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INTRODUCTION: Infertility affects millions of couples worldwide causing psycho-social problems and conflicts in families. Despite the establishment of multiple causes of infertility in both males and females, there have been no studies carried out in Rwanda about primary infertility caused by chromosomal abnormalities. Thus, the aim of this study is to determine the prevalence of primary infertility caused by chromosomal abnormalities and to assess the clinical manifestations in Rwandan patients. METHODS: We performed a cross-sectional retrospective assessment of the data extracted from medical files and OpenClinic (an electronic data recording system) of patients transferred to one genetic lab in Huye that works with three main referral hospitals: Kigali University Teaching Hospital (CHUK), Huye University Teaching Hospital (CHUB) and Rwanda Military Hospital (RMH) from June 2009 to June 2019. RESULTS: This study showed that the overall prevalence of primary infertility caused by chromosomal abnormalities was 25.4% (N=15/59) among the patients who consulted the genetic department. Females were more affected than males with 32% (N=8/25) of females being primarily infertile due to chromosomal abnormalities and 20.58% (N=7/34) of males respectively. Our study also found that the majority (66.1%) of infertile patients had a normal karyotype in both genders with 40.7% of the males (46, XY) and 25.4% of the females (46,XX). CONCLUSION: Chromosomal abnormalities contribute significantly to primary infertility in the Rwandan population. Thus, clinicians should consider these chromosomal abnormalities in patients attending fertility clinics.

Salt tolerance has been an important issue as a solution for soil salinization and groundwater depletion. To challenge this issue, genetic diversity of wild plants must be harnessed. Here we report a discovery of a candidate gene for salt tolerance in Vigna nakashimae , one of the coastal species in the genus Vigna . Using intraspecific variation, we performed a forward genetic analysis and identified a strong QTL region harboring ~200 genes. To further narrow down the candidate genes, we performed a comparative transcriptome analysis, using the genome sequence of azuki bean ( V. angularis ) as a reference. However the detected differentially-expressed genes (DEGs) did not include those related to salt tolerance. As we suspected that the target gene in V. nakashimae is missing in V. angularis , we sequenced the whole genome sequence of V. nakashimae with long-reads. By re-analyzing the transcriptome data with the new reference genome, we successfully identified POCO1 as a candidate gene, which was missing not only in V. angularis but also in the salt-sensitive accession of V. nakashimae . Further comparative analysis revealed that the tolerant genotypes conserved the ancestral form of the locus, while the sensitive genotypes did not. We also emphasize the pitfalls in our study, such as position effect in a growth chamber, missing important genes in the reference genome, and limited reproducibility of RNA-seq experiments., (Copyright © 2024 by JAPANESE SOCIETY OF BREEDING.)

Background and Objective: Giant anterior mediastinal tumors sometimes may cause circulatory collapse and respiratory failure, known as mediastinal mass syndrome (MMS). The prediction and prevention of MMS is challenging. The aim of this study is to summarize the evaluation methods for MMS and formulate treatment strategies for giant anterior mediastinal tumors., Methods: We performed a thorough analysis of recent international literature on giant anterior mediastinal tumors (>10 cm in diameter) and MMS published in the PubMed database. The search spanned the duration of the preceding 10 years from August 19, 2023, and only studies published in English were included., Key Content and Findings: Mature teratomas and liposarcomas are the most common giant anterior mediastinal tumors and MMS develops most frequently in case of malignant lymphomas. Here, we propose a new treatment strategy for giant anterior mediastinal tumors. Based on imaging findings, giant anterior mediastinal tumors can be classified as cystic or solid and further blood investigation data are useful for a definitive diagnosis. When malignant lymphoma or malignant germ cell tumor is highly suspected, the first choice of treatment is not surgery but chemotherapy and radiotherapy. Moreover, image-guided drainage may be effective if giant cystic anterior tumors develop into MMS. The risk classification of MMS is important for treating giant anterior mediastinal tumors. If the MMS risk classification is 'unsafe' or 'uncertain', the intraoperative management deserves special attention. The surgical approach should however be based on tumor localization and invasion of surrounding tissues. Multidisciplinary team coordination is indispensable in the treatment of giant anterior mediastinal tumors., Conclusions: When giant anterior mediastinal tumors are encountered, it is important to follow the appropriate treatment strategy, focusing on the development of MMS based on imaging findings and symptoms., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-23-40/coif). The authors have no conflicts of interest to declare., (2024 Mediastinum. All rights reserved.)

To increase food production under the challenges presented by global climate change, the concept of de novo domestication-utilizing stress-tolerant wild species as new crops-has recently gained considerable attention. We had previously identified mutants with desired domestication traits in a mutagenized population of the legume Vigna stipulacea Kuntze (minni payaru) as a pilot for de novo domestication. Given that there are multiple stress-tolerant wild legume species, it is important to establish efficient domestication processes using reverse genetics and identify the genes responsible for domestication traits. In this study, we identified VsPSAT1 as the candidate gene responsible for decreased hard-seededness, using a Vigna stipulacea isi2 mutant that takes up water from the lens groove. Scanning electron microscopy and computed tomography revealed that the isi2 mutant has lesser honeycomb-like wax sealing the lens groove than the wild-type, and takes up water from the lens groove. We also identified the pleiotropic effects of the isi2 mutant: accelerating leaf senescence, increasing seed size, and decreasing numbers of seeds per pod. While doing so, we produced a V. stipulacea whole-genome assembly of 441 Mbp in 11 chromosomes and 30,963 annotated protein-coding sequences. This study highlights the importance of wild legumes, especially those of the genus Vigna with pre-existing tolerance to biotic and abiotic stresses, for global food security during climate change., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Takahashi, Sakai, Ariga, Teramoto, Shimada, Eun, Muto, Naito and Tomooka.)

The objective for the present analyses was to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling for prediction of the pharmacokinetics (PK) in Chinese and Japanese populations with a panel of Pfizer internal compounds. Twelve compounds from Pfizer internal development pipeline with available Westerner PK data and available PK data in at least one of the subpopulations of Japanese and Chinese populations were identified and included in the current analysis. These selected compounds represent various elimination pathways across different therapeutic areas. The Simcyp ® PBPK simulator was used to develop and verify the PBPK models of individual compounds. The developed models for these compounds were verified by using the clinical PK data in Westerners. The verified PBPK models were further used to predict the PK of these compounds in Chinese and Japanese populations and the predicted PK parameters were compared with the observed PK parameters. Ten of the 12 compounds had PK data in Chinese, and all the 12 compounds had PK data in Japanese. In general, the PBPK models performed well in predicting PK in Chinese and Japanese, with 8 of 10 drugs in Chinese and 7 of 12 drugs in Japanese has AAFE values less than 1.25-fold. PBPK-guided predictions of the relative PK difference were successful for 75% and 50%, respectively, between Chinese and Western and between Japanese and Western of the tested drugs using 0.8-1.25 as criteria. In conclusion, well verified PBPK models developed using data from Westerners can be used to predict the PK in Chinese and Japanese populations., Competing Interests: Competing Interests: YY, JL, CM, YL, YM, RKM, ST, JL, BKG, and JL are employees of Pfizer Inc. and own stock in Pfizer Inc., (© The author(s).)

Agricultural weeds are the most important biotic constraints to global crop production, and chief among these is weedy rice. Despite increasing yield losses from weedy rice in recent years worldwide, the genetic basis of weediness evolution remains unclear. Using whole-genome sequence analyses, we examined the origins and adaptation of Japanese weedy rice. We find evidence for a weed origin from tropical japonica crop ancestry, which has not previously been documented in surveys of weedy rice worldwide. We further show that adaptation occurs largely through different genetic mechanisms between independently-evolved temperate japonica- and tropical japonica-derived strains; most genomic signatures of positive selection are unique within weed types. In addition, some weedy rice strains have evolved through hybridization between weedy and cultivated rice with adaptive introgression from the crop. Surprisingly, introgression from cultivated rice confers not only crop-like adaptive traits (such as shorter plant height, facilitating crop mimicry) but also weedy-like traits (such as seed dormancy). These findings reveal how hybridization with cultivated rice can promote persistence and proliferation of weedy rice., (© 2021. The Author(s).)

Mucormycoses are invasive infections by Rhizopus species and other Mucorales. Over 10 months, four solid organ transplant (SOT) recipients at our centre developed mucormycosis due to Rhizopus microsporus ( n =2), R. arrhizus ( n =1) or Lichtheimia corymbifera ( n =1), at a median 31.5 days (range: 13-34) post-admission. We performed whole genome sequencing (WGS) on 72 Mucorales isolates (45 R . arrhizus , 19 R . delemar , six R . microsporus , two Lichtheimia species) from these patients, from five patients with community-acquired mucormycosis, and from hospital and regional environments. Isolates were compared by core protein phylogeny and global genomic features, including genome size, guanine-cytosine percentages, shared protein families and paralogue expansions. Patient isolates fell into six core phylogenetic lineages (clades). Phylogenetic and genomic similarities of R. microsporus isolates recovered 7 months apart from two SOT recipients in adjoining hospitals suggested a potential common source exposure. However, isolates from other patients and environmental sites had unique genomes. Many isolates that were indistinguishable by core phylogeny were distinct by one or more global genomic comparisons. Certain clades were recovered throughout the study period, whereas others were found at particular time points. In conclusion, mucormycosis cases could not be genetically linked to a definitive environmental source. Comprehensive genomic analyses eliminated false associations between Mucorales isolates that would have been assigned using core phylogenetic or less extensive genomic comparisons. The genomic diversity of Mucorales mandates that multiple isolates from individual patients and environmental sites undergo WGS during epidemiological investigations. However, exhaustive surveillance of fungal populations in a hospital and surrounding community is probably infeasible.

Loss of pod shattering is one of the most important domestication-related traits in legume crops. The non-shattering phenotypes have been achieved either by disturbed formation of abscission layer between the valves, or by loss of helical tension in sclerenchyma of endocarp, that split open the pods to disperse the seeds. During domestication, azuki bean ( Vigna angularis ) and yard-long bean ( Vigna unguiculata cv-gr. Sesquipedalis) have reduced or lost the sclerenchyma and thus the shattering behavior of seed pods. Here we performed fine-mapping with backcrossed populations and narrowed the candidate genomic region down to 4 kbp in azuki bean and 13 kbp in yard-long bean. Among the genes located in these regions, we found MYB26 genes encoded truncated proteins in azuki bean, yard-long bean, and even cowpea. As such, our findings indicate that independent domestication on the two legumes has selected the same locus for the same traits. We also argue that MYB26 could be a target gene for improving shattering phenotype in other legumes, such as soybean., (Copyright © 2020 Takahashi, Kongjaimun, Muto, Kobayashi, Kumagai, Sakai, Satou, Teruya, Shiroma, Shimoji, Hirano, Isemura, Saito, Baba-Kasai, Kaga, Somta, Tomooka and Naito.)

Preserved rice ( Oryza sativa L.) seeds stored for nearly a century as an emergency food stocks from the Mikawa area were investigated for their genetic diversity. Morphologically, the seeds appeared to be typical Japonica. One chloroplast INDEL petN-trnC , two nuclear INDELs Acp1 and Cat1 , and three SNP markers in Starch synthase IIa were amplified to characterize the molecular profile. The efficiency of amplification varied among the markers. Most of preserved seeds were classified as Japonica, but some were identified as Indica. The heterozygous genotypes detected suggested a high frequency of outcrossing at that time. On the other hand, 21 SSR markers showed quite a high degree of amplification efficiency. Principal coordinate analysis and STRUCTURE analysis based on the SSR polymorphisms proved that the preserved seeds contained alleles that were not detected among current landraces and breeding varieties, and there were the expected three subpopulations among 96 preserved seeds. These results indicated that these preserved seeds from Mikawa area in Meiji era had high genetic diversity and consisted of some subpopulations including Indica landraces with typical Japonica seed shape. These lines were considered to have been lost from current genetic resources., (Copyright © 2020 by JAPANESE SOCIETY OF BREEDING.)

Though crossing wild relatives to modern cultivars is a usual means to introduce alleles of stress tolerance, an alternative is de novo domesticating wild species that are already tolerant to various kinds of stresses. As a test case, we chose Vigna stipulacea Kuntze, which has fast growth, short vegetative stage, and broad resistance to pests and diseases. We developed an ethyl methanesulfonate-mutagenized population and obtained three mutants with reduced seed dormancy and one with reduced pod shattering. We crossed one of the mutants of less seed dormancy to the wild type and confirmed that the phenotype was inherited in a Mendelian manner. De novo assembly of V. stipulacea genome, and the following resequencing of the F2 progenies successfully identified a Single Nucleotide Polymorphism (SNP) associated with seed dormancy. By crossing and pyramiding the mutant phenotypes, we will be able to turn V. stipulacea into a crop which is yet primitive but can be cultivated without pesticides., (Copyright © 2019 Takahashi, Sakai, Yoshitsu, Muto, Anai, Pandiyan, Senthil, Tomooka and Naito.)

We assessed genetic variation in rice germplasm in northern Laos and Vientiane province from polymorphism data of SSR markers. We classified 314 accessions into three clusters; Ia (corresponding to the lowland Japonica Group), Ib (upland Japonica Group) and II (Indica Group). The accessions of cluster Ib grew mainly in mountainous fields, and those of cluster II grew commonly in basins and along rivers. The few accessions of cluster Ia grew in only three provinces: Houaphanh, Xiangkhouang and Vientiane. Lowland cultivars in cluster II were predominant in Vientiane. Variations in heading date under short-day conditions in 2014 and long-day conditions in 2015 indicate that many accessions were sensitive to the photoperiod on account of complex genetic mechanisms underlying both photoperiod sensitivity and basic vegetative growth. A total of 219 among whole accessions were classified into 6 groups: E1-3 and L1-3. E2 and E3 were dominant in clusters Ib and II; E1 and L1-3 were minor groups. These results demonstrate characteristic distributions of the Indica and Japonica Group's germplasms in northern Laos and their genetic variation in heading date.

Wild relatives of crop plants are thought as reservoir of prominent genetic resources for abiotic stress tolerance. However, insufficient information on genetic variation and phenotypic traits restricts their use for crop breeding. This study focused on wild species of genus Vigna (family Fabaceae) originated from highly humid to arid regions. To clarify the diversity of drought tolerance during the vegetative stage, 69 accessions, including 15 domesticated, and 54 wild accessions, were evaluated under two drought conditions of non-terminal and terminal stresses. In the non-terminal drought condition, the plants were grown in pipes of different heights where surface soil water content decreased faster in pipes with greater height. Relative shoot biomass was used for tolerance evaluation and we identified 19 drought tolerant accessions. Almost of them were wild accessions showing higher relative shoot biomass than that in the domesticated accessions. Domesticated species were mostly classified as drought susceptible but could be improved using tolerant conspecific wild ancestors with cross-compatibility. The tolerance was related with higher plant water status presumably due to small water consumption. However, the variation of drought tolerance could not be explained by simple tolerance factor alone, and other tolerance mechanisms such as deep rooting and increasing in root biomass were found in the tolerant accessions. In the terminal drought condition, the plants were grown in small pots, and the watering was stopped to expose them extreme and rapid soil water scarcity. The tolerance was evaluated as the number of days until wilting. However, the accessions found to be tolerant in the pot experiment were not the same as those in the pipe experiment. In this condition, plant water status was not related with the length of days to wilting. This indicates that different mechanisms are necessary for adaptation to each of the non-terminal and terminal drought conditions. Many accessions were tolerant to one of the conditions, although we identified that some accessions showed tolerance in both experiments. The great diversity in drought tolerance in the genus Vigna might serve to both improve crop drought tolerance and understand the mechanisms of adaptation in drought-prone environments.

Objective: The aim of the study was to compare the two approaches to chronic right ventricular pacing currently adopted in clinical practice: right ventricular apical (RVA) and non-RVA pacing., Background: Chronic RVA pacing is associated with an increased risk of atrial fibrillation, morbidity, and even mortality. Non-RVA pacing may yield more physiologic ventricular activation and provide potential long-term benefits and has recently been adopted as standard procedure at many implanting centers., Methods: The Right Pace study was a multicenter, prospective, single-blind, nonrandomized trial involving 437 patients indicated for dual-chamber pacemaker implantation with a high percentage of RV pacing., Results: RV lead-tip target location was the apex or the interventricular septum. RVA (274) and non-RVA patients (163) did not differ in baseline characteristics. During a median follow-up of 19 months (25th-75th percentiles, 13-25), 17 patients died. The rates of the primary outcome of death due to any cause or hospitalization for heart failure were comparable between the groups (log-rank test, p = 0.609), as were the rates of the composite of death due to any cause, hospitalization for heart failure, or an increase in left ventricular end-systolic volume ≥ 15% as compared with the baseline evaluation (secondary outcome, p = 0.703). After central adjudication of X-rays, comparison between adjudicated RVA (239 patients) and non-RVA (170 patients) confirmed the absence of difference in the rates of primary ( p = 0.402) and secondary ( p = 0.941) outcome., Conclusions: In patients with indications for dual-chamber pacemaker who require a high percentage of ventricular stimulation, RVA or non-RVA pacing resulted in comparable outcomes. This study is registered with ClinicalTrials.gov (identifier: NCT01647490).

Aim: To evaluate at a 12-month follow-up, the clinical and echocardiographic outcomes in postmyocardial infarction (MI) heart failure patients who underwent cardiac resynchronization therapy (CRT) device implantation., Materials & Methods: A total of 100 patients received a CRT device, and the study population was divided into three groups, according to the site of MI and left ventricular (LV) lead placed downstream of the ischemic area, as evaluated by echocardiography., Results: At the end of the 12-month follow-up, we reported a general improvement of LV ejection fraction from 28 ± 7% to 35 ± 9% (p < 0.001) and a significant reverse remodeling: LV end-systolic volume changed from 147 ± 54 to 125 ± 63 (p = 0.001) with a 53% of echocardiographic responders. We also observed 67% of CRT responders in the group with optimal LV lead placement compared with 38% in the remaining population (p = 0.01)., Conclusion: The optimal positioning of LV lead is a feasible method to improve the percentage of CRT responders in post-MI heart failure patients.

The design, synthesis and application of N-acetylneuraminic acid-derived compounds bearing anomeric sulfo functional groups are described. These novel compounds, which we refer to as sulfo-sialic acid analogues, include 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid and its 4-deoxy-3,4-dehydrogenated pseudoglycal. While 2-decarboxy-2-deoxy-2-sulfo-N-acetylneuraminic acid contains no further modifications of the 2-deoxy-pyranose ring, it is still a more potent inhibitor of avian-origin H5N1 neuraminidase (NA) and drug-resistant His275Tyr NA as compared to the oxocarbenium ion transition state analogue 2,3-dehydro-2-deoxy-N-acetylneuraminic acid. The sulfo-sialic acid analogues described in this report are also more potent inhibitors of influenza NA (up to 40-fold) and bacterial NA (up to 8.5-fold) relative to the corresponding anomeric phosphonic acids. These results confirm that this novel anomeric sulfo modification offers great potential to improve the potency of next-generation NA inhibitors including covalent inhibitors.

Breeding salt tolerant plants is difficult without utilizing a diversity of wild crop relatives. Since the genus Vigna (family Fabaceae) is comprised of many wild relatives adapted to various environmental conditions, we evaluated the salt tolerance of 69 accessions of this genus, including that of wild and domesticated accessions originating from Asia, Africa, Oceania, and South America. We grew plants under 50 mM and 200 mM NaCl for two weeks and then measured the biomass, relative quantum yield of photosystem II, leaf Na+ concentrations, and leaf K+ concentrations. The accessions were clustered into four groups: the most tolerant, tolerant, moderately susceptible, and susceptible. From the most tolerant group, we selected six accessions, all of which were wild accessions adapted to coastal environments, as promising sources of salt tolerance because of their consistently high relative shoot biomass and relative quantum yield. Interestingly, variations in leaf Na+ concentration were observed between the accessions in the most tolerant group, suggesting different mechanisms were responsible for their salt tolerance. Phylogenetic analysis with nuclear DNA sequences revealed that salt tolerance had evolved independently at least four times in the genus Vigna, within a relatively short period. The findings suggested that simple genetic changes in a few genes might have greatly affected salt tolerances. The elucidation of genetic mechanisms of salt tolerances in the selected accessions may contribute to improving the poor salt tolerance in legume crops., Competing Interests: The authors have declared that no competing interests exist.

A glutinous texture of endosperm is one of the important traits of rice ( Oyza sativa L.). Northern Laos is known as a center of glutinous rice diversity. We genotyped INDEL, SSR and SNP markers in a sample of 297 rice landraces collected in northern Laos. These glutinous varieties were confirmed to share a loss-of-function mutation in Granule bound starch synthase I ( Wx ). INDEL markers revealed a high frequency of recombinant genotypes between indica and japonica . Principal component analysis using SSR genotypes of Wx flanking region revealed that glutinous indica landraces were scattered between non-glutinous indica and glutinous- japonica types. High ratios of heterozygosity were found especially in glutinous indica . Haplotype analysis using SNP markers around Wx locus revealed that glutinous indica landraces would have a few chromosome segments of glutinous japonica . Frequent recombinations were confirmed outside of this region in glutinous indica . This intricate genetic structure of landraces suggested that glutinous indica landraces in Laos were generated through repeated natural crossing with glutinous- japonica landraces and severe selection by local farmers.

The genus Vigna (Fabaceae) consists of five subgenera, and includes more than 100 wild species. In Vigna, 10 crops have been domesticated from three subgenera, Vigna, Plectrotropis, and Ceratotropis. The habitats of wild Vigna species are so diverse that their genomes could harbor various genes responsible for environmental stress adaptation, which could lead to innovations in agriculture. Since some of the gene bank Vigna accessions were unidentified and they seemed to be novel genetic resources, these accessions were identified based on morphological traits. The phylogenetic positions were estimated based on the DNA sequences of nuclear rDNA-ITS and chloroplast atpB-rbcL spacer regions. Based on the results, the potential usefulness of the recently described species V. indica and V. sahyadriana, and some wild Vigna species, i.e., V. aconitifolia, V. dalzelliana, V. khandalensis, V. marina var. oblonga, and V. vexillata, was discussed.

Genus Vigna comprise several domesticated species including cowpea and mungbean, and diverse wild species. We found an introgressive hybrid population derived from two wild species, Vigna umbellata and Vigna exilis, in Ratchaburi district, Thailand. The hybrid was morphologically similar to V. umbellata but habituated in a limestone rock mountain, which is usually dominated by V. exilis. Analyzing simple sequence repeat loci indicated the hybrid has undergone at least one round of backcross by V. umbellata. We found the hybrid acquired vigorous growth from V. umbellata and drought tolerance plus early flowering from V. exilis, and thus has taken over some habitats of V. exilis in limestone karsts. Given the wide crossability of V. umbellata, the hybrid can be a valuable genetic resource to improve drought tolerance of some domesticated species.

Second-generation sequencers (SGS) have been game-changing, achieving cost-effective whole genome sequencing in many non-model organisms. However, a large portion of the genomes still remains unassembled. We reconstructed azuki bean (Vigna angularis) genome using single molecule real-time (SMRT) sequencing technology and achieved the best contiguity and coverage among currently assembled legume crops. The SMRT-based assembly produced 100 times longer contigs with 100 times smaller amount of gaps compared to the SGS-based assemblies. A detailed comparison between the assemblies revealed that the SMRT-based assembly enabled a more comprehensive gene annotation than the SGS-based assemblies where thousands of genes were missing or fragmented. A chromosome-scale assembly was generated based on the high-density genetic map, covering 86% of the azuki bean genome. We demonstrated that SMRT technology, though still needed support of SGS data, achieved a near-complete assembly of a eukaryotic genome.

Vitamin E analog, such as α- and γ-tocopherol, can undergo ω-oxidation without cleavage of the chroman ring, and this pathway is responsible for generation of the major urinary vitamin E metabolite, carboxyethyl hydroxychroman. However, it is still unclear how carboxyethyl hydroxychroman is changed in various tissues after vitamin E intake. We therefore investigated changes in the concentrations of α- and γ-tocopherol and their metabolites in rat liver and kidney. The concentration of α-tocopherol in rat liver increased until 6 h after oral administration, and then decreased. The change in the concentration of α-carboxyethyl hydroxychroman in rat liver in the α-Toc group slowly increased until 12 h after oral administration. Cytochrome P450 3A1 mRNA expression significantly increased from 12 h after the start of α-tocopherol administration. The change in the concentration of γ-carboxyethyl hydroxychroman in rat liver in the γ-Toc group markedly increased until 12 h after oral administration. On the other hand, γ-carboxyethyl hydroxychroman in rat kidney showed greater accumulation than α-carboxyethyl hydroxychroman from 3 h to 24 h after oral administration. From these results, we considered that γ-carboxyethyl hydroxychroman formed in the liver continues to be released into the bloodstream and is transported to the kidney rapidly.

The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-to-oral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to-oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and ≥50 kg). The steady-state area under the curve over the 12-h dosing interval (AUC0-12,ss) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC0-12,ss values for the intravenous and oral regimens were 51.1 μg · h/ml (68%) and 45.8 μg·h/ml (90%), respectively; there was a high correlation between AUC0-12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment-related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first-order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Among patients with implantable pacemakers and defibrillators, subclinical atrial fibrillation (SCAF) is associated with an increased risk of stroke; however, there is limited understanding of their temporal relationship., Methods and Results: The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) enrolled 2580 pacemaker and defibrillator patients aged ≥65 years with a history of hypertension but without a history of atrial fibrillation. Pacemakers and implantable cardioverter-defibrillators precisely logged the time and duration of all episodes of SCAF and recorded electrograms that were adjudicated by experts. We examined the temporal relationship between SCAF >6 minutes in duration and stroke or systemic embolism. Of 51 patients who experienced stroke or systemic embolism during follow-up, 26 (51%) had SCAF. In 18 patients (35%), SCAF was detected before stroke or systemic embolism. However, only 4 patients (8%) had SCAF detected within 30 days before stroke or systemic embolism, and only 1 of these 4 patients was experiencing SCAF at the time of the stroke. In the 14 patients with SCAF detected >30 days before stroke or systemic embolism, the most recent episode occurred at a median interval of 339 days (25th to 75th percentile, 211-619) earlier. Eight patients (16%) had SCAF detected only after their stroke, despite continuous monitoring for a median duration of 228 days (25th to 75th percentile, 202-719) before their event., Conclusions: Although SCAF is associated with an increased risk of stroke and embolism, very few patients had SCAF in the month before their event., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00256152., (© 2014 American Heart Association, Inc.)

Aims: The aims of this study were to develop a population pharmacokinetic (PK) model of ampicillin and sulbactam, to identify patient characteristics influencing the PK, and to explore the relationship between dose regimen and degree of renal impairment with exposure and time above minimum inhibitory concentration (MIC)., Methods: This analysis was performed on PK data for ampicillin and sulbactam and MIC data from a clinical trial in Japanese patients with community acquired pneumonia. Simulations were performed to investigate the effects of different dosing intervals on exposure and time above MIC in various degrees of renal impairment., Results: The plasma concentrations from 47 patients were adequately described by a two compartment model with simultaneous fit of ampicillin and sulbactam PK data, where creatinine clearance on clearance and body weight on volume in the peripheral compartment were identified as covariates for both drugs. Creatinine clearance contributed to reducing inter-individual variability of clearance by 16%. Mean clearance (inter-individual variability) for ampicillin and sulbactam was estimated to be 10.7 l h(-1) (14.8%) and 10.4 l h(-1) (15.2%), respectively. The time above MIC for each pathogen was generally > 50% of the treatment period. Simulations for exposure and time above MIC supported currently recommended dose adjustments., Conclusions: This study provided a PK model for ampicillin and sulbactam, the time above MICs for identified pathogens and associated simulation results. These findings provide useful information and augment evidence for the established dosage regimens in patients with various degrees of renal impairment., (© 2013 The British Pharmacological Society.)

Background: Cardiac resynchronization therapy (CRT) is an established therapy for patients with chronic heart failure (CHF) and a broad QRS complex. Gender-related safety and efficacy data are necessary for informed patient decision-making for female patients with CHF. The aim of the study was to assess the effects of gender on the outcome of CRT in highly symptomatic heart failure patients., Hypothesis: Gender may have an effect on the outcome of heart failure patients undergoing cardiac resynchronisation therapy., Methods: The study analyzed the 2-year follow-up of 393 New York Heart Association (NYHA) class III/IV patients with a class I CRT indication enrolled in the Management of Atrial Fibrillation Suppression in AF-HF Comorbidity Therapy (MASCOT) study., Results: In female patients (n = 82), compared with male patients (n = 311), CHF was more often due to dilated cardiomyopathy (74% vs 44%, respectively; P < 0.0001). Females also had a more impaired quality-of-life score and a smaller left ventricular end-diastolic diameter (LVEDD). Women were less likely than men to have received a CRT defibrillator (35% vs 61%, respectively; P < 0.0001). After 2 years, the devices had delivered more biventricular pacing in women than in men (96% ± 13% vs 94% ± 13%, respectively; P < 0.0004). Women had a greater reduction in LVEDD than did men (-8.2 mm ± 11.1 mm vs -1.1 mm ± 22.1 mm, respectively; P < 0.02). Both genders improved similarly in NYHA functional class. Women reported greater improvement than men in quality-of-life score (-21.1 ± 26.5 vs -16.2 ± 22.1, respectively; P < 0.0001). After adjustment for cardiovascular history, women had lower all-cause mortality (P = 0.0007), less cardiac death (P = 0.04), and fewer hospitalizations for worsening heart failure (P = 0.01)., Conclusions: Females exhibited a better response to CRT than did males. Because females have such impressive benefits from CRT, improved screening and advocacy for CRT implantation in women should be considered., (© 2013 Wiley Periodicals, Inc.)

Background: Current recommendations require a QRS duration of ≥120 ms as a condition for prescribing cardiac resynchronization therapy (CRT). This study was designed to test the hypothesis that patients with heart failure (HF) of ischemic origin, current indications for defibrillator implantation, and QRS <120 ms may benefit from CRT in the presence of marked mechanical dyssynchrony., Methods and Results: Patients with intraventricular dyssynchrony on echocardiography were randomly assigned to CRT or dual-chamber defibrillator implantation (CRT defibrillator and dual-chamber implantable cardioverter-defibrillator arm, respectively). The primary end point was the HF clinical composite response, which scores patients as improved, unchanged, or worsened. The secondary end point was the cumulative survival from HF hospitalization and HF death. An additional secondary end point was the composite of HF hospitalization, HF death, and spontaneous ventricular fibrillation. Twenty-three of 56 patients with CRT defibrillator showed an improvement in their clinical composite response at 1 year, compared with 9 of 55 patients with dual-chamber implantable cardioverter-defibrillator (41% versus 16%; P=0.004). After a median follow-up of 16 months, the CRT defibrillator arm showed a nonsignificant higher survival from HF hospitalization and HF death (P=0.077), and a significantly higher survival from the combined end point of HF hospitalization, HF death, and spontaneous ventricular fibrillation (P=0.028)., Conclusions: In this comparison of CRT defibrillator and dual-chamber implantable cardioverter-defibrillator, CRT improved clinical status in some patients with ischemic cardiomyopathy, mild-to-moderate symptoms, narrow QRS duration, and mechanical dyssynchrony on echocardiography., Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT01577446.

It has been reported that α-tocopherol (α-Toc), a vitamin E analog, is effective for treatment of non-alcoholic steatohepatitis (NASH). However, it is unknown whether or not other vitamin E analogs are effective. Therefore we designed a new rat model of steatohepatitis induced by tumor necrosis factor-α (TNF-α) stimulation, and used it to investigate the effects of vitamin E analogs. The rat liver triglyceride content increased with the dosage of TNF-α/d-galactosamine (GalN), but was suppressed by intake of both tocotrienol (T3) and α-tocopherol. Moreover, lipid peroxides (thiobarbituric acid-reactive substances) level in the liver level was also lower in both groups after tocotrienol and α-Toc intake. Intake of both tocotrienol and α-tocopherol also tended to control the increase of liver damage marker activity. In the tocotrienol and α-tocopherol groups, increases of inflammatory cytokines mRNA expression in the liver were inhibited, and these effects were considered to contribute to improvement of inflammation and fibrosis. The expression of mRNAs for inflammatory cytokines in rat primary hepatocytes was increased by TNF-α stimulation, but was inhibited by addition of α-tocotrienol and γ-tocotrienol. Transforming growth factor-β1 mRNA expression in particular was significantly inhibited by γ-tocotrienol. These findings suggest that tocotrienol species are effective for amelioration of steatohepatitis, and that tocotrienol and α-tocopherol exert a synergistic effect.

Aims: The decision to implant a cardiac resynchronization therapy (CRT) system with (defibrillator, CRT-D) or without (pacemaker, CRT-P) cardioverter defibrillator should weigh its benefits and risks. This study examined the (i) incidence of loss of capture and infectious complications and (ii) 1-year clinical outcomes of 402 CRT-D and CRT-P recipients enrolled in the MASCOT study., Methods and Results: The indications for CRT-D or CRT-P were posed by the implanting physicians. All (i) losses of atrial and right and left ventricular capture, (ii) system-related infections, and (iii) clinical outcomes, including hospitalizations for worsening heart failure (HF) and deaths from all causes, were recorded up to 1 year of follow-up. Cardiac resynchronization therapy-defibrillator was implanted in 228 (57%) and CRT-P in 174 (43%) patients. The incidence of loss of capture was greater in CRT-D with 21 patients (9.2%) than in CRT-P with 6 patient (3.5%) recipients (P = 0.01), while the infection rates were 1.3% (3 patients) and 1.2% (2 patients), respectively (ns). In the CRT-D group, 42 of 228 patients (18.4%) died or were hospitalized for HF, compared with 38 of 174 patients (21.8%) in the CRT-P group (ns). In the CRT-D group, 23 patients (10.1%) were hospitalized for worsening HF and 20 (8.8%) patients died, vs. 22 (12.6%) and 19 (10.9%) patients, respectively, in the CRT-P group (ns for both comparisons)., Conclusions: Cardiac resynchronization therapy-defibrillator was implanted in 57% of candidates for CRT. Within 1 year after device implant, the incidence of loss of capture at any lead was nearly three-fold greater among CRT-D than among CRT-P recipients. System-related infections were infrequent and clinical outcomes were similar in both groups.

The present study was carried out to investigate the effect of vitamin E analogs, especially gamma-tocotrienol (γ-T3), on hepatic TG accumulation and enzymes related to fatty acid metabolism in three types of rat primary hepatocytes: (1) normal hepatocytes, (2) hepatocytes incubated in the presence of palmitic acid (PA), and (3) hepatocytes with fat accumulation. Our results showed that γ-T3 significantly reduced the TG content of normal hepatocytes. γ-T3 also increased the expression of carnitine palmitoyltransferase 1 (CPT1A) mRNA, and tended to reduce that of sterol regulatory element binding protein 1c (SREBP-1c) mRNA. In addition, γ-T3 markedly suppressed the gene expression of both C/EBP homologous protein (CHOP) and SREBP-1c induced by PA. As these two genes are located downstream of endoplasmic reticulum (ER) stress, their suppression by γ-T3 might result from a decrease of ER stress. Moreover, γ-T3 suppressed the expression of interleukin 1β (IL-1β), which lies downstream of CHOP signaling. Taken together, our data suggest that γ-T3 might prevent hepatic steatosis and ameliorate ER stress and subsequent inflammation in the liver.

Oxidative stress plays pivotal roles in aging, neurodegenerative disease, and pathological conditions such as ischemia. We investigated the effect of sulforaphane and 6-(methysulfinyl) hexyl isothiocyanate (6-HITC), a naturally occurring isothiocyanate, on oxidative stress-induced cytotoxicity using primary neuronal cultures of rat striatum. Pretreatment with sulforaphane and 6-HITC significantly protected against H(2)O(2)- and paraquat-induced cytotoxicity in a concentration-dependent manner. Sulforaphane and 6-HITC induced the translocation of nuclear factor E2-related factor 2 (Nrf2) into the nucleus and increased the expression of γ-glutamylcysteine synthetase (γ-GCS), a rate-limiting enzyme in glutathione synthesis, and the intracellular glutathione content. Treatment with reduced glutathione (GSH) and N-acetyl-L-cysteine, a substance for glutathione synthesis, significantly prevented the cytotoxicity induced by H(2)O(2) and paraquat. Moreover, exposure to L-buthionine-sulfoximine, an irreversible inhibitor of γ-GCS, suppressed the protective effects of sulforaphane and 6-HITC. In contrast, sulforaphane and 6-HITC increased heme oxygenase-1 (HO-1) expression in neurons. However, zinc-protophorphyrin IX, a competitive inhibitor of HO-1, did not influence the protective effects of sulforaphane and 6-HITC. These results suggest that sulforaphane and 6-HITC prevent oxidative stress-induced cytotoxicity in rat striatal cultures by raising the intracellular glutathione content via an increase in γ-GCS expression induced by the activation of the Nrf2-antioxidant response element pathway.

Incisional sustained tachycardias are frequent in patients who have undergone a surgical repair of interatrial defect. A 43-year-old woman with drug refractory, highly symptomatic, persistent atrial tachycardia in the last year, was referred to our unit for catheter ablation. The patient had undergone a cardiac operation for repairing interatrial secundum ostium type defect with a patch five years before. A previous radiofrequency ablation procedure had been performed for common atrial flutter. We describe a case of incisional atrial tachycardia ablation guided by the new EnSite NavX system equipped with a new electroanatomic mapping system.