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A 59-year-old man presented with exertional dyspnoea and pretibial oedema that had lasted 6 months. He was referred to our hospital with suspected constrictive pericarditis (CP). Several examinations, including CT, echocardiography and cardiac catheterisation, indicated heart failure associated with CP that had been induced by trauma 13 years prior. The CP and heart failure were unresponsive to medical treatment, therefore, a surgical pericardiectomy was performed, which is considered the only definitive treatment. Pathological examination of the resected pericardium revealed a fatty texture and dense fibrous connective tissues, which are associated with old haemorrhage and focal calcification. The patient’s symptoms were improved to New York Heart Association Class I, and his peripheral oedema disappeared 6 months after leaving hospital.

Chronotropic incompetence (CI) is broadly defined as the inability of the heart to increase its rate commensurate with increased activity. In this study, we tried to clarify the link between CI and UPDRS part II (off-on), which was calculated by subtracting part II (on) from part II (off), in patients with Parkinson's disease (PD).Thirty-six hospitalized patients were examined by using cardiopulmonary exercise testing (CPET) for exercise tolerance (ΔVO2/ΔWR and peak VO2/W) and the presence of CI (ΔHR/ΔWR), and using electrocardiogram for heart rate variability.We originally divided the patients into three groups; Group I (ΔHR/ΔWR x100 15) (N = 3), Group II (15≥,60) (N = 28), Group III (60) (N = 5). Since Group I and III were significantly smaller and older than Group II, we focused and divided into two groups; Group II CI (+), the PD patients with CI (15≤ ΔHR/ΔWR x100 35), and Group II CI (-), those patients without that (35≤ ΔHR/ΔWR x100 60). ΔVO2/ΔWR and peak VO2/W in CI (+) patients was lower than CI (-) (P = 0.022 and P = 0.096, respectively). HF power (parasympathetic activity) tends to be decreased, whereas LF/HF ratio (sympathetic activity) was increased in CI (+) patients as compared with CI (-). The UPDRS part II (off-on) of CI (+) patients was significantly higher than CI (-) (P = 0.023).In PD patients, the difference between 'on' and 'off' in activities of daily living might be predicted by using ΔHR/ΔWR x100 obtained from CPET as an index.

Residual insomnia is associated with a risk of depression recurrence.In this retrospective, longitudinal cohort study, the recurrence pattern of depression in patients with or without residual insomnia was assessed using a health insurance claims database. Patients who were diagnosed with major depressive disorder and prescribed antidepressants, between January 2006 and June 2017 in Japan, were enrolled in the study. Residual insomnia was defined by a prescription of hypnotics, and recurrence of depression by prescription of antidepressants. Main outcomes included time to recurrence and the 1-year recurrence rate. Factors associated with recurrence of depression were assessed by multivariate analyses. The effect of residual insomnia on the frequency of recurrence was assessed by Chi-square test.Of the 30,381 patients analyzed, there were 4,166 and 26,215 patients with or without residual insomnia, respectively. Time to recurrence in patients with residual insomnia was significantly shorter compared with those without residual insomnia (p0.001), with a 1-year recurrence rate (95% CI) of 43.4% (41.9-45.0) and 7.4% (7.1-7.7), respectively. The frequency of recurrence was significantly higher in patients with residual insomnia than in those without (p0.0001). A higher risk of depression recurrence (odds ratio 9.98, 95% CI 9.22-10.81) was found for residual insomnia compared with other significant factors.The diagnosis stated in the receipt data may not accurately reflect the patient's condition, and medication adherence was unknown but assumed.Residual insomnia is a significant risk factor for depression recurrence in Japanese patients.

Background Major depressive disorder (MDD) is highly prevalent in Japan and frequently accompanied by insomnia that may persist even with MDD remission. Hypnotics are used for the pharmacological treatment of insomnia, but their influence on MDD recurrence or residual insomnia following MDD remission is unclear. This retrospective, longitudinal, cohort study utilized a large Japanese health insurance claims database to investigate patterns of hypnotic prescriptions among patients with MDD, and the influence of hypnotic prescription pattern on MDD recurrence. Methods Eligible patients (20–56 years) were those registered in the Japan Medical Data Center database between 1 January 2005 and 31 December 2018, and prescribed antidepressant and hypnotic therapy after being diagnosed with MDD. Patients who had ceased antidepressant therapy for > 180 days were followed for 1 year to evaluate depression recurrence, as assessed using Kaplan-Meier estimates. Logistic regression modelling was used to analyze the effect of hypnotic prescription pattern on MDD recurrence. Results Of the 179,174 patients diagnosed with MDD who initiated antidepressant treatment between 1 January 2006 and 30 June 2017, complete prescription information was available for 2946 eligible patients who had been prescribed hypnotics. More patients were prescribed hypnotic monotherapy (70.8%) than combination therapy (29.2%). The most prescribed therapies were benzodiazepine monotherapy (26.2%), non-benzodiazepine monotherapy (28.9%), and combination therapy with two drugs (21.1%). Among patients prescribed multiple hypnotics, concomitant prescriptions for anxiolytics, antipsychotics, mood stabilizers and sedative antidepressants were more common. The 1-year recurrence rate for MDD was approximately 20%, irrespective of hypnotic mono- versus combination therapy or class of hypnotic therapy. Being a spouse (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.03–2.02) or other family member (OR, 1.46, 95% CI, 0.99–2.16) of the insured individual, or being prescribed a sedative antidepressant (OR, 1.50, 95% CI, 1.24–1.82) conferred higher odds of MDD recurrence within 1 year of completing antidepressant therapy. Conclusions Benzodiazepines are the most prescribed hypnotic among Japanese patients with MDD, though combination hypnotic therapy is routinely prescribed. Hypnotic prescription pattern does not appear to influence real-world MDD recurrence, though hypnotics should be appropriately prescribed given class differences in efficacy and safety.

Background Human exposure to mercury (Hg) is widespread and both organic and inorganic Hg are routinely found in the human brain. Millions of people are exposed to methyl Hg (MeHg) due to the consumption of fish and to inorganic Hg from dental amalgams, small scale gold mining operations, use of Hg containing products, or their occupations. Neuropathology information associated with exposures to different species of Hg is primarily based on case reports of single individuals or collections of case studies involving a single species of Hg at toxic exposure levels such as occurred in Japan and Iraq. Methods/Results This study brings together information on the neuropathological findings and deposition of Hg in the central nervous system of people exposed to different species of Hg at varying concentrations. The low dose exposures were lifetime exposures while the high dose exposures were generally acute or short term by different exposure routes with survival lasting various lengths of time. Total and inorganic Hg deposits were identified in formalin-fixed, paraffin embedded tissues from both low and high exposure Hg cases. Low concentration exposures were studied in adult brains from Rochester, New York (n = 4) and the Republic of Seychelles (n = 17). Rochester specimens had mean total Hg concentrations of 16−18 ppb in the calcarine, rolandic, and cerebellar cortices. Inorganic Hg averaged between 5–6 ppb or 30–37% for the cerebral and cerebellar cortices of the Rochester subjects. Total Hg was approximately 10-fold higher in specimens from Seychelles, where consumption of ocean fish is high and consequently results in exposure to MeHg. The predominant Hg species was MeHg in both the Rochester and Seychelles brain specimens. Histologically, cerebral and cerebellar cortices from Rochester and Seychelles specimens were indistinguishable. High concentration exposures were studied in brains from four adults who were autopsied at variable time periods after exposure to organic Hg (methyl or dimethyl) or inorganic Hg (inhaled vapor or intravenous injection of metallic Hg). In contrast to the Seychellois adults, these individuals had acute or subacute exposures to lethal or significantly higher concentrations. The pattern of Hg deposition differed between subjects with high organic Hg exposure and high inorganic Hg exposure. In the organic Hg cases, glia (astrocytes and microglia) and endothelial cells accumulated more Hg than neurons and there were minimal Hg deposits in cerebellar granule and Purkinje cells, anterior horn motor neurons, and neocortical pyramidal neurons. In the inorganic Hg cases, Hg was seen predominantly in neurons, vascular walls, brainstem, and cerebellar and cerebral deep gray nuclei. The presence of inorganic Hg in neural and neural supporting cells in the four high exposure Hg cases was not closely correlated with cellular pathology; particularly in the inorganic Hg cases. Conclusions Different Hg species are associated with differing neuropathological patterns. No neuropathological abnormalities were present in the brains of either Rochester or Seychelles residents despite substantial differences in dietary MeHg exposure. Increasing concentrations of inorganic Hg were present in the brain of relatively low exposure subjects with increasing age.

Biliary disease is a common surgical problem. A unique case of a 53-year-old male with an enormous gallstone precluding safe laparoscopic cholecystectomy is presented. The patient was a 53-year-old male who presented to the emergency department with a 1-day history of abdominal pain for which clinical findings were consistent with acute cholecystitis. A laparoscopic cholecystectomy was attempted, but could not be safely completed due to an enormous gallstone prohibiting attainment of the critical view of safety. The stone measured 12.2 cm × 5.2 cm × 5.2 cm. Although biliary disease is very common and its management well documented, it is rare to uncover stones larger than 5 centimeters in diameter. Clinicians should be aware that enormous gallstones require prompt surgical intervention if discovered in the elective setting to minimize future morbidity should cholecystitis develop; early elective cholecystectomy should be considered upon discovery of large gallstones to prevent encountering a gallbladder with decreased mobilization in the setting of inflamed tissues.

The developing perinatal brain is vulnerable to methylmercury (MeHg) exposure. The contribution of breast milk to tissue MeHg levels in offspring is a significant public health concern because breast milk contains a certain amount of MeHg. Here, the contribution of MeHg transferred via breast milk to the Hg levels in the tissues of pups (Wistar rats) was investigated. Mated maternal rats were fed a MeHg (2 ppm)-supplemented or a control diet during pregnancy. Following parturition, male neonates from each group were cross-fostered between exposed or control dams, and they were further raised by dams fed a MeHg-supplemented diet or a control diet during lactation. Consequently, we evaluated three pup groups, which were raised by dams exposed to MeHg during pregnancy (P pups), lactation (L pups), or pregnancy and lactation (PL pups). Total mercury (THg) concentrations in the tissues of the offspring were measured at birth (postnatal day 0 [PD0]), during lactation (PD6, PD12, and PD19), and after weaning (PD29 and PD36). Blood and brain THg levels in the P and PL pups declined dramatically during lactation, however, there were no considerable differences between the two groups at PD6 and PD12. In contrast, blood and brain THg levels in the L pups increased slightly during lactation. The increase in the THg levels in the blood and brain of L pups at PD12 were approximately 3.3% and 1.5%, respectively, compared to the corresponding THg levels in the neonates in the P and PL groups. Our results suggest that if the MeHg exposure level during pregnancy is not high enough to cause neuronal development defects in the fetus, the exposure via breast milk is not a significant concern.

For women with breast cancer in whom multiple Oncotype DX

Cognitive symptoms in major depressive disorder (MDD) contribute to impaired functional abilities and work productivity, particularly presenteeism. We investigated the association between baseline cognitive symptoms and subsequent presenteeism, and global functional impairment in Japanese patients with MDD from PERFORM-J (Prospective Epidemiological Research on Functioning Outcomes Related to Major Depressive Disorder in Japan) - a 6-month, multicenter, epidemiological study data. A total of 518 patients initiating antidepressant monotherapy (first-line or switched from another drug) were enrolled. Assessments include Perceived Deficits Questionnaire - Depression (PDQ-D) for cognitive complaints, Sheehan Disability Scale (SDS) for global function (analysed n = 318), and Work Productivity and Activity Impairment Questionnaire for presenteeism (analysed n = 122). A strong association between changes in presenteeism and changes in SDS scores (r: total = 0.636; work/school = 0.686) was observed. After adjusting for sociodemographic and MDD-related factors, patients without cognitive complaints at baseline showed lower odds of impaired presenteeism at 6 months versus patients with cognitive complaints (0.243, 95% CI: 0.079 to 0.747, p = 0.014) and also in patients with first episode of MDD against with recurrent MDD (0.327 (95% CI: 0.136 to 0.787). Similarly, patients without cognitive complaints had healthier global functioning (lower mean SDS total score) than patients with cognitive complaints (8.3 vs 11.2; 95% CI, -5.189 to -0.578; p = 0.014). First depressive episode (lower risk of presenteeism), being male, and low baseline SDS total score (better global functioning) were also associated with improved outcomes. These results highlight the potential value of baseline PDQ-D scores in predicting subsequent workplace and global functioning in patients undergoing treatment for MDD.

Introduction Fibroepithelial lesions of the breast (FEL) are heterogeneous lesions ranging from fibroadenomas (FA) to phyllodes tumors (PT). FEL with cellular stroma are diagnostic challenges on core needle biopsy (CNB) as it is difficult to distinguish cellular FA from PT. The purpose of this study was to determine the features of FEL on CNB that may be predictive of PT, the upstage rate to PT after excision, and the outcomes of those who did not undergo excision. Methods Overall, 305 patients with FEL on CNB between 2009 and 2019 were identified from a prospectively maintained institutional database. Presentation, imaging, and pathology were evaluated. Results Mean age at diagnosis was 43.8 years. Pathology on CNB included 97 cases of FEL favoring FA, 19 cases of FEL favoring PT, 3 cases of FEL versus pseudoangiomatous stromal hyperplasia, and 186 cases of FEL not otherwise specified. Following CNB, 96 (31.5%) patients were observed, 158 (51.8%) patients had an excisional biopsy, 48 (15.7%) patients underwent segmental mastectomy, and 3 (1.0%) patients underwent a mastectomy. The upgrade rate from FEL on CNB to PT upon excision was 25.8%. PT on final pathology was more commonly seen when the CNB identified stromal overgrowth, necrosis, and diagnosis of FEL favoring PT. On multivariable analysis, a final diagnosis of PT was associated with age >50 years, larger tumor size >2 cm, stromal overgrowth, and ≥1 mitoses/10 high power fields (HPF) on CNB. Patients who were observed had smaller tumors compared with those who underwent excision. Conclusion In this 10-year single-institution experience of FEL, the upstage rate to PT was 25.8%. Excision of FEL is recommended. Furthermore, the observation of lesions appeared to be safe in select cases, specifically in patients with smaller tumor size.

BACKGROUND: Single-nephron dynamics in progressive IgA nephropathy (IgAN) have not been studied. We applied novel methodology to explore single-nephron parameters in IgAN. METHODS: Nonglobally sclerotic glomeruli (NSG) and globally sclerotic glomeruli (GSG) per kidney were estimated using cortical volume assessment via unenhanced computed tomography and biopsy-based stereology. Estimated single-nephron GFR (eSNGFR) and single-nephron urine protein excretion (SNUPE) were calculated by dividing eGFR and UPE by the number of NSG. Associations with CKD stage and clinicopathologic findings were cross-sectionally investigated. RESULTS: This study included 245 patients with IgAN (mean age 43 years, 62% male, 45% on renin-angiotensin aldosterone system [RAAS] inhibitors prebiopsy) evaluated at kidney biopsy. CKD stages were 10% CKD1, 43% CKD2, 19% CKD3a, 14% CKD3b, and 14% CKD4–5. With advancing CKD stage, NSG decreased from mean 992,000 to 300,000 per kidney, whereas GSG increased from median 64,000 to 202,000 per kidney. In multivariable models, advancing CKD stage associated with lower numbers of NSG, higher numbers of GSG, and lower numbers of GSG + NSG, indicating potential resorption of sclerosed glomeruli. In contrast to the higher mean glomerular volume and markedly elevated SNUPE in advanced CKD, the eSNGFR was largely unaffected by CKD stage. Lower SNGFR associated with Oxford scores for endocapillary hypercellularity and crescents, whereas higher SNUPE associated with segmental glomerulosclerosis and tubulointerstitial scarring. CONCLUSIONS: SNUPE emerged as a sensitive biomarker of advancing IgAN. The failure of eSNGFR to increase in response to reduced number of functioning nephrons suggests limited capacity for compensatory hyperfiltration by diseased glomeruli with intrinsic lesions.

Four chain-extended analogs (12a–12d) and two related de-O-sulfonated analogs (13a and 13c) by introducing alkyl groups (a: R = C3H7, b R = C6H13, c: R = C8H17, d: R = C10H21) to the side chains of salacinol (1), a natural α-glucosidase inhibitor from Ayurvedic traditional medicine “Salacia”, were synthesized. The α-glucosidase inhibitory activities of all the synthesized analogs were evaluated in vitro. Against human intestinal maltase, the inhibitory activities of 12a and 13a with seven-carbon side chain were equal to that of 1. In contrast, analogs (12b–12d, and 13c) exhibited higher level of inhibitory activity against the same enzyme than 1 and had equal or higher potency than those of the clinically used anti-diabetics, voglibose, acarbose, and miglitol. Thus, elongation of the side chains of 1 was effective for specifically increasing the inhibitory activity against human intestinal maltase.

Patients with atypical hemolytic uremic syndrome (aHUS) associated with a C3 p.Ile1157Thr mutation show a relatively high renal survival and low mortality rates, but renal histopathological findings after recurrence have been rarely reported. A 30-year-old man with a C3 p.Ile1157Thr mutation experienced a third recurrence of thrombotic microangiopathies with neurological and gastrointestinal disorders. A renal biopsy performed during the recovery phase of acute kidney injury revealed collapsed glomeruli and arteriolar vacuolization. Approximately 10% of glomeruli were globally sclerotic, despite the absence of arterio-/arteriolo-sclerosis. These findings suggest substantial progression of irreversible injuries in multiple organs, including kidneys, which occurs in aHUS patients with repeated thrombotic microangiopathies.

Sudden unexpected death in epilepsy (SUDEP) has been defined as a sudden/unexpected, witnessed/unwitnessed, nontraumatic, and nondrowning death in epileptic patients with/without seizure evidence and documented status epilepticus. Identified as the leading cause of epilepsy-related deaths, SUDEP cases are highly unrecognized and underreported due to diagnostic difficulty. We report a case of a successfully revived hemodialysis patient who developed cardiopulmonary arrest after a witnessed convulsive seizure. Electroencephalogram revealed epileptic abnormalities. Therefore, this case could be seizure-induced cardiopulmonary arrest and near-SUDEP. Hence, the possibility of SUDEP should be considered even in hemodialysis patients having conventional coronary risk factors for sudden cardiac death.

To compare the intraocular pressure (IOP)-lowering effects of ripasudil, a rho-kinase inhibitor, and selective laser trabeculoplasty (SLT) as adjuvant therapy in Japanese glaucoma patients and to identify the factors associated with treatment success. We performed a retrospective medical chart review of patients with glaucoma who received ripasudil or SLT as an adjuvant therapy. We collected data on 65 eyes (65 patients) with primary open-angle glaucoma, normal-tension glaucoma, or exfoliation glaucoma with at least 12 months of follow-up. IOP and number of glaucoma medications at 0, 1, 3, 6, 9, and 12 months were compared between and within groups. A repeated-measures mixed model was used to perform statistical analysis. We also investigated factors associated with treatment success, which was defined as ≥ 20% reduction in IOP at all follow-up periods, using univariate and multivariate logistic regression analysis. Significant IOP reduction was observed at all time-points after treatment in the ripasudil group (n = 33) and in the SLT group (n = 32), with no statistically significant difference between the groups before or after treatment. Patients in the SLT group used more anti-glaucoma medications before treatment, but fewer during follow-up, than those in the ripasudil group. Regardless of treatment, higher baseline IOP was associated with treatment success [crude odds ratio: 1.21 (95% confidence interval: 1.06–1.38), adjusted odds ratio: 1.37 (95% confidence interval: 1.06–1.77)]. Adjuvant SLT or ripasudil in patients with inadequately controlled glaucoma both reduced IOP to a similar degree, but SLT contributed to reducing the number of medications used.

Aims Nocturia, due to nocturnal polyuria and other conditions associated with nocturnal voiding, affects sleep quality and daytime quality of life (QOL). We aimed to investigate the relationship among nocturia, sleep quality, and daytime QOL in a young Japanese population. Methods This epidemiological study analyzed data from a retrospective data set containing sleep data from wearable devices worn by 9446 Japanese users and a prospective data set containing answers to a 10-item questionnaire completed by a subset of 605 users in the retrospective dataset. We recorded the first uninterrupted sleep period (FUSP), total sleep time (TST), number of nocturnal voids, sleep quality, daytime QOL, bothering nocturnal voids, and early wake-ups in the morning. Results The subjects were 18-65 years old. The mean TST was 6.7 ± 0.9 h, and the mean number of wake-ups was 2.11 ± 1.1. FUSP and TST decreased (from 334 ± 114 to 173 ± 74 min and 5.9 ± 1.0 to 5.5 ± 1.0 h, respectively) with an increasing number of nocturnal voids, and the change was statistically significant. Logistic regression analysis showed a statistically significant relationship between nocturia and FUSP and the number of wake-ups. Conclusion Nocturia has close relationships with FUSP and the number of wake-ups and can result in decreased daytime QOL in young Japanese people.

A facile and highly diastereoselective approach toward the synthesis of potent salacinol-type α-glucosidase inhibitors, originally isolated from plants of the genus "Salacia", was developed using the S-alkylation of thiosugars with epoxides in HFIP (∼90%, dr, α/β = ∼ 26/1). The dr ratio of the product was significantly improved by the protocol as compared to that of the conventional S-alkylation of thiosugars (dr, α/β = ∼ 8/1). The protocol could be used for gram scale synthesis of the desired compounds. The 3'-O-benzylated salacinol analogs, which are the most potent in vitro inhibitors to date, were synthesized and evaluated in vivo; all analogs suppressed blood glucose levels in maltose-loaded mice, at levels comparable to those of the antidiabetic agent, voglibose.

Lung branching morphogenesis has been studied for decades, but the underlying developmental mechanisms are still not fully understood. Cellular movements dynamically change during the branching process, but it is difficult to observe long-term cellular dynamics by in vivo or tissue culture experiments. Therefore, developing an in vitro experimental model of bronchial tree would provide an essential tool for developmental biology, pathology, and systems biology. In this study, we succeeded in reconstructing a bronchial tree in vitro by using primary human bronchial epithelial cells. A high concentration gradient of bronchial epithelial cells was required for branching initiation, whereas homogeneously distributed endothelial cells induced the formation of successive branches. Subsequently, the branches grew in size to the order of millimeter. The developed model contains only two types of cells and it facilitates the analysis of lung branching morphogenesis. By taking advantage of our experimental model, we carried out long-term time-lapse observations, which revealed self-assembly, collective migration with leader cells, rotational motion, and spiral motion of epithelial cells in each developmental event. Mathematical simulation was also carried out to analyze the self-assembly process and it revealed simple rules that govern cellular dynamics. Our experimental model has provided many new insights into lung development and it has the potential to accelerate the study of developmental mechanisms, pattern formation, left-right asymmetry, and disease pathogenesis of the human lung.

Atrophy and protracted recovery of normal function of the ipsilateral quadriceps femoris muscle following anterior cruciate ligament reconstruction surgery is well documented. The Accelerated Recovery Performance trainer is a type of electrical stimulation device that delivers a high-pulse frequency via a direct current, making it unique from many other devices on the market. The purpose of the present study was to investigate the effects of the direct current (via the Accelerated Recovery Performance trainer protocol) on gains in thigh circumference following anterior cruciate ligament reconstruction. Twenty-five patients were enrolled following isolated anterior cruciate ligament reconstruction and randomly assigned to either an isometric rehabilitation protocol augmented with the Accelerated Recovery Performance trainer protocol (experimental group) or the isometric rehabilitation protocol alone (control group). The two groups participated in sixteen sessions of directed rehabilitation over a two-month time period. Patients were followed with serial thigh circumference measurements at 5, 10, 15, and 20 centimeters above the superior patellar pole. Comparison of the overall mean circumferential gains in thigh circumference of the involved leg demonstrated approximately 3:1 gains in the ARP group over the control group, demonstrating it to be superior to isometric rehabilitation alone with regards to gains in thigh girth. The Accelerated Recovery Performance trainer protocol should be considered for post-anterior cruciate ligament reconstruction rehabilitation in order to reverse disuse atrophy of the ipsilateral quadriceps femoris.

Objectives: To compare the effects of inpatient enhanced multidisciplinary care (EMC) and multidisciplinary rehabilitation (MR) on the symptoms and quality of life (QOL) of patients with Parkinson disease (PD) and to clarify the relation between reduction in symptoms and the improved QOL. Methods: This study was a quasi-randomized controlled (alternate allocation), assessor-blinded, single-center study. We recruited 80 patients with idiopathic Parkinson disease, Hoehn and Yahr stage 2 to 4, on stable medication. Patients were included in an EMC or MR group. Both rehabilitation programs were performed for 8 weeks (17 h/wk). Main outcome measures were Parkinson’s Disease Questionnaire-39 and Unified Parkinson’s Disease Rating Scale. Results: The EMC induced significant improvements in QOL compared to MR. We found that body axis symptoms (rising from a chair, posture, postural stability, falling, and walking) as well as nonmotor symptoms (depression) in patients with PD were relieved by the inpatient EMC. Conclusions: Enhanced multidisciplinary care for patients with PD appears to be effective in improving the QOL. The improvement in motor and nonmotor symptoms, including depression, may contribute to the improved QOL.

Purpose This study aimed to identify regional asymmetry in dopaminergic and serotoninergic dysfunction in degenerative parkinsonisms, using dopamine transporter single-photon emission computed tomography images. Material and methods This study included 213 consecutive participants (Parkinson's disease [n = 111], dementia with Lewy bodies [n = 64], progressive supranuclear palsy with Richardson's syndrome [n = 18], and healthy participants [n = 20]) who underwent both magnetic resonance imaging and 123I-labelled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane single-photon emission computed tomography/computed tomography. Using normalized specific binding ratio images, we created voxel-wise regional asymmetry index images to identify the regional specific pattern of regional asymmetries in degenerative parkinsonisms. Results Compared with healthy controls, patients with Parkinson's disease showed a regional asymmetry index increase in the nigrostriatal dopaminergic pathway, and those with dementia with Lewy bodies showed a regional asymmetry index increase confined to the bilateral caudate. Individuals with progressive supranuclear palsy exhibited a distinct regional asymmetry index increase in the pallido-subthalamic pathway. Notably, the regional asymmetry index increase in the subthalamic nucleus was significantly greater in progressive supranuclear palsy than in Parkinson's disease. Conclusion The current study revealed distinctive regional asymmetry in dopaminergic and serotoninergic dysfunction in degenerative parkinsonisms. The present findings highlight the potential application of visual diagnosis in degenerative parkinsonisms.

The metabolism of the norisoprenoid β-ionone was investigated in vitro using human liver microsomes and 11 different recombinant cytochrome P450 enzymes expressed in Trichoplusia ni cells. β-Ionone was found to be oxidized via 4S-hydroxylation by CYP2B6 in human liver microsomes. CYP1A2 also regioselectively catalyzed the hydroxylation of β-ionone to yield 4-hydroxylation; this conversion was not stereoselective. Further kinetic analysis revealed that CYP2B6 exhibited the highest activity for β-ionone 4-hydroxylation. Kinetic analysis showed that K m and V max for oxidation of β-ionone by CYP1A2 and CYP2B6 was 107.9 ± 36.0 µM and 3200.3 ± 323.0 nmol/min/nmol P450 and 5.6 ± 1.2 µM and 572.8 ± 29.8 nmol/min/nmol P450, respectively. The reaction rates observed using human liver microsomes and recombinant CYP2B6 were very high compared with those of other CYP2B6 substrates reported thus far. These results suggest that β-ionone, a norisoprenoid present in nature, is one of the effective substrates for CYP2B enzymes in human liver microsomes. To the best of our knowledge, this is the first time that 4-hydroxy β-ionone has been described as a human metabolite of β-ionone.

Urotensin II (U-II) has been found to be one of the most potent vasoconstrictor (Ames et al., 1999; Bohm et al., 2002) reported till date. U-II exerts its response via activation of a G-protein coupled receptor, Urotensin II receptor(UT). Binding of U-II to UT leads to an instant increase in the inositol phosphate turnover and intracellular Ca2+. Such an instant Ca2+ release and potent vasoconstriction exerted by U-II is expected to have an important role in the progression of cardiac diseases. We have previously shown that UT antagonist DS37001789 prevents U-II induced blood pressure elevation in mice (Nishi et al., 2019) in a dose dependent manner, with potent efficacy at 30 and 100 mg/kg. Further to this, we have also shown that DS37001789 ameliorates mortality in pressure-overload mice with heart failure (Nishi et al., 2020). We therefore conducted an extensive structure-activity relationship studies to identify molecules with superior efficacy. In the present manuscript, we report the identification of two potent, non-peptide small molecule antagonists of Urotensin II receptor (UT), RCI-0879 and RCI-0298 which blocked the action of U-II, both in vitro and in vivo. These molecules were found to be very potent in in vitro Ca2+ and radioligand binding assays using human and mouse UT over-expressing CHO cells. RCI-0879 and RCI-0298 also exhibited superior efficacy in in vivo mouse pressor response model using C57BL/6 mice, compared to our initial molecules (Nishi et al., 2019) and demonstrated ED50 values of 3.2 mg/kg and 6.8 mg/kg respectively. Our findings reported herewith, further strengthen our concept and belief in UT antagonization as a potential therapeutic approach for the management of chronic heart failure.

Fibroadenomas are common benign tumors of the female breast. In the appropriate clinical setting, they are often managed expectantly without excision. Rarely, cancer may arise within a fibroadenoma, and this diagnosis mandates prompt treatment for malignancy. We present the case of a 70-year-old Samoan woman with ductal carcinoma in situ (DCIS) arising within a fibroadenoma. Health care practitioners should be aware of the possibility, particularly in older women, of finding carcinoma within a fibroadenoma, which informs the rationale for prompt surgical evaluation and follow up of all breast masses.

This study was designed to characterize the pharmacological profile of DS37001789, which is a structurally novel piperazine derivative that acts as urotensin II (U-II) receptor antagonist. DS37001789 inhibited [I]-U-II binding to human GPR14, U-II receptor, with an IC50 value 0.9 nM. Its potency was superior to that of ACT-058362, a nonpeptide U-II receptor antagonist whose IC50 was 120 nM. Human U-II-induced vascular contraction was blocked by DS37001789. The dose-response curve of DS37001789 in rats and monkeys did not show species differences, and it shifted to the right without any effects on the maximum vascular response. Moreover, orally administered DS37001789 dose-dependently prevented human U-II-induced blood pressure elevation in mice, and this effect was significant at dose and higher dose (30 and 100 mg/kg), and its potency was superior to that of ACT-058362 (100 mg/kg). These results suggest that DS37001789 is a highly potent U-II receptor antagonist both in vitro and in vivo, with no marked species difference. DS37001789 would be a useful tool to clarify the physiological roles of U-II/GPR14 system. In addition, it can serve as a novel therapeutic agent for diseases in which the U-II/GPR14 system is upregulated, such as hypertension, heart failure, renal dysfunction, and diabetes.

This paper describes an electrocardiograph (ECG) monitoring SoC using a non-volatile MCU (NVMCU) and a noise-tolerant instantaneous heartbeat detector. The novelty of this work is the combination of the non-volatile MCU for normally off computing and a noise-tolerant-QRS (heartbeat) detector to achieve both low-power and noise tolerance. To minimize the stand-by current of MCU, a non-volatile flip-flop and a 6T-4C NVRAM are used. Proposed plate-line charge-share and bit-line non-precharge techniques also contribute to mitigate the active power overhead of 6T-4C NVRAM. The proposed accurate heartbeat detector uses coarse-fine autocorrelation and a template matching technique. Accurate heartbeat detection also contributes system-level power reduction because the active ratio of ADC and digital block can be reduced using heartbeat prediction. Measurement results show that the fully integrated ECG-SoC consumes 6.14 $\mu$ A including 1.28- $\mu$ A non-volatile MCU and 0.7- $\mu$ A heartbeat detector.

Background and Purpose Spasticity, an aspect of upper motor neuron syndrome, is a widespread problem in patients with stroke. To date, no study has reported the long-term (up to 1 year) outcomes of botulinum toxin (BTX) injection in combination with constraint-induced movement therapy in patients with chronic stroke. In this case report, the long-term (1 year) effects of the combination of BTX type A injection and constraint-induced movement therapy on spasticity and arm function in a patient with chronic stroke and arm paresis are described. Case Description The patient was a 66-year-old man who had had an infarction in the right posterior limb of the internal capsule 4 years before the intervention. At screening, the patient was not able to voluntarily extend his interphalangeal or metacarpophalangeal joints beyond the 10 degrees required for constraint-induced movement therapy. From 12 days after BTX type A injection, the patient received 5 hours of constraint-induced movement therapy for 10 weekdays. Outcomes All outcome measures (Modified Ashworth Scale, Fugl-Meyer Assessment, Action Research Arm Test, and amount of use scale of the Motor Activity Log) improved substantially over the 1-year period (before intervention to 1 year after intervention). Repeat BTX type A injections were not necessary because muscle tone and arm function did not worsen during the observation period. Discussion The improved arm function may have reflected improvements in volitional movements and coordination or speed of movements in the paretic arm as a result of a reduction in spasticity, a reduction of learned nonuse behaviors, or use-dependent plasticity after the combination of BTX type A injection and constraint-induced movement therapy. In addition, the possibility of an influence of the passage of time or the Hawthorne effect cannot be ruled out. If this approach proves useful in future controlled studies, it may reduce the rising medical costs of the treatment of stroke.

Despite the confirmed short-term effects of constraint-induced movement therapy, the long-term effects have not been sufficiently verified in terms of functional improvement of the affected arm.To evaluate the long-term effects and relationship between arm use in activities of daily living and arm improvement with modified constraint-induced movement therapy in chronic stroke patients.At 1 year after completing modified constraint-induced movement therapy, arm function (Fugl-Meyer Assessment) and amount of daily arm use (motor activity log) were assessed.Fourteen post-stroke patients with mild to moderate impairment of arm function were analyzed. One year after completing modified constraint-induced movement therapy, participants consistently showed improvements in arm function and amount of daily arm use (analysis of variance: Fugl-Meyer Assessment, P 0.001; Motor Activity Log, P 0.001). For the Fugl-Meyer Assessment, post-hoc tests detected significant improvements (pre versus post, P = 0.009; pre versus 1 year, P 0.0001; post versus 1 year, P 0.036). For the Motor Activity Log, post-hoc tests also detected significant improvements (pre versus post, P = 0.0001; pre versus 1 year, P 0.0001; post versus 1 year, P = 0.0014). The magnitude of the change in Fugl-Meyer Assessment score correlated significantly with the change in Motor Activity Log score (R = 0.778, P = 0.001).Among post-stroke patients with mild to moderate impairments of arm function, modified constraint-induced movement therapy without any other rehabilitation after intervention may improve arm function and increase arm use for 1 year. In addition, increasing arm use may represent an important factor in improving arm function, and vice versa.

Background No previous studies have determined how the post-stroke integrity of non-corticospinal neural pathways relates to the efficacy of constraint-induced movement therapy (CIMT). Objectives We aimed to clarify the relationship between several non-corticospinal neural pathway integrities and the short- and long-term benefits of CIMT. Methods This was a pilot cohort study (UMIN registration number: R00027136UMIN000023566), for which we enrolled 13 patients with chronic stroke and hemiparesis who had undergone CIMT. We assessed patients' motor function improvement by comparing the Fugl-Meyer Assessment (FMA) scores, as well as the Amount of Use (AOU) and Quality of Movement (QOM) scales of the Motor Activity Log before, immediately after (short-term), and 6 months after (long-term) CIMT. We assessed neural pathway integrity by calculating fractional anisotropy (FA) in diffusion tensor images acquired before CIMT. We then assessed correlations between FA and short- and long-term post-CIMT motor function improvements. Results The patients showed significant improvements in all functional assessments at both short- and long-term follow-ups. Immediate FMA score improvements were significantly correlated with FA of the affected anterior limb of the internal capsule (ALIC), body of the corpus callosum, column and body of the fornix (CBF), cingulate cortex (CgC), cerebral peduncle (CP), and posterior limb of the internal capsule. Six-month FMA score improvements were significantly correlated with FA of the affected ALIC, CgC, CBF, CP, and superior frontooccipital fasciculus. Conclusions The integrity of the affected corticospinal and non-corticospinal motor pathways was associated with CIMT-induced motor learning at least 6 months after CIMT.

Inhibition of β-secretase (BACE1) is currently regarded as the leading treatment strategy for Alzheimer's disease. In the present study, we aimed to screen the in vitro inhibitory activity of 80 types of aroma compounds (monoterpenes, sesquiterpenes, and C

To describe and summarize published research on accelerated resolution therapy (ART), a promising and relatively new psychotherapy with the potential to offer rapid and effective resolution of a wide range of psychiatric symptoms. Unlike most evidence-based psychotherapies, ART is a predominately imaginative therapy that relies upon the rescripting of distressing events and metaphors as one of its key therapeutic elements. The number of studies conducted on ART is limited, primarily consisting of one randomized, controlled trial (RCT) with 57 subjects and two large cohort studies involving 80 and 117 subjects, respectively. However, a growing body of research in the neuroscience field involving the initial creation (consolidation), activation, and reconsolidation of memories may also be relevant and is summarized herein. ART appears to be an effective, efficient, and versatile form of psychotherapy. Future studies, particularly high-quality RCTs, are needed to more fully understand the potential reach of this promising therapeutic modality.

Infectious complications in patients with multiple myeloma remain the main cause of mortality because of disease-related immunodeficiency. A mycotic aortic aneurysm caused by Burkhoderia cepacia, which has been recognized as nosocomial pathogen in immunocompromised populations, is very rare and only few cases have been reported in the literature. We describe an unusual case of a ruptured mycotic aneurysm of the descending thoracic aorta with a DeBakey IIIb aortic dissection caused by Burkhoderia cepacia in a patient with active multiple myeloma during chemotherapy with anti-myeloma agents. Successful treatment of this mycotic aneurysm included appropriate antibiotic therapy and replacement of the aortic arch and the descending aorta for the extensive debridement of all infected aortas. This was followed by the wrapping of a prosthetic graft with a well-vascularized tissue flap of the greater omentum and of the latissimus dorsi muscle.

We assessed the relationship between fractional anisotropy (FA) values of magnetic resonance-diffusion tensor imaging (DTI) and long-term outcome (3-7 months after onset) in patients with hemiparesis after intracerebral hemorrhage (N = 12). DTI data were obtained on days 14-18. FA values within the cerebral peduncle were analyzed using a computer-automated method. Motor outcome of hemiparesis was evaluated using Brunnstrom stage (six-point scale: severe to normal) for separate shoulder/elbow/forearm, wrist/hand, and lower extremity functions when patients were discharged from a long-term rehabilitation facility 3-7 months after onset. In addition, the motor component of the functional independence measure (FIM-motor) was scored. The ratio of FA values in the affected hemisphere to those in the unaffected hemisphere (rFA) was assessed in relation to the clinical data (Spearman's rank correlation test, P < 0.05). Analysis revealed a statistically significant relationship between rFA and upper extremity function (R = 0.863 for shoulder/elbow/forearm; 0.834 for wrist/hand). Although statistically significant, the relationship between rFA and lower extremity function was less evident (R = 0.609). In contrast, analysis of rFA and FIM-motor scores did not reveal statistical significance. FA values within the cerebral peduncle are tightly associated with long-term outcomes of upper extremity function.

The elderly population with severe aortic stenosis (AS) requiring aortic valve replacement (AVR) is increasing. The optimal timing of AVR in these patients has been under discussion. We retrospectively reviewed the data from severe AS patients (n = 84) who underwent AVR with/without concomitant procedures from 2005 to 2010. The symptom status, preoperative data, operative outcome, late survival and freedom from cardiac events were compared between elderly patients (age ≥80 years [n = 31]) and younger patients (age

Objective: To investigate the long-term effects of the ‘transfer package’ in constraint-induced movement therapy, which is an optional protocol to facilitate actual use of the trained affected arm in activities of daily living. Design: A pilot quasi-randomized controlled trial with a blinded single assessor with six-month follow-up. Setting: Hospitalized care at university hospital. Subjects: Twenty-one post-stroke patients were quasi-randomized to either a group with transfer package during constraint-induced movement therapy or a control group (without transfer package). Interventions: The transfer package group received 4.5 hours of intensive task training and 0.5 hours of transfer package whereas the control group received 5.0 hours of intensive task training per day during 10 consecutive weekdays. Main measures: Arm function was measured with Fugl-Meyer Assessment and Amount of Use score of Motor Activity Log. Results: Twenty-three patients were quasi-randomized, but data from two patients were missing from the long-term follow-up. Both groups showed increase in arm function postintervention. However, at six months’ follow-up only the transfer package group showed consistent increase in arm function (with transfer package group versus control group; Fugl-Meyer Assessment, mean (± SD) from 48.6 ± 7.8 (preintervention) to 55.7 ± 4.5 (postintervention) and 59.0 ± 3.6 (six months postintervention) versus from 49.1 ± 5.5 to 52.8 ± 6.0 and 53.3 ± 4.9, P= 0.003; Amount of Use scale of Motor Activity Log, mean from 1.3 ± 0.55 (preintervention) to 2.12 ± 0.55 (postintervention) and 2.79 ± 0.98 (six months postintervention) versus from 1.18 ± 0.70 to 1.61 ± 0.54 and 1.65 ± 0.68, P= 0.002). Conclusions: Our results confirmed the long-term effects of the transfer package in constraint-induced movement therapy.

Although oncolytic virotherapy is a promising anticancer therapy, antitumor efficacy is hampered by low tumor selectivity. To identify a potent and selective oncolytic virotherapy, we carried out large-scale two-step screening of 28 enteroviral strains and found that coxsackievirus B3 (CVB3) possessed specific oncolytic activity against nine human non–small cell lung cancer (NSCLC) cell lines. CVB3-mediated cytotoxicity was positively correlated with the expression of the viral receptors, coxsackievirus and adenovirus receptor, and decay-accelerating factor, on NSCLC cells. In vitro assays revealed that the CVB3 induced apoptosis and phosphoinositide 3-kinase/Akt and mitogen-activated protein (MAP)/extracellular signal-regulated (ERK) kinase (MEK) survival signaling pathways, leading to cytotoxicity and regulation of CVB3 replication. Intratumoral injections of CVB3 elicited remarkable regression of preestablished NSCLC tumors in vivo. Furthermore, administrations of CVB3 into xenografts on the right flank resulted in significantly durable regression of uninjected xenografts on the left flank, where replication-competent CVB3 was detected. All treatments with CVB3 were well tolerated without treatment-related deaths. In addition, after CVB3 infection, NSCLC cells expressed abundant cell surface calreticulin and secreted ATP as well as translocated extranuclear high-mobility group box 1, which are required for immunogenic cell death. Moreover, intratumoral CVB3 administration markedly recruited natural killer cells and granulocytes, both of which contributed to the antitumor effects as shown by depletion assays, macrophages, and mature dendritic cells into tumor tissues. Together, our findings suggest that CVB3 is a potent and well-tolerated oncolytic agent with immunostimulatory properties active against both localized and metastatic NSCLC. Cancer Res; 72(10); 2609–21. ©2012 AACR.

Diffusion tensor imaging (DTI) using a 3.0 tesla magnetic resonance scanner was used to investigate white matter changes caused by idiopathic normal pressure hydrocephalus (INPH) in 10 patients diagnosed by clinical symptoms (gait disturbance, dementia, and/or urinary incontinence) and Evans index >0.3, and compared with findings for 10 age-matched controls (≥60 years). Then, using a computer-automated method, fractional anisotropy (FA) brain maps were generated and finally transformed into the standard space. Voxel-based FA values within two regions of interests (ROIs), the forceps minor and corticospinal tracts, were then separately evaluated. Within each ROI, statistical comparisons of results from the INPH and control groups were performed. In addition, for INPH patients, grading scores for clinical symptoms and FA values were correlated. The forceps minor mean FA value was much smaller for the INPH group (0.504) than for the control group (0.631). The corticospinal tract mean FA value was slightly smaller for the INPH group (0.588) than for the control group (0.632). Additional analyses indicated that lower FA values within the forceps minor tended to be associated with clinical symptoms such as urinary incontinence and gait disturbance. Our findings indicate FA values decreased in the forceps minor of INPH patients. We also found that lower values were associated with severer clinical symptoms, implying that DTI techniques may be developed for more accurate diagnosis.

This study was designed to investigate the antigenotoxic effects of a series of naturally occurring furanocoumarins (NOFs) including isoimperatorin, imperatorin, (+)-oxypeucedanin, (+)-byakangelicol, and (+)-byakangelicine on antigenotoxic activities against genotoxicity induced by carcinogens [furylfuramide and N-methyl-N′-nitro-N-nitrosoguanidine], and procarcinogens 2-[2-(acetylamino)−4-amino-5-methoxyphenyl]−5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-4) and 2-amino-3,4-dimethyl-3H-imidazo-[4,5-f] quinoline (MeIQ)] to genotoxic metabolites catalyzed by rat S9 or rat and human recombinant cytochrome P450 (CYP) 1As by using the umu test based on SOS response. Five different NOFs, which were found in the human diets, strongly inhibited the umuC induction by procarcinogens, but did not be affected by carcinogens. Notably, isoimperatorin and (+)-byakangelicol were found to be potent inhibitors on the metabolic activation of PBTA-4 and MeIQ to genotoxic metabolites catalyzed by rat and human CYP1A1, or rat and human CYP1A2, respectively. In addition, to elucidate the mechanism of their antigenotoxic effects against procarcinogens, the effects of NOFs on rat and human CYP1A1- or rat and human CYP1A2-related enzyme activities of 7-ethoxyresorufin-O-deethylase (EROD) were also investigated. Reduction of the EROD activities by some of the NOFs with IC50 values of 0.23–20.64 μM was found to be due to strong inhibition of CYP1A1 and CYP1A2 dependent monooxygenases. Furthermore, the mechanism of inhibitions by NOFs on human CYP1A1 and CYP1A2 was analyzed by means of Dixon plots plus Cornish-Bowden plots. The kinetic studies of inhibition types revealed that these compounds inhibited the human CYP1A1 and CYP1A2 a variety of modes rather than by a uniform one. Moreover, experiments with a two-stage incubation indicated that NOFs, except for imperatorin, inhibited human CYP1A1 in a mechanism-based manner, but directly inhibited human CYP1A2. This data suggest that certain NOFs, to which humans are exposed in the diet, may be capable of affecting the metabolic activation of procarcinogens due to inhibitions of CYP1A1 and CYP1A2 enzymes. Environ. Mol. Mutagen., 2011. © 2011 Wiley-Liss, Inc.

We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP-controlled lentiviral vectors expressing oncogenes. Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein-positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested. Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus. However, tumors were rarely detected when the mice were transduced in the cortex. Transplantation of brain tumor cells into naive recipient mouse brain resulted in the formation of glioblastoma multiforme-like tumors, which contained CD133(+) cells, formed tumorspheres and could differentiate into neurons and astrocytes. We suggest that the use of Cre-loxP-controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice.

In 2003, we started autologous bone marrow cell infusion (ABMi) therapy for treating liver cirrhosis. ABMi therapy uses 400 mL of autologous bone marrow obtained under general anesthesia and infused mononuclear cells from the peripheral vein. The clinical study expanded and we treated liver cirrhosis induced by HCV and HBV infection and alcohol consumption. We found that the ABMi therapy was effective for cirrhosis patients and now we are treating patients with combined HIV and HCV infection and with metabolic syndrome-induced liver cirrhosis. Currently, to substantiate our findings that liver cirrhosis can be successfully treated by the ABMi therapy, we are conducting randomized multicenter clinical studies designated "Advanced medical technology B" for HCV-related liver cirrhosis in Japan. On the basis of our clinical study, we developed a proof-of-concept showing that infusion of bone marrow cells (BMCs) improved liver fibrosis and sequentially activated proliferation of hepatic progenitor cells and hepatocytes, further promoting restoration of liver functions. To treat patients with severe forms of liver cirrhosis, we continued translational research to develop less invasive therapies by using mesenchymal stem cells derived from bone marrow. We obtained a small quantity of BMCs under local anesthesia and expanded them into mesenchymal stem cells that will then be used for treating cirrhosis. In this review, we present our strategy to apply the results of our laboratory research to clinical studies. Copyright © 2014, Mary Ann Liebert, Inc.

We designed a phase I trial to investigate the safety, immune responses and clinical benefits of a five-peptide cancer vaccine in combination with chemotherapy. Study subjects were patients positive for HLA-A2402 with locally advanced, metastatic, and/or recurrent gastrointestinal, lung or cervical cancer. Eighteen patients including nine cases of colorectal cancer were treated with escalating doses of cyclophosphamide 4days before vaccination. Five HLA-A2402-restricted, tumor-associated antigen (TAA) epitope peptides from KOC1, TTK, URLC10, DEPDC1 and MPHOSPH1 were injected weekly for 4weeks. Treatment was well tolerated without any adverse events above grade 3. Analysis of peripheral blood lymphocytes showed that the number of regulatory T cells dropped from baseline after administration of cyclophosphamide and confirmed that TAA-specific T cell responses were associated significantly with longer overall survival. This phase I clinical trial demonstrated safety and promising immune responses that correlated with vaccine-induced T-cell responses. Therefore, this approach warrants further clinical studies.

Background Abdominal surgery in critically ill patients has high mortality, contributing to high US healthcare costs. This study sought to identify specific predictors of mortality in this population. Methods Using the National Surgical Quality Improvement Program database 2006 to 2012, we identified 4,901 patients who were intubated for more than 48 hours before undergoing common abdominal procedures. Mortality and predictors of mortality were determined using chi-square and/or regression analysis. Results Overall 30-day mortality was 44.2% with increasing mortality for additional procedures performed. Ventilated patients with the following preoperative risk factors were 2 to 3 times as likely to die within 30 days of surgery: age greater than 65-years old, coma, preoperative international normalized ratio greater than 3.0, esophageal varices, and disseminated cancer. Conclusions Mortality is significant in ventilated patients who undergo abdominal surgery and is especially high with advanced age, disseminated cancer, and complications of liver disease. Physicians should carefully discuss this with patients and/or family and consider palliative options when appropriate.

A 26-year-old man had a history of severe atopic dermatitis. He was taking immunosuppressive drug. Mitral valve replacement (MVR) had been performed for infective endocarditis March 2008. He came to our hospital in July 2012 complaining of fever of 39 degrees Celsius. According to computed tomography (CT) and transesophageal echocardiography (TEE), we diagnosed that he had cerebral embolism and bacterial infection of prosthetic valve. Antibiotic treatment was performed for 2 weeks after the onset of cerebral infarction. Then we conducted re-MVR. The postoperative course was satisfactory. He showed a gradual improvement in the level of consciousness and was discharged. In patients with atopic dermatitis, bacteria can penetrate into the blood from the skin easily. So they are often affected by bacteremia. There are some reports that infective endocarditis is likely to occur in immunosuppressed patients. It is suggested that immunosuppressive drug was involved in the development of prosthetic valve endocarditis (PVE) in addition to atopic dermatitis in this patient.

Scrub typhus is likely endemic in Palau., Scrub typhus, caused by Orientia tsutsugamushi, is a severe febrile illness transmitted to humans by trombiculid mites, which normally feed on rodents. The first known outbreak of scrub typhus in Palau occurred in 2001 to 2003 among residents of the remote southwest islands. To determine the extent of scrub typhus distribution in Palau, we tested serum samples from humans and rodents for antibodies to O. tsutsugamushi. Of 212 Palau residents surveyed in 2003, 101 (47.6%) had immunoglobulin G (IgG) antibody titers >1:64, and 56 (26.4%) had concurrent IgG and IgM antibody titers >1:512 and 1:64, respectively. Of 635 banked serum samples collected from Palau residents in 1995, 34 (5.4%) had IgG antibody titers >1:64. Sera collected from rodents (Rattus norvegicus and R. rattus) in 2003 and 2005 were tested, and 18 (28.6%) of 63 had IgG antibody titers >1:64. These findings suggest that scrub typhus is endemic in Palau.

Drosophila tumor suppressor WARTS (Wts) is an evolutionally conserved serine / threonine kinase and participates in a signaling complex that regulates both proliferation and apoptosis to ensure the proper size and shape of the fly. Human counterparts of this complex have been found to be frequently downregulated or mutated in cancers. WARTS, a human homolog of Wts, is also known as tumor suppressor and mitotic regulator, but its molecular implications in tumorigenesis are still obscure. Here, we show that WARTS binds via its C-terminus to the PDZ domain of a proapoptotic serine protease Omi / HtrA2. Depletion of WARTS inhibited Omi / HtrA2-mediated cell death, whereas overexpression of WARTS promoted this process. Furthermore, WARTS can enhance the protease activity of Omi / HtrA2 both in vivo and in vitro. Activation of Omi / HtrA2-mediated cell death is thus a potential mechanism for the tumor suppressive activity of WARTS.

Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents that damage DNA. This process is facilitated by defects in the G1 and G2 checkpoints of the cell cycle that are apparent in most cancer cells and which allow the cells to enter mitosis with DNA damage. We have now characterized the dynamics of mitotic catastrophe induced by DNA-damaging agents in p53-deficient cancer cells. Cells that entered mitosis with DNA damage transiently arrested at metaphase for more than 10 h without segregation of chromosomes and subsequently died directly from metaphase. In those metaphase arrested precatastrophic cells, anaphase-promoting complex appeared to be inactivated and BubR1 was persistently localized at kinetochores, suggesting that spindle checkpoint is activated after the DNA damage. Furthermore, suppression of spindle checkpoint function by BubR1 or Mad2 RNA interference in the DNA damaged cells led to escape from catastrophic death and to subsequent abnormal mitosis. Dysfunction of the spindle checkpoint in p53-deficient cancer cells is thus likely a critical factor in resistance to DNA-damaging therapeutic agents.

Defects in chromosomes or mitotic spindles activate the spindle checkpoint, resulting in cell cycle arrest at prometaphase. The prolonged activation of spindle checkpoint generally leads to mitotic exit without segregation after a transient mitotic arrest and the consequent formation of tetraploid G(1) cells. These tetraploid cells are usually blocked to enter the subsequent S phase by the activation of p53/pRb pathway, which is referred to as the G(1) tetraploidy checkpoint. A human homologue of the Drosophila warts tumor suppressor, WARTS, is an evolutionarily conserved serine-threonine kinase and implicated in development of human tumors. We previously showed that WARTS plays a crucial role in controlling mitotic progression by forming a regulatory complex with zyxin, a regulator of actin filament assembly, on mitotic apparatus. However, when WARTS is activated during cell cycle and how the loss of WARTS function leads to tumorigenesis have not been elucidated. Here we show that WARTS is activated during mitosis in mammalian cells, and that overexpression of a kinase-inactive WARTS in Rat1 fibroblasts significantly induced mitotic delay. This delay resulted from prolonged activation of the spindle assembly checkpoint and was frequently followed by mitotic slippage and the development of tetraploidy. The resulting tetraploid cells then abrogated the G(1) tetraploidy checkpoint and entered S phase to achieve a DNA content of 8N. This impairment of G(1) tetraploidy checkpoint was caused as a consequence of failure to induce p53 expression by expressing a kinase-inactive WARTS. WARTS thus plays a critical role in maintenance of ploidy through its actions in both mitotic progression and the G(1) tetraploidy checkpoint.