A randomized, double-blind, placebo-controlled phase II study of olanzapine-based prophylactic antiemetic therapy for delayed and persistent nausea and vomiting in patients with HER2-positive or HER2-low breast cancer treated with trastuzumab deruxtecan: ERICA study (WJOG14320B).

BACKGROUND: Nausea and vomiting are common adverse events associated with trastuzumab deruxtecan (T-DXd). We evaluated the efficacy of an olanzapine-based triplet regimen for preventing nausea and vomiting in patients receiving their first cycle T-DXd. PATIENTS AND METHODS: This multi-institutional, randomized, double-blind, placebo-controlled (ERICA) phase II study enrolled patients with human epidermal growth factor receptor 2-positive/human epidermal growth factor receptor 2-low metastatic breast cancer receiving their first cycle of T-DXd. Patients were randomized to olanzapine 5 mg or placebo once daily (1 : 1 ratio) from day 1 to day 6, plus a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone 6.6 mg intravenously or 8 mg orally on day 1. The total observation period was 504 h (21 days) from the first T-DXd administration. The primary endpoint was complete response (CR), defined as no emetic events and no rescue medications, in the delayed phase (24-120 h after T-DXd), with the type I error rate of 0.2 (one-sided) for the comparison. Secondary endpoints included no nausea rate in the delayed and persistent phases (120-504 h), adverse event by Common Terminology Criteria for Adverse Events (CTCAE) and patient-reported outcomes version of the CTCAE (PRO-CTCAE). RESULTS: In total, 168 patients were enrolled at 43 sites in Japan (November 2021-September 2023) with 162 patients (olanzapine, n = 80; placebo, n = 82) included in the per protocol set. The primary endpoint was met as the delayed phase CR rate was significantly greater with olanzapine than placebo (70.0% versus 56.1%, P = 0.047). Efficacy was maintained in the persistent phase (63.9% versus 44.4%). No nausea rate was also greater with olanzapine (delayed phase: 57.5% versus 37.8%; persistent phase: 51.4% versus 31.9%). CR rates in the delayed phase favored olanzapine across subgroups. Appetite loss was also decreased with olanzapine. Hyperglycemia and somnolence were mostly of low-grade severity. CONCLUSION: Olanzapine 5 mg for 6 days with 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone appears effective for T-DXd-treated patients to prevent delayed and persistent nausea and vomiting.

Plasma MMP-9 Levels as the Future Risk of Conversion to Dementia in ApoE4-Positive MCI Patients: Investigation Based on the Alzheimer's Disease Neuroimaging Initiative Database.

BACKGROUND: Matrix metalloproteinase 9 (MMP-9) has been reported to be correlated with declines in hippocampal volume and cognitive function in ApoE4-positive MCI patients. OBJECTIVES: The present study was aimed to investigate the effects of plasma matrix MMP-9 on the conversion risk between mild cognitive impairment (MCI) patients with and without ApoE4. DESIGN AND SETTING: Retrospective observational study using the data extracted from the Alzheimer's Disease Neuroimaging Initiative database. PARTICIPANTS: We included 211 ApoE4-positive MCI subjects (ApoE4+ MCI) and 184 ApoE4-negative MCI subjects (ApoE4- MCI). MEASUREMENTS: We obtained demographic and data including plasma MMP-9 levels at baseline and longitudinal changes in Clinical Dementia Rating (CDR) up to 15 years. We compared conversion rates between ApoE4+ MCI and ApoE4- MCI by the Log-rank test and calculated the hazard ratio (HR) for covariates including age, sex, educational attainment, drinking and smoking histories, medications, and plasma MMP-9 levels using a multiple Cox regression analysis of ApoE4+ MCI and ApoE4- MCI. RESULTS: No significant differences were observed in baseline plasma MMP-9 levels between ApoE4+ MCI and ApoE4- MCI. High plasma MMP-9 levels increased the conversion risk significantly more than low plasma MMP-9 levels (HR, 2.46 [95% CI, 1.31-4.48]) and middle plasma MMP-9 levels (HR, 1.67 [95% CI, 1.04-2.65]) in ApoE4+ MCI, but not in ApoE4- MCI. CONCLUSION: Plasma MMP-9 would be the risk of the future conversion to dementia in ApoE4+ MCI.

Difference between "Physical Fitness Age" Based on Physical Function and Chronological Age Is Associated with Obesity, Hyperglycemia, Depressive Symptoms, and Low Serum Albumin.

OBJECTIVES: This study aimed to (1) develop the physical fitness age, which is the biological age based on physical function, (2) evaluate the validity of the physical fitness age for the assessment of sarcopenia, and (3) examine the factors associated with the difference between physical fitness age and chronological age. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Community-dwelling older adults and outpatients. MEASUREMENTS: A formula for calculating the physical fitness age was created based on the usual walking speed, handgrip strength, one-leg standing time, and chronological age of 4,076 older adults from the pooled data of community-dwelling and outpatients using the principal component analysis. For the validation of the physical fitness age, we also used pooled data from community-dwelling older adults (n = 1929) and outpatients (n = 473). Sarcopenia was diagnosed according to the Asian Working Group for Sarcopenia 2019 consensus. The association of D-age (the difference between physical and chronological ages) with cardiovascular risk factors, renal function, and cardiac function was examined. RESULTS: The receiver operating characteristic analysis, with sarcopenia as the outcome, showed that the area under the curve (AUC) of physical fitness age was greater than that of chronological age (AUC 0.87 and 0.77, respectively, p < 0.001). Binomial logistic regression analysis revealed that the D-age was significantly associated with sarcopenia after adjustment for covariates (odds ratio 1.22, 95% confidence interval 1.19-1.26; p <0.001). In multivariate linear regression analysis with D-age as the dependent variable, D-age was independently associated with a history of diabetes mellitus (or hemoglobin A1c as a continuous variable), obesity, depression, and low serum albumin level. D-age was also correlated with estimated glomerular filtration rate derived from serum cystatin C, brain natriuretic peptide, and ankle-brachial index, reflecting some organ function and arteriosclerosis. CONCLUSIONS: Compared to chronological age, physical fitness age calculated from handgrip strength, one-leg standing time, and usual walking speed was a better scale for sarcopenia. D-age, which could be a simple indicator of physical function, was associated with modifiable factors, such as poor glycemic control, obesity, depressive symptoms, and malnutrition.

Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.

Identification of the Novel Tooth-Specific Transcription Factor AmeloD.

Basic-helix-loop-helix (bHLH) transcription factors play an important role in various organs' development; however, a tooth-specific bHLH factor has not been reported. In this study, we identified a novel tooth-specific bHLH transcription factor, which we named AmeloD, by screening a tooth germ complementary DNA (cDNA) library using a yeast 2-hybrid system. AmeloD was mapped onto the mouse chromosome 1q32. Phylogenetic analysis showed that AmeloD belongs to the achaete-scute complex-like ( ASCL) gene family and is a homologue of ASCL5. AmeloD was uniquely expressed in the inner enamel epithelium (IEE), but its expression was suppressed after IEE cell differentiation into ameloblasts. Furthermore, AmeloD expression showed an inverse expression pattern with the epithelial cell-specific cell-cell adhesion molecule E-cadherin in the dental epithelium. Overexpression of AmeloD in dental epithelial cell line CLDE cells resulted in E-cadherin suppression. We found that AmeloD bound to E-box cis-regulatory elements in the proximal promoter region of the E-cadherin gene. These results reveal that AmeloD functions as a suppressor of E-cadherin transcription in IEE cells. Our study demonstrated that AmeloD is a novel tooth-specific bHLH transcription factor that may regulate tooth development through the suppression of E-cadherin in IEE cells.

Lactobacillus gasseri PA-3, but not L. gasseri OLL2996, reduces the absorption of purine nucleosides in rats.

Lactobacillus gasseri PA-3 (PA-3) is a bacterial strain with a strong ability to degrade purine nucleosides. We previously showed that PA-3 incorporates purines in vitro and that oral administration of PA-3 and purines to rats attenuated their absorption of purines. It remains unclear whether these effects of PA-3 depend on bacterial strains. This study therefore compared the abilities of PA-3 and another bacterial strain of L. gasseri, OLL2996, which has shown decreased ability to degrade purine nucleosides in vitro, to incorporate purine nucleosides and to inhibit the absorption of purines fed to rats. Each bacterial strain was incubated in the presence of 14C-adenosine or 14C-inosine and the incorporation of each purine was evaluated by measuring their radioactivity. In vivo, rats were fed 14C-labeled purines along with PA-3 or OLL2996 and the absorption of these 14C-labeled purines was evaluated by analyzing radioactivity of blood samples. PA-3 incorporated about twice as much 14C-adenosine and 14C-inosine as OLL2996. The elevation of radioactivity levels in blood was 10-20% lower in rats treated with PA-3 than in control rats, after feeding with both 14C-adenosine and 14C-inosine as purines. In contrast, treatment with OLL2996 did not have statistically significant effects on radioactivity compared with the control group. These results indicate that the magnitude of bacterial inhibition of purine absorption is dependent on bacterial strain, correlating at least partly with the ability to incorporate and degrade purines.

Lactobacillus gasseri PA-3 utilizes the purines GMP and guanosine and decreases their absorption in rats.

Excessive intake of purine-rich foods elevates serum uric acid levels, making it a risk factor for hyperuricemia. We hypothesized that lactic acid bacteria ingested with food might utilize purines and contribute to their decreased absorption in the intestines, thereby preventing hyperuricemia. We previously reported that Lactobacillus gasseri PA-3 (PA-3) incorporates adenosine/inosine and related purines and that oral ingestion of PA-3 reduced the absorption of these purines in rats. However, it is unclear whether PA-3 also decreases the absorption of other purines, such as guanosine 5'-monophosphate (GMP) and guanosine. This study investigated whether PA-3 incorporates GMP and guanosine and reduces their absorption in rats. PA-3 incorporated both purines, with 14C-GMP uptake being greater than that of 14C-guanosine. Radioactivity in rat blood was significantly lower 30, 45, and 60 minutes after administration of 14C-GMP plus PA-3 than after administration of 14C-GMP alone and was significantly lower 15 minutes after administration of 14C-guanosine plus PA-3 than after administration of 14C-guanosine alone. PA-3 incorporates GMP and guanosine in vitro. Oral administration of PA-3 with GMP and guanosine reduces the intestinal absorption of these purines in vivo. These findings, together with those of previous studies, indicate that PA-3 reduces the absorption of major purines contained in foods. PA-3 may also attenuate the excessive absorption of dietary purines in humans, protecting these individuals against hyperuricemia.

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.

BACKGROUND: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. PATIENTS AND METHODS: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). RESULTS: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. CONCLUSION: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

Diagnostic and Prognostic Value of 11C-Methionine PET for Nonenhancing Gliomas.

BACKGROUND AND PURPOSE: Noninvasive radiologic evaluation of glioma can facilitate correct diagnosis and detection of malignant transformation. Although positron-emission tomography is considered valuable in the care of patients with gliomas, (18)F-fluorodeoxyglucose and (11)C-methionine have reportedly shown ambiguous results in terms of grading and prognostication. The present study compared the diagnostic and prognostic capabilities of diffusion tensor imaging, FDG, and (11)C-methionine PET in nonenhancing gliomas. MATERIALS AND METHODS: Thirty-five consecutive newly diagnosed, histologically confirmed nonenhancing gliomas that underwent both FDG and (11)C-methionine PET were retrospectively investigated (23 grade II and 12 grade III gliomas). Apparent diffusion coefficient, fractional anisotropy, and tumor-to-normal tissue ratios of both FDG and (11)C-methionine PET were compared between grade II and III gliomas. Prognostic values of these parameters were also tested by using progression-free survival. RESULTS: Grade III gliomas showed significantly higher average tumor-to-normal tissue and maximum tumor2-to-normal tissue than grade II gliomas in (11)C-methionine (P = .013, P = .0017, respectively), but not in FDG-PET imaging. There was no significant difference in average ADC, minimum ADC, average fractional anisotropy, and maximum fractional anisotropy. (11)C-methionine PET maximum tumor-to-normal tissue ratio of 2.0 was most suitable for detecting grade III gliomas among nonenhancing gliomas (sensitivity, 83.3%; specificity, 73.9%). Among patients not receiving any adjuvant therapy, median progression-free survival was 64.2 ± 7.2 months in patients with maximum tumor-to-normal tissue ratio of <2.0 for (11)C-methionine PET and 18.6 ± 6.9 months in patients with maximum tumor-to-normal tissue ratio of >2.0 (P = .0044). CONCLUSIONS: (11)C-methionine PET holds promise for World Health Organization grading and could offer a prognostic imaging biomarker for nonenhancing gliomas.

Immunoreactivity of glucose transporter 5 is located in epithelial cells of the choroid plexus and ependymal cells.

High fructose intake is associated with increased plasma triglyceride concentration, hepatic steatosis, impaired glucose tolerance, insulin resistance, and high blood pressure. In addition, increased fructose intake has recently been supposed to be a risk factor for dementia. However, direct effects of fructose on the brain function remain to be clarified. The localization of glucose transporter 5 (Glut5), a representative transporter of fructose, was immunohistochemically examined in the brains of humans, rats, and mice to clarify whether fructose was transported from the blood into the brain. Glut5 immunoreactivity was demonstrated to be located in the epithelial cells of the choroid plexus and the ependymal cells in the brains of humans and rats using commercial antibodies for Glut5. In addition, mRNA expression of mouse Glut5 was confirmed in the brains of mice. Immunohistochemical examination using a custom-made antibody against two regions of amino acid sequences of mouse Glut5 revealed that Glut5 immunoreactivity was also seen in the epithelial cells of the choroid plexus and the ependymal cells in the brains of mice. These findings show that Glut5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the brain parenchyma.

Generation of functional human vascular network.

BACKGROUND: One of the major obstacles in regenerating thick, complex tissues such as the liver is their need for vascularization, which is essential to maintain cell viability during tissue growth and to induce structural organization. Herein, we have described a method to engineer a functional human vascular network. METHODS: Enhanced green fluorescence protein-labeled human umbilical vein endothelial cells (GFP-HUVECs) were cocultivated with kusabira orange-labeled human mesenchymal stem cells (KO-hMSCs) inside a collagen/fibronectin matrix. Premature vascular network formation was visualized by fluorescence microscopy imaging. Furthermore, constructs prevascularized in vitro were implanted into a transparency window in immunodeficient mice. RESULTS: Following several days of cultivation, GFP-HUVECs formed vessel-like structures that were stabilized by pericytes differentiated from KO-hMSCs. After implantation in vivo, the patency of human vascular structures was proved by rhodamine dextran infusion. These functional vascular structures remained for over 2 months. DISCUSSION: Vascularization is the key challenge to organ generation. We successfully generated human vascular networks inside a matrix. Integration of parenchymal cells using our engineering technique should facilitate future efforts to reconstitute vascularized human organ systems in vitro.

Phorbol 12,13-dibutyrate-mediated contraction of the stimulated bronchial smooth muscles of mice.

Increasing evidence suggests that protein kinase C (PKC) is involved in the Ca(2+) sensitization of various smooth muscle contractions. However, the exact role of PKC on bronchial smooth muscle (BSM) contraction is still unclear. In the present study, to determine the role of PKC activation in the BSM contraction, the effects of phorbol 12,13-dibutyrate (PDBu) on BSM tone were examined in the absence and presence of contractile stimulation. Although PDBu had no effect on the basal tone, the contraction induced by acetylcholine, high K(+) depolarization or Ca(2+) ionophore A23187 was significantly augmented by PDBu. Western blot analyses also revealed that the increase in the level of phosphorylated myosin light chain (MLC) induced by high K(+) depolarization was significantly augmented by PDBu treatment. Interestingly, neither high K(+) depolarization alone nor PDBu alone caused CPI-17 phosphorylation, but a significant phosphorylation of CPI-17 was observed when BSMs were co-stimulated by high K(+) and PDBu. Thus, a certain level of intracellular Ca(2+) might be needed both for an activation of CPI-17 and an induction of contraction induced by PDBu in mouse BSMs.

Tonsillectomy in the treatment of pediatric Henoch-Schönlein nephritis.

The exact pathophysiology of HSN remains to be elucidated. Hence, a therapeutic strategy that enables curative treatments for all the various grades of HSN patients has yet to be established. We report our experience performing tonsillectomy combined with steroid therapy for 16 pediatric proteinuric Henoch-Schönlein nephritis (HSN) patients. All patients exhibited hematuria and proteinuria in their first HSN attack with the mean age of onset 7.7 years (range 4.75 - 13.9 years). Nine patients were diagnosed with clinically severe HSN presenting with massive proteinuria (> 1 g/m(2)/day). Renal biopsy findings performed in 6 patients were Grade II (3), Grade III (2) and Grade IV (1) according to the International Study of Kidney Diseases in childhood classification. Tonsillectomy was performed after 1-4 cycles of methylprednisolone pulses during oral prednisolone (0.5 - 1.5 mg/kg/day) therapy. In 2 patients, oral cyclophosphamide therapy was added before the tonsillectomy. The interval between the onset of HSN and tonsillectomy was 97.4 +/- 24.5 days (range 27 424 days). In all patients, proteinuria had disappeared by 6 months after the tonsillectomy and the urine findings had normalized. The interval between therapy initiation and complete remission was 9.6 +/- 2.0 months (range 2 - 26 months). Over follow-up periods of 4.9 +/- 0.6 years (range 2.2 - 9.3 years), no recurrences of Henoch-Schonlein purpura or HSN were observed. There was a significant correlation between early tonsillectomy performance and decreased time until normalization of the urine findings, indicating that the tonsils may have pivotal roles in the initiation and progression of HSN. Their elimination might promote the reversal of nephritis. Although this study is retrospective, we suggested that tonsillectomy at an early stage of HSN may be beneficial by shortening the period of illness and contributing to clinical recovery. Randomized controlled trials will be needed to confirm this supposition.

Changes in HRCT findings in patients with respiratory bronchiolitis-associated interstitial lung disease after smoking cessation.

High-resolution computed tomography (HRCT) findings in patients with respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) are varied and nonspecific. There is no known report of changes in HRCT findings and respiratory function test results for RB-ILD patients following the cessation of smoking. Five patients with RB-ILD, confirmed by surgical lung biopsy, were retrospectively studied. Each stopped cigarette smoking and did not receive corticosteroid therapy after diagnosis. The clinical symptoms, respiratory function test results and HRCT findings obtained at the final observation were compared with those from the time of diagnosis. Ground-glass opacity and centrilobular nodules corresponding to pathological respiratory bronchiolitis, as well as intralobular fine linear-reticular opacity corresponding to fibrosis involving the subpleural alveolar septa, showed computed tomography-pathological correlations. Both clinical symptoms and the diffusing capacity of the lungs for carbon monoxide improved significantly following smoking cessation, as did ground-glass opacity and centrilobular nodules seen during the initial HRCT examination. Centrilobular nodules and ground-glass opacity, which are the main features of high-resolution computed tomography of respiratory bronchiolitis-associated interstitial lung disease patients and represent pathological respiratory bronchiolitis, can be improved by smoking cessation. The diffusing capacity of the lung for carbon monoxide in respiratory function tests can be also improved.

Highly selective localization of leukotriene C4 synthase in hypothalamic and extrahypothalamic vasopressin systems of mouse brain.

While leukotriene C4 (LTC4) was originally identified as a potent bronchoconstrictor, the compound has versatile biological activities besides inflammatory reactions. Although the high content of LTC4 has been reported in the hypothalamus and median eminence, the precise localization of the compound remained obscure. To elucidate its possible functions in the neuroendocrine systems, we determined immunohistochemical localization of LTC4 synthase, a key enzyme to produce LTC4 using mouse brains. Light microscopy and confocal laser scanning microscopy showed that LTC4 synthase was selectively localized in the vasopressinergic magnocellular neurons of the hypothalamic paraventricular, supraoptic and suprachiasmatic nuclei and in the retrochiasmatic area, as well as in axons that emanated from these neurons to the pars nervosa of the pituitary gland. At subcellular level, however, LTC4 synthase and arginine vasopressin appeared to localize differently within individual neurons. LTC4 synthase immunoreactivity was also observed in the axons of the extrahypothalamic system including the bed nucleus of the stria terminalis, lateral habenular nucleus, midbrain central gray, medial amygdaloid nucleus and ventral septal area, although this immunoreactivity was relatively minor. The other brain regions did not contain LTC4 synthase immunoreactivity. The distribution of LTC4 synthase did not overlap with that of either oxytocin or luteinizing hormone releasing hormone. Therefore, LTC4 is considered to be involved in neural functions of the brain magnocellular vasopressinergic system such as water retention. LTC4 may also be involved in extrahypothalamic vasopressinergic neural functions including the regulation of learning and memory, social recognition memory, sexual and aggressive behavior, etc.

Autoregulation of the gene for cystathionine gamma-synthase in Arabidopsis: post-transcriptional regulation induced by S-adenosylmethionine.

Cystathionine gamma-synthase (CGS) catalyses the first committed step of methionine biosynthesis in higher plants. CGS is encoded by the CGS1 gene in Arabidopsis. Stability of CGS1 mRNA is down-regulated in response to methionine application and the exon 1-coding region of CGS1 itself is necessary and sufficient for this regulation. mto1 (for methionine overaccumulation) mutants of Arabidopsis, which carry single-amino-acid sequence alterations within CGS1 exon 1, are deficient in this regulation and overaccumulate methionine. Since CGS1 exon 1 acts in cis during this regulation, we have proposed a model that the regulation occurs during translation of CGS1 mRNA when the nascent polypeptide of CGS and its mRNA are in close proximity. In fact, application of the translation inhibitor cycloheximide abolished this regulation in vivo. This model predicts that the regulation can be reproduced in an in vitro translation system. Studies using the in vitro translation system of wheatgerm extract have indicated that S-adenosylmethionine, a direct metabolite of methionine, is the effector of this regulation. A 5'-truncated RNA species, which is a probable degradation intermediate of CGS1 mRNA in vivo, was also detected in vitro, suggesting that the wheatgerm in vitro translation system reflects the in vivo regulation.

[Thoracic outlet syndrome with arterial complication treated by the subclavicular transsternal approach: report of a case].

A 42-year-old female was referred to our vascular service because of her right arm fatigue and cold sensitivity. On elevation of right arm, her radial pulse was absent with pallor of the hand. Angiography demonstrated a significant stenosis of the right subclavian artery, which was considered to be complication of thoracic outlet syndrome. We performed resection of the first rib using the standard subclavicular approach and the subclavian-subclavian artery bypass using a new transsternal extension approach to the subclavian artery. After follow-up 18 months, she was working and asymptomatic. This transsternal extension is effective to treat the arterial complication after decompression of the thoracic outlet.

Initial experiences of tissue harmonic imaging in the diagnosis of fetal cardiac tumors.

The usefulness of tissue harmonic imaging in prenatal diagnosis is illustrated in two fetuses with a cardiac tumor. Tissue harmonic imaging provided more informative images than conventional B-mode imaging, enabling the detection of the site of attachment of the cardiac tumor and estimation of intracardiac blood flow. The advantages of tissue harmonic imaging over conventional B-mode imaging in prenatal diagnosis are discussed.

The first exon coding region of cystathionine gamma-synthase gene is necessary and sufficient for downregulation of its own mRNA accumulation in transgenic Arabidopsis thaliana.

Expression of the gene for cystathionine gamma-synthase (CGS), which catalyzes the key step of methionine biosynthesis, is feedback regulated at the level of mRNA stability. The first exon polypeptide of CGS is suggested to be involved in this regulation and amino acid sequence alterations caused by mto1 mutations in that region lead to an overaccumulation of CGS mRNA [Chiba et al. (1999) Science 286: 1371-1374]. Transgenic Arabidopsis thaliana harboring chimeric constructs in which wild-type or mto1 mutant CGS exon 1 are fused in-frame to reporter genes and driven by the cauliflower mosaic virus 35S RNA promoter were constructed. Studies with these transgenic lines demonstrated that the coding region of CGS exon 1 is necessary and sufficient for downregulation of its own mRNA accumulation in response to methionine application and that this region acts in cis in this process.

Hyperamylasemia and subclinical pancreatitis after cardiac surgery.

Hyperamylasemia after cardiac surgery is common but typically causes no clinical concern because it consists mainly of the salivary isoenzyme. In this study we evaluated the incidence, source, and time course of postoperative hyperamylasemia with special attention to the possibility of subclinical pancreatitis. In 88 patients prospectively tested for serum amylase and lipase concentrations, elastase 1 activity, and amylase isoenzyme characteristics, 57 (64%) showed hyperamylasemia during the early postoperative period. In most cases early hyperamylasemia was not of pancreatic origin, but two patients were diagnosed with subclinical pancreatitis. Among the last 23 patients, 5 of 10 patients with early hyperamylasemia exceeding 1000 IU/L showed late hyperamylasemia on the seventh postoperative day, when it represented mainly the pancreatic isoenzyme. Lipase concentrations and elastase 1 activities were elevated in these cases. Late hyperamylasemia following cardiac surgery may be of pancreatic origin and indicative of subclinical pancreatitis, even if early hyperamylasemia was of salivary origin.