Long-term monitoring of antibody titers against microorganisms in human intravenous immunoglobulin lots derived from healthy donors in Japan manufactured during 1998-2018.

BACKGROUND: Studies evaluating long-term trends of intravenous immunoglobulin (IVIG) titers against microorganisms such as bacteria and fungi have not been conducted. We herein evaluated long-term trends of titers of IVIG lots manufactured from 1998 to 2018, derived from donors in Japan, against microorganisms affecting patients with primary or secondary immunodeficiency diseases. STUDY DESIGN AND METHODS: Titers against four strains of Pseudomonas aeruginosa, three strains of Staphylococcus aureus, four strains of Haemophilus influenzae, two strains of Klebsiella pneumoniae, one strain of Streptococcus pneumoniae, Enterococcus faecium, Bordetella pertussis, Serratia marcescens, and Candida albicans, were tested immediately after lot release in a commercial clinical testing facility in 1998. The long-term (whole period) and short-term (first and second half of the period) trends of titers were evaluated using regression analysis. RESULTS: The IVIG lots indicated meaningful titers against all microorganisms that were stable in the short term. The long-term trends could be categorized into stable, slightly decreasing, or decreasing trends, except for the metallo-ß-lactamase-producing K. pneumoniae, which indicated a slight increase. Notably, three strains of P. aeruginosa showed remarkable decreasing long-term trends in the titer. DISCUSSION: Some titers indicate decreasing trends against microorganisms over the long-term, however, is not clear whether the phenomenon diminishes the performance of IVIG. The titers of the IVIG lots could provide helpful information to optimize replacement therapy, such as considering trough values based on the titers in the patient plasma. Therefore, continuous monitoring of IVIG titers against microorganisms is important to understand titer fluctuation and epidemiological background.

RABL2 positively controls localization of GPCRs in mammalian primary cilia.

The primary cilium, a solitary protrusion from most mammalian cells, functions as a cell sensor by receiving extracellular signals through receptors and channels accumulated in the organelle. Certain G-protein-coupled receptors (GPCRs) specifically localize to the membrane compartment of primary cilia. To gain insight into the mechanisms that regulate ciliary GPCR sorting, we investigated the atypical small GTPase RAB-like 2 (RABL2; herein referring to the near-identical human paralogs RABL2A and RABL2B). RABL2 recruitment to the mother centriole is dependent on the distal appendage proteins CEP164 and CEP83. We found that silencing of RABL2 causes mis-targeting of ciliary GPCRs, GPR161 and HTR6, whereas overexpression of RABL2 resulted in accumulation of these receptors in the organelle. Ablation of CEP19 and the intraflagellar transport B (IFT-B) complex, which interact with RABL2, also leads to mis-localization of GPR161. RABL2 controls localization of GPR161 independently of TULP3, which promotes entry of ciliary GPCRs. We further demonstrate that RABL2 physically associates with ciliary GPCRs. Taken together, these studies suggest that RABL2 plays an important role in trafficking of ciliary GPCRs at the ciliary base in mammalian cells.

Expression of fatty-acid-binding protein 5 in intrahepatic and extrahepatic cholangiocarcinoma: the possibility of different energy metabolisms in anatomical location.

The biliary tract cancer (BTC) covers a range of carcinomas, including intrahepatic cholangiocarcinoma (ICC), cholangiolocellular carcinoma (CoCC), perihilar cholangiocarcinoma (perihilar CC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC), defined according to the anatomical location. These adenocarcinomas mostly comprise biliary epithelial cell-derived malignant cells. In addition to anatomical differences, there are morphological and biological differences in BTC starting from embryonic development of the tissues extending to physiological differences. Fatty acid-binding proteins (FABPs) are closely associated with the energy metabolism. Using surgical specimens from 74 BTCs, we performed immunohistochemistry for FABP5 and its associated molecules, including peroxisome proliferator-activated receptor γ (PPARγ), PPARγ coactivator 1 (PGC-1), and estrogen-related receptor α (ERRα). We found that the expression patterns of small BTCs (ICC and CoCC) considerably differed from those of large BTCs (perihilar CC, ECC, and GBC). Expression of FABP5 and PGC-1 in large BTCs was high compared with those of small BTCs, but no difference in the expression of PPARγ and ERRα was observed. FABP5 appears to play a role in malignant progression in large BTCs. Small and large BTCs possess different energy metabolism systems owing to their different anatomical locations and course of carcinogenesis, although all BTCs originate from biliary epithelial cells.

Long-term monitoring of virus antibody titers in human intravenous immunoglobulin lots derived from donors in Japan.

BACKGROUND: Intravenous immunoglobulin (IVIG) contains immunoglobulin G against various viruses, except those that have been screened, such as human immunodeficiency and hepatitis C viruses. Antivirus titers reflect the serostatus of the blood donor population in the collection region and are of clinical interest. STUDY DESIGN AND METHODS: During the past 10 years, measles, mumps, rubella, varicella-zoster, hepatitis A and B, Epstein-Barr, and human respiratory syncytial viruses; human parainfluenza viruses 1, 2, and 3; human herpes simplex viruses 1 and 2; human herpesvirus 6; cytomegalovirus (CMV); human adenoviruses (HAdVs) 1, 2, 3, 7, and 11; human parvovirus B19; and human echovirus 9 and 11 titers in IVIG lots have been measured by a commercial testing facility. A viral neutralizing assay for CMV has been used at our facility. Herein, we summarize the measurements and results of a regression analysis of the trends in virus antibody titers. RESULTS: IVIG lots contained significant titers against all of the above viruses, except for HAdV 7. Three patterns-stable, increasing, and decreasing-were observed, without any drastic changes. Although these trends reflect the seroprevalence in Japan, the titers were not obviously affected by the cycle of epidemics. On the other hand, the prevalence data suggest that titers against hepatitis A virus and other viruses will decrease in the near future, although they are currently stable. CONCLUSION: Monitoring the titer of IVIG lots and seroprevalence of donor populations is important for anticipating future changes in virus antibody titers of IVIG lots and can provide useful information of clinical interest.

Association between long-range temporal correlations in intrinsic EEG activity and subjective sense of identity.

The long-range temporal correlation (LRTC) in resting-state intrinsic brain activity is known to be associated with temporal behavioral patterns, including decision making based on internal criteria such as self-knowledge. However, the association between the neuronal LRTC and the subjective sense of identity remains to be explored; in other words, whether our subjective sense of consistent self across time relates to the temporal consistency of neural activity. The present study examined the relationship between the LRTC of resting-state scalp electroencephalography (EEG) and a subjective sense of identity measured by the Erikson Psychosocial Stage Inventory (EPSI). Consistent with our prediction based on previous studies of neuronal-behavioral relationships, the frontocentral alpha LRTC correlated negatively with identity confusion. Moreover, from the descriptive analyses, centroparietal beta LRTC showed negative correlations with identity confusion, and frontal theta LRTC showed positive relationships with identity synthesis. These results suggest that more temporal consistency (reversely, less random noise) in intrinsic brain activity is associated with less confused and better-synthesized identity. Our data provide further evidence that the LRTC of intrinsic brain activity might serve as a noise suppression mechanism at the psychological level.

[Rapid-tests detection evaluation of Clostridium difficile toxins and microbiological investigation].

We evaluated two rapid toxin tests for C. difficile combined with stool specimen cultures used from January 2006 to March 2009. Stool specimens numbered 877, 102 among which were from the cases of diagnosed clinical C. difficile-associated diarrhea (CDAD). Rapid toxin A 'Uniquick' detection kits were used until October 2007 and toxin A&B 'TOX A/B' detection kits thereafter. Clinical CDAD was considered the detection gold standard. Uniquick sensitivity, specificity, and positive and negative predictive values were 54.3%, 99.1%, 90.5%, and 93.2% while those for TOX A/B were 46.2%, 97.6%, 65.2%, and 95.0% and for culture 42.2%, 95.5%, 55.1%, and 92.6%. Rapid toxin tests tended to have better sensitivity than culture results although not significantly so, and Uniquick showed significantly better positive predictive value than TOX A/B or culture results. Among clinical CDAD cases, concordance with culture was 24.3% for Uniquick and 53.1% for TOX A/B. For stored strains, 27 were typed toxin A+B+ (48.1%), toxin A-B+ (37.0%) and toxin A-B- (14.8%) with toxin gene detection by PCR. Eight of the 10 toxin A-B+ strains were classified into two cluster by ribotyping, and 7 of those were detected in two hospital wards, indicated the possibility of nosocomial toxin A-B+ strain spread. The rapid toxin test for both toxins A and B should be used if toxin A-B+ predominate. Simultaneous culture testing may be useful for detecting clinical CDAD more accurately, however.

Resting-state theta/beta ratio is associated with distraction but not with reappraisal.

Although previous research indicated that resting-state theta/beta ratio (TBR) is related to unspecified emotion regulation (ER), the ER strategies associated with TBR remain unclear. We examined whether representative ER strategies-distraction and reappraisal-are related to resting-state TBR. Data from sixty-one healthy Japanese university students were recorded in an eyes-closed resting-state with an electroencephalogram (EEG). Their self-reported tendencies of distraction and reappraisal were assessed. Rank-correlation analyses revealed that lower frontal and parietal TBR were associated with high distraction tendency. However, frontal and parietal TBR were not correlated with reappraisal. Given that TBR is linked to attention control, distraction may be associated with TBR. Consequently, TBR can be used to identify persons with ER difficulties, based on the results of this study.

Development of sensitive derivatization method for aldosterone in liquid chromatography-electrospray ionization tandem mass spectrometry of corticosteroids.

A highly sensitive quantification method of aldosterone by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was investigated in a positive mode using recently developed picolinyl derivatization. Aldosterone was smoothly and quantitatively converted to the ethyl ether-picolinyl derivative by treatment with HCl-ethanol followed by the esterification with picolinic acid in the presence of 2-methyl-6-nitrobenzoic anhydride and 4-dimethylaminopyridine. The positive ion-ESI mass spectrum of the ethyl ether-picolinyl derivative was characterized by an appearance of protonated molecule ([M+H](+)) as a base peak. The ethyl ether-picolinyl derivatization gave a successful result in a separation of aldosterone from corticosterone, dehydrocorticosterone and cortexolone, and also provided an approximately 10-fold higher ESI response in the positive-LC-ESI-MS/MS (selected reaction monitoring; SRM) when compared to that of underivatized molecule (negative mode). The limit of quantification of aldosterone by SRM using ethyl ether-picolinyl derivatization (m/z 494-->m/z 448) was 1 pg/0.2 ml serum with accuracy and precision of 92.6% and 5.6%, respectively.

Simultaneous determination of tetrahydrocortisol, allotetrahydrocortisol and tetrahydrocortisone in human urine by liquid chromatography-electrospray ionization tandem mass spectrometry.

Simultaneous quantification method of three major metabolites of cortisone and cortisol, tetrahydrocortisol, allotetrahydrocortisol and tetrahydrocortisone by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was investigated in a positive mode using a recently developed picolinyl derivatization. Conversion of each steroid into the corresponding picolinyl derivatives (1b, 2b or 3b) was performed by mixed anhydride method using picolinic acids and 2-methyl-6-nitrobenzoic anhydride. Derivatization proceeded smoothly to afford the corresponding 3, 21-dipicolinyl derivatives. Positive ion-ESI mass spectra of the picolinyl derivatives were dominated by an appearance of [M+H](+) as base peaks in all cases. The picolinyl derivatives provided 15 to 80-fold higher ESI response in the LC-ESI-MS/MS (selected reaction monitoring: SRM) when compared to those of underivatized molecules in a positive LC-ESI mode. The use of the picolinyl ester, solid-phase extraction, and deuterium labeled internal standards enabled the concentrations of these metabolites in human urine to be determined simultaneously by LC-ESI-MS/MS (SRM) with a small sample volume of less than 1microl urine.

Time lapse imaging analysis of the effect of ER stress modulators on apoptotic cell assessed by caspase3/7 activation in NG108-15 cells.

This paper reports the data from the long term time lapse imaging of neuronal cell line NG108-15 that were treated with apoptosis inducer or various ER stress inducers. Use of the fluorescent reporter for activated caspase3/7 in combination with the conventional light microscope allowed us to investigate the time course of apoptosis induction at the single cell level. Quantitative as well as qualitative data are presented here to show the effect of two different ER stress modulating chemical compounds on caspase3/7-dependent apoptosis in neuronal cell line NG108-15 cells. Additional results and interpretation of our data concerning ER stress and apoptosis in NG108-15 cells can be found in Suga et al. (2015) [1] and in Suga et al. (2015) [2].

Dynamic component of sports is an important determinant factor of heart rate recovery.

OBJECTIVE: It is usually suggested that life expectancy of top athletes especially in endurance sports is longer than that of sedentary people. On the other hand, heart rate recovery (HRR) after exercise is an independent risk factor for cardiovascular disease and mortality, but differences in HRR between various top athletes are unclear. We examined HRR in various top athletes to clarify a role of HRR that may affect their life expectancy. METHODS: HRR was defined as the difference between the heart rate at peak exercise and that at 2 min after the finish of exercise using symptom-limited maximal graded bicycle ergometer exercise testing. The relationships between HRR with the grade of static and dynamic component of classification of sports, age, and body mass index (BMI) were estimated. SUBJECTS: The subjects were 720 male athletes participating in the National Sports Festival Japan in 2005-2008 and age-matched 28 sedentary controls. RESULTS: HRR was significantly correlated (p<0.0001) with the higher grade of dynamic component of sports, younger age, and lower BMI in both univariate and multivariate analysis. CONCLUSIONS: HRR of top athletes is predicted by increased dynamic component of sports, younger age, and lower BMI.