The Cyclotron and Radioisotope Center (CYRIC) of Tohoku University is a joint-use institution for education and research in a wide variety of fields ranging from physics to medicine. Accelerator facilities at the CYRIC provide opportunities for implementing a broad research program, including medical research using positron emission tomography (PET), with accelerated ions and radioisotopes. At the Great East Japan Earthquake on March 11, 2011, no human injuries occurred and a smooth evacuation was made in the CYRIC, thanks to the anti-earthquake measures such as the renovation of the cyclotron building in 2009 mainly to provide seismic strengthening, fixation of shelves to prevent the falling of objects, and securement of the width of the evacuation route. The preparation of an emergency response manual was also helpful. However, the accelerator facilities were damaged because of strong shaking that continued for a few minutes. For example, two columns on which a 930 cyclotron was placed were damaged, and thereby the 930 cyclotron was inclined. All the elements of beam transport lines were deviated from the beam axis. Some peripheral devices in a HM12 cyclotron were broken. Two shielding doors fell from the carriage onto the floor and blocked the entrances to the rooms. The repair work on the accelerator facilities was started at the end of July 2011. During the repair work, the joint use of the accelerator facilities was suspended. After the repair work was completed, the joint use was re-started at October 2012, one and a half years after the earthquake.
The optimal timing for initiating continuous renal replacement therapy (CRRT) remains controversial, and it is not obvious which parameters should be considered during this process. We investigated the predictive value of physiological parameters among critically ill patients receiving CRRT due to acute kidney injury (AKI). A total of 496 patients who started CRRT were prospectively enrolled. The following physiological parameters were significantly associated with mortality even after multivariate adjustments: level of pH [hazard ratio (95% CI): 7.15 < pH ≤ 7.20, 1.971 (1.319-2.946); pH ≤ 7.15, 2.315 (1.586-3.380); reference > 7.25, P-for-trend < 0.001]; bicarbonate level (HCO3−) [≤ 14 mmol/L, 2.010 (1.542-2.620); reference > 18 mmol/L, P-for-trend < 0.001]; phosphorus level [> 7 mmol/L, 1.736 (1.313-2.296); reference ≤ 5 mmol/L, P-for-trend < 0.001]; and urine output < 0.3 ml/kg/hr [1.509 (1.191-1.912); reference > 0.3 ml/kg/hour]. Weight gain over 2 kg was associated with mortality exclusively according to univariate analysis [1.516 (1.215-1.892)]. The diagnostic value of the composite of these factors (pH, bicarbonate level, phosphorus level, urine output, weight gain, and potassium levels) [area under the curve (AUC) 0.701, 95% CI 0.644-0.759] was comparable to or higher than the blood urea nitrogen level (AUC 0.571, 95% CI 0.511-0.630), serum creatinine level (AUC 0.462, 95% CI 0.399-0.525), eGFR (AUC 0.541, 95% CI 0.478-0.605), and AKI Network stage (AUC 0.627, 95% CI 0.561-0.692). In conclusion, the physiological parameters are useful in predicting post-AKI mortality and should be considered when initiating CRRT in critically ill patients with AKI.
Elective Cesarean section performed before 39 weeks of gestation may be associated with increased risk of neonatal complications. We retrospectively investigated differences in the neonatal complication rate between 684 newborns delivered by elective Cesarean section at 37 weeks of gestation (n = 390) and those delivered by the same procedure at 38 weeks (n = 294) between 2006 and 2012 at our hospital in order to ascertain whether adverse outcomes differ between the groups. Newborns delivered at 37 weeks had a significantly higher incidence of neonatal intensive care unit admission (p = 0.03), adverse respiratory complications (p < 0.01), low birth weight (p < 0.001), and hypoglycemia (p < 0.005) than those delivered at 38 weeks. Compared with normal weight neonates, low birth weight neonates were more likely to have hypoglycemia (p < 0.001). Multivariate logistic regression analysis revealed that an adverse respiratory outcome was independently associated with gestational age (p < 0.01; odds ratio [OR], 3.26; 95% confidence interval [CI], 1.36-7.81), while hypoglycemia was independently associated with birth weight (p < 0.01; OR, 16.34; 95% CI, 7.72-34.56). Respiratory disorders were significantly associated with gestational age even in normal birth weight newborns without any other complications such as hyperbirilubinemia, hypoglycemia or bacterial infections. In conclusion, the incidence of neonatal complications was higher in newborns delivered at 37 weeks of gestation than in those delivered at 38 weeks via elective Cesarean section. Thus, the procedure should be scheduled at 38 weeks to improve neonatal outcomes.
Tumor-associated macrophages play a key role in cancer metastasis. On the other hand, C-reactive protein (CRP), a widely used biomarker of inflammation, has been shown to have inhibitory effects on tumor proliferation and metastasis. Here we used an implanted tumor mouse model to assess the effect of CRP on tumor-associated macrophage numbers and on their phenotype, as well as on intratumoral angiogenesis. NR-S1M murine oral squamous cell carcinoma cells were implanted subcutaneously in the backs of anesthetized C3H/HeN mice. Some of the mice were also subcutaneously administered 1 μg of recombinant mouse CRP in 100 μL of phosphate-buffered saline (PBS) (CRP group, n = 10) near the neck every 2 days for 30 days (15 injections in all). Control mice received PBS without CRP. The mice were then sacrificed and the excised tumors were analyzed. Tumor weight and size did not differ between the two groups, but immunohistochemical analysis showed the F4/80+ macrophage (total macrophages) count to be significantly larger in the CRP group (P = 0.0028), while the relative number of CD206+ anti-inflammatory M2 macrophages was significantly reduced (P = 0.0091). In addition, expression of colony stimulating factor 1 mRNA, which is associated with the M2 macrophage phenotype, was significantly lower in the CRP group. Intratumoral angiogenesis, indicated by the presence of CD31+ vessels within the tumor, was reduced in the CRP group (P = 0.0028). These findings suggest that CRP has therapeutic potential against cancer through decreasing the accumulation of M2 macrophages and angiogenesis within tumors.
Leukoaraiosis (LA) is a leading cause of gait disturbance in the elderly and well known as a type of cerebrovascular diseases. LA is mainly caused by the focal ischemic damage in cerebral white matter. Cognitive impairment in patients with LA is difficult to treat. Carotid artery stenting (CAS) has been reported to improve the cognitive function in patients with cognitive impairment. However, whether CAS can ameliorate the cognitive impairment in patients with LA remains unknown. To address this problem, we prospectively enrolled 105 LA patients with carotid stenosis and 206 healthy subjects, who are free of carotid artery stenosis and brain diseases or injuries, as the control. Neuropsychological functions were tested in these LA patients before and after 1-, 6- and 12-month CAS, and compared with the data of control subjects. Mini-Mental State Examination (MMSE) and Wechsler Adult Intelligence Scale-Revised China (WAIS-RC) scores were lower in LA patients than those in healthy controls (P < 0.05), indicating the cognitive impairment in the LA patients. Compared with the scores before CAS, there is a time-dependent increase in MMSE and WAIS-RC scores after 1-, 6- and 12-month CAS (P < 0.05). Moreover, CAS treatment reduced Clinical Dementia Rating scale in LA patients. The cognitive impairment of LA patients with carotid stenosis was severe, but their cognitive impairment was ameliorated with carotid stenosis (P < 0.01). Thus, CAS can improve cognitive function of the LA patients with carotid stenosis.
Patulin is a mycotoxin that is found mainly in apple products and causes symptoms such as bleeding from the digestive tract and diarrhea. Efforts to elucidate the mechanism of its toxicity have focused on protein tyrosine phosphatases (PTPs), which regulate the function of tight junctions (TJs) in colon epithelial cells. Patulin reacts with the conserved cysteine residues in the catalytic domains of PTP isoforms. Treatment of Caco-2 human colon cancer cells, used as a colon epithelial model, with 50 µM patulin decreased the level of density-enhanced phosphatase-1 (DEP-1) protein to 30% of the control level after 6 h. The level of DEP-1 mRNA was also decreased during 24 h after treatment with patulin. Moreover, knockdown of DEP-1 increased the level of phosphorylated claudin-4. Destruction of TJs by patulin treatment was observed by immunostaining with an antibody against zonula occludens (ZO)-1. To better understand the mechanistic basis of the decrease in DEP-1 mRNA levels, we searched for a cis-element upstream of the DEP-1 gene and found an element responsive to the peroxisome proliferator-activated receptor gamma (PPARγ) protein. Using a PPARγ-specific antibody, we showed a decrease in PPARγ abundance to 42% of the control level within 6 h after treatment with patulin. PPARγ has four cysteine residues that are involved in zinc finger formation. Our data suggest that DEP-1 affects TJ function and that PPARγ might control DEP-1 expression. Therefore, the toxicity of patulin to cellular functions might be attributable to its ability to down-regulate the expression of DEP-1 and PPARγ.
Citrin is the liver-type aspartate/glutamate carrier isoform 2 (AGC2) encoded by SLC25A13 gene, playing important roles in the urea cycle and the malate-aspartate shuttle. Citrin deficiency (CD) has proven a disease entity with high prevalence in south China, including Guangdong with the largest population, but CD epidemiology in this province has not been well characterized. This study aims to screen for five prevalent SLC25A13 mutations, c.851_854del (p.R284fs286X), c.1638_1660dup (p.A554fs570X), c.615+5G>A (p.A206fs212X), IVS16ins3kb (p.A584fs585X) and c.1399C>T (p.R467X), to calculate the mutation carrier rate in Guangdong. A total of 2,428 used blood samples for health examination were collected as the research subjects, including 1,558 from 5 cities in the Pearl River Delta area and the remaining 870 from 4 peripheral cities, and the 5 mutations screened using High Resolution Melting Assay and HybProbe assay. A total of 52 carriers were detected, including 2 carriers of a novel c.1420G>A (p.V474M) mutation that impairs citrin function, as judged by the functional analysis in the yeast system. The carrier rate was higher in Pearl River Delta area than that in the peripheral cities (26/1,558 vs. 26/870, with χ2 = 4.639 and P < 0.05). The carrier rate was around 1/47 (52/2,428), theoretically with the CD morbidity of 1/8,800 and the number of CD patients over 11,800 in Guangdong population. This study has provided primary epidemiologic data for the evaluation of CD effect in Guangdong province. Moreover, the newly identified c.1420G>A mutation that impairs AGC2 function has enriched the mutation spectrum of human SLC25A13 gene.
Cyclosporine, a calcineurin inhibitor, is a potent immunosuppressive agent that acts chiefly through the inactivation of T-lymphocytes. Several clinical studies have demonstrated the effectiveness of cyclosporine for treating fibrotic lung disease, but the underlying mechanism remains elusive. We hypothesized that cyclosporine exerts direct effects against fibrogenesis of lung myofibroblasts, and aimed to elucidate the mechanism of this anti-fibrotic effect through gene-expression profiling using DNA microarray analysis. We found that cyclosporine suppressed the expression of alpha-smooth muscle actin and collagen type I in myofibroblasts that had been differentiated from a fetal human lung fibroblast cell line by induction with transforming growth factor (TGF)-β. Furthermore, microarray analysis revealed that cyclosporine down-regulated 57 genes whose expression levels were increased by TGF-β, and up-regulated 73 genes, whose expression was decreased by TGF-β. Classifying these 57 down-regulated and 73 up-regulated genes with the Database for Annotation, Visualization and Integrated Discovery (DAVID) web tool, we have identified the involvement of several functional categories, including innate immunity, cytokine interaction, growth factor, and cancer pathway. Of the identified genes, we selected three fibrosis-related genes, insulin-like growth factor binding protein 2 (IGFBP2), inhibitor of DNA binding 1 (ID1) and peroxisome proliferator-activated receptor gamma (PPARG), and validated their expression patterns by quantitative reverse transcription-polymerase chain reaction. Cyclosporine treatment decreased the expression levels of IGFBP2 and ID1, but increased PPARG expression. These results suggest that cyclosporine is a potent anti-fibrotic agent acting on myofibroblasts. Therefore, cyclosporine shows potential as a novel remedy for fibrotic lung disease.
Fluid overload is linked to hypertension and cardiovascular diseases in patients on peritoneal dialysis (PD). It is important to monitor the residual urinary volume in patients with end-stage renal disease (ESRD). In fact, fluid overload and residual urinary volume have been considered the risk factors of mortality in ESRD patients on PD. However, the relationship between residual urinary volume and fluid overload was still controversial. Therefore, the objective of this cross-sectional study was to evaluate the association between residual urinary volume and the volume status of PD patients. Body composition was measured using a portable multifrequency whole-body bioimpedance assessment. Relative overhydration was defined when the ratio of overhydration to extracellular water was > 0.15. We examined 75 patients, with a mean age of 50.7 years and mean body mass index of 23.5 kg/m2. Dialysis vintage was 46.5 months. The patients were divided into the anuric group (n = 30; urine output ≤ 100 mL/day) and the group of urine output > 100 mL/day (n = 45). The anuric group showed higher degree of relative overhydration compared to the patients with the urine output of > 100 mL/day (p = 0.020). In a multivariable linear regression analysis, anuria, diabetes, and serum albumin level were independently associated with relative overhydration. In conclusion, volume status should be closely monitored in anuric patients, and the preservation of residual urinary volume is one of important goals to maintain volume status in PD patients.
Bacterial meningitis is responsible for significant morbidity and mortality worldwide, despite that modern antibiotics effectively penetrate cerebrospinal fluid to eradicate bacteria. A clinical suspicion of bacterial meningitis should be recognized early for the rapid diagnostic workup. Bacterial meningitis associated with ventriculoperitoneal shunt (VPS) is not uncommon and infrequently presents as abdominal symptoms and signs. Infections of the central nervous system caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae (ESBL-KP) are extremely rare, and such multiple drug-resistant pathogens frequently cause inappropriate treatments and mortality. β-Lactamases are bacterial enzymes that inactivate β-lactam antimicrobial agents. The increased prevalence of ESBL-producing organism infections has become a worldwide problem. Timely and appropriate treatment is important to reduce mortality and morbidity of infections caused by ESBL-producing organisms. Here, we report a 61-year-old male patient who underwent VPS implantation for consequent hydrocephalus following spontaneous intracranial hemorrhage six months before this presentation. He was admitted for intermittent fever and right lower quadrant abdominal pain, and he was initially managed as acute appendicitis with its typical presentation. Finally, he was diagnosed VPS-associated meningitis caused by ESBL-KP. This patient was successfully treated with the combination of meropenem, a carbapenem antibiotic that is the drug of choice for treating ESBL-producing organisms, and high-dose fosfomycin, a phosphonic acid derivative antibiotic that is effective in treating some drug-resistant pathogens. In the present report, we emphasize the clinical presentations of catheter-related meningitis and risk factors for infections caused by ESBL-producing pathogens. Antibiotic combination therapy can provide synergistic effect and maximize anti-bacterial activity in ESBL-KP meningitis.