Sociogeographic Variation in the Effects of Heat and Cold on Daily Mortality in Japan

Background

Ambient temperature affects mortality in susceptible populations, but regional differences in this association remain unclear in Japan. We conducted a time-series study to examine the variation in the effects of ambient temperature on daily mortality across Japan.

Methods

A total of 731 558 all-age non-accidental deaths in 6 cities during 2002–2007 were analyzed. The association between daily mortality and ambient temperature was examined using distributed lag nonlinear models with Poisson distribution. City-specific estimates were combined using random-effects meta-analysis. Bivariate random-effects meta-regressions were used to examine the moderating effect of city characteristics.

Results

The effect of heat generally persisted for 1 to 2 days. In warmer communities, the effect of cold weather lasted for approximately 1 week. The combined increases in mortality risk due to heat (99th vs 90th percentile of city-specific temperature) and cold (first vs 10th percentile) were 2.21% (95% CI, 1.38%–3.04%) and 3.47% (1.75%–5.21%), respectively. City-specific effects based on absolute temperature changes were more heterogeneous than estimates based on relative changes, which suggests some degree of acclimatization. Northern populations with a cool climate appeared acclimatized to low temperature but were still vulnerable to extreme cold weather. Population density, average income, cost of property rental, and number of nurses appeared to influence variation in heat effect across cities.

Conclusions

We noted clear regional variation in temperature-related increases in mortality risk, which should be considered when planning preventive measures.Key words: heat, cold, mortality, time-series, distributed lag     

Interactive effects of exercise and sleep on frailty severity in community-dwelling older adults: a cross-sectional study

Objectives: This study examined the effects of the interaction between exercise and sleep on frailty severity in community-dwelling older adults.Materials and Methods: This was a cross-sectional study. Data were collected in July 2019. In total, 2021 adults participated who responded to a questionnaire. Among them, 672 participants (317 men and 355 women) with valid responses were included in the analysis. Ordinal logistic regression analysis was performed to examine the association between frailty severity and the interaction between exercise and sleep. The dependent variable represents three different levels of frailty. The independent variables included basic information and interaction between exercise and sleep.Results: The results of ordinal logistic regression analysis (odds ratio [OR]) showed that the period from the start of exercise (OR=0.96), age (OR=1.00 for participants in their 60 s, OR=1.65 for those in their 70s, and OR=3.13 for those aged >80 years), poor subjective health perception (OR=2.12), poor quality of sleep (OR=1.88), stress (OR=1.62), and exercise–sleep interaction (OR=1.00 based on good-exercise–good-sleep interaction, OR=3.09 poor-exercise–good-sleep interaction, and OR=3.50 poor-exercise–poor-sleep interaction) significantly contributed to the model. The Nagelkerke coefficient of determination adjusted for degrees-of-freedom (R²), which represents the contribution rate of the regression equation, was 0.334.Conclusions: Our results suggest that a combination of good exercise and good sleep is needed to prevent frailty progression in community-dwelling older adults.     

Amlodipine, but not MDR1 polymorphisms, alters the pharmacokinetics of cyclosporine A in Japanese kidney transplant recipients

BACKGROUND: Cyclosporine A (CsA) is a critical immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Many factors, including P-glycoprotein (PGP), influence the oral bioavailability and interpatient variability of CsA. A number of polymorphisms have been identified in the human MDR1 gene, and some of them have been found to be associated with an altered expression of PGP. We have investigated the role of these polymorphisms in CsA absorption from kidney transplant recipients. In addition, we also investigated the effect of amlodipine on CsA absorption. METHODS: The area under the time-concentration curve from 0 to 2 hr (AUC(0-2)) estimated by the trapezoidal rule was used for the evaluation of extent of CsA absorption. The genotypes were identified by a polymerase chain reaction, restriction fragment length polymorphism analysis. RESULTS: No association was found between polymorphisms in the MDR1 and CsA AUC(0-2)/dose/kg. In contrast, the combination of amlodipine significantly increased CsA AUC(0-2)/dose/kg (706.2 microg x hr/L to 819.2 microg x hr/L, P<0.05). Furthermore, we attempted to compare MDR1 polymorphisms and the absorption of CsA again without patients receiving amlodipine, but there was still no significant difference. CONCLUSIONS: There is no relationship between polymorphisms for MDR1 and CsA absorption, suggesting polymorphisms for MDR1 cannot account for the interpatient variability of CsA. Amlodipine, which is the substrate of PGP, significantly increased CsA absorption. These results indicate that PGP plays a significant role in CsA absorption, but its polymorphisms could not influence the CsA absorption.     

Oral administration of taurine improves experimental pancreatic fibrosis

Background and Aim: The mechanism of pancreatic fibrosis is unclear. Taurine is used in the clinical treatment of a wide variety of diseases, but its effect on improving pancreatic fibrosis is unknown. We examined whether a diet with added taurine improves pancreatic fibrosis induced by dibutyltin dichloride (DBTC) in an experimental chronic pancreatitis rat model. In addition, we examined the influence of taurine on pancreatic stellate cells. Methods: Pancreatic fibrosis was induced by DBTC. Rats were fed a taurine‐containing diet or a normal diet and were killed at 4 weeks. Pancreatic stellate cells were isolated from male Wistar rats. Cultured pancreatic stellate cells were incubated with or without taurine chloramine. Type I collagen and transforming growth factor‐β1 secretion was evaluated by ELISA, and matrix metalloproteinase activity was assessed by gelatin zymography. Interleukin‐6, interleukin‐2, and transforming growth factor‐β1 levels in the supernatants of pancreatic tissue homogenates were measured. Results: Pancreatic fibrosis induced by DBTC was improved remarkably by the oral administration of the taurine‐containing diet. Taurine chloramine decreased type I collagen, transforming growth factor‐β1, and matrix metalloproteinases 2 of the pancreatic stellate cell culture supernatant. Increased interleukin‐6 and decreased interleukin‐2 were found in the supernatants of the pancreatic tissue homogenates of DBTC‐induced pancreatitis rats compared with other groups. Conclusion: The oral administration of taurine improves pancreatic fibrosis. Taurine chloramine inhibits transforming growth factor‐β1 produced from activated pancreatic stellate cells and improves pancreatic fibrosis.     

Targeting oncogenic interleukin‐7 receptor signalling with N‐acetylcysteine in T cell acute lymphoblastic leukaemia

Activating mutations of the interleukin‐7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T‐ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand‐independent activation of STAT5. We hypothesized that the reducing agent N‐acetylcysteine (NAC), a well‐tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R‐mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R‐mutant DND‐41 cells as assessed by non‐reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND‐41 cells, and Ba/F3 cells transformed by an IL7R‐mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND‐41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T‐ALL.     

Impact of statin therapy on late target lesion revascularization after sirolimus-eluting stent implantation (from the CREDO-Kyoto Registry Cohort-2)

Therapeutic strategies preventing late target lesion revascularization (TLR) after drug-eluting stent implantation have not been yet adequately investigated. In 13,087 consecutive patients undergoing first percutaneous coronary intervention in the CREDO-Kyoto Registry Cohort-2, we identified 10,221 patients who were discharged alive after implantation of sirolimus-eluting stents (SESs) only (SES stratum 5,029) or bare-metal stents (BMSs) only (BMS stratum 5,192). Impact of statin therapy at time of discharge from the index hospitalization on early (within the first year) and late (1 year to 4 years) TLR, was assessed in the SES stratum (statin group 2,735; nonstatin group 2,294) and in the BMS stratum (statin group 2,576; nonstatin group 2,616). Despite a significantly lower incidence of early TLR (7.8% vs 22.2%, p <0.0001), SES use compared to BMS use was associated with a significantly higher incidence of late TLR (7.7% vs 3.0%, p <0.0001). In the SES and BMS strata, the incidence of early TLR was similar regardless of statin use. In the SES stratum, the incidence of late TLR was significantly lower in the statin group than in the nonstatin group (6.1% vs 9.6%, p = 0.002), whereas no significant difference was found in the BMS stratum (2.6% vs 3.3%, p = 0.38). After adjusting confounders, risk for late TLR significantly favored statin use in the SES stratum (hazard ratio 0.73, 95% confidence interval 0.54 to 0.98, p = 0.04), whereas the risk decrease was not significant in the BMS stratum (hazard ratio 0.74, 95% confidence interval 0.46 to 1.20, p = 0.23). In conclusion, statin therapy at hospital discharge was associated with a significantly lower risk for late TLR after SES implantation.     

Screening of chondrogenic factors with a real‐time fluorescence‐monitoring cell line ATDC5‐C2ER: Identification of sorting nexin 19 as a novel factor

Objective

To establish a cell culture system for noninvasive and real‐time monitoring of chondrogenic differentiation in order to screen for chondrogenic factors.

Methods

The optimum reporter construct transfected into chondrogenic ATDC5 cells was selected by a luciferase reporter assay and fluorescence analysis during cultures with insulin. The established cell line was validated according to its fluorescence following stimulation with SOX proteins, bone morphogenetic protein 2 (BMP‐2), or transforming growth factor β (TGFβ) and was compared with the level of messenger RNA for COL2A1 as well as with the degree of Alcian blue staining. Screening of chondrogenic factors was performed by expression cloning using a retroviral expression library prepared from human tracheal cartilage. The expression pattern of the identified molecule was examined by in situ hybridization and immunohistochemistry. Functional analysis was performed by transfection of the identified gene, the small interfering RNA, and the mutated gene.

Results

We established an ATDC5 cell line with 4 repeats of a highly conserved enhancer ligated to a COL2A1 basal promoter and the DsRed2 reporter (ATDC5‐C2ER). Fluorescence was induced under the stimulations with SOX proteins, BMP‐2, or TGFβ, showing good correspondence to the chondrogenic markers. Screening using the ATDC5‐C2ER system identified several chondrogenic factors, including sorting nexin 19 (SNX19). SNX19 was expressed in the limb cartilage of mouse embryos and in the degraded cartilage of adult mouse knee joints during osteoarthritis progression. The gain‐of‐function and loss‐of‐function analyses revealed a potent chondrogenic activity of SNX19.

Conclusion

We established the ATDC5‐C2ER system for efficient monitoring of chondrogenic differentiation by fluorescence analysis, and we identified a novel chondrogenic factor (SNX19) using this system. This system will be useful for elucidating the molecular network of chondrogenic differentiation.

     

Long-Term Outcomes of Japanese Type 2 Diabetic Patients With Biopsy-Proven Diabetic Nephropathy

OBJECTIVE

We evaluated the structural-functional relationships and the prognostic factors for renal events, cardiovascular events, and all-cause mortality in type 2 diabetic patients with biopsy-proven diabetic nephropathy.

RESEARCH DESIGN AND METHODS

Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy (n = 260) were enrolled. Patients were stratified by albuminuria (proteinuria) and estimated glomerular filtration rate (eGFR) at the time of renal biopsy. The outcomes were the first occurrence of renal events (requirement of dialysis or a 50% decline in eGFR from baseline), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, coronary interventions, or nonfatal stroke), and all-cause mortality.

RESULTS

The factors associated with albuminuria (proteinuria) regardless of eGFR were hematuria, diabetic retinopathy, low hemoglobin, and glomerular lesions. The factors associated with low eGFR regardless of albuminuria (proteinuria) were age and diffuse, nodular, tubulointerstitial, and vascular lesions. The glomerular, tubulointerstitial, and vascular lesions in patients with normoalbuminuria (normal proteinuria) and low eGFR were more advanced compared to those in patients with normoalbuminuria (normal proteinuria) and maintained eGFR. In addition, compared to patients with micro-/macroalbuminuria (mild/severe proteinuria) and low eGFR, their tubulointerstitial and vascular lesions were similar or more advanced in contrast to glomerular lesions. The mean follow-up period was 8.1 years. There were 118 renal events, 62 cardiovascular events, and 45 deaths. The pathological determinants were glomerular lesions, interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis for renal events, arteriosclerosis for cardiovascular events, and IFTA for all-cause mortality. The major clinical determinant for renal events and all-cause mortality was macroalbuminuria (severe proteinuria).

CONCLUSIONS

Our study suggests that the characteristic pathological lesions as well as macroalbuminuria (severe proteinuria) were closely related to the long-term outcomes of biopsy-proven diabetic nephropathy in type 2 diabetes.Diabetic nephropathy occurs in 20–40% of patients with diabetes (1). The prevalence of diabetic nephropathy is increasing in proportion to the increase in prevalence of diabetes, and it has been predicted to continue to increase in future (2). Diabetes is a risk factor of cardiovascular disease and death, and diabetic nephropathy further increases these risks (3). In addition, diabetic nephropathy is the leading cause of end-stage renal disease requiring dialysis or transplantation in developed countries (4–6).In recent years, many clinical studies have suggested strict glycemic control and blood pressure management by use of appropriate medication to suppress the onset and progression of diabetic nephropathy. Thus, it is important to identify patients at risk in the early stages to improve prognosis in patients with diabetic nephropathy (1). Albuminuria and glomerular filtration rate (GFR) are recommended for use as clinical markers of diabetic nephropathy (1,7–9). On the other hand, selection of pathological markers is complicated because a variety of renal lesions can be found in diabetic nephropathy in addition to factors such as obesity, hypertension, dyslipidemia, and aging, which are frequently complicated in type 2 diabetes, causing a wide variety of pathological changes (10).We previously reported on the clinical factors related to the development and progression of renal lesions in diabetic nephropathy by the evaluation of serial renal biopsies or autopsy (11). In this report, we demonstrated a significant relationship between the progression of diabetic glomerulosclerosis and clinical factors such as the control of blood glucose, type of diabetes, age at onset, type of treatment, and degree of obesity.After this study, we conducted a long-term retrospective study to evaluate the structural-functional relationships and the predictive impacts of clinicopathological parameters for renal events, cardiovascular events, and all-cause mortality among Japanese patients with biopsy-proven diabetic nephropathy in type 2 diabetes.     

An intermolecular-split G-quadruplex DNAzyme sensor for dengue virus detection

Nucleic acids have special ability to organize themselves into various non-canonical structures, including a four-stranded DNA structure termed G-quadruplex (G4) that has been utilized for diagnostic and therapeutic applications. Herein, we report the ability of G4 to distinguish dengue virus (DENV) based on its serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) using a split G4-hemin DNAzyme configuration. In this system, two separate G-rich oligonucleotides are brought together upon target DNA strand hybridization to form a three-way junction architecture, allowing the formation of a G4 structure. The G4 formation in complexation with hemin can thus provide a signal readout by generating a DNAzyme that is able to catalyze H₂O₂-mediated oxidation of 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS). This results in a change of color providing a sensing platform for the colorimetric detection of DENV. In our approach, betaine and dimethyl sulfoxide were utilized for better G4 generation by enhancing the target-probe hybridization. In addition to this serotype-specific assay, a multi-probe cocktail assay, which is an all-in-one assay was also examined for DENV detection. The system highlights the potential of split G-quadruplex configurations for the development of DNA-based detection and serotyping systems in the future.

Application of split G-quadruplex as DNAzyme reporter system for DNA sensing.