Aim
To assess prevalence and characteristics of vasomotor symptoms in community‐dwelling Japanese women.
Methods
These were cross‐sectional analyses using data from the National Institute for ...Longevity Sciences‐Longitudinal Study of Aging. The main outcome measures were prevalence and severity of hot flashes and sweating. Associations between hot flashes/sweating (slight, moderate, or severe vs none) and sleep problems were explored using logistic regression, with and without adjustment for age, daily physical activity, and number of urinations/night. Associations between hot flashes/sweating and sleep problems, depressive symptoms, and dietary variables were explored in logistic regression models or general linear models.
Results
A total of 1152 women between 40 and 91 years of age were enrolled. Hot flashes were reported by 24.5% of participants; with prevalence and severity highest in those 50–54 years or 2–5 years postmenopause. Sleep problems were reported 15 percentage points more frequently by women who reported hot flashes than by those without hot flashes. Adjusted odds ratios 95% CI for difficulty in falling asleep and difficulty in sleeping through were 2.09 1.565–2.796 and 2.07 1.549–2.763), respectively. Also, hot flashes were associated with higher risk of depressive symptoms (adjusted odds ratio 95% CI: 2.99 2.07–4.32) and lower life satisfaction, self‐esteem, and self‐rated health status. A similar pattern was observed in women with and without sweating. No associations were found between hot flashes and dietary factors.
Conclusions
Clear associations were found between hot flashes and sleeping problems, even after adjusting for potential confounding factors. Women who reported hot flashes also reported worse mental and physical health than those who did not report hot flashes.
Abstract L-type Ca channels (LTCC), which play a key role in cardiac excitation–contraction coupling, are located predominantly at the transverse (t-) tubules in ventricular myocytes. Caveolae and ...the protein caveolin-3 (Cav-3) are also present at the t-tubules and have been implicated in localizing a number of signaling molecules, including protein kinase A (PKA) and β2 -adrenoceptors. The present study investigated whether disruption of Cav-3 binding to its endogenous binding partners influenced LTCC activity. Ventricular myocytes were isolated from male Wistar rats and LTCC current (ICa ) recorded using the whole-cell patch-clamp technique. Incubation of myocytes with a membrane-permeable peptide representing the scaffolding domain of Cav-3 (C3SD) reduced basal ICa amplitude in intact, but not detubulated, myocytes, and attenuated the stimulatory effects of the β2 -adrenergic agonist zinterol on ICa . The PKA inhibitor H-89 also reduced basal ICa ; however, the inhibitory effects of C3SD and H-89 on basal ICa amplitude were not summative. Under control conditions, myocytes stained with antibody against phosphorylated LTCC (pLTCC) displayed a striated pattern, presumably reflecting localization at the t-tubules. Both C3SD and H-89 reduced pLTCC staining at the z-lines but did not affect staining of total LTCC or Cav-3. These data are consistent with the idea that the effects of C3SD and H-89 share a common pathway, which involves PKA and is maximally inhibited by H-89, and suggest that Cav-3 plays an important role in mediating stimulation of ICa at the t-tubules via PKA-induced phosphorylation under basal conditions, and in response to β2 -adrenoceptor stimulation.
The zinc transporter protein ZIP13 plays critical roles in bone, tooth, and connective tissue development, and its dysfunction is responsible for the spondylocheirodysplastic form of Ehlers‐Danlos ...syndrome (SCD‐EDS, OMIM 612350). Here, we report the molecular pathogenic mechanism of SCD‐EDS caused by two different mutant ZIP13 proteins found in human patients: ZIP13G64D, in which Gly at amino acid position 64 is replaced by Asp, and ZIP13ΔFLA, which contains a deletion of Phe‐Leu‐Ala. We demonstrated that both the ZIP13G64D and ZIP13ΔFLA protein levels are decreased by degradation via the valosin‐containing protein (VCP)‐linked ubiquitin proteasome pathway. The inhibition of degradation pathways rescued the protein expression levels, resulting in improved intracellular Zn homeostasis. Our findings uncover the pathogenic mechanisms elicited by mutant ZIP13 proteins. Further elucidation of these degradation processes may lead to novel therapeutic targets for SCD‐EDS.
Synopsis
The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutants are degraded by the ubiquitin‐proteasome pathway. Inhibition of this pathway restores ZIP13 levels with consequent improvement of intracellular Zn homeostasis.
The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutant proteins: ZIP13G64D and ZIP13ΔFLA, are degraded by the ubiquitin‐proteasome pathway.
Valosin‐containing protein (VCP) is involved in the degradation of the pathogenic mutant ZIP13 proteins.
The reduced expression levels of the ZIP13 mutant proteins are rescued by inhibition of the degradation pathways, resulting in improved intracellular zinc homeostasis.
The Spondylocheirodysplastic Ehlers‐Danlos syndrome pathogenic ZIP13 mutants are degraded by the ubiquitin‐proteasome pathway. Inhibition of this pathway restores ZIP13 levels with consequent improvement of intracellular Zn homeostasis.
Microbial rhodopsin is a photoreceptor protein found in various bacteria and archaea, and it is considered to be a light-utilization device unique to heterotrophs. Recent studies have shown that ...several cyanobacterial genomes also include genes that encode rhodopsins, indicating that these auxiliary light-utilizing proteins may have evolved within photoautotroph lineages. To explore this possibility, we performed a large-scale genomic survey to clarify the distribution of rhodopsin and its phylogeny. Our surveys revealed a novel rhodopsin clade, cyanorhodopsin (CyR), that is unique to cyanobacteria. Genomic analysis revealed that rhodopsin genes show a habitat-biased distribution in cyanobacterial taxa, and that the CyR clade is composed exclusively of non-marine cyanobacterial strains. Functional analysis using a heterologous expression system revealed that CyRs function as light-driven outward H
pumps. Examination of the photochemical properties and crystal structure (2.65 Å resolution) of a representative CyR protein, N2098R from Calothrix sp. NIES-2098, revealed that the structure of the protein is very similar to that of other rhodopsins such as bacteriorhodopsin, but that its retinal configuration and spectroscopic characteristics (absorption maximum and photocycle) are distinct from those of bacteriorhodopsin. These results suggest that the CyR clade proteins evolved together with chlorophyll-based photosynthesis systems and may have been optimized for the cyanobacterial environment.
Introduction
The aim of this study was to evaluate the characteristics of new users of sodium glucose co-transporter-2 inhibitors (SGLT2i) in comparison with those of new users of other oral ...antidiabetic drugs (OADs) using data retrieved from three administrative databases in Japan.
Methods
This study included adult patients from each database who started an OAD between 2014 and 2017. Outpatients who started SGLT2i therapy were included in the SGLT2i cohort. The remaining outpatients were grouped according to the OAD class of their earliest initial prescription after no use of the index OAD during the 6-month pre-index period. Diabetes-related complications were evaluated using the Diabetes Complication Severity Index.
Results
In total, 176,355 patients in the hospital-based administrative database (H-dataset), 98,361 in the pharmacy claims database (P-dataset) and 37,786 in the insurance claims database (I-dataset) were analyzed. In the H-dataset, SGLT2i users, compared with users of other OADs, tended to be younger (mean age at index: 57.7 vs. 60.3–69.2 years) and to have a higher prevalence of hypercholesterolemia (73.5 vs. 55.2–71.4%), a higher mean body weight (74.4 vs. 60.5–70.8 kg), a higher body mass index (27.6 vs. 23.5–26.4 kg/m
2
) and a higher glycated hemoglobin level (8.4 vs. 7.4–8.1%). There were no distinct differences in the prevalence of complications between SGLT2i users and users of other OADs in the H-dataset. Similar trends were noted in the other datasets.
Conclusion
Patients initiating SGLT2i therapy differed in several characteristics from new users of other OADs. SGLT2i were prescribed more frequently to younger patients, those at increased cardiovascular risk or those with poorer glycemic control.
Funding
Astellas Pharma Inc., Tokyo, Japan.
Chronic obstructive pulmonary disease is a known risk factor for cardiovascular death in Western countries. Because Japan has a low cardiovascular death rate, the association between a lower level of ...forced expiratory volume in 1 s (FEV1) and mortality in Japan's general population is unknown. To clarify this, we conducted a community-based longitudinal study. This study included 3253 subjects, who received spirometry from 2004 to 2006 in Takahata, with a 7-year follow-up. The causes of death were assessed on the basis of the death certificate. In 338 subjects, airflow obstruction was observed by spirometry. A total of 127 subjects died. Cardiovascular death was the second highest cause of death in this population. The pulmonary functions of the deceased subjects were significantly lower than those of the subjects who were alive at the end of follow-up. The relative risk of death by all causes, respiratory failure, lung cancer, and cardiovascular disease was significantly increased with airflow obstruction. The Kaplan-Meier analysis showed that all-cause and cardiovascular mortality significantly increased with a worsening severity of airflow obstruction. After adjusting for possible factors that could influence prognosis, a Cox proportional hazard model analysis revealed that a lower level of FEV1 was an independent risk factor for all-cause and cardiovascular mortality (per 10% increase; hazard ratio HR, 0.89; 95% confidence interval CI, 0.82-0.98; and HR, 0.72; 95% CI, 0.61-0.86, respectively). In conclusion, airflow obstruction is an independent risk factor for all-cause and cardiovascular death in the Japanese general population. Spirometry might be a useful test to evaluate the risk of cardiovascular death and detect the risk of respiratory death by lung cancer or respiratory failure in healthy Japanese individuals.
Voltage-dependent K(+) (Kv) channels play crucial roles in nerve and muscle action potentials. Voltage-sensing domains (VSDs) of Kv channels sense changes in the transmembrane potential, regulating ...the K(+)-permeability across the membrane. Gating modifier toxins, which have been used for the functional analyses of Kv channels, inhibit Kv channels by binding to VSD. However, the structural basis for the inhibition remains elusive. Here, fluorescence and NMR analyses of the interaction between VSD derived from KvAP channel and its gating modifier toxin, VSTx1, indicate that VSTx1 recognizes VSD under depolarized condition. We identified the VSD-binding residues of VSTx1 and their proximal residues of VSD by the cross-saturation (CS) and amino acid selective CS experiments, which enabled to build a docking model of the complex. These results provide structural basis for the specific binding and inhibition of Kv channels by gating modifier toxins.
BACKGROUNDVentilator-associated pneumonia (VAP) has emerged as a critical issue in the intensive care unit (ICU) because of its high burden on patients and medical staff. Here, we examined the ...potential for reducing VAP incidence through physical oral care interventions without any medication. METHODSThis prospective interventional study compared VAP incidence during an 8-month baseline period (usual oral care) and a 9-month intervention period (physical oral care with sponge brush) among patients who received mechanical ventilation for >48 h in a tertiary care hospital in Vietnam from 2017 to 2019. Physical oral care was provided by general ICU nurses who had been trained by dentists and infection control nurses. VAP was diagnosed using the Clinical Pulmonary Infection Score. RESULTSIn total, 423 patients were enrolled in the baseline group and 454 patients were enrolled in the intervention group; 303 and 300 patients, respectively, were included in the analysis. Two hundred thirty-eight VAP episodes were identified: 135 (44.6%) during the baseline period and 103 (34.3%) during the intervention period. Univariate analysis revealed significant reduction of VAP occurrence in the intervention period (odds ratio = 0.65; 95% confidence interval = 0.47-0.90; P = 0.010). The incidences of VAP per 1000 ventilator-days were 63.4 (135/2128) during the baseline period and 48.4 (103/2128) during the intervention period (P = 0.038). CONCLUSIONSPhysical oral care without any medication (e.g., chlorhexidine) reduced VAP incidence in the ICU. This method could be used to reduce VAP incidence, particularly in countries with limited medical resources.
Introduction
The prevalence of polymorphisms among the metabolising enzymes and pharmacodynamic receptors relevant for the thiazolidinediones differs by ethnic group, a factor that may modify risk of ...adverse drug events.
Objective
The aim of the study was to determine if the risk of oedema or heart failure associated with the thiazolidinediones varies in populations in Australia, Canada, Hong Kong, Japan, Korea and Taiwan.
Methods
Sequence symmetry analyses were undertaken to investigate the risk of peripheral oedema, as measured by incident furosemide dispensing, and risk of hospitalisations for heart failure. Results were pooled, with Australia and Canada representing predominantly Caucasian population and all other countries contributing to Asian population estimates.
Results
Pooled estimates of risk for furosemide initiation in the Caucasian populations were significantly increased for pioglitazone adjusted sequence ratio (ASR) 1.47; 95 % confidence interval (CI) 1.14–1.91 and rosiglitazone (ASR 1.65; 95 % CI 1.58–1.72), while in the Asian populations, the pooled risk estimates were lower (ASR 1.11; 95 % CI 0.93–1.32 and ASR 1.21; 95 % CI 1.01–1.45 for pioglitazone and rosiglitazone, respectively). Results for hospitalisation for heart failure showed a similar trend, with elevated risk in the Australian data (ASR 1.88; 95 % CI 1.01–3.5 and ASR 1.25; 95 % CI 0.76–2.05 for pioglitazone and rosiglitazone, respectively), while no increased risk was found in the pooled results for the Asian populations.
Conclusion
The risk of both oedema and heart failure with thiazolidinediones was higher in predominantly Caucasian countries than in the Asian countries assessed. Assessment of adverse events by ethnicity may support safer medicine use.
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