Gustave Roussy Immune score as a prognostic biomarker in patients with platinum-refractory metastatic urothelial carcinoma treated with pembrolizumab: YUSHIMA study.

BACKGROUND: This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab. METHODS: This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model. RESULTS: During the median follow-up period of 7.3 months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2 g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42 mg/L was a significant prognostic factor for OS (p = 0.001). CONCLUSION: The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.

Outcomes and prognostic factors in patients with synchronous and metachronous oligometastatic urothelial carcinoma with visceral metastases.

OBJECTIVES: To evaluate the clinical characteristics of oligometastatic disease (OMD) in metastatic urothelial carcinoma (mUC) with visceral metastases when classified into synchronous and metachronous metastases. METHODS: Of 957 cases of de novo mUC treated between 2008 and 2023, 374 with visceral metastases were analyzed. Cases were classified into OMD with up to three metastatic lesions and polymetastatic disease (PMD), and into synchronous and metachronous metastases. The clinical characteristics and overall survival (OS) for each group were analyzed. RESULTS: Overall, 196 (52.4%) had synchronous metastasis and 178 (47.6%) had metachronous metastasis. Median OS for synchronous metastases was significantly shorter than for metachronous metastases (12.1 months vs. 15.3 months, p = 0.011). Among the synchronous metastases, 48 (24.5%) were OMD and 148 (75.6%) were PMD. There was no significant difference in OS between the OMDs and PMDs (median 14.9 months vs. 11.7 months, p = 0.32), and only decreased albumin level was identified as a significant predictor of poor OS. Among the metachronous metastases, 64 (36.0%) were OMD and 114 (64.0%) were PMD. There was no significant difference in OS between the OMD and PMD (median 21.2 months vs. 15.0 months, p = 0.35), and no significant predictors of poor OS were identified. CONCLUSIONS: For mUC with visceral metastases, the timing of metastasis appearance was associated with prognosis, with synchronous metastases being a poorer prognostic factor compared to metachronous metastases. There was no prognostic difference between OMD and PMD with visceral metastases when classified into synchronous or metachronous metastases.

The relationship between central fatigue and Attention Deficit/Hyperactivity Disorder of the inattentive type.

Chronic fatigue and central fatigue with malaise significantly impair quality of life. Inattention caused by central fatigue is closely related to attention deficit/hyperactivity disorder (ADHD) symptoms, but the neurochemical mechanism of central fatigue remains hypothetical. The serotonin hypothesis of central fatigue was proposed first, serving as the central dogma for the molecular and neural mechanisms of central fatigue, and underpinning many studies. The tryptophan hypothesis was proposed because tryptophan released into the synaptic cleft of neurons in the brain coincides with and responds sensitively to development of fatigue. Tryptophan is highly bioactive, with brain concentrations of 50 to 200 times that of serotonin. The tryptophan-kynurenic acid-synergy hypothesis posits that central fatigue is not monocausal but a synergistic effect between tryptophan itself and its catabolite kynurenic acid. Central fatigue is associated with mental health problems and is a cause of inattention, thereby warranting scrutiny for its relationship with ADHD. Fatigability in ADHD is mediated by tryptophan, in which abnormal enhancement of the tryptophan-kynurenine-kynurenic acid pathway causes an imbalance in monoamine nervous system function. Notably, noradrenergic neuronal dysfunction is associated with the characteristic inattention of ADHD. Neutral amino acids such as branched-chain amino acids (BCAAs) can assist recovery from attentional and cognitive decline caused by central fatigue. Since they are transported by the same L-amino acid transporter as tryptophan, BCAAs compete with tryptophan to inhibit its brain uptake. Controlling central fatigue this way may improve attentional cognitive performance.

Impact of intensively lowered low-density lipoprotein cholesterol on deferred lesion prognosis.

OBJECTIVES: The aim of this study was to investigate the impact of intensively lowered low-density lipoprotein cholesterol (LDL-C) level on the deferred lesion prognosis after revascularization deferral based on fractional flow reserve (FFR). BACKGROUND: Lowering LDL-C is associated with lower cardiovascular event rate, but its benefit on the deferred lesion prognosis has not been well evaluated. METHODS: This retrospective, single-center, observational study analyzed 192 deferred lesions with FFR value >0.80 in 192 patients with stable coronary artery disease. According to the first follow-up LDL-C level, they were assigned to the LOW group (<70 mg/dL) or the HIGH group (≥70 mg/dL). Deferred lesion failure (DLF) was defined as the composite of deferred lesion revascularization and deferred vessel myocardial infarction. RESULTS: Of all participants, 61 and 131 patients were assigned to the LOW and the HIGH group, respectively. During the median follow-up of 2.8 years, DLF occurred in 1 and 14 patients in the LOW group and the HIGH group (1.6% and 10.7%, log-rank p = .043), respectively. The incidence of any unplanned revascularization was also significantly lower in the LOW group than in the HIGH group (3.3% vs. 14.5%, log-rank p = .032). CONCLUSIONS: The incidence of DLF was significantly lower in the patients with LDL-C < 70 mg/dL than in those with LDL-C ≥ 70 mg/dL at the first follow-up after FFR-based deferral of revascularization.

A Novel Rotablator Technique (Low-Speed following High-Speed Rotational Atherectomy) Can Achieve Larger Lumen Gain: Evaluation Using Optimal Frequency Domain Imaging.

BACKGROUND: While the evaluation of burr speed was discussed regarding platelet aggregation, the association between platform speed and acute lumen gain of rotational atherectomy remains unknown. METHODS: Through the evaluation of the potential of low-speed rotational atherectomy (LSRA) in in-vitro experiments, minimum lumen diameter (MLD) and minimum lumen area (MLA) after conventional high-speed rotational atherectomy (HSRA group) and those after LSRA following HSRA (LSRA+HSRA group) treated by 1.5 mm burrs were measured by optical frequency domain imaging (OFDI) in 30 consecutive human lesions. RESULTS: The in-vitro experiments demonstrated that MLD and MLA after LSRA+HSRA were significantly larger (MLD: LSRA+HSRA=1.50 ±0.05 mm, HSRA= 1.43 ±0.05 mm, p=0.015; MLA: LSRA+HSRA= 1.90 ±0.17 mm2, HSRA= 1.71±0.11 mm2, and p= 0.037), requiring more crossing attempts (LSRA= 134 ±20 times, HSRA= 72 ±11 times, and p< 0.001). In human studies, there was no significance in reference vessel diameter and lesion length before the procedure between two groups. MLDs after LSRA+HSRA were significantly larger than those in HSRA (LSRA+HSRA= 1.22 ±0.16 mm, HSRA= 1.07 ±0.14 mm, and p= 0.0078), while MLAs after LSRA+HSRA tended to be larger (LSRA+HSRA= 1.79 ±0.51 mm2, HSRA= 1.55 ±0.47 mm2, and p= 0.19). There was no significance in the occurrence of in-hospital complication, including slow flow or no reflow, major dissection, and procedural myocardial infarction, between LSRA+HSRA and HSRA. CONCLUSIONS: LSRA can achieve larger lumen gain compared, whereas HSRA can pass calcified lesions easily. Combination of LSRA and HSRA is a safe and feasible strategy for severely calcified lesions in clinical practice.

Nationwide Survey of Multidisciplinary Care and Cardiac Rehabilitation for Patients With Heart Failure in Japan　- An Analysis of the AMED-CHF Study.

BACKGROUND: The purpose of this study was to clarify the implementation rate of multidisciplinary heart failure (HF) care and cardiac rehabilitation (CR) in Japan, as well as the relationship between implementation rates and characteristics of the facility.Methods and Results:Survey participants were cardiologists who are members of the Japan Heart Failure Society and belonged to 1 of 845 medical institutions that are members of the Japan Heart Failure Society, as of April 2016. A total of 288 institutions (34.1%) returned the questionnaire. The percentages of hospitals implementing multidisciplinary HF care were 78.5% for inpatients and 32.6% for outpatients with HF. Inpatient and outpatient CR for HF had implementation rates of 80.4% and 56.5%, respectively. In addition, very few HF patients (7.3%, 3,741/51,323 patients) received outpatient CR. Both the presence of nurses certified in chronic HF care and registered CR instructors on staff were consistently associated with implementation of multidisciplinary HF care, and Japanese Circulation Society training hospitals, lower number of hospital beds, and presence of registered CR instructors on staff were consistently associated with implementation of CR. CONCLUSIONS: This first nationwide survey demonstrated that the implementation rates of multidisciplinary care and CR for HF, especially for outpatients, are low in Japan. Skilled healthcare professionals are expected to play important roles in the widespread implementation of this type of HF care in Japan.

Effectiveness of the proximal optimization technique for longitudinal stent elongation caused by post-balloon dilatation.

OBJECTIVES: To evaluate the effectiveness of the proximal optimization technique (POT) to prevent longitudinal stent elongation. BACKGROUND: The mechanism of stent elongation, which occurs after post-balloon dilation, is still unclear. METHODS: A total of 103 lesions treated with optical coherence tomography guided coronary intervention between May 2013 and November 2017 were retrospectively analyzed. Lesions were divided according to the circumferential degree of malapposition at the stent edge immediately after deployment into well-apposed group (<180°) and malapposed group (≥180°). Post-dilation was performed from distal to proximal within the stent until August 2016 (non-POT cohort), and POT was applied thereafter (POT cohort). In the POT cohort, post-dilation was done at the proximal portion of the stent with sufficiently large balloon to minimize malapposition followed by distal dilatations. Stent elongation length was defined as the change in stent length from stent deployment to after post-dilatation. RESULTS: In the non-POT cohort, 72 lesions, including 54 lesions in the well-apposed group and 18 in the malapposed group were analyzed. Stent elongation length was significantly longer in the malapposed group than in the well-apposed group (1.51 ± 1.34 mm vs 0.13 ± 0.84 mm, P < 0.01). In the POT cohort, 31 lesions including 21 in the well-apposed group and 10 in the malapposed group were analyzed. Stent elongation length was not significantly different between the groups (-0.09 ± 0.91 mm vs 0.30 ± 0.99 mm, P = 0.29). CONCLUSIONS: Malapposition of the stent edge is responsible for longitudinal stent elongation caused by post-dilatation. POT appeared to effectively prevent longitudinal stent elongation.

Influence of estrogen deficiency on guided bone augmentation: investigation of rat calvarial model and osteoblast-like MC3T3-E1 cells.

The effect of estrogen deficiency in bone augmentation, and the mechanisms by which estrogen deficiency impedes osteoblast differentiation and collagen matrix production, were examined. Twenty female Jcl:Wistar rats were divided into two groups: ovariectomized rats; and control rats. Guided bone augmentation was performed by positioning plastic caps in the calvarium of all animals at 8 wk after ovariectomy or sham surgery. Micro-computed tomography and histological sections were used to determine the amount of bone augmentation within the plastic caps. At 8 wk, there was statistically significantly less newly formed bone volume in ovariectomized rats. Immunohistological staining revealed the rare alignment of runt-related transcription factor 2-positive osteoblast-like cells and collagen I-positive bundle fibers in ovariectomized rats. In cell culture experiments, pre-osteoblast-like cells, MC3T3-E1, were treated with the estrogen receptor antagonist, fulvestrant. In treated cells, alkaline phosphatase activity remained high, whereas Alizarin Red staining was completely inhibited. Extracellular staining intensity of collagen I was decreased after fulvestrant treatment. Consistent with these observations, gene-expression analysis confirmed that fulvestrant treatment led to weaker expression of mRNA for osteogenic transcription factors and bone matrix protein-related genes. The results demonstrate that estrogen deficiency suppresses osteoblast differentiation and collagen matrix production in bone augmentation.

Does digital rectal examination predict prostate volume greater than 30 mL?

OBJECTIVES: To investigate the accuracy of digital rectal examination in estimating prostate volume in patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. METHODS: A community-based study was carried out in Japan to investigate the prevalence of lower urinary tract symptoms suggestive of benign prostatic hyperplasia. A total of 457 men were screened and deemed eligible for the present analysis. Findings on digital rectal examination were compared with prostate volume measurement by transrectal ultrasound. Five groups were identified on digital rectal examination: flat, normal, slightly enlarged, moderately enlarged and markedly enlarged. RESULTS: The median age and prostate volume were 64 years and 19.7 mL, respectively. Prostate volumes for the flat, normal, slightly enlarged, moderately enlarged, and markedly enlarged groups were 16.4, 18.3, 27.0, 41.9 and 86.3 mL, respectively. There were significant differences in prostate volume between the groups. The positive predictive value was 94.1% if flat, and normal were assumed to have a prostate volume <30 mL. The value was 80.8% if moderately enlarged, and markedly enlarged were assumed to have a prostate volume ≥30 mL. Of the men in the slightly enlarged group, 61.0% had a prostate volume <30 mL. CONCLUSIONS: It is possible to stratify prostate volume according to digital rectal examination. We could determine the prostates in the flat and normal groups to have a prostate volume <30 mL, and those in the moderately enlarged and markedly enlarged groups to have a prostate volume ≥30 mL by digital rectal examination with high accuracy. Transrectal ultrasound was required for those in the slightly enlarged group.

How do we understand the disagreement in the frequency of surgical site infection between the CDC and Clavien-Dindo classifications?

To clarify the discrepancy in the incidence and severity of surgical site infections (SSI) for radical cystectomy between reports based on the CDC guideline and those using the Clavien-Dindo classification we evaluated 449 consecutive patients who underwent radical cystectomy for bladder cancer between 1990 and 2012. Of the 115 (25.6%) patients with SSI defined by the CDC guideline, 89 could be analyzed. We compared the SSI rates and severity defined by the CDC guideline and Clavien-Dindo classifications. There were 58 patients with superficial SSI, 16 with deep SSI, and 15 with organ/space SSI according to the CDC guideline. All patients with organ/space SSI were judged as "not having SSI" by the Clavien-Dindo classification. They were classified as having "intestinal prolapse", "intestinal fistula", "abdominal abscess" and "pelvic abscess." There was a significant association between the treatment duration and depth of SSI based on the CDC guideline by Spearman's rank-correlation coefficient (p < 0.001, r = 0.614) and with the grade of complications (p < 0.001, r = 0.632) in the Clavien-Dindo classification. Multivariate analysis showed that patients with grade III SSI in the Clavien-Dindo classification needed a significantly longer treatment duration. It is necessary to be aware that a discrepancy can occur automatically due to the different natures of the definitions. Using the CDC guideline, we can effectively estimate the future treatment period when SSI occurs. With the Clavien-Dindo classification, grade III SSI requires a longer treatment duration.

[Polyorchidism: a case report and review of the literature].

A 10-year-old boy presented with a painless left scrotal mass that had been present for 2 years. Ultrasound examination revealed 2 left testes measuring 2.4 ml and 1.0 ml with the same echogenicity. Atsurgery, there were 2 similarly sized testes connecting with other spermatic vascular, but the supernumerary testis had no connection with the vas deferens. Histological findings showed immature testicular tissue without malignancy. We report the 26th case of polyorchidism in Japan and discuss this condition.

Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury.

Yap1 is an important regulator of cardiomyocyte proliferation and embryonic heart development, yet the function of endogenous Yap1 in the adult heart remains unknown. We studied the role of Yap1 in maintaining basal cardiac function and in modulating injury after chronic myocardial infarction (MI). Cardiomyocyte-specific homozygous inactivation of Yap1 in the postnatal heart (Yap(F/F)Cre) elicited increased myocyte apoptosis and fibrosis, dilated cardiomyopathy, and premature death. Heterozygous deletion (Yap(+/F)Cre) did not cause an overt cardiac phenotype compared with Yap(F/F) control mice at base line. In response to stress (MI), nuclear Yap1 was found selectively in the border zone and not in the remote area of the heart. After chronic MI (28 days), Yap(+/F)Cre mice had significantly increased myocyte apoptosis and fibrosis, with attenuated compensatory cardiomyocyte hypertrophy, and further impaired function versus Yap(+/F) control mice. Studies in isolated cardiomyocytes demonstrated that Yap1 expression is sufficient to promote increased cell size and hypertrophic gene expression and protected cardiomyocytes against H(2)O(2)-induced cell death, whereas Yap1 depletion attenuated phenylephrine-induced hypertrophy and augmented apoptosis. Finally, we observed a significant decrease in cardiomyocyte proliferation in Yap(+/F)Cre hearts compared with Yap(+/F) controls after MI and demonstrated that Yap1 is sufficient to promote cardiomyocyte proliferation in isolated cardiomyocytes. Our findings suggest that Yap1 is critical for basal heart homeostasis and that Yap1 deficiency exacerbates injury in response to chronic MI.

[Rhabdomyolysis after radical nephrectomy in the lateral decubitus position: report of 2 cases].

Rhabdomyolysis is a rare perioperative complication, however, potentially lead to fatal outcome. We experienced 2 cases of rhabdomyolysis after radical nephrectomy and nephroureterectomy in the lateral decubitus position. (Case 1) A 40-years old man was seen in our hospital because of asymptomatic grosshematuria. Computed tomography revealed right renal pelvic cancer, cT3N0M0. Right radical nephroureterectomy, lymph node dissection, partial cystectomy was underwent, and the operation was finished without any trouble. At the post-operative day 1, serum creatinine level was elevated to the point of 4.2 mg/dl, and serum creatine kinase was 1,945 IU/l. Continuous hemodiafiltration (CHDF) was done at intensive-care unit (ICU), and serum creatinine and creatine kinase level were decreased. At the post-operative day 1, urine myoglobin level was prominently elevated (2,943.7 ng/ml), so we diagnosed acute renal failure due to rhabdomyolysis. (Case 2) A 40-years old man was incidentally pointed out of right renal tumor that was seen as renal cell carcinoma, cT1aN0M0. Open partial nephrectomy was underwent, and there was no trouble during the operation. After recovering from anesthesia, the patient felt left thigh pain strongly. Serum creatine kinase was 888 IU/L after the operation. At the postoperative day 1, serum creatine kinase level was markedly increased (31,138 IU/L). Serum creatinine level was 1.34 mg/dl. Urine and serum myoglobin level was prominently elevated (89,000 ng/ml and 8,634 ng/ml, respectively). We diagnosed it rhabdomyolysis, and he received large amount of fluid intravenously at intensive-care unit. Serum creatine kinase was peak out at the post-operative day 3 (20,709 IU/L), and hemodialysis was not performed.

Phase I/II multicenter study of transarterial chemoembolization with a cisplatin fine powder and porous gelatin particles for unresectable hepatocellular carcinoma: Japan Interventional Radiology in Oncology Study Group Study 0401.

PURPOSE: A multicenter phase I/II study of transarterial chemoembolization with a fine cisplatin powder and gelatin particles (GPs) for multifocal hepatocellular carcinoma (HCC) was conducted. Primary endpoints were dose-limiting toxicity (DLT) and recommended dose (RD). Secondary endpoints were the incidence and severity of adverse events and tumor response. MATERIALS AND METHODS: Nonselective transarterial chemoembolization was performed until all tumor enhancement disappeared. Lipiodol was not used. In the phase I study, the cisplatin dose was escalated from 35 mg/m(2) to 65 mg/m(2) in 15-mg/m(2) increments to determine DLT and RD. In the phase II study, 40 patients were treated with the RD. Toxicity was assessed by Common Toxicity Criteria for Adverse Effects (version 3.0), and tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) and European Association for the Study of the Liver (EASL) criteria. RESULTS: A total of 46 patients were enrolled. As no DLT occurred at any dose level in the phase I study, RD was determined as 65 mg/m(2). In the phase II study, the treatment was discontinued in one patient as a result of vasovagal response. Toxicities of grade 3 or higher included nausea (2.2%), pancreatitis (2.2%), cholecystitis (2.2%), thrombocytopenia (8.7%), hyperbilirubinemia (2.2%), and increased aspartate aminotransferase (28.3%) and alanine aminotransferase (21.7%) levels. Tumor response rates under RD were 25.6% and 64.1% by RECIST and EASL criteria, respectively. CONCLUSIONS: Nonselective transarterial chemoembolization with fine cisplatin powder and GPs was well tolerated and effective in patients with multifocal HCC at the RD of 65 mg/m(2).

Essential role of excessive tryptophan and its neurometabolites in fatigue.

PURPOSE: Serotonin, a neurotransmitter synthesized from tryptophan, has been proposed to play a key role in central fatigue. In this study, we examined whether tryptophan itself and/or its two metabolites, kyneurenic acid (KYNA) and quinolinic acid (QUIN), are involved in central fatigue. MATERIALS AND METHODS: Experiments were conducted using Sprague-Dawley rats (SDR) and Nagase analbuminemic rats (NAR). Central fatigue was assessed by treadmill running and a Morris water maze test. Microdialysis was used to collect samples for measurement of extracellular concentration of tryptophan, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) and to infuse test agents. To examine the kinetics of release, synaptosomes in the striatum were prepared in vitro to measure intra- and extrasynaptosomal concentration of tryptophan, serotonin and 5-HIAA. RESULTS: The concentration of tryptophan secreted into the extracellular space of the striatum was higher during fatigue only, and quickly returned to basal levels with recovery from fatigue. Running time to exhaustion was reduced by activation of tryptophan receptors. Time to exhaustion was shorter in NAR, which maintain a higher extracellular level of striatum tryptophan than SDR. Impaired memory performance in a water maze task after tryptophan treatment was attributable to high levels of KYNA and QUIN in the hippocampus acting synergistically on N-methyl-D-aspartic acid receptors. When branched-chain amino acids were administered, tryptophan transport to the extracellular space of the striatum was drastically inhibited. CONCLUSION: Our findings demonstrate that the increase in fatigue which occurs because of excessively elevated brain tryptophan can be further amplified by the use of synthetic KYNA and QUIN.

Comparison of Macro-and Micro-porosity of a Titanium Mesh for Guided Bone Regeneration: An In Vivo Experimental Study.

BACKGROUND/AIM: Guided bone regeneration (GBR) is one of the surgical methods used for vertical ridge augmentation prior to dental implant placements. Titanium meshes have been used for osteogenic space maintenance in GBR sites by clinicians. We aimed to compare the influence of micropores and macropores in a titanium mesh on bone regeneration in a rat calvarial vertical GBR model. MATERIALS AND METHODS: The calvaria of nine rats were exposed, and plastic cylinders were set bilaterally. Eighteen surgical sites were randomly allocated into three groups according to the materials of titanium lid and bone substitutes: microporous titanium lid+deproteinized bovine bone mineral (DBBM), macroporous titanium lid +DBBM, microporous titanium lid+carbonate apatite. Newly generated bone inside the cylinders was evaluated using micro-computed tomography (micro-CT). Furthermore, bone regeneration and angiogenesis were evaluated histologically at 12 weeks. RESULTS: Quantitative volumetric analyses using micro-CT showed a gradual increase in bone volume inside the cylinders in all three groups. Histological observation confirmed vigorous bone regeneration in the microporous groups compared to that in the macroporous group. In the upper part of the cylinders, soft tissue invaded the GBR site by passing through the pores of the macroporous mesh. The blood vessels in the upper part of the cylinders were smaller in the microporous groups than in the macroporous group. There was no difference in bone formation between cylinders filled with DBBM or carbonate apatite. CONCLUSION: Microvasculature penetrates 50-µm diameter micropores and accelerates bone formation inside the cylinder, which was set on rat calvaria. The microporous titanium mesh can facilitate angiogenesis from both the dura mater and periosteal in vertical ridge augmentation. Our data showed superiority of microporous titanium vascular permeability and osteoconductivity, supporting bone growth.

Silent information regulator 1 protects the heart from ischemia/reperfusion.

BACKGROUND: Silent information regulator 1 (Sirt1), a class III histone deacetylase, retards aging and protects the heart from oxidative stress. We here examined whether Sirt1 is protective against myocardial ischemia/reperfusion (I/R). METHODS AND RESULTS: Protein and mRNA expression of Sirt1 is significantly reduced by I/R. Cardiac-specific Sirt1(-/-) mice exhibited a significant increase (44±5% versus 15±5%; P=0.01) in the size of myocardial infarction/area at risk. In transgenic mice with cardiac-specific overexpression of Sirt1, both myocardial infarction/area at risk (15±4% versus 36±8%; P=0.004) and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive nuclei (4±3% versus 10±1%; P<0.003) were significantly reduced compared with nontransgenic mice. In Langendorff-perfused hearts, the functional recovery during reperfusion was significantly greater in transgenic mice with cardiac-specific overexpression of Sirt1 than in nontransgenic mice. Sirt1 positively regulates expression of prosurvival molecules, including manganese superoxide dismutase, thioredoxin-1, and Bcl-xL, whereas it negatively regulates the proapoptotic molecules Bax and cleaved caspase-3. The level of oxidative stress after I/R, as evaluated by anti-8-hydroxydeoxyguanosine staining, was negatively regulated by Sirt1. Sirt1 stimulates the transcriptional activity of FoxO1, which in turn plays an essential role in mediating Sirt1-induced upregulation of manganese superoxide dismutase and suppression of oxidative stress in cardiac myocytes. Sirt1 plays an important role in mediating I/R-induced increases in the nuclear localization of FoxO1 in vivo. CONCLUSIONS: These results suggest that Sirt1 protects the heart from I/R injury through upregulation of antioxidants and downregulation of proapoptotic molecules through activation of FoxO and decreases in oxidative stress.

[Clinical analysis of 3 cases with primary splenic diffuse large B-cell lymphoma].

The definition of primary splenic lymphoma is controversial, but it has been reported to be a rare disease that comprises less than 1% of all malignant lymphomas. Three cases of primary splenic diffuse large B-cell lymphoma treated at our institution are described here. Median follow-up was 34.6 months (range 8.7∼39.2) and median age at diagnosis was 72 years old (range 65∼73). In all three cases, the diagnosis was definitively established not by splenectomy but by ultrasonically guided percutaneous splenic tissue core biopsy. Using the Hans classifier, one of the cases was subclassified as the germinal center B-cell like (GCB) subtype and two as non-GCB subtype. One case was CD5-positive diffuse large B-cell lymphoma. Two patients were in Ann Arbor stage II and one was in stage III. Using the International Prognostic Index, one was categorized as Low/intermediate risk, one as high/intermediate risk, and one as high risk. All patients underwent eight cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone followed by irradiation therapy. These three patients attained complete response. Although the follow-up period to date has been short, all patients have maintained a complete response and are currently alive. To determine whether our management protocol is valid, further observations are needed.

Impact of Long-Rope Jumping on Monoamine and Attention in Young Adults.

Previous research has shown that rope jumping improves physical health; however, little is known about its impact on brain-derived monoamine neurotransmitters associated with cognitive regulation. To address these gaps in the literature, the present study compared outcomes between 15 healthy participants (mean age, 23.1 years) after a long-rope jumping exercise and a control condition. Long-rope jumping also requires co-operation between people, attention, spatial cognition, and rhythm sensation. Psychological questionnaires were administered to both conditions, and Stroop task performance and monoamine metabolite levels in the saliva and urine were evaluated. Participants performing the exercise exhibited lower anxiety levels than those in the control condition. Saliva analyses showed higher 3-methoxy-4-hydroxyphenylglycol (a norepinephrine metabolite) levels, and urine analyses revealed higher 3-methoxy-4-hydroxyphenylglycol and 5-hydroxyindoleacetic acid (a serotonin metabolite) levels in the exercise condition than in the control. Importantly, urinary 5-hydroxyindoleacetic acid level correlated with salivary and urinary 3-methoxy-4-hydroxyphenylglycol levels in the exercise condition. Furthermore, cognitive results revealed higher Stroop performance in the exercise condition than in the control condition; this performance correlated with salivary 3-methoxy-4-hydroxyphenylglycol levels. These results indicate an association between increased 3-methoxy-4-hydroxyphenylglycol and attention in long-rope jumping. We suggest that long-rope jumping predicts central norepinephrinergic activation and related attention maintenance.

Ser9 phosphorylation of GSK-3ß promotes aging in the heart through suppression of autophagy.

INTRODUCTION: Glycogen synthase kinase-3ß (GSK-3ß) is a serine/threonine kinase and a negative regulator of cardiac hypertrophy. Phosphorylation of GSK-3ß at Ser9 negatively regulates its kinase activity. The role of GSK-3ß in cardiac aging remains poorly understood. AIM: The study aimed to elucidate the role of GSK-3ß Ser9 phosphorylation in mediating cardiac aging and the underlying mechanism. METHODS AND RESULTS: Phosphorylation of GSK-3ß at Ser9 and the levels of ß-catenin and Mcl-1 were increased in the mouse heart during aging, suggesting that GSK-3ß is inactivated during aging in the heart. Age-induced cardiac hypertrophy, fibrosis, left ventricular dysfunction, and increases in cardiomyocyte apoptosis and senescence were all attenuated in constitutively active GSK-3ßS9A knock-in (KI) mice compared to littermate wild type mice. Although autophagy is inhibited in the heart during aging, KI of GSK-3ßS9A reversed the age-associated decline in autophagy in the mouse heart. GSK-3ß directly phosphorylates Ulk1, a regulator of autophagy, at Ser913, thereby stimulating autophagy in cardiomyocytes. Ulk1Ser913A KI mice exhibited decreased autophagic flux and increased senescence in cardiomyocytes. CONCLUSION: Our results suggest that GSK-3ß is inactivated during aging through Ser9 phosphorylation, which in turn plays an important role in mediating cardiac aging. GSK-3ß promotes autophagy through phosphorylation of Ulk1 at Ser913, which in turn prevents aging in the heart.