Author Correction: Structural basis for the drug extrusion mechanism by a MATE multidrug transporter.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

The structure of MgtE in the absence of magnesium provides new insights into channel gating.

MgtE is a Mg2+ channel conserved in organisms ranging from prokaryotes to eukaryotes, including humans, and plays an important role in Mg2+ homeostasis. The previously determined MgtE structures in the Mg2+-bound, closed-state, and structure-based functional analyses of MgtE revealed that the binding of Mg2+ ions to the MgtE cytoplasmic domain induces channel inactivation to maintain Mg2+ homeostasis. There are no structures of the transmembrane (TM) domain for MgtE in Mg2+-free conditions, and the pore-opening mechanism has thus remained unclear. Here, we determined the cryo-electron microscopy (cryo-EM) structure of the MgtE-Fab complex in the absence of Mg2+ ions. The Mg2+-free MgtE TM domain structure and its comparison with the Mg2+-bound, closed-state structure, together with functional analyses, showed the Mg2+-dependent pore opening of MgtE on the cytoplasmic side and revealed the kink motions of the TM2 and TM5 helices at the glycine residues, which are important for channel activity. Overall, our work provides structure-based mechanistic insights into the channel gating of MgtE.

Human movement avoidance decisions during Coronavirus disease 2019 in Japan.

Understanding host behavioral change in response to epidemics is important to forecast the disease dynamics. To predict the behavioral change relevant to the epidemic situation (e.g., the number of reported cases), we need to know the epidemic situation at the moment of decision, which is difficult to identify from the records of actually performed human mobility. In this study, the largest travel accommodation reservation data covering half of the existed accommodations in Japan was analyzed to observe decision-making timings and how it responded to the changing epidemic situation during Japan's Coronavirus Disease 2019 until February 2023. To this end, we measured mobility avoidance index proposed in Ito et al., 2022 to indicate people's decision of mobility avoidance and quantified it using the time-series of the accommodation booking/cancellation data. We observed matches of the peak dates of the mobility avoidance and the number of reported cases, and mobility avoidance changed proportional to the logarithmic number of reported cases. We also found that the slope of mobility avoidance against the change of the logarithmic number of reported cases were similar among the epidemic waves, while the intercept of that was much reduced as the first epidemic wave passed by. People measure the intensity of epidemic by logarithm of the number of reported cases. The sensitivity of their response is established during the first wave and the people's response became weakened after the first experience, as if the number of reported cases were multiplied by a constant small factor.

Efficacy of antiviral therapy for the prevention of mother-to-child transmission of hepatitis B virus and the risk of postpartum hepatitis flare after discontinuation of antiviral therapy.

The use of nucleos(t)ide analogs (NAs) is recommended for mothers with a high viral load of hepatitis B virus (HBV) during the second or third trimester of pregnancy. However, postpartum hepatitis flares can occur in some cases. We examined the efficacy of NA administration for the prevention of mother-to-child transmission of hepatitis B virus, and evaluated the risk of postpartum hepatitis flares in mothers after NA discontinuation. Nine pregnant women with a high viral load (HBV DNA ≥5.3 log IU/mL) received tenofovir disoproxil fumarate (TDF) at approximately 28 weeks of gestation, and TDF was discontinued at 4-10 weeks after delivery. We evaluated the virological and biochemical parameters in mothers after TDF discontinuation. Hepatitis flares in mothers were defined as alanine transaminase level ≥60 U/L. None of the infants developed any congenital anomaly or acquired HBV infection during infancy. Hepatitis flares occurred within 6 months after TDF discontinuation in five of seven cases, whereas two cases were lost to follow-up. Furthermore, three cases required the resumption of NA use. NA administration was highly effective against mother-to-child-transmission of HBV in pregnant women with high HBV DNA levels. However, hepatitis flares were commonly observed after NA discontinuation in the postpartum period. Patients should be followed up carefully after NA discontinuation, and NA resumption should be considered based on a comprehensive assessment of virological and biochemical parameters.

Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

Impact of the quality of resected thyroid cancer tissue sample on next-generation sequencing testing.

Activating rearranged during transfection (RET) proto-oncogene alterations can be identified using next-generation sequencing (NGS) of tumor DNA/RNA. We assessed factors associated with NGS (Oncomine Dx Target Test [ODxTT]) success for resected thyroid cancer (TC) specimens, including sample age, processing conditions, and DNA/RNA quality. TC samples were from three Japanese hospitals, with sample age <1-<10 years, fixative 10%/15% neutralized buffered formalin (NBF), and fixation time ≤48 h/>48 h-≤72 h. NGS success rate was defined as the percentage of samples returning validated NGS results (RET fusion-positive/negative [RNA] or RET mutation-positive/negative [DNA], detected using ODxTT). DNA/RNA quality was assessed with indexes based on electrophoresis (DNA/RNA integrity number, DV200 ) and quantitative polymerase chain reaction (DNA/RNA integrity score [ddCq/ΔCq]). NGS success rate (N = 202) was 90%/93% (DNA/RNA) overall, 98%-100% (DNA and RNA) for samples <3 years old, and 91% (DNA and RNA) for samples ≥3-<5 years old fixed in 10% NBF for ≤48 h. Multivariate logistic regression analysis identified ddCq and ΔCq as significant predictors of DNA and RNA NGS success rates, respectively. Quality assessment of nucleic acid extracted from archival tissue samples is important for achieving high NGS success rates in clinical practice, especially for samples ≥3 years old.

Dose-dependent incidence of agranulocytosis in patients treated with methimazole and propylthiouracil.

Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves' disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

Continuous irregular dynamics with multiple neutral trajectories permit species coexistence in competitive communities.

The colonization model formulates competition among propagules for habitable sites to colonize, which serves as a mechanism enabling coexistence of multiple species. This model traditionally assumes that encounters between propagules and sites occur as mass action events, under which species distribution can eventually reach an equilibrium state with multiple species in a constant environment. To investigate the effects of encounter mode on species diversity, we analyzed community dynamics in the colonization model by varying encounter processes. The analysis indicated that equilibrium is approximately neutrally-stable under perfect ratio-dependent encounter, resulting in temporally continuous variation of species' frequencies with irregular trajectories even under a constant environment. Although the trajectories significantly depend on initial conditions, they are considered to be "strange nonchaotic attractors" (SNAs) rather than chaos from the asymptotic growth rates of displacement. In addition, trajectories with different initial conditions remain different through time, indicating that the system involves an infinite number of SNAs. This analysis presents a novel mechanism for transient dynamics under competition.

Comparison of pancreatic enzyme abnormalities and protease-activated receptor-2-positive eosinophils in the duodenum of patients with functional dyspepsia-irritable bowel syndrome overlap with functional dyspepsia alone in Asian populations.

BACKGROUND AND AIM: Some patients with functional gastrointestinal disorders exhibit pancreatic dysfunctions and pancreatic enzyme abnormalities. Thus, we aimed to clarify whether significant differences in clinical characteristics, prevalence of pancreatic enzyme abnormalities, duodenal inflammation, and protease-activated receptor 2 (PAR2) expression levels related to hypersensitivity exist between functional dyspepsia (FD) alone and FD-irritable bowel syndrome (IBS) overlap group. METHODS: Ninety-three patients based on the Rome IV criteria, FD alone (n = 44) and FD overlapped with IBS (n = 49) group were enrolled. The patients scored their own clinical symptoms after consuming high-fat meals. Serum trypsin, PLA2, lipase, p-amylase, and elastase-1 levels were measured. PAR2, eotaxin-3, and TRPV4 mRNA levels in duodenum were determined using real-time polymerase chain reaction methods. PRG2- and PAR2 in the duodenum were evaluated using immunostaining. RESULTS: FD score and global GSRS in patients with FD-IBS overlap were significantly higher than FD alone. Although the prevalence of pancreatic enzyme abnormalities in patients with FD alone was significantly (P < 0.01) higher than that in FD-IBS overlap, the ratio of aggravation of clinical symptoms following high-fat intake in patients with FD-IBS overlap was significantly higher (P = 0.007) than that in patients with FD alone. PAR2- and PRG2-double positive cells were localized in the degranulated eosinophils in the duodenum of patients with FD-IBS overlap. The number of PAR2- and PRG2-double positive cells in FD-IBS overlap was significantly (P < 0.01) higher than FD alone. CONCLUSIONS: Pancreatic enzyme abnormalities and PAR2 expression on degranulated eosinophils infiltrations in the duodenum may be associated with the pathophysiology of patients with FD-IBS overlap in Asian populations.

The importance of early-stage blood pressure control in thyroid cancer patients treated with lenvatinib from the perspective of dose intensity.

PURPOSE: Lenvatinib (LEN) is a multikinase inhibitor that strongly inhibits tyrosine kinase receptors, especially VEGFR-2, which can cause hypertension, as well as strong tumor shrinkage. Though control of any side effects (SEs) is important for maintaining dose intensity (DI), hypertension is particularly important, because blood pressure (BP) can change quickly and respond to LEN administration and withdrawal, and it can be controlled with antihypertensive medications. Focusing on the early phase of treatment, the effect of BP 8 weeks after LEN initiation (BP8w) on DI at 8 weeks (DI8w) was investigated. METHODS: The subjects were 85 thyroid cancer patients who started LEN at 24 mg/day and continued for ≥8 weeks. The BP at the start of LEN (BPbase), BP8w grade, and DI8w were examined. RESULTS: Median (range) systolic BP changed significantly from BPbase of 117 (84-167) mmHg to BP8w of 134 (103-168) mmHg (p<0.001). Antihypertensive treatment at baseline, systolic BPbase, and male sex were related to higher DI8w on multivariate analysis. The median DI8w of the 23 patients who required dose modification due to hypertension was 20.2 mg/day (n=6) in grade 1, 15.8 mg/day (n=13) in grade 2, and 14.5 mg/day (n=4) in grade 3, showing a trend toward lower DI8w as the grade level increased. CONCLUSION: LEN can increase BP by 20 mmHg at 8 weeks even with intensive antihypertensive management. Baseline antihypertensive treatment and BPbase can affect DI8w. A higher DI8w may be achieved by aiming for a low 8-week BP with more intensive antihypertensive therapy after LEN initiation.

New Insights on the Importance of the Extent of Vascular Invasion in Widely Invasive Follicular Thyroid Carcinoma.

BACKGROUND: This study aimed to investigate the association between the extent of vascular invasion (VI) and the outcome of widely invasive follicular thyroid carcinoma (WI-FTC). METHODS: The records of 107 patients with WI-FTC confirmed by surgical specimens from January 2005 to December 2016 were retrospectively reviewed. RESULTS: Among the 107 patients with WI-FTC, those with a VI of < 4 (n = 62) and ≥ 4 (n = 45) had a 10 year cause-specific survival (CSS) rate of 97.7% and 89.4% (p = 0.008), respectively. Univariate analysis identified M1 (p = 0.001), and the number of VI of ≥ 4 as significant negative prognostic factors for CSS. Multivariate analysis identified M1 (hazard ratio [HR] = 9.366) as independent negative prognostic factor for CSS. Among the 72 patients with M0 WI-FTC, those with a VI of < 2 (n = 33) and ≥ 2 (n = 39) had a 10-year distant metastasis-free survival (DMFS) rate of 96.8% and 56.8% (p = 0.001), respectively. Univariate analysis identified age ≥ 55 years (p = 0.011), presence of VI, the number of VI of ≥ 2, and resection margin status (p < 0.001) as significant negative prognostic factors for DMFS. Multivariate analysis identified the number of VI ≥ 2 (HR = 9.137), and resection margin status (HR = 5.853) as independent negative prognostic factors for DMFS. CONCLUSIONS: It may be unnecessary that WI-FTC with curative resection margin status and a VI of < 2, especially in capsular invasion only, routinely undergo completion thyroidectomy and postoperative ablation.

Impact of Age on Prognosis in Papillary Thyroid Carcinoma: How Should Age be Incorporated into the Treatment Strategy?

BACKGROUND: Age has been recognized as one of the strong prognostic indicators for thyroid cancer. However, treatment strategies for papillary thyroid cancer (PTC) are usually determined only by the extent of disease progression, without considering the patient's age. The aim of this study was to investigate how the surgical strategy for PTC should take into account patient age. METHODS: To exclude the effect of treatment strategy, 837 patients treated with uniform treatment strategies (hemithyroidectomy without radioiodine therapy) between 1986 and 1995 were the subjects of this study. Using a Cox proportional hazard model, clinical risk factors related to disease-specific survival (DSS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were analyzed. A receiver-operating characteristic (ROC) curve analysis was performed to identify the optimal cutoff points. RESULTS: Significant risk factors related to DSS and DMFS were age, extrathyroidal extension (ETE), and numbers of metastatic lymph nodes (NMLNs), but age was not significantly related to DFS. The 20-year DSS and DMFS rates were fair in patients without ETE regardless of age or NMLNs. However, in patients with ETE, DSS and DMFS rates were significantly worse in elderly patients than in young patients. ROC curve analysis showed that the optimal cutoff age was 48 years for discriminating DSS in patients with ETE. CONCLUSION: Regardless of age, PTC patients without ETE are candidates for a treatment strategy not using RAI, and more aggressive treatment may be recommended for elderly PTC patients with ETE.

Clinical features of moyamoya disease with Graves' disease: a retrospective study of 394,422 patients with thyroid disease.

Graves' disease has been reported to affect the clinical features of moyamoya disease (MMD), an occlusion of the circle of Willis. This study aimed to clarify the characteristics of MMD in patients with Graves' disease. This was a single-center, retrospective study. The prevalence and clinical features of MMD patients among all patients with thyroid disease who visited Ito Hospital from January 2005 to December 2019 were evaluated. The relationship between MMD and hyperthyroidism was analyzed in new-onset Graves' disease patients during the same period. Of all 394,422 patients with thyroid disease, 88,180 had Graves' disease, and 40 had MMD with Graves' disease, i.e., the prevalence was 45.36 per 100,000 patients with Graves' disease (0.0454%). The median age at onset of MMD was 39 years (interquartile range, 31-54 years), with a male to female ratio of 1:12. The most common time that MMD was diagnosed was within 1 year after the onset of Graves' disease, in 9 of 40 patients (22.5%), and 19 of 40 patients (47.5%) underwent bypass surgery for MMD. In MMD with Graves' disease, headache was the most frequent symptom, and ischemic types of stroke and bilateral lesions were common. Of 23,347 patients with new-onset Graves' disease, 7 were diagnosed with MMD and the incidence of MMD was 5.94 patients per 100,000 person-years. Most patients developed MMD symptoms during hyperthyroidism. Although MMD is a rare condition, it should be noted that it can occur with Graves' disease.

Radioiodine uptake after monotherapy with potassium iodide in patients with Graves' disease.

The effect of potassium iodide (KI) on radioiodine uptake (RAIU) before radioisotope therapy in Graves' disease (GD) patients was investigated. A total of 82 patients who had been treated with KI monotherapy before 24-hour RAIU (24 h RAIU) were evaluated and 354 of those who had been treated with thiamazole (MMI) monotherapy were extracted from the 1,130 GD patients who were identified as having had appropriate iodine restriction based on urinary iodine excretion. Urinary iodine excretion (UIE) <200 µg/day was confirmed in all subjects. Propensity score-matching was performed to identify the difference in 24 h RAIU between the KI group and the MMI group. In addition, multiple regression analysis was performed to evaluate related to 24 h RAIU. Propensity score-matching resulted in 57 matched patients in each group. After matching, 24 h RAIU was still significantly lower in the KI group than in the MMI group (median 53% (interquartile range 47-61%) vs. 63% (56-66%); p = 0.001). In addition, KI monotherapy was weakly negatively correlated with 24 h RAIU, whereas the female sex and FT3 were very weakly positively correlated on multiple regression analysis. The results suggest that KI monotherapy likely suppressed 24 h RAIU more than MMI monotherapy in GD patients with appropriate iodine restriction, given the difference in the mechanism of hormone suppression.

Establishment of reference intervals for fT3, fT4, and TSH levels in Japanese children and adolescents.

The present study aimed to establish new reference intervals (RIs) for serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels in Japanese children and adolescents aged 4 to 19 years. A total of 2,036 (1,611 girls, 425 boys) participants were included over a 17-year period; they all tested negative for antithyroid antibodies (TgAb, TPOAb) and were found to have no abnormalities on ultrasonography. RIs were determined by nonparametric methods. The results showed that serum fT3 was significantly higher in the 4-15-year-olds than in the 19-year-olds. The serum fT4 was significantly higher in the 4-10-year-olds than in the 19-year-olds. The serum TSH was significantly higher in the 4-12-year-olds than in the 19-year-olds. All of them gradually decreased with age to approximate the adult levels. The upper limit of TSH was lower in those aged 13 to 19 years than in adults. The differences were examined by sex. The serum fT3 was significantly higher in boys than in girls between the ages of 11 and 19 years. The serum fT4 was significantly higher in boys than in girls between the ages of 16 and 19 years. There did not seem to be any sex difference in those under 10 years of age. In conclusion, serum fT3, fT4, and TSH levels in children and adolescents differ from those in adults. It is important to evaluate thyroid function using the new RIs that are appropriate for chronological age.

Incidence and risk factors for Graves' orbitopathy in patients who underwent anti-inflammatory and immunosuppressive treatment during medical treatment for Graves' disease: investigation of 1,553 cases with newly diagnosed Graves' disease and proposal of a predictive score.

Appropriate administration of anti-inflammatory and immunosuppressive treatment (AIIST) is important for patients with Graves' orbitopathy (GO). This study aimed to clarify the incidence and risk factors for GO treated with AIIST and propose a predictive score, among newly diagnosed Graves' disease (GD) patients in Japan. A total of 1,553 GD patients who were newly diagnosed during the year 2011 were investigated. AIIST included local and/or systemic glucocorticoid administration and retrobulbar irradiation. A multivariable Cox proportional hazards model was used to investigate the risk factors for GO underwent AIIST during medical treatment, including at diagnosis, of GD. Then, a GO score was created by summing each point assigned to risk factors based on their coefficient obtained in the Cox model. AIIST was administered to 107 patients (6.9%). The risk factors and hazard ratios for GO underwent AIIST were: age (per 10 years), 1.32 (95% confidence interval: 1.16-1.50), p < 0.0001; TSH binding inhibitory immunoglobulin (TBII) (per 10 IU/L), 1.33 (1.15-1.54), p = 0.0001; and thyroglobulin antibody (TgAb) negativity, 2.98 (1.96-4.59), p < 0.0001. The GO score, ranging from 0 to 8 points, showed moderate performance (area under the curve: 0.71, cut-off value: 5 points, sensitivity: 0.76, specificity: 0.59, positive predictive value: 0.12, negative predictive value: 0.97). AIIST was performed for patients with active manifestations of GO in 6.9% of newly diagnosed GD patients. The risk factors for GO underwent AIIST were higher age, higher TBII, and TgAb negativity. The GO score based on these factors may be useful in managing GO.

Novel Mg 2+ binding sites in the cytoplasmic domain of the MgtE Mg 2+ channels revealed by X-ray crystal structures.

MgtE is a Mg 2+-selective channel regulated by the intracellular Mg 2+ concentration. MgtE family proteins are highly conserved in all domains of life and contribute to cellular Mg 2+ homeostasis. In humans, mutations in the SLC41 proteins, the eukaryotic counterparts of the bacterial MgtE, are known to be associated with various diseases. The first MgtE structure from a thermophilic bacterium, Thermus thermophilus, revealed that MgtE forms a homodimer consisting of transmembrane and cytoplasmic domains with a plug helix connecting the two and that the cytoplasmic domain possesses multiple Mg 2+ binding sites. Structural and electrophysiological analyses revealed that the dissociation of Mg 2+ ions from the cytoplasmic domain induces structural changes in the cytoplasmic domain, leading to channel opening. Thus, previous works showed the importance of MgtE cytoplasmic Mg 2+ binding sites. Nevertheless, due to the limited structural information on MgtE from different species, the conservation and diversity of the cytoplasmic Mg 2+ binding site in MgtE family proteins remain unclear. Here, we report crystal structures of the Mg 2+-bound MgtE cytoplasmic domains from two different bacterial species, Chryseobacterium hispalense and Clostridiales bacterium, and identify multiple Mg 2+ binding sites, including ones that were not observed in the previous MgtE structure. These structures reveal the conservation and diversity of the cytoplasmic Mg 2+ binding site in the MgtE family proteins.

Evaluation of factors predicting postoperative recurrence and metastasis of parathyroid cancer: a single-center study.

PURPOSE: The purpose of this study was to examine the postoperative clinical course of parathyroid carcinoma to determine factors that predict postoperative recurrence and distant metastasis. METHODS: In this retrospective study, we included 38 patients with parathyroid carcinoma who received surgical intervention at Itoh Hospital between 1979 and 2020. Clinicopathologic characteristics (age, sex, intact PTH, serum Ca level, operation type, parathyroid weight, parathyroid size, histopathologic findings: vascular invasion, capsular invasion, necrosis, histological type, and Ki-67 staining) were used. The median follow-up observation period was 63.7 months. RESULTS: Postoperatively, 5 patients (13.2%) developed distant metastasis or had localized recurrence, and 3 patients died (7.9%). The results of the univariate analysis revealed three factors affecting distant metastasis and recurrence, which were Ki-67 (p = 0.0041), the presence or absence of necrosis (p = 0.0163), and tumor weight (p = 00,189). Using the cutoff values obtained by ROC analysis, which were 4.1 for Ki-67 (sensitivity of 80% and specificity of 96.9%) and 4890 mg for tumor weight (sensitivity of 100% and specificity of 60.9%), we calculated the cumulative incidence of recurrence and distant metastasis by the three factors retained. We found that the presence of the three factors was associated with a high possibility of distant metastasis or recurrence during the 5-year follow-up period. CONCLUSIONS: Three factors, Ki-67, necrosis, and tumor weight in parathyroid carcinoma, may predict outcomes of postoperative recurrence and distant metastasis.

Measurement of the anchoring force of covered self-expandable and lumen-apposing metal stents for interventional endoscopic ultrasonography.

OBJECTIVES: Interventional endoscopic ultrasonography is performed for various situations that require drainage, after which stent migration is the most severe adverse event. Several lumen-apposing metal stents (LAMS) and covered self-expandable metal stents (CSEMS) provide antimigration systems; however, their anchoring ability has not been studied well. Therefore, we measured and compared the anchoring force (ACF) of commercially available LAMS and CSEMS. METHODS: Anchoring force was measured for five types of LAMS (NAGI, SPAXUS, Plumber, and AXIOS 8 and 10 mm) and seven types of CSEMS (BCL, SHCL, BCG, BPD [four types of HANAROSTENT], HILZO, Niti-S [Spring Stopper], and Wallflex). We created a phantom model for inducing stent migration. It has a rotatable part as a curved fixture, and we measured ACF at angles between 0° and 40°. RESULTS: The mean ACF at 0° and 20° were NAGI 1.50, 1.84 N, SPAXUS 1.73, 1.72 N, Plumber 2.64, 2.03 N, and AXIOS 3.96, 3.61 N, respectively; and BCL 0.48, 0.53 N, Wallflex 0.53, 0.48 N, SHCL 0.64, 0.73 N, HILZO 1.09, 1.09 N, BCG 1.22, 1.20 N, BPD 1.78, 1.67 N, and Spring Stopper 2.29, 2.51 N. CONCLUSION: We measured ACF in LAMS and CSEMS with a new phantom model. The highest value among the LAMS was for the AXIOS and among the CSEMS was for the Spring Stopper. Some of the ACF values varied with the direction of pull. These findings may have a significant impact on stent selection for interventional endoscopic ultrasonography, and this model can be used to evaluate newly developed stents.

Dietary lysine restriction induces lipid accumulation in skeletal muscle through an increase in serum threonine levels in rats.

We previously reported that dietary amino acid restriction induces the accumulation of triglycerides (TAG) in the liver of growing rats. However, differences in TAG accumulation in individual cell types or other tissues were not examined. In this study, we show that TAG also accumulates in the muscle and adipose tissues of rats fed a low amino acid (low-AA) diet. In addition, dietary lysine restriction (low-Lys) induces lipid accumulation in muscle and adipose tissues. In adjusting the nitrogen content to that of the control diet, we found that glutamic acid supplementation to the low-AA diet blocked lipid accumulation, but supplementation with the low-Lys diet did not, suggesting that a shortage of nitrogen caused lipids to accumulate in the skeletal muscle in the rats fed a low-AA diet. Serum amino acid measurement revealed that, in rats fed a low-Lys diet, serum lysine levels were decreased, while serum threonine levels were significantly increased compared with the control rats. When the threonine content was restricted in the low-Lys diet, TAG accumulation induced by the low-Lys diet was completely abolished in skeletal muscle. Moreover, in L6 myotubes cultured in medium containing high threonine and low lysine, fatty acid uptake was enhanced compared with that in cells cultured in control medium. These findings suggest that the increased serum threonine in rats fed a low-Lys diet resulted in lipid incorporation into skeletal muscle, leading to the formation of fatty muscle tissue. Collectively, we propose conceptual hypothesis that "amino-acid signal" based on lysine and threonine regulates lipid metabolism.