13.3%, respectively. The median OS was 11.9 months (95% CI: 0.8-23.0 months). Good performance status and responder of previous PD-(L)1 inhibitor therapy were independent predictors of PFS. Grade 3 or higher toxicities included leukopenia (27.6%), neutropenia (31.0%), peripheral sensory neuropathy (6.9%), increased alanine aminotransferase and aspartate aminotransferase levels (3.4%), and interstitial lung disease (3.4%). CONCLUSIONS: Nab-paclitaxel therapy improved ORR after PD-(L)1 inhibitor treatment failure with a durable response of 13% and acceptable toxicities in patients with advanced NSCLC.

Comparison of antigenicity between recently isolated bovine rotaviruses A and vaccine strains by cross-neutralizing antibody tests and their significance for immunization.

Three bovine rotaviruses A (RVAs) isolated from a cattle farm in Japan were serotyped by serum neutralization assay, as compared with the RVA strains contained in a vaccine used on the same farm. Antisera were prepared against the three isolates and the vaccine strains of bovine RVA. The results of cross-neutralization tests revealed that the RVA isolates from this farm differed somewhat in serotype. Collected plasma from calves for 6 weeks after colostrum ingestion showed that maternal antibodies acquired against all isolates gradually decreased, but antibodies toward one isolate increased by 6 weeks after the mentioned decreasing. These results suggest that rotavirus vaccines administered to cows should include all serotypes commonly found in calves with diarrhea.

Isolation, molecular characterization, and disinfectants susceptibility of swine-carried mammalian orthoreoviruses in Japan in 2020-2022.

Biosecurity enhancement contributes to the reduction of various microbial pathogens. Mammalian orthoreoviruses (MRVs) which are increasingly recognized as potentially serious problems on swine industry were used as indicators of biosecurity enhancement on two pig farms. Twelve MRVs were detected and isolated from fecal specimens of healthy pigs collected from one of the two farms in Japan. By sequencing based on the partial S1 gene, MRV isolates were classified as MRV1 and MRV2. Additionally, the virucidal activities of disinfectants toward the isolated MRV1 were evaluated using quaternary ammonium compound (QAC) diluted 500 times with water (QAC-500), 0.17% food additive glade calcium hydroxide (FdCa(OH)2) solution, QAC diluted with 0.17% FdCa(OH)2 solution (Mix-500), sodium hypochlorite at 100 or 1,000 parts per million (ppm) of total chlorine (NaClO-100 or NaClO-1000, respectively). To efficiently inactivate MRV1 (≥3 log10 reductions), 0.17% FdCa(OH)2, Mix-500 and NaClO-1000 required 5 min, whereas it took 30 min for QAC-500. The number of MRV detections has decreased over time, after using Mix-500 for disinfection on the positive farm. These results suggest that different serotypes of MRVs are circulating among pigs, and that the occurrence of MRVs in the farms decreased consequent to more effective disinfection.

Equine placental extract supplement as a night barking remedy in dogs with cognitive dysfunction syndrome.

With the aging of pet dogs, there has been an increasing trend in senility-related diseases; additionally, cognitive disorders accompanied by abnormal behaviours are a major burden for owners. Recently, there have been a series of consultations regarding the fact that night barking, which is an abnormal behaviour, remarkably interferes with the owner's sleep and adversely affects the owner's quality of life. However, there has been no effective solution to this problem. In this study, three aged pet dogs diagnosed with dementia were administered an equine placental extract (eqPE) as pet supplement, which has been shown in laboratory models to improve cognitive function. Consequently, night barking ceased 1 week after the administration of eqPE in case 2 and it was observed to decrease in the other two dogs. Furthermore, night barking disappeared 2 and 3 weeks after the administration of eqPE in cases 1 and 3, respectively. No recurrence or exacerbation of night barking was observed in the three cases treated with the eqPE, and no adverse events were observed. These results suggest that eqPE may be useful for improving night barking in pet dogs with dementia, and it is expected to be a new treatment method.

Isolation, Identification, and Molecular Characterization of Newcastle Disease Virus from Field Outbreaks in Chickens in Afghanistan.

Newcastle disease viruses (NDVs) in Afghanistan were isolated from three chicken farms and identified using a hemagglutination test and reverse transcription-polymerase chain reaction assay. Three isolates from each farm were sequenced to characterize the part of their fusion protein gene around the cleavage site. The characteristics of the fusion protein genes of the three isolates shown by phylogenic analysis indicated that the isolates were velogenic, belonged to the class II subgenotype VII 1.1, and were closely related to an identified Chinese NDV isolate. To our knowledge, this is the first time that NDV isolates from Afghanistan have been partially sequenced.

Aislamiento, identificación y caracterización molecular del virus de la enfermedad de Newcastle de brotes de campo en pollos en Afganistán Se aislaron virus de la enfermedad de Newcastle (NDV) en Afganistán de tres granjas de pollos y se identificaron mediante una prueba de hemaglutinación y un ensayo de transcripción reversa y reacción en cadena de la polimerasa. Se secuenciaron tres aislados de cada granja para caracterizar la parte correspondiente al gene de la proteína de fusión alrededor del sitio de disociación. Las características de los genes de la proteína de fusión de los tres aislamientos mostrados por el análisis filogenético indicaron que los aislamientos eran velogénicos, pertenecían a la clase II subgenotipo VII 1.1 y estaban estrechamente relacionados con un aislado del virus de Newcastle identificado en China. Hasta donde se sabe, esta es la primera vez que los aislamientos del virus de Newcastle de Afganistán se han secuenciado parcialmente.

G and P genotype profiles of rotavirus a field strains circulating in a vaccinated bovine farm as parameters for assessing biosecurity level.

After improvement of hygiene protocols on boots in a bovine operation (farm A) in Ibaraki, Japan in September 2017, mortality of calves and the detection of 4 viral pathogen indicators, including bovine rotavirus A (RVA), became significantly low for one year. Subsequently, in the present study, these indicators and mortality were monitored and confirmed all were still low, except for the detection rate of bovine RVA in calves less than 3 weeks old. The present study aimed to investigate G and P genotypic profiles of RVAs in farm A from 2018 to 2020. Molecular analysis using semi-nested multiplex RT-PCR of positive RVAs (n=122) and sequencing of selected samples revealed the presence of G6, G8, G10, P[1], P[5] and P[11] genotypes and the prevalence of G and/or P combination and mixed infections. The most common combination of G and P types was G10P[11] (41.8%), followed by mixed infection with G6+G10P[5] (11.5%). Phylogenetic analysis of RVAs showed clustering with bovine and other animal-derived RVA strains, suggesting the possibility of multiple reassortant events with strains of bovine and others animal origins. Noteworthy as well is that vaccinated cattle might fail to provide their offspring with maternal immunity against RVA infections, due to insufficient colostrum feeding. Our findings further highlight the importance of RVA surveillance in bovine populations, which may be useful to improving effective routine vaccination and hygiene practices on bovine farms.

Isolation and Molecular Characterization of Fowl Adenovirus and Avian Reovirus from Breeder Chickens in Japan in 2019-2021.

Fowl adenoviruses (FAdVs) and avian reoviruses (ARVs) are ubiquitous in poultry farms and most of them are not pathogenic, yet often cause damage to chicks. A total of 104 chicken fecal samples were collected from 7 farms of breeder chickens (layers and broilers) in Japan from 2019 to 2021, and yielded 26 FAdV plus 14 ARV isolates. By sequencing, FAdV isolates were classified as FAdV-1, 5 and 8b. ARV isolates were classified as genotype II, IV and V. These results suggest that FAdVs and ARVs are resident in the breeder chicken farms in Japan.

Rapid in vitro virucidal activity of slightly acidic hypochlorous acid water toward aerosolized coronavirus in simulated human-dispersed droplets.

The virucidal activities were evaluated by spraying slightly acidic hypochlorous acid waters (SAHWs) containing various concentrations of free available chlorine - 100, 200, 300 and 500 ppm (SAHW-100, -200, -300 and -500, respectively) - toward aerosol of an avian coronavirus (infectious bronchitis virus: IBV). The viral solution was supplemented with 0.5% fetal bovine serum (FBS) to simulate normal human droplets generated by sneezing or coughing in a real-life scenario. The virus containing 0.5% FBS was sprayed and exposed to SAHWs for a few seconds in a closed chamber, before reaching the air sampler. The results showed that IBV exposed to SAHW-100 and -200 for a few seconds decreased by 0.21 log10 and 0.80 log10, respectively, compared to the pre-exposed samples to SAHWs as controls. On the other hand, reductions of 1.16 log10 and 1.67 log10 were achieved following the exposure to SAHW-300 and -500, respectively, within a few seconds. These results suggest that SAHWs have rapid in vitro virucidal activity toward aerosolized IBV. The findings obtained for IBV might basically be applicable in relation to SARS-CoV-2, given the resemblance between the two viruses. To prevent human-to-human transmissions by aerosols, the inactivation of viruses in the air by exposure to SAHWs for a few seconds seems to be an effective way.

Synergistic effects of quaternary ammonium compounds and food additive grade calcium hydroxide on microbicidal activities at low temperatures.

The microbicidal activities of mixtures of quaternary ammonium compounds (QACs) and food additive grade calcium hydroxide (FdCa(OH)2) were evaluated in a suspension test at -20°C using an anti-freeze agent (AFA) containing methanol, or at 1°C, with varying contact time, toward avian influenza virus (AIV), Newcastle disease virus (NDV), fowl adenovirus (FAdV), avian reovirus (ARV), Salmonella Infantis (SI) and Escherichia coli (EC). At -20°C, the mixtures could inactivate AIV and NDV within 30 min, FAdV and ARV within 5 sec, and SI and EC within 3 min, respectively. AFA did not inactivate viruses and bacteria within 30 min and 10 min, respectively. At 1°C, the mixtures inactivated FAdV and ARV within 30 sec, AIV within 10 min, and NDV within 30 min. A mixture of slaked lime (SL) and QAC could inactivate FAdV and ARV within 30 sec, but could not inactivate AIV and NDV even after 60 min at 1°C. SL could not substitute FdCa(OH)2 in order to exert the synergistic effects with QAC. Thus, QACs microbicidal activities were maintained or enhanced by adding FdCa(OH)2. It is hence recommended to use QACs with FdCa(OH)2, especially in the winter season.

Surfactant protein D: a useful marker for differentiation of drug-induced pneumonia and bacterial pneumonia.

BACKGROUND: Drug-induced pneumonia (d-pneumonia) and bacterial pneumonia (b-pneumonia) are often difficult to differentiate; therefore, this study examined the possibility of differentiating them using serum biomarkers. METHODS: The study included 22 and 16 patients diagnosed with b- and d-pneumonia, respectively, at our institution or affiliated institutions. For d-pneumonia, the causative drug was minocycline hydrochloride in four patients, gefitinib in two patients, nivolumab in two patients, pembrolizumab in two patients, sulfasalazine in two patients, loxoprofen in one patient, Bouiougitou in one patient, edoxaban tosilate hydrate in one patient, and abemaciclib in one patient. White blood cell (WBC), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6), surfactant protein (SP)-D, and SP-A levels were measured in each patient and compared between the groups. RESULTS: Significant differences were noted in the WBC and SP-D levels between the two groups (P < 0.05, P < 0.001), but not in the CRP, KL-6, or SP-A levels. CONCLUSION: The study results suggest that SP-D is a useful marker for differentiating b-pneumonia and d-pneumonia.

Virucidal activity of slightly acidic hypochlorous acid water toward influenza virus and coronavirus with tests simulating practical usage.

Slightly acidic hypochlorous acid waters (SAHWs) with pH of 5.2-5.8 containing different concentrations of free available chlorine - 62, 119, 220, 300, and 540 ppm (SAHW-62, -119, -220, -300, and -540, respectively) - were evaluated for their virucidal activity toward a low pathogenic H7N1 avian influenza virus (AIV) and an infectious bronchitis virus (IBV) in suspension, abiotic carrier, and direct spray tests, with the presence of organic materials. In the carrier test, the dropping and wiping techniques were performed toward viruses on carriers. In the suspension test, SAHW-62 could decrease the viral titer of both AIV and IBV by more than 1000 times within 30 s. With the dropping technique, IBV on carriers showed high resistance to SAHW, while AIV on plastic carrier was inactivated to an effective level (≧3 log virus reduction) within 1 min. With the wiping technique, SAHW-62 could inactivate both AIV and IBV on wiped plastic carriers to an effective level within 30 s. However, SAHW-220 could not inactivate IBV in the wiping rayon sheet to an effective level. In the direct spray test, sprayed SAHW-300 within 10 min, and SAHW-540 within 20 min, inactivated AIV and IBV on the rayon sheets to undetectable level, respectively. Our study indicates that the usage of wipes with SAHW could remove viruses from plastic carriers, while viruses remained in the wipes. Besides, a small volume of sprayed SAHW was effective against the viruses on the rayon sheets for daily cleaning in the application area. The findings we obtained concerning IBV might basically be applicable in relation to SARS-CoV-2, given the resemblance between the two viruses.

Establishment and utilization of an evaluation system for virucidal activity of disinfectants against a coronavirus with apparent applicability to SARS-CoV-2.

Decontamination of pathogens on surfaces of substances is very important for controlling infectious diseases. In the present experiments, we tested various disinfectants in aqueous phase as well as on plastic surface carrying a viral inoculum, through dropping and wiping decontamination techniques, comparatively, so as to evaluate virucidal efficacies of those disinfectants toward an avian coronavirus (infectious bronchitis virus: IBV). We regard this evaluation system applicable to SARS-CoV-2. The disinfectants evaluated were 0.17% food additive glade calcium hydroxide (FdCa(OH)2) solution, sodium hypochlorite at 500 or 1,000 ppm of total chlorine (NaClO-500 or NaClO-1,000, respectively), NaClO at 500 ppm of total chlorine in 0.17% FdCa(OH)2 (Mix-500) and quaternary ammonium compound (QAC) diluted 500-fold in water (QAC-500). In the suspension test, all solutions inactivated IBV inoculum that contained 5% fetal bovine serum (FBS) under detectable level within 30 sec. In the carrier test, all solutions, except NaClO-500, could inactivate IBV with 0.5% FBS on a carrier to undetectable level in the wiping-sheets and wiped-carriers. We thus conclude that suspension and carrier tests should be introduced to evaluate disinfectants for the field usage, and that this evaluation system is important and workable for resultful selection of the tested disinfectants against avian coronavirus and SARS-CoV-2 on surfaces, particularly on plastic fomite.

Regression of viral pathogen indicators due to improvement of hygiene protocols on boots in a bovine farm.

Rotavirus A (RVA), bovine torovirus (BToV), bovine enterovirus (BEV) and bovine coronavirus (BCV) at a bovine farm in Ibaraki prefecture were monitored by one-step multiplex reverse transcription polymerase chain reaction (RT-PCR), with the aim of confirming the reduction of "viral pathogen indicators". A total of 960 bovine fecal samples were collected from calves less than 2 month-old within the period from October 2016 to October 2018 every 2 months at the bovine farm. In each sampling, 40 samples were taken from calves 3 week-old or less, and 40 samples from calves over 3 week-old, in principle. At the end of September 2017, the farm introduced improvement of hygiene protocols on boots by exchanging boots and appropriate usage of a footbath at the entrance of calf sheds. In the comparison of the virus detection by RT-PCR, prevalence of all 4 viruses was significantly reduced (P<0.01) in calves 3 week-old or less after the improvement. The mortality of calves less than 2 month-old was also significantly reduced after the improvement of hygiene protocols. These data suggest that the proper control of boots at calf sheds is important, perhaps even vital, for rearing hygiene measures at bovine farms so as to attain substantial decrease in the prevalence of pathogens.

A Soup Service for Advanced Digestive Cancer Patients with Severe Anorexia in Palliative Care.

BACKGROUND/AIMS: The palliative care team (PCT), nutrition support team (NST), and department of nutrition in our hospital developed a special soup service for patients with terminal cancer. We evaluated the usefulness of this soup service for improving the mood in patients with advanced digestive cancer with severe anorexia. MATERIAL AND METHODS: We retrospectively reviewed the clinical data of 18 patients with advanced cancer originating in digestive organs who received soup service at our institution between 2015 and 2016. Members of the PCT, NST, and a licensed cook visited the bedside of each patient and served them a cup of soup twice a week. RESULTS: Fifteen patients (83%) were able to taste the soup with no adverse events, and 11 (73%) of them enjoyed the taste of the soup. In the five patients who died in our hospital during the service, the time between their last soup intake and death ranged from two to seven days (median three days). CONCLUSION: Even terminally ill patients suffering from advanced digestive cancer with severe anorexia were able to enjoy the taste of the soup served to them. The establishment of special meal service, such as this soup service, may not only relieve their stress but also support the strength of living and help improve their spiritual quality of life.

Efficacy and safety of nanoparticle albumin-bound paclitaxel monotherapy as second-line therapy of cytotoxic anticancer drugs in patients with advanced non-small cell lung cancer.

BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX), which avoids toxicities associated with a vehicle used in solvent-based PTX, has already shown safety and efficacy in patients with non-small cell lung cancer (NSCLC). METHODS: A phase II study was performed to assess the safety and efficacy of nab-PTX monotherapy as second-line chemotherapy after cytotoxic anticancer drugs for previously treated advanced NSCLC. Thirty-two patients with advanced NSCLC who had previously undergone 1 regimen of cytotoxic anticancer drugs were enrolled. Nab-PTX was administered intravenously at a dose of 100 mg/m on days 1, 8, and 15 of a 28-day cycle. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile were evaluated. RESULTS: The ORR was 28.1%, the DCR was 71.9%, median PFS was 3.9 months (95% confidence interval [CI] 2.7-5.1 months), and median OS was 10.9 months (95% CI 9.5-12.3 months). The mean relative dose intensity of nab-PTX was 77%. Grade 3 or 4 neutropenia, and grade 3 febrile neutropenia were observed in 11 and 1 of 32 patients, respectively. As nonhematologic toxicities, grade 3 peripheral sensory neuropathy and pneumonitis were each observed in 2 of 32 patients. CONCLUSION: Nab-PTX is an active and well-tolerated regimen in patients with previously treated NSCLC.

An antioxidant, N,N'-diphenyl-p-phenylenediamine (DPPD), affects labor and delivery in rats: a 28-day repeated dose test and reproduction/developmental toxicity test.

A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N'-diphenyl-p-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats were dosed with DPPD by gavage for 28 days at 0, 100, 300, or 1000 mg/kg bw/day or for a total of 42-46 days at 0, 8, 50, or 300 mg/kg bw/day. No significant adverse effects were observed in the repeated dose toxicity study up to 1000 mg/kg bw/day in both sexes. In the reproduction/developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one died and the other showed dystocia on day 23 of pregnancy at 300 mg/kg bw/day. Another female delivered only three live pups at 300 mg/kg bw/day. A significantly prolonged gestation period was observed at 50 and 300 mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/developmental toxicity were considered to be 1000 and 8 mg/kg bw/day, respectively.

A 12-month feeding study of reproduction/development in rats fed meat/milk powder supplemented diets derived from the progeny of cloned cattle produced by somatic cell nuclear transfer.

The present 12-month feeding study was carried out with rat groups fed a diet supplemented with meat or milk (meat/milk) derived from the progeny of clones produced by somatic cell nuclear transfer (SCNT) technology. It was conducted to obtain data concerning the chronic toxicities of these edible products during the process of development and reproduction in rats fed such products. The rats were subjected to clinical observations for general health condition and examinations such as sensory/reflex function, grip strength, motor activity, body weight, food consumption, ophthalmology and urinalysis. Moreover, sexually matured rats fed the test diets were mated and examined for items such as the reproductive performances of the dams and health of their pups. After the feeding period, factors related to rat health status, based on the findings for hematology, blood biochemistry, necropsy, organ weight and histology, were examined. There were no biologically significant differences in these factors between the rat groups fed meat/milk powder supplemented diets derived from the progeny and those fed meat/milk powder supplemented diets derived from conventionally bred cattle. Therefore, the present chronic toxicity study suggests that meat and milk derived from the progeny of SCNT cattle might be equivalent to those derived from conventionally bred cattle in use as dietary supplements for rats.