Rationale and study design of the GOREISAN for heart failure (GOREISAN-HF) trial: A randomized clinical trial.

BACKGROUND: The decongestion strategy using loop diuretics is essential for improving signs and symptoms of heart failure (HF). However, chronic use of loop diuretics in HF has been linked to worsening renal function and adverse clinical outcomes in a dose-dependent manner. Goreisan, a traditional Japanese herbal medicine, has a long history of use in Japan for regulating body fluid homeostasis and has been recognized as causing less adverse outcomes such as dehydration in contrast to loop diuretics in clinical practice. Therefore, we designed the GOREISAN-HF trial to evaluate the long-term effects of a new decongestion strategy adding Goreisan to usual care in patients with HF and volume overload. METHODS: The GOREISAN-HF trial is an investigator-initiated, multicenter, pragmatic, randomized, comparative effectiveness trial in which we will enroll 2,192 patients hospitalized for HF at 68 hospitals in Japan. All study participants will be randomly assigned to either a decongestion strategy that adds Goreisan at a dose of 7.5 g daily on top of usual care or usual care alone. Investigators have the flexibility to change the existing diuretic regimen in both groups. The primary end point is the improvement rate of cardiac edema at 12-month follow-up, and the co-primary end point is a composite of all-cause death or hospitalization up to the end of the planned follow-up period. Secondary end points include longitudinal changes in patient-reported outcomes, loop diuretics dose, and renal function. CONCLUSIONS: The GOREISAN-HF is the first large-scale randomized pragmatic trial to assess the efficacy and safety of a new congestion control strategy adding Goreisan to usual care in patients with HF and volume overload. REGISTRATION NUMBER: NCT04691700.

An unusual spliced variant of DELLA protein, a negative regulator of gibberellin signaling, in lettuce.

DELLA proteins are negative regulators of the signaling of gibberellin (GA), a phytohormone regulating plant growth. DELLA degradation is triggered by its interaction with GID1, a soluble GA receptor, in the presence of bioactive GA. We isolated cDNA from a spliced variant of LsDELLA1 mRNA in lettuce, and named it LsDELLA1sv. It was deduced that LsDELLA1sv encodes truncated LsDELLA1, which has DELLA and VHYNP motifs at the N terminus but lacks part of the C-terminal GRAS domain. The recombinant LsDELLA1sv protein interacted with both Arabidopsis GID1 and lettuce GID1s in the presence of GA. A yeast two-hybrid assay suggested that LsDELLA1sv interacted with LsDELLA1. The ratio of LsDELLA1sv to LsDELLA1 transcripts was higher in flower samples at the late reproductive stage and seed samples (dry seeds and imbibed seeds) than in the other organ samples examined. This study suggests that LsDELLA1sv is a possible modulator of GA signaling in lettuce.

Kampo medicine for the holistic approach to older adults with heart failure.

Heart failure (HF) is a leading cause of hospitalization, morbidity, and mortality in older adults and represents a significant clinical and economic burden on the health care system. However, there are many challenges in assessing and managing HF in elderly patients, who often have coexisting multimorbidity, frailty, and malnutrition. Therefore, it is often difficult to solve these problems with Western medicine alone, and a holistic approach, including Kampo medicine, can be helpful. In particular, managing volume control and frailty by adding Kampo formulas may help improve health-related quality of life and substantially impact prognosis in HF. This review article summarizes the role of Kampo medicine for older patients with HF and frailty.

Pulmonary pleomorphic carcinoma metastasizing to the anterior mandibular gingiva: A case report and literature review.

INTRODUCTION AND IMPORTANCE: Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of non-small cell lung cancer. No standard therapy has been established for advanced disease, which results in poor prognosis. Some cases of PPC metastasizing to mandibular gingiva have been reported, and the involved site in these reports is all unilateral mandible. CASE PRESENTATION: We report a case of PPC metastasizing to the anterior mandibular gingiva in a 68-year-old man. The patient was referred to our hospital with tumor bleeding and difficulty with intake. One month before, he had been diagnosed as PPC. The size of oral tumor was 28 × 25 mm, and we performed surgical resection. Although there was no recurrence of oral lesion, he died of systemic metastases after 3 months since the surgery. CLINICAL DISCUSSION: The prognosis of patients with metastatic tumor in oral region is poor. Radical treatment for oral lesion is often difficult due to the existence of other metastasis or the refractory, in particular cases with high grade malignancies such as PPC. On the other hand, because of the development of cancer treatment and the arrival of super-aging society, the number of patients with metastatic tumor in oral region has been expected to increase in future. CONCLUSION: PPC metastasizing to the gingiva of mandibular symphysis is extremely rare. If there are possibilities to improve the prognosis or quality of life, radical or palliative treatment for metastatic tumor in oral region should be performed.

Clinical course of masticatory function recovery following arthrocentesis in patients with unilateral mandibular condyle head fracture.

The aim of this study was to investigate the clinical course of masticatory function recovery following arthrocentesis. Patients with a unilateral condylar head fracture who underwent arthrocentesis for therapeutic reasons were evaluated and compared with patients with a unilateral condylar head fracture who did not undergo arthrocentesis. At 3 months after treatment, the occlusal contact area and maximum bite force in patients with a fracture treated with arthrocentesis were greater than in those who did not receive arthrocentesis at the same time points, although the differences were not significant. Moreover, at 1 and 3 months following arthrocentesis, mean (±SD) occlusal contact area (1 month: 1.99 ± 0.55 mm2, p = 0.01; 3 months: 2.90 ± 1.36 mm2, p = 0.03) and maximum bite force (1 month: 82.45 ± 15.04 N, p = 0.01; 3 months: 101.11 ± 14.53 N, p = 0.01) on the fractured side in patients who underwent that treatment were significantly reduced when compared with those on the non-fractured side. The authors conclude that if the priority is to avoid open reduction and internal fixation, then the arthrocentesis approach might be a less invasive alternative, albeit with the price of a prolonged healing interval.

Gibberellin biosynthesis and signalling during development of the strawberry receptacle.

The enlargement of receptacle cells during strawberry (Fragaria × ananassa) fruit development is a critical factor determining fruit size, with the increase in cell expansion being one of the most important physiological processes regulated by the phytohormone gibberellin (GA). Here, we studied the role of GA during strawberry fruit development by analyzing the endogenous content of bioactive GAs and the expression of key components of GA signalling and metabolism. Bioactive GA(1) , GA(3) and GA(4) were monitored during fruit development, with the content of GA(4) being extremely high in the receptacle, peaking at the white stage of development. •Genes with high homology to genes encoding GA pathway components, including receptors (FaGID1(GIBBERELLIN-INSENSITIVE DWARF1)b and FaGID1c), DELLA (FaRGA(REPRESSOR OF GA) and FaGAI(GA-INSENSITIVE)), and enzymes involved in GA biosynthesis (FaGA3ox) and catabolism (FaGA2ox), were identified, and their expression in different tissues and developmental stages of strawberry fruit was studied in detail. The expression of all of these genes showed a stage-specific pattern during fruit development and was highest in the receptacle. FaGID1c bound GA in vitro, interacted with FaRGA in vitro and in vivo, and increased GA responses when ectopically expressed in Arabidopsis. This study thus reveals key elements of GA responses in strawberry and points to a critical role for GA in the development of the receptacle.

Association between Takayasu arteritis and ulcerative colitis - case report and review of serological HLA analysis.

BACKGROUND: Takayasu arteritis and ulcerative colitis are immune-mediated inflammatory diseases; genetic factors are assumed to play an important role in the pathogenesis of these 2 diseases. However, the coexistence of these 2 diseases has rarely been reported. CASE REPORT: In this report, we present a rare case of a 29-year-old man with a 4 years history of ulcerative colitis who developed Takayasu arteritis. He was found to carry the following human leukocyte antigens (HLA): A11, A24, B52, B62, DR4, and DR9. CONCLUSIONS: We present a case report and review of the pertinent literature on serological analysis of HLA haplotype of the patients who exhibit both these diseases. In patients with both Takayasu arteritis and ulcerative colitis, high frequency of HLA-A24, B52, and DR 2 is observed. The pathological relevance of HLA-A24, B52, and DR2 to concomitant Takayasu arteritis and ulcerative colitis requires further investigation.

Differential expression and affinities of Arabidopsis gibberellin receptors can explain variation in phenotypes of multiple knock-out mutants.

In Arabidopsis, three receptors exist for the phytohormone gibberellin. Of the three, only a double loss-of-function mutant (atgid1a atgid1c) shows a dwarf phenotype, while other double and all single mutants show no abnormality in height. In this study we show that the expression of AtGID1b-GUS mRNA, driven by the AtGID1b promoter, is low in inflorescence stems, but may be 10% of AtGID1a-GUS mRNA, driven by the AtGID1a promoter. However, AtGID1b-GUS enzymatic activity does not exist in them. This factor strongly suggests that atgid1a atgid1c lacks sufficient AtGID1b protein for normal stem growth. In the stamens of pAtGID1c::AtGID1c-GUS transformants, we detected clear AtGID1c-GUS activity, while another atgid1a atgid1b, which has short stamens in its flowers, causes the adhesion of little pollen to stigmas thus leading to its low fertility. We then evaluated the affinity of the AtGID1-DELLA interaction by a competitive yeast three-hybrid system and also by QCM apparatus. AtGID1c showed a quite lower affinity to RGL2, the major DELLA protein in floral buds, than AtGID1a or AtGID1b. The low affinity of the AtGID1c-RGL2 interaction is likely to be responsible for the failure of AtGID1c to hold RGL2, which is required for normal stamen development. Taken together with expressional information of DELLA genes, we propose that in a double loss-of-function mutant of gibberellin receptors, the emergence of any phenotype(s) depends on the abundance of the remaining receptor and its preference to DELLA proteins existing at a target site.

Successful endoscopic clipping for bleeding from colonic angiodysplasia in a case of Heyde syndrome.

BACKGROUND: Aortic valve sclerosis, calcification, and stenosis are common in the elderly. Increased life expectancy has resulted in a growing population of elderly people, with a corresponding increase in the number of patients with these degenerative aortic valve diseases. CASE REPORT: We report a case of severe aortic stenosis in an 82-year-old woman with bleeding due to colonic angiodysplasia. The patient presented with anemia unexpectedly before her aortic valve replacement. Colon fiberscopy revealed that colonic angiodysplasia was responsible for the bleeding. The lesion was treated with endoscopic clipping before the successful aortic valve replacement. Additionally, her immunoblot analysis detected a decrease of large molecular weight multimers of von Willebrand factor. CONCLUSIONS: The relationship between aortic valve stenosis, acquired von Willebrand disease and gastrointestinal bleeding in elderly patients is known as Heyde syndrome. Clinicians should be aware of the possibilities of acquired von Willebrand disease and gastrointestinal bleeding from angiodysplasia in patients with aortic valve stenosis.

Germination of photoblastic lettuce seeds is regulated via the control of endogenous physiologically active gibberellin content, rather than of gibberellin responsiveness.

Phytochrome regulates lettuce (Lactuca sativa L. cv. Grand Rapids) seed germination via the control of the endogenous level of bioactive gibberellin (GA). In addition to the previously identified LsGA20ox1, LsGA20ox2, LsGA3ox1, LsGA3ox2, LsGA2ox1, and LsGA2ox2, five cDNAs were isolated from lettuce seeds: LsCPS, LsKS, LsKO1, LsKO2, and LsKAO. Using an Escherichia coli expression system and functional assays, it is shown that LsCPS and LsKS encode ent-copalyl diphosphate synthase and ent-kaurene synthase, respectively. Using a Pichia pastoris system, it was found that LsKO1 and LsKO2 encode ent-kaurene oxidases and LsKAO encodes ent-kaurenoic acid oxidase. A comprehensive expression analysis of GA metabolism genes using the quantitative reverse transcription polymerase chain reaction suggested that transcripts of LsGA3ox1 and LsGA3ox2, both of which encode GA 3-oxidase for GA activation, were primarily expressed in the hypocotyl end of lettuce seeds, were expressed at much lower levels than the other genes tested, and were potently up-regulated by phytochrome. Furthermore, LsDELLA1 and LsDELLA2 cDNAs that encode DELLA proteins, which act as negative regulators in the GA signalling pathway, were isolated from lettuce seeds. The transcript levels of these two genes were little affected by light. Lettuce seeds in which de novo GA biosynthesis was suppressed responded almost identically to exogenously applied GA, irrespective of the light conditions, suggesting that GA responsiveness is not significantly affected by light in lettuce seeds. It is proposed that lettuce seed germination is regulated mainly via the control of the endogenous content of bioactive GA, rather than the control of GA responsiveness.

Real-time monitoring system for evaluating the acid-producing activity of oral squamous cell carcinoma cells at different environmental pH.

This study aimed to establish a real-time monitoring system for evaluating the acid-producing activity of cells and the effects of microenvironmental pH on their metabolism. Oral squamous cell carcinoma (HSC-2, HSC-3) and normal (HaCaT) cells were used. Their acid-producing activity from glucose, glutamine, and glutamate was monitored at various pH values using a pH stat system. Their production of lactic acid and ammonia was also measured. The acid-producing activity was monitored successfully. Both the cancer and normal cells produced acids from glucose, glutamine, and glutamate. All of the cells decreased their acid-producing activity as the environmental pH fell, but in glucose-derived acid-producing activity the cancer cells were more acid-tolerant than HaCaT cells. In the cancer cells, the proportion of lactic acid among all acids produced from glucose at the acidic environment tended to be higher than that in HaCaT cells. All of the cells produced ammonia from glutamine, while only HaCaT cells produced ammonia from glutamate. We established a real-time monitoring system for evaluating the acid-producing activity of cells. Our results suggest that the cancer cells possess acid-tolerant glucose metabolism with a tendency of metabolic shift to lactic acid production at acidic pH and they metabolise glutamate without ammonia production.

Genome-Wide Deletion Screening with the Array CGH Method in Mouse Offspring Derived from Irradiated Spermatogonia Indicates that Mutagenic Responses are Highly Variable among Genes.

Until the end of the 20th century, mouse germ cell data on induced mutation rates, which were collected using classical genetic methods at preselected specific loci, provided the principal basis for estimates of genetic risks from radiation in humans. The work reported on here is an extension of earlier efforts in this area using molecular methods. It focuses on validating the use of array comparative genomic hybridization (array CGH) methods for identifying radiation-induced copy number variants (CNVs) and specifically for DNA deletions. The emphasis on deletions stems from the view that it constitutes the predominant type of radiation-induced genetic damage, which is relevant for estimating genetic risks in humans. In the current study, deletion mutations were screened in the genomes of F1 mice born to unirradiated or 4 Gy irradiated sires at the spermatogonia stage (100 offspring each). The array CGH analysis was performed using a "2M array" with over 2 million probes with a mean interprobe distance of approximately 1 kb. The results provide evidence of five molecularly-confirmed paternally-derived deletions in the irradiated group (5/100) and one in the controls (1/100). These data support a calculation, which estimates that the mutation rate is 1 × 10-2/Gy per genome for induced deletions; this is much lower than would be expected if one assumes that the specific locus rate of 1 × 10-5/locus per Gy (at 34 loci) is applicable to other genes in the genome. The low observed rate of induced deletions suggests that the effective number of genes/genomic regions at which recoverable deletions could be induced would be only approximately 1,000. This estimate is far lower than expected from the size of the mouse genome (>20,000 genes). Such a discrepancy between observation and expectation can occur if the genome contains numerous genes that are far less sensitive to radiation-induced deletions, if many deletion-bearing offspring are not viable or if the current method is substandard for detecting small deletions.

[Giant, invasive sacral schwannoma extending to the 4th lumbar spine].

In this report, we describe a case with giant sacral schwannoma, which invasively extended to the 4th lumbar spine and to the surrounding sacral and iliac bone. A 26-year-old female was admitted to our hospital because of numbness and transient weakness of the right leg, and dysuria. Radiological examinations revealed that a giant sacral tumor, associated with multiple cystic formations, had invasively extended to the 4th lumbar spine, sacrum, and iliac bone. She underwent partial removal of the tumor, followed by irradiation. Pathological diagnosis was schwannoma. Subsequently, she underwent a second operation because of tumor regrowth 15 months later, and the tumor was totally removed. Numbness of the right leg resolved after surgery. No tumor recurrence has been noted during 5-year follow-up period. Previously, only 5 cases have been reported of invasive sacral schwannoma extending to the lumbar spine. Our experience in this rare case strongly suggests that aggressive resection should be aimed to improve long-term outcome.

[Three cases of successful stenting for radiation-induced carotid arterial stenosis].

We report three cases of radiation-induced carotid arterial stenosis that underwent successful angioplasty with stenting. The patients had received radiation therapy for tongue or laryngeal cancers and developed minor completed strokes 6 to 14 years after irradiation. All patients had multiple and bilateral stenosis, measuring more than 50%, of the carotid arteries. The stenosis was located in the internal, external, and common carotid arteries. We performed percutaneous transluminal angioplasty with stenting. All interventions were successful and carotid stenosis decreased to less than 28%. No permanent complications occurred. During follow-up periods of up to 26 months, all of these cases were free from ischemic symptoms. Neither carotid angiography nor ultrasound sonography showed evidence of restenosis. The present results suggest the usefulness of angioplasty with stenting for radiation-induced carotid arterial stenosis.

Factors influencing left atrial volume in treated hypertension.

BACKGROUND: Left atrial (LA) enlargement has been documented to occur in hypertension (HT), and has been an index for evaluating the diastolic function of the left ventricle. Enlargement of the LA is one of the vital factors that induce heart failure and atrial fibrillation (AF) in patients with HT. METHODS AND SUBJECTS: 130 treated hypertensive patients were enrolled. All recruits participated in an echocardiogram, electrocardiogram, a routine blood examination including brain natriuretic peptide (BNP), and physical examinations. RESULTS: Left ventricular mass (LVM) indexed to height(2.7) had a significant positive correlation with left atrial volume index (LAVI) (p<0.0001), as well as natural logarithm BNP (p<0.001). Blood pressure levels were not associated with LAVI, neither body mass index nor age. LAVI had a positive correlation with factors involving the left ventricle volume, LVM, and right ventricle systolic pressure (RVSP) (r=0.687, p<0.0001). The parameters of LV diastolic function were positively but weakly associated with LA size. In the subgroup of LAVI, the evidence of paroxysmal atrial fibrillation (PAF): LAVI<32 ml/m(2) had no PAF, whereas the incidence of PAF was 7.5%, 11.4%, and 15.2%, respectively in the LAVI>32 ml/m(2) group. Of anti-hypertension drugs, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers had a tendency to reduce LAVI; however, there was no statistical significance within the groups. CONCLUSIONS: Left ventricular volume and mass are independent factors affecting LAVI in treated HT. The incidence of PAF is associated with LA size. In patients with treated HT, LA size may be a useful surrogate marker for monitoring the effectiveness of medical therapy and occurrence of AF.

A case of unforeseen intractable severe bacteremia due to Acinetobacter baumannii--an efficacy of sulbactam--.

We report the case of a 62-year-old woman with Acinetobacter baumannii bacteremia. She was admitted to our hospital with ventricular tachycardia and was subsequently diagnosed with idiopathic ventricular tachycardia, with no structural heart disease. However, 12 days after admission, she suddenly developed a high-grade fever with chills and diarrhea. Her blood cultures revealed A. baumannii, and the patient was treated with meropenem and amikacin sulfate. Yet, the patient's symptoms and clinical signs became worse. We then began to administer a large quantity of intravenous ampicillin-sulbactam, and the patient improved dramatically. Although rare, bloodstream infection caused by A. baumannii tends to be severe. Therefore, when A. baumannii is found in a patient's bloodstream, clinicians should start appropriate treatment immediately and should recall ampicillin-sulbactam as a sensible option for treatment.

Functional analysis of cotton orthologs of GA signal transduction factors GID1 and SLR1.

Gibberellic acid (GA) is both necessary and sufficient to promote fiber elongation in cultured fertilized ovules of the upland cotton variety Coker 312. This is likely due to the temporal and spatial regulation of GA biosynthesis, perception, and subsequent signal transduction that leads to alterations in gene expression and morphology. Our results indicate that the initiation of fiber elongation by the application of GA to cultured ovules corresponds with increased expression of genes that encode xyloglucan endotransglycosylase/hydrolase (XTH) and expansin (EXP) that are involved in promoting cell elongation. To gain a better understanding of the GA signaling components in cotton, that lead to such changes in gene expression, two GA receptor genes (GhGID1a and GhGID1b) and two DELLA protein genes (GhSLR1a and GhSLR1b) that are orthologous to the rice GA receptor (GID1) and the rice DELLA gene (SLR1), respectively, were characterized. Similar to the GA biosynthetic genes, expression of GhGID1a and GhGID1b is under the negative regulation by GA while GA positively regulates GhSLR1a. Recombinant GST-GhGID1s showed GA-binding activity in vitro that was augmented in the presence of GhSLR1a, GhSLR1b, or rice SLR1, indicating complex formation between the receptors and repressor proteins. This was further supported by the GA-dependent interaction of these proteins in yeast cells. Ectopic expression of the GhGID1a in the rice gid1-3 mutant plants rescued the GA-insensitive dwarf phenotype, which demonstrates that it is a functional GA receptor. Furthermore, ectopic expression of GhSLR1b in wild type Arabidopsis led to reduced growth and upregulated expression of DELLA-responsive genes.

Pierre-Robin syndrome associated with Chiari type I malformation.

CASE REPORT: Pierre-Robin syndrome (PRS) is a rare congenital malformation that shows severe micrognathia and cleft soft palate. A 15-year-old boy who was admitted with occipital headache and gait disturbance was diagnosed with PRS. Radiological evaluation revealed severe herniation of the cerebellar tonsil and multiple craniovertebral osseous anomalies. We carried out foramen magnum decompression (FMD) with duroplasty. Postoperative MRI showed the cerebellar tonsil was freed from strangulation. RESULT AND CONCLUSION: This patient presented with the common finding between PRS and Chiari type I on the embryological aspect by illustrating pathophysiology of the Chiari I malformation. To our knowledge, this is the first reported case of PRS associated with Chiari malformation type I.