Levels and ages of selenium and metals in sedimentary cores of Ise Bay as determined by 210-Pb dating technique

Bulletin of Environmental Contamination and Toxicology -     

Circadian Changes in Urine Volume and Frequency In Elderly Men

Purpose

Circadian changes in urinary frequency, diuresis and bladder capacity were evaluated in middle-aged and elderly patients.

Materials and Methods

A total of 2,703 urinations from 50 men (median age 66 years) was recorded with a 24-hour uroflowmetry system.

Results

During a 24-hour period the elderly group showed increased frequency and decreased bladder capacity. No difference was observed in diuresis between the 2 age groups. From midnight to 6 a.m. frequency in the elderly group was significantly greater (p less than 0.01) than that in the middle-aged group.

Conclusions

Increased frequency in the elderly group during these hours was primarily due to an increase in diuresis.     

Relationship between neutrophil elastase and acute lung injury in humans

We conducted clinical trials in patients with acute lung injury (ALI) associated with systemic inflammatory response syndrome using a selective neutrophil elastase inhibitor, sivelestat sodium hydrate (Sivelestat), to investigate the involvement of neutrophil elastase in ALI. In the phase III double-blind study (Study 1) in 230 patients, the efficacy of Sivelestat was evaluated with the pulmonary function improvement (PFI) rating as the primary endpoint, and the weaning rate from mechanical ventilator, the discharge rate from intensive care unit (ICU), and the survival rate as secondary endpoints. Afterwards, an unblinded study (Study 2) in 20 patients was conducted using procedures for weaning from mechanical ventilation to reevaluate its efficacy with ventilator-free days (VFD) value, the primary endpoint, and to compare with that of Study 1 subgroup, which met the selection criteria used in Study 2. Sivelestat increased PFI rating, reduced duration of mechanical ventilation, and shortened stay in ICU in Study 1, although there was no significant efficacy on the survival rate. VFD value in Study 2 was comparable to that in the optimal-dose group of Study 1 subgroup, and increase in VFD value correlated with PFI rating and increase in ICU free days. It was concluded that neutrophil elastase may be involved in the pathogenesis of ALI in humans.     

Tyrosine 201 of the cytoplasmic tail of CTLA‐4 critically affects T regulatory cell suppressive function

Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) is a major negative regulatory molecule for T‐cell activation with a complex biology and function. CTLA‐4 is known to regulate homeostatic lymphoproliferation as well as tolerance induction and has been proposed to be an important effector molecule by which Treg cells suppress immunity. The immunoregulatory properties of CTLA‐4 are primarily mediated by competition with the costimulator CD28 for ligand binding but also by delivering negative signals to T cells through its cytoplasmic tail. In this study, we addressed the effect of directly mutating the amino acid residue, Tyrosine 201 (Tyr201), of the intracellular domain of CTLA‐4 in situ and its implications in T‐cell function in the context of autoimmunity. Therefore, a novel CTLA‐4 knock‐in mouse (Y201V KI) was generated, in which Tyr201 was replaced by a valine that could not be phosphorylated. Mice expressing the CTLA‐4 mutant molecule were generally healthy and did not show signs of disruption of T‐cell homeostasis under steady‐state conditions seen in CTLA‐4 deficient mice. However, T cells isolated from Y201V KI mice expressed higher levels of CTLA‐4 on the cell surface and displayed a Th2‐biased phenotype following TCR stimulation. Furthermore, Y201V KI mice developed exacerbated disease as compared to wild‐type upon antigen‐specific T‐cell activation in an in vivo model of EAE. Importantly, the Y201V mutation resulted in impaired suppressive activity of Treg cells while T effector function remained intact. These data suggest that effects associated with and mediated through Tyr201 of CTLA‐4s intracellular domain are critical for Treg‐cell function.     

Involvement of the protein kinase Cgamma isoform in development of tolerance to nitrous oxide-induced antinociception in mice

Prolonged exposure to nitrous oxide (N2O) results in development of acute tolerance to its antinociceptive effect. Cross-tolerance to N2O-induced antinociception is also observed in morphine-tolerant animals. Despite increasing evidence of tolerance development to N2O-induced antinociception, the details of the mechanisms that underlie this tolerance remain unknown. The present study was conducted to investigate the involvement of brain protein kinase C (PKC) isoform in these two types of tolerance to N2O-induced antinociception in mice. Prolonged exposure (41 min in total, including 30 min pre-exposure and 11 min of antinociceptive testing) to 70% N2O produced a reduction in N2O-induced antinociception, indicating development of acute tolerance. The prolonged exposure to 70% N2O caused an activation of PKCgamma isoform in the brain, but not the PKCepsilon isoform. Pretreatment with a PKCgamma-antisense oligonucleotide but not the corresponding mismatch oligonucleotide (i.c.v.) prevented the development of acute tolerance to N2O-induced antinociception. Chronic morphine treatment (10 mg/kg, s.c., b.i.d. for 5 days) resulted in development of tolerance to morphine-induced antinociception and cross-tolerance to N2O-induced antinociception. The development of tolerance to morphine and cross-tolerance to N2O were both inhibited by pretreatment with PKC inhibitor, chelerythrine (1 nmol, i.c.v.). Morphine-tolerant mice showed an activation of PKC within the brain, which was suppressed by pretreatment with chelerythrine (1 nmol, i.c.v.). Thus, activation of brain PKC, in particular, the PKCgamma isoform, appears to play an important role in the development of both acute tolerance and cross-tolerance to N2O-induced antinociception in mice.     

Suppressive effect of clozapine but not haloperidol on the increases of neuropeptide-degrading enzymes and glial cells in MK-801-treated rat brain regions

MK-801, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces neurotoxicity in adult rodent brain, and causes schizophrenia-like psychosis and cognitive dysfunction. Since neuropeptides and neuropeptide-degrading enzymes play important roles in cognitive function, we examined whether or not MK-801-induced schizophrenia-like psychosis is co-related with the changes of these enzymes in rat brain regions. In the present study, we investigated the effect of systemic treatment with MK-801 (0.5mg/kg) on neuropeptide-degrading enzymes, prolyl oligopeptidase (POP) and thimet oligopeptidase (EP 24.15), and glial marker proteins GFAP and CD11b in rat brain regions. The levels of POP and EP 24.15 activities increased significantly three days after treatment with MK-801 in the posterior cingulate/retrosplenial cortices (PC/RSC). Since atypical neuroleptic clozapine but not typical neuroleptic haloperidol prevents the MK-801-induced schizophrenia-like symptoms, we further examined the pretreated effects of the neuroleptics. Clozapine, but not haloperidol, significantly attenuated MK-801-induced changes in the levels of the neuropeptide-degrading enzymes. Immunohistochemical studies on GFAP and CD11b showed the increase in the PC/RSC of MK-801-treated rat brain and the pretreatment with clozapine suppressed these changes. Double immunostain experiments of EP 24.15 and GFAP antibodies demonstrated some co-localization of the neuropeptidase with astrocytes. The present findings suggest that change of neuropeptidases in the brain is in part correlated with changes of glial cells, and may play an important role in the control of schizophrenia-like psychotic disorders.     

Criteria revision and performance comparison of three methods of signal detection applied to the spontaneous reporting database of a pharmaceutical manufacturer.

BACKGROUND AND OBJECTIVE: Several statistical methods exist for detecting signals of potential adverse drug reactions in spontaneous reporting databases. However, these signal-detection methods were developed using regulatory databases, which contain a far larger number of adverse event reports than the databases maintained by individual pharmaceutical manufacturers. Furthermore, the composition and quality of the spontaneous reporting databases differ between regulatory agencies and pharmaceutical companies. Thus, the signal-detection criteria proposed for regulatory use are considered to be inappropriate for pharmaceutical industry use without modification. The objective of this study was to revise the criteria for signal detection to make them suitable for use by pharmaceutical manufacturers. METHODS: A model comprising 40 drugs and 1000 adverse events was constructed based on a spontaneous reporting database provided by a pharmaceutical company and used in a simulation to investigate appropriate criteria for signal detection. In total, 1000 pseudo datasets were generated with this model, and three statistical methods (proportional reporting ratio [PRR], Bayesian Confidence Propagation Neural Network [BCPNN] and multi-item gamma Poisson shrinker [MGPS]) for signal detection were applied to each dataset. The sensitivity and specificity of each method were evaluated using these pseudo datasets. The optimum critical value for signal detection (i.e. the value that achieved the highest sensitivity with 95% specificity) was identified for each method. The optimum values were also examined with the adverse events classified into two categories according to frequency. The three original detection methods and their revised versions were applied to a real pharmaceutical company database to detect 173 known adverse reactions of four drugs. RESULTS: The 1000 pseudo datasets consisted of an average of 81 862 reports and 11,407 drug-event pairs, including 1192 adverse drug reactions. The sensitivities of PRR, BCPNN and MGPS methods were 49%, 45% and 26%, respectively, whereas their specificities were 95%, 99.6% and 99.99%, respectively; these sensitivities were unacceptably low for pharmaceutical manufacturers, whereas the specificities were acceptable. The highest sensitivity for each method, obtained by changing critical values and maintaining specificity at 95%, was 44%, 62% and 62%, respectively. When adverse events were classified into two categories, sensitivities as high as 75% for regular events and 39% for rare events were achieved with the revised BCPNN method. The critical values of the information component minus two standard deviations (IC - 2SD) index of the revised BCPNN method were greater than -0.7 for regular events and greater than -0.6 for rare events. The revised BCPNN method yielded 51% sensitivity and 89% specificity for the real dataset. CONCLUSION: A lower critical value may be needed when signal-detection methodology is applied to the spontaneous reporting databases of pharmaceutical manufacturers. For example, it is recommended that pharmaceutical manufacturers use the BCPNN method with IC - 2SD criteria of greater than -0.7 for regular events and greater than -0.6 for rare events.     

An individual patient data meta-analysis of adjuvant therapy with carmofur in patients with curatively resected colon cancer

BACKGROUND: Oral carmofur, either as a single or in combination with other chemotherapeutic agents, has been used as adjuvant chemotherapy for curatively resected colon cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with this cancer. The objective of this study was to perform a reappraisal of randomized clinical trials conducted in this regard. METHODS: We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of oral carmofur for curatively resected colon cancer in terms of overall survival (OS) and disease-free survival (DFS). RESULTS: We analyzed individual patient data of three randomized clinical trials, which met the predetermined inclusion criteria. These three trials had a combined total of 2152 patients, carmofur as adjuvant chemotherapy compared with surgery-alone, 5 years follow-up, intention-to-treat-based analytic strategy and similar end points (OS and DFS). In a pooled analysis, 5 year OS rates were 80.4 and 76.4%, and 5 year DFS rates 76.9 and 71.0%, respectively, in carmofur and surgery-alone group. Oral carmofur had significant advantage over surgery-alone in terms of both OS [pooled hazard ratio, 0.82; 95% confidence interval (CI) = 0.68-0.99; P = 0.043] and DFS (pooled hazard ratio, 0.77; 95% CI = 0.65-0.91; P = 0.003). CONCLUSIONS: This individual patient-based meta-analysis demonstrated that oral carmofur significantly improves both OS and DFS in patients with curatively resected colon cancers.     

Creutzfeldt-Jakob disease and cadaveric dura mater grafts in Japan: an updated analysis of incubation time

The incubation time for 76 patients with cadaveric dura mater-transmitted Creutzfeldt-Jakob disease reported in Japan by November 2001 was analyzed to clarify its distributional feature and the risk factors which affect the earlier onset of the disease. Cluster analysis indicated that cases could be divided into 3 clusters with respect to the incubation time, i.e., short (1.4-6.2 years), medium (7.0-11.9 years) and long (12.9-17.6 years). The incubation time in females was significantly shorter than those in males. Patients who were transplanted dura mater for facial spasms had a significantly shorter incubation time than those who received transplantation for other diseases including meningioma, aneurysm, or acoustic schwannoma. These results suggest that some host factors may have an influence on the incubation time of the disease.     

Autosynchronized systolic unloading during left ventricular assist with a centrifugal pump

OBJECTIVES: The purpose of this study was to investigate how the inflow cannulation site of the left ventricular assist system with a centrifugal pump would influence cardiac function on failing heart models. METHODS: In 10 sheep, a left ventricular assist system was instituted by an outflow cannula in the descending aorta, two inflow cannulas in the left atrium and the left ventricle, and connecting those cannulas to a magnetically suspended centrifugal pump. A conductance catheter and a tipped micromanometer for monitoring the pressure-volume loop were also inserted into the left ventricle. Myocardial oxygen consumption was directly measured. Heart failure was induced by injection of microspheres into the left main coronary artery. The assist rate was varied from 0% to 100% at each inflow cannulation site. RESULTS: The pump flow with left ventricular cannulation increased during the systolic phase and decreased during the diastolic phase, whereas it was constant with left atrial cannulation. Ejection fraction with left atrial cannulation decreased as the assist rate increased, whereas that with left ventricular cannulation was maintained up to 75% assist. The external work with left atrial cannulation decreased gradually as the assist rate increased, whereas the external work with left ventricular cannulation did not decrease until the assist rate reached 75%. The myocardial oxygen consumption in both cannulations decreased proportionally as the assist rate increased; they were significantly less with left ventricular cannulation at the 100% assist rate than with left atrial cannulation. CONCLUSION: Left ventricular cannulation during left ventricular assistance maintains ejection fraction and effectively reduces oxygen consumption.