Association between trajectories of systolic blood pressure and frailty outcome in middle-aged and older adults.

OBJECTIVES: The association between blood pressure and frailty outcome in the middle-aged and older population remains controversial. This study aimed to examine the relationship between trajectories of systolic blood pressure (SBP) and new-onset frailty. DESIGN: Cohort study with a 7-year follow-up. SETTING AND PARTICIPANTS: Data were derived from 4 waves (2011, 2013, 2015 and 2018) of the China Health and Retirement Longitudinal Study and 6168 participants aged ≥45 years were included in the study. METHODS: The frailty index (FI) was constructed based on 40 scored items, with FI ≥ 0.25 defined as frailty. We identified the 5-year trajectory of SBP by latent class trajectory modeling. The association between SBP trajectories and frailty was explored based on hazard ratios (HR) by four Cox proportional hazards models. Furthermore, we also investigated the relationship between mean SBP and systolic blood pressure variability (SBPV) and frailty. RESULTS: 6168 participants were included in this study with a mean age of 59 years. We identified five trajectories based on SBP, which are maintained low-stable SBP (T0), moderate-stable SBP (T1), remitting then increasing SBP (T2), increasing then remitting SBP (T3), and remaining stable at high SBP levels (T4). During the 7-year follow-up period, frailty outcome occurred in 1415 participants. After adjusting for other confounders, the two trajectories labeled "T2" and "T4" were associated with a higher risk of frailty compared with T0. In addition, elevated SBP and increased SBPV were associated with risk of frailty. CONCLUSIONS: Higher risk of frailty occurred in two trajectories, remitting then increasing and remaining stable at high SBP levels, were associated with a relatively higher risk of frailty.

[Relationship between overnight urinary sodium to potassium ratio and the risk of cardiovascular disease].

Objective: To explore the relationship between overnight urinary sodium to potassium ratio and the risk of cardiovascular disease (CVD). Methods: A subsample of 10 percent of the participants (35-59 years old) from the People's Republic of China-United States Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology (prospective survey) were used. Three consecutive overnight urine samples were collected in the autumn of 1983-1984 and the spring in 1985-1986, respectively. Urinary sodium and potassium were detected and calculated for 8 hours excretion. The occurrences of cardiovascular events were recorded in 2 years interval from 1987-1988 until December 31, 2005. Participants were divided into first ratio group, second ratio group, and third ratio group based on the tertiles of sodium to potassium ratio. Cox proportional hazard regression model was used to determine the relationship between sodium to potassium ratio and risk of CVD. In addition, participants were divided into 2 subgroups by the median of overnight urinary sodium and potassium, and then combined each other for 4 subgroups including low sodium-low potassium group, low sodium-high potassium group, high sodium-low potassium group, and high sodium-high potassium group, to explore the relationship between different sodium-potassium combinations and the risk of CVD. Results: A total of 954 participants were included in the final analysis, of whom 459 (48.1%) were males. There were 318 cases in the first, second and third ratio group, respectively. There were 347 cases in low sodium-low potassium group and high sodium-high potassium group, and 130 cases in low sodium-high potassium group and high sodium-low potassium group. After a median follow-up of 18.6 (18.3, 19.3) years, cardiovascular events occurred in 81 participants, including 64 stroke and 20 coronary heart disease events. Multivariate analysis showed that comparing with the first ratio group, the hazard ratios (HR) in the second and the third ratio groups were 2.04 (95%CI 1.06-3.95, P=0.034) and 2.07 (95%CI 1.07-4.03, P=0.032), respectively. The CVD risk in low sodium-low potassium group was 24% higher than the low sodium-high potassium group (reference), but this result did not reach statistical significant level (P=0.685). The risks in high sodium-high potassium group (HR=3.32, 95%CI 1.26-8.76,P=0.015) and high sodium-low potassium (HR=3.04, 95%CI 1.05-8.83, P=0.041) group were both significantly increased. Conclusions: Overnight urinary sodium to potassium ratio is positively correlated with the risk of cardiovascular events. High urinary sodium plays a more important role for the increased risk of cardiovascular events than low potassium.

[A new perspective of survival data on clinical epidemiology: introduction of competitive risk model].

Competing risks occur frequently in the analysis of survival data that should be dealt with competing risk models. Competing risk is an event whose occurrence precludes the occurrence of the primary event of interest. Previous commonly used Kaplan-Meier method tends to overestimate the cumulative survival functions, while the traditional Cox proportional hazards model falsely evaluates the effects of covariates on the hazard related to the occurrence of the event. There are few domestic reports mentioning the concept, application and methodology of competing risk model as well as the implementation procedures or resolution of model conditions and parameters. The current work aims to explain the core concept and methodology of the competing risk model and to illustrate the process of analysis on cumulative incidence rate, using both the cause-specific hazard function model and the sub-distribution hazard function model. Software macro code in SAS 9.4 is also provided to assist clinical researchers to further understand the application of the model so to properly analyze the survival data.

[The mechanism of bone marrow-derived mesenchymal stem cells excessive senescence in severe aplastic anemia mouse model].

Objective: To explore the mechanism of excessive senescence in bone marrow-derived mesenchymal stem cells (BM-MSC) of mouse model with severe aplastic anemia (SAA) . Methods: 40 BALB/c mice were randomly assigned to two groups of control (n=20) and AA (n=20) . SAA mouse model was induced by intraperitoneal injection with IFN-γ and intragastric infusion with busulfan. BM-MSC were isolated and cultured from bone marrow of SAA and healthy mice. The cell morphology was observed by inverted microscope and cell cytoskeleton was stained by Rhodamine-Phalloidin; The level of proliferation was analyzed by CCK-8 method, and cell cycle was tested by flow cytometry. Senescence-associated ß-galactosidase (SA-ß-gal) assay was used to detect senescent BM-MSC; The expression of mTOR protein was detected by Western blot method. Results: BM-MSC from normal mice presented spindle-shaped, clear boundaries and stress fibers were arranged in parallel, neat. while BM-MSCs from SAA mice presented cell volume increases, tiled, ill-shaped and the stress fiber appeared to be disordered. The decreased activity of proliferation [more cells restricted in G(0)/G(1) phase [ (77.461±1.567) % vs (46.045±2.055) %, t=-34.384, P<0.001], increased percentage of SA-ß-gal positive cells [ (75±11) % vs (28±8) %, t=15.454, P<0.001] and notably enhanced expression of mTOR of BM-MSC from SAA mice were observed when compared with those from normal mice. Conclusion: This study clarified senescent BM-MSCs from SAA model mice, which could be caused by the excessive activation of mTOR pathway.

[Application of SAS macro to evaluated multiplicative and additive interaction in logistic and Cox regression in clinical practices].

Conditional logistic regression analysis and unconditional logistic regression analysis are commonly used in case control study, but Cox proportional hazard model is often used in survival data analysis. Most literature only refer to main effect model, however, generalized linear model differs from general linear model, and the interaction was composed of multiplicative interaction and additive interaction. The former is only statistical significant, but the latter has biological significance. In this paper, macros was written by using SAS 9.4 and the contrast ratio, attributable proportion due to interaction and synergy index were calculated while calculating the items of logistic and Cox regression interactions, and the confidence intervals of Wald, delta and profile likelihood were used to evaluate additive interaction for the reference in big data analysis in clinical epidemiology and in analysis of genetic multiplicative and additive interactions.

[Changes of synaptic transmission efficiency in the MF-CA3 and PP-CA3 pathways of rat hippocampus during discrimination learning].

Electrophysiological and behavioral studies were performed in rat to investigate the changes of synaptic efficacy of the two inputs of hippocampal CA3 area [Mossy Fiber (MF) -CA3 and Perforant Path (PP) -CA3] during discrimination learning. The results showed that: (1) Amplitude of the population spike (PS) of both from MF-CA3 and PP-CA3 increased simultaneously with the establishment of conditioned response (CR) and both reached their maxima before CR reached the criterion of acquisition. (2) During natural extinction of CR, the amplitude of PS of both inputs decreased also simultaneously to their per-training level. These results indicated that the learning-dependent long-term potentiation (LTP) in both MF-CA3 and PP-CA3 inputs developed and extinguished synchronously, suggesting that the changes of synaptic efficacy of different inputs of hippocampal CA3 area coordinated during discrimination learning.

[Effects of 6-OHDA lesions of the bilateral dorsal noradrenergic bundle on learning-dependent long-term synaptic potentiation in dentate gyrus].

In the present study, the role of NE in learning-dependent long-term potentiation (LdLTP) was investigated by examining the effects of 6-hydroxydopamine (6-OHDA) lesion made in the bilateral dorsal noradrenergic bundle on the changes of synaptic efficacy in dentate gyrus (DG) and related conditioned response during drinking conditioning. Bilateral injection of 6-OHDA (12 micrograms/4 microliters) into the dorsal noradrenergic bundle caused a continuous decrease of the amplitude of population spike (PS) reaching a value of 50 +/- 6.3% and 28 +/- 6.4% respectively at the 6th and the 12th day after injection of the drug. During this period of 7 days, the LdLTP could not be produced in spite of 20 trainings per day for a total of 140 trials, and the conditioned drinking response could not be established. The above results indicate that normal levels of norepinephrine in the hippocampus are necessary to the establishment of LdLTP in the DG and suggest that the development of LdLTP in the DG may be modulated by the nucleus locus ceruleus via the dorsal noradrenergic bundle.

[Role of N-methyl-D-aspartate receptor in the maintenance of learning-dependent long-term potentiation in rat hippocampal CA3 area].

The effect of microinjection of 2-amino-5-phosphonovaleric acid (APV), a selective NMDA receptor antagonist, into the rat hippocampal CA3 area on the synaptic efficacy and related conditioned behavior during the acquisition and consolidation of discrimination learning behavior was examined. The results showed: (1) After population spike (PS) amplitude had just increased to the maximum through training i.e. learning-dependent LTP had just formed, APV 1 microliter (2 mmol/L) was injected into CA3 area, then the rats were trained during the time of efficacy of the drug in every experimental block. The result demonstrated that the PS amplitude could not be maintained at the highest level but decreased to the pre-experiment level after 8 blocks. Correct response percentage of rats could not be consolidated with further training but decreased to less than 10%. (2) After the PS amplitude had kept up at the highest level, APV 1 microliter (2 mmol/L) was injected into CA3 area, then the rats were trained during the time of efficacy of the drug in every experimental block, in which case the PS amplitude also could not be maintained at the highest level but decreased to the pre-experiment level after 14 blocks. Correlatively, when the correct response percentage of rats decreased gradually to less than 10%, the conditioned response of the animals extinguished, but its extinction speed was slower than it was in result (1). These results suggest that the NMDA receptor in CA3 area plays an important role in the maintenance of the learning-dependent long-term potentiation.

[Effect of scopolamine and picrotoxin on the learning-dependent long-term synaptic potentiation].

The purpose of this study was to investigate the effects of microinjection of scopolamine, a M-cholinergic antagonist and picrotoxin, a GABA-ergic antagonist into the rat hippocampal CA3 area on the learning-dependent long-term potentiation (LDLTP) during the establishment, extinction and re-establishment of conditioned drinking response. Following stimulation of the perforant path, field potentials of hippocampal CA3 of freely moving rats were recorded. The results were as follows: the synaptic efficacy and the development of LDLTP in hippocampal CA3 were depressed significantly by scopolamine, but the extinction of LDLTP was accelerated. Picrotoxin significantly enhanced synaptic efficacy and facilitated the development of LDLTP, but it depressed the extinction of LDLTP. Meanwhile, the establishment or extinction of drinking conditioning was correspondingly depressed or accelerated. Moreover, the development of LDLTP and its extinction preceded the development and extinction of drinking conditioning. The results provide further evidence indicating that LDLTP might be one of the neuronal mechanisms underlying behavioral learning and memory. Moreover, it seems that M-cholinergic receptors and GABA-ergic receptors in rat hippocampal CA3 area are involved in the development and retention of LDLTP.

[Effect of electroshock on learning-dependent long-term potentiation in rat hippocampal CA3 area].

Population spikes were recorded from hippocampal CA3 of freely moving rats following stimulation of the perforant path. Six rats were trained to perform conditioned drinking behavior. (1) Animals were treated with electroshock in less than 15 minutes after daily training session for a period of 6 consecutive days. Synaptic efficacy did not increase and the conditioned response could not be established during the behavioral training in four rats, synaptic efficacy was increased, the long-term potentiation (LTP) appeared and the conditioned behavior was established in other two rats. (2) After consolidation of conditioned behavior, electroshock temporarily caused suppression of the learning-dependent LTP and the correlative conditioned response. Both LTP and the correlative conditioned response recovered in one to four hours after electroshock. In these cases, the maximal development of LTP preceded the development of conditioned behavior. The results indicated that the learning-dependent LTP might be one of the neural substrates underlying learning and memory.

[The learning dependent long-term synaptic potentiation in the rat hippocampal CA3 region].

The purpose of this study is to investigate the changes of synaptic efficacy in the rat hippocampal CA3 region during establishment, extinction and re-establishment of conditioned drink response by means of implanted electrodes and behavioral observation. The monosynaptic population excitatory postsynaptic potential (EPSPs) and population spike (PS) elicited by stimulating the perforant path were recorded. The results showed that the long-term potentiation (LTP) in the hippocampal CA3 region appeared with the establishment of conditioned response, the LTP extinguished with experimental extinction of conditioned response and reappeared during the re-establishment of conditioned response. Moreover, both maximal level of LTP and its complete extinction preceded those of conditioned behavior, suggesting that the LTP was learning-dependent. In addition, the enhanced PS was not presented immediately after behavioral training, and developed within subsequent 24 h, with a maximum at the 4th hour. The magnitude of conditioned response depended on the level of LTP. A cross-correlation analysis of the slopes of PS and EPSPs indicated that the changes of PS were caused by alterations of synaptic transmission. These results suggest that the learning-dependent LTP might be one of the neuronal substrates underlying behavioral learning and memory.