Remnant cholesterol and intensive blood pressure control in older patients with hypertension: a post hoc analysis of the STEP randomized trial†.

AIMS: Emerging evidence shows a close relationship between remnant cholesterol (RC) and hypertension. However, it is unknown whether RC is associated with the effects of intensive systolic blood pressure (SBP) lowering on cardiovascular outcomes. METHODS AND RESULTS: We performed a post hoc analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Participants were randomly allocated to intensive (110 to <130 mmHg) or standard (130 to <150 mmHg) treatment groups. The effects of intensive SBP lowering on the primary composite outcome (stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularization, atrial fibrillation, or cardiovascular death), the components thereof, and all-cause mortality were analysed by the tertile of baseline RC (lowest, middle, and highest). We followed 8206 patients for 3.33 years (median). The adjusted hazard ratios (HRs) [95% confidence interval (CI)] for the primary outcome were 1.06 (0.73-1.56), 0.58 (0.38-0.87), and 0.67 (0.46-0.96) in the lowest, middle, and highest RC tertiles, respectively (P for interaction = 0.11). However, significant heterogeneity in the treatment effects was observed when comparing the upper two tertiles with the lowest tertile (P for interaction = 0.033). For all-cause mortality, the adjusted HRs (95% CI) were 2.48 (1.30-4.73), 1.37 (0.71-2.65), and 0.42 (0.22-0.80) in the lowest, middle, and highest RC tertiles, respectively (P for interaction <0.0001). CONCLUSION: Baseline RC concentrations were associated with the effects of intensive SBP lowering on the primary composite cardiovascular outcome and all-cause mortality in hypertensive patients. These results are hypothesis-generating and merit further study. REGISTRATION: STEP ClinicalTrials.gov number: NCT03015311.

In our post hoc analysis of the STEP trial, baseline remnant cholesterol (RC) concentrations were associated with the effects of intensive systolic blood pressure (SBP) lowering on the primary composite cardiovascular outcome and all-cause mortality in hypertensive patients.Patients with a higher RC experienced greater cardiovascular benefits from intensive SBP lowering, while a lower RC was associated with attenuated benefits or even negative effects of intensive SBP lowering. These results are hypothesis-generating and merit further study.If confirmed, RC measurements could permit the identification of a subset of patients with high RC and hypertension, who may receive greater benefit from intensive SBP lowering to <130 mmHg.

Molecular spectrum and prevalence of thalassemia investigated by third-generation sequencing in the Dongguan region of Guangdong Province, Southern China.

BACKGROUND: PCR, Sanger sequencing and NGS are often employed for carrier screening of thalassemia but all of these methods have limitations. In this study, we evaluated a new third-generation sequencing-based approach termed comprehensive analysis of thalassemia alleles (CATSA) to explore the prevalence of thalassemia in the Dongguan region of southern China. METHODS: 19,932 subjects were recruited for thalassemia screening and hemoglobin testing was performed for each of them. Routine PCR was performed for all the hemoglobin testing-positive subjects and CATSA was conducted for randomly selected subjects from hemoglobin testing-positive and negative subjects. RESULTS: In the 2716 subjects tested both by PCR and CATSA, 2569 had the same results and 147 had discordant results between the two methods. Sanger sequencing, specially designed PCR and MLPA confirmed the results of CATSA were all correct. In total, CATSA correctly detected 787 subjects with variants while routine PCR correctly detected 640 subjects with variants. CATSA yielded a 5.42% (147 of 2716) increment compared with routine PCR. In the 447 hemoglobin testing-negative subjects, CATSA identified pathogenic variants in 12 subjects. Moreover, CATSA identified a novel deletion (chr16:171262-202032) in the α-globin gene cluster. As a result, the deduced carrier frequency of α-thalassemia,ß-thalassemia and α-/ß-thalassemia was 5.62%, 3.85% and 0.93%, respectively. CONCLUSIONS: Our study demonstrated CATSA was a more comprehensive and precise approach than the routine PCR in a large scale of samples, which is highly beneficial for carrier screening of thalassemia. It provided a broader molecular spectrum of hemoglobinopathies and a better basis for a control program in Dongguan region.

Detecting rare thalassemia in children with anemia using third-generation sequencing.

BACKGROUND: In China, conventional genetic testing methods can only detect common thalassemia variants. Accurate detection of rare thalassemia is crucial for clinical diagnosis, especially for children that need long-term blood transfusion. This study aims to explore the application value of third-generation sequencing (TGS) in the diagnosis of rare thalassemia in children with anemia. METHODS: We enrolled 20 children with anemia, excluding from iron deficiency anemia (IDA). TGS was employed to identify both known and novel thalassemia genotypes, while sanger sequencing was used to confirm the novel mutation detected. RESULTS: Among the 20 samples, we identified 5 cases of rare thalassemia. These included ß-4.9 (hg38,Chr11:5226187-5231089) at HBB gene, α-91(HBA2:c.*91delT), αCD30(HBA2:c.91-93delGAG), Chinese Gγ+(Aγδß)0(NG_000007.3: g .48795-127698 del 78904) and delta - 77(T > C)(HBD:c.-127T>C). Notably, the -SEA/α-91α genotype associated with severe non-deletional hemoglobin H disease (HbH disease) has not been previously reported. Patients with genotypes ß654/ß-4.9 and -SEA/α-91α necessitate long-term blood transfusions, and those with the -SEA/αCD30α, Chinese Gγ+(Aγδß)0 and delta thalassemia demonstrate mild anemia. CONCLUSIONS: TGS demonstrates promising potential as a diagnostic tool for suspected cases of rare thalassemia in children, especially those suspected to have transfusion-dependent thalassemia (TDT).

Intensive Blood Pressure Lowering Improves Left Ventricular Hypertrophy in Older Patients with Hypertension: The STEP Trial.

BACKGROUND: Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, its effect on cardiac remodeling remains not fully understood. This secondary analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients trial aims to determine the changes in left ventricular hypertrophy (LVH) that occur in the context of intensive SBP lowering. METHODS: A total of 7141 older patients with hypertension were randomly assigned to intensive treatment (SBP target, 110-130 mm Hg) or standard treatment (130-150 mm Hg). LVH was defined according to the Peguero-Lo Presti criteria on a standard 12-lead echocardiogram. RESULTS: At baseline, the prevalence of LVH (16.6% versus 16.5%) and the mean Peguero-Lo Presti value (1811 versus 1808 µV) were comparable between the treatment groups. During a median follow-up of 3.24 years, intensive SBP lowering was associated with a significantly lower risk of new LVH occurrence (hazard ratio, 0.76 [95% CI, 0.66-0.89]; P=0.001) and slower progression of the mean Peguero-Lo Presti index value by -23.47 µV/y (95% CI, -34.93 to -12.01; P=0.000). However, the rates of regression of baseline LVH did not differ significantly. Notably, the beneficial effect of intensive SBP lowering in terms of cardiovascular events (hazard ratio, 0.75 [95% CI, 0.59-0.97]) was not markedly attenuated after adjusting for LVH as a time-varying covariate (hazard ratio, 0.76 [95% CI, 0.59-0.97]). CONCLUSIONS: Intensive SBP lowering protects against LVH development in older hypertensive patients, however, this favorable effect could not explain most of the reduction in cardiovascular events associated with intensive SBP lowering.

Achieved systolic blood pressure and cardiovascular outcomes in 60-80-year-old patients: the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial.

AIMS: Intensive systolic blood pressure (SBP) lowering has been increasingly used; however, data is missing on patients who had target-achieved (TA). This study aims to show the cardiovascular effect of maintaining SBP at intensive levels. METHODS: The Strategy of Blood Pressure Intervention in Elderly Hypertensive Patients (STEP) trial was a multicentre, randomized, controlled trial which enrolled 8511 young-older (60-80 years) hypertensive patients without prior stroke to compare the cardiovascular prognosis of the intensive treatment (SBP target, 110 to <130 mmHg) vs. the standard treatment (130 to <150 mmHg). This secondary analysis assessed data in patients who achieved a mean SBP within target values. The association of mean achieved SBP and cardiovascular events was examined using a cubic spline function. RESULTS: In total, 3053 patients (72.0%) in the intensive-treatment group and 3427 (80.3%) in the standard-treatment group had an SBP target achieved, with mean follow-up SBP values of 124.2 mmHg and 137.4 mmHg, respectively. Throughout the median 3.38-year follow-up, the cardiovascular risk was significantly lower in the TA intensive-treatment group than in the TA standard-treatment group [adjusted hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.46-0.80; P < 0.001]. In the intensive-treatment group, patients failing to achieve SBP targets presented higher cardiovascular risk than those TA patients (HR 2.04, 95% CI 1.44-2.88; P < 0.001). A J-shaped relationship was observed between the mean achieved SBP and risk of cardiovascular events, with the lowest risk at an SBP of 126.9 mmHg. CONCLUSIONS: Maintaining SBP at <130 mmHg offers additional cardiovascular benefits among young-older patients with hypertension. REGISTRATION: ClinicalTrials.gov: NCT03015311.

This present study is a secondary analysis that investigated the association between mean achieved BP in the two treatment groups (SBP target, 110 to <130 vs. 130 to <150 mmHg) and their cardiovascular outcomes in the STEP study (60­80-year-old patients with hypertension).Patients achieving a target in the intensive-treatment group have better cardiovascular outcome than patients achieving a target in the standard treatment arm, supporting the cardiovascular benefits of maintaining SBP <130 mmHg.J-shaped relationships were observed between mean achieved SBP and cardiovascular outcomes (with the nadir around 130 mmHg), but not for stroke.

Synergistic Effect of TMSPi and FEC in Regulating the Electrode/Electrolyte Interfaces in Nickel-Rich Lithium Metal Batteries.

Nickel-rich LiNi0.8Co0.1Mn0.1O2 (NCM811) with respect to Li metal can enhance the energy density of lithium batteries effectively. However, the unstable Li deposition, together with the dissolution and migration of transition metal (TM) ions toward the anode deteriorate the cycle performance of NCM811||Li battery, especially when commercial carbonate electrolyte is used. Herein, tris(trimethylsilyl)phosphite (TMSPi) and fluoroethylene carbonate (FEC) are used to construct a dual-additive electrolyte, by which both electrodes can be protected. It is found that TMSPi can be preferentially adsorbed on the cathode surface through its strong coordination with Ni4+, playing the role as a HF scavenger and suppressing TM ions dissolution, as well as mitigating the structural degradation of the cathode effectively. When it comes to the lithium anode, the presence of TMSPi may lead to side reactions with Li metal, accompanied by fast dendrite growth. The introduction of FEC could facilitate the formation of stable electrode/electrolyte interfaces on both sides. Particularly, reduce the direct contact between TMSPi and Li anode, thus ameliorate the incompatibility issue. Consequently, the NCM811||Li cell with dual-additive demonstrates excellent capacity retention of 81.2% after 500 cycles at 1 C rate. As a sharp contrast, it only retains 13.9% in the one with blank electrolyte. The findings of this work provide a new insight into enhancing the cycle performance of NCM811||Li system via the synergistic effect between additives.

Suppression of MIF-induced neuronal apoptosis may underlie the therapeutic effects of effective components of Fufang Danshen in the treatment of Alzheimer's disease.

Fufang Danshen (FFDS or Compound Danshen) consists of three Chinese herbs Danshen (Salviae miltiorrhizae radix et rhizome), Sanqi (Notoginseng radix et rhizome) and Tianranbingpian (Borneolum, or D-borneol), which has been show to significantly improve the function of the nervous system and brain metabolism. In this study we explored the possible mechanisms underlying the therapeutic effects of the combination of the effective components of FFDS (Tan IIA, NG-R1 and Borneol) in the treatment of Alzheimer's disease (AD) based on network pharmacology. We firstly constructed AD-related FFDS component protein interaction networks, and revealed that macrophage migration inhibitory factor (MIF) might regulate neuronal apoptosis through Bad in the progression of AD. Then we investigated the apoptosis-inducing effects of MIF and the impact of the effective components of FFDS in human neuroblastoma SH-SY5Y cells. We observed the characteristics of a "Pendular state" of MIF, where MIF (8 ng/mL) increased the ratio of p-Bad/Bad by activating Akt and the IKKα/ß signaling pathway to assure cell survival, whereas MIF (50 ng/mL) up-regulated the expression of Bad to trigger apoptosis of SH-SY5Y cells. MIF displayed neurotoxicity similar to Aß1-42, which was associated with the MIF-induced increased expression of Bad. Application of the FFDS composite solution significantly decreased the expression levels of Bad, suppressed MIF-induced apoptosis in SH-SY5Y cells. In a D-galactose- and AlCl3-induced AD mouse model, administration of the FFDS composite solution significantly improved the learning and memory, as well as neuronal morphology, and decreased the serum levels of INF-γ. Therefore, the FFDS composite solution exerts neuroprotective effects through down-regulating the level of Bad stimulated by MIF.

[Effect of calcineurin Aalpha gene overexpression on the myocardium apoptosis induced by hypoxia-reoxygenation and adrenergic receptors].

OBJECTIVE: To investigate the effect of calcineurin AalphacDNA (AdCnAalpha) overexpression as a result of adenovirally mediated gene transfer on neonatal rat cardiac myocyte apoptosis induced by hypoxia-reoxygenation (H/R) and adrenergic receptors. METHODS: Neonatal rat cardiac myocytes were cultured for 20 h after AdCnAalpha transfection, and treated with isoproterenol (10 micromol/L) and 24 h of hypoxia followed by 4 h of reoxygenation (24H/4R). The cardiac myocyte apoptosis induced by the treatments was assessed by flow cytometry and DNA laddering, and the levels of calcineurin, p38 and phosphorylation p38 (p-p38) were determined by Western blotting and (or) RT-PCR. RESULTS: AdCnAalpha transfection promoted cultured neonatal rat cardiac myocyte apoptosis induced by isoproterenol+24H/4R as compared with the treated cells without transfection (14.247-/+0.525 vs 10.763-/+1.554, P<0.01), along with greater phosphorylation p38 protein expression (1.60-/+0.22 vs 2.42-/+0.19, P<0.01). The levels of p38 underwent no obvious change after AdCnAalpha transfection (P<0.05). CONCLUSIONS: AdCnAalpha transfection can promote cardiac myocyte apoptosis induced by H/R and adrenergic receptors, the mechanism of which might be associated with p38 mitongen-activated protein kinase (p38MAPK) activation.

Construction of rat calcineurin A alpha cDNA recombinant adenovirus vector and its identification.

Rat calcineurin (CaN) A alpha isoform (Ppp3ca) cDNA recombinant adenovirus vector was constructed in order to explore the effect of CaN on the myocardium apoptosis induced by ischemia-reperfusion injury. Total RNA was isolated from the heart of the adult Wistar rat, and Ppp3ca CDS segment of approximate 1.59 kb size was amplified by reverse transcriptional PCR method. Ppp3ca cDNA segment was cloned into pMD18-T Simple vector for sequencing, and the right clone was named T-Ppp3ca. Ppp3ca cDNA segment obtained from T-Ppp3ca was ligated with pShuttle2-IRES-EGFP to construct a recombinant plasmid pShuttle2-Ppp3ca-IRES-EGFP. Ppp3ca-IRES-EGFP expression cassette containing CMV, Ppp3ca-IRES-EGFP and SV40 polyA DNA fragment (3.97 kb) obtained from pShuttle2-Ppp3ca-IRES-EGFP was connected with pAdeno-X backbone sequence to construct a recombinant plasmid pAdeno-Ppp3ca. After being identified by PCR and enzyme digestion, recombinant plasmid pAdeno-Ppp3ca was packaged in HEK293 cells. Supernatant of adenovirus from HEK293 cells was collected after a visible cytopathic effect (CPE) appeared. The DNA of the recombinant adenovirus was extracted with the standard method. The presence of the recombinant adenovirus was verified by PCR. The results showed that sequencing results verified that the PCR product of Ppp3ca gene was identical to GenBank. Agarose electrophoresis showed the bands of recombined plasmid pAdeno-Ppp3ca and the recombinant adenovirus identified by enzyme digestion and PCR were in the right range corresponding with expectation. It was concluded that the recombinant adenovirus carrying rat calcineurin A alpha (Ppp3ca) cDNA as well as a report gene-enhancer green fluorescent protein gene was successfully constructed in this experiment.