Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues.

Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between ß-oxo esters and ß-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Retraction of "0D/2D Coordination Complexes: Magnetic Studies, Protection, and Mechanism against Ischemic Myocardial Damage by Reducing the Activation of the PI3K/Akt Signaling Pathway".

[This retracts the article DOI: 10.1021/acsomega.0c05601.].

Focal vibration of the plantarflexor and dorsiflexor muscles improves poststroke spasticity: a randomized single-blind controlled trial.

BACKGROUND: Post-stroke spasticity is a cause of gait dysfunction and disability. Focal vibration (FV) of agonist-antagonist upper limb muscle pairs reduces flexor spasticity; however, its effects on ankle plantarflexor spasticity are uncertain. OBJECTIVE: To assess the effects of focal vibration administered by a trained operator to the ankle plantarflexor and dorsiflexor muscles on post-stroke lower limb spasticity. METHODS: A randomized, single-blind controlled trial of 64 participants with stroke and plantarflexor spasticity assigned to 3 groups by centralized, computer-generated randomization (1:1:1): 1) physiotherapy alone (CON), 2) physiotherapy+gastrocnemius vibration (FV_GM) and 3) physiotherapy+tibialis anterior vibration (FV_TA). Physiotherapists and assessors were blinded to group assignment. The experimental groups underwent 15, 20-min vibration sessions at 40 Hz. We performed evaluations at baseline and after the final treatment: Modified Ashworth Scale (MAS), Clonus scale, Functional Ambulation Categories (FAC), Fugl-Meyer Assessment - Lower Extremity (FMA_LE), Modified Barthel Index (MBI), and electromyography and ultrasound elastography. Primary outcome was remission rate (number and proportion of participants) of the MAS. RESULTS: MAS remission rate was higher in FV_GM and FV_TA than CON groups (CON vs. FV_GM: p=0.009, odds ratio 0.15 [95% confidence interval 0.03-0.67]; CON vs. FV_TA: p=0.002, 0.12 [0.03-0.51]). Remission rate was higher in the experimental than CON groups for the Clonus scale (CON vs. FV_GM: p<0.001, OR 0.07 [95% CI 0.01-0.31]; CON vs. FV_TA: p=0.006, 0.14 [95% CI 0.03-0.61]). FAC remission rate was higher in the FV_TA than the CON (p=0.009, 0.18 [0.05-0.68]) and FV_GM (p=0.014, 0.27 [0.07-0.99]) groups. Ultrasound variables of the paretic medial gastrocnemius decreased more in FV_GM than CON and FV_TA groups (shear modulus: p=0.006; shear wave velocity: p=0.008). CONCLUSIONS: Focal vibration reduced post-stroke spasticity of the plantarflexor muscles. Vibration of the tibialis anterior improved ambulation more than vibration of the gastrocnemius or physiotherapy alone. Gastrocnemius vibration may reduce spasticity by changing muscle stiffness.

0D/2D Coordination Complexes: Magnetic Studies, Protection, and Mechanism against Ischemic Myocardial Damage by Reducing the Activation of the PI3K/Akt Signaling Pathway.

The synthesis of two new coordination compounds was carried out by applying 4-(3-carboxyphenyl)picolinic acid (H2cppa) as building units under the hydrothermal reaction conditions, whose chemical formulae are [Cu(Hcppa)2(H2O)2]·2H2O (1) and [Cu(µ3-cppa)(H2O)2] (2). The analysis of structures suggested that 1 featured a discrete molecular structure, which was extended into the three-dimensional supramolecular network with the topology of pcu topology, whereas complex 2 showed a two-dimensional layered network with the fes topology. The magnetic performances of the two synthesized compounds reveal antiferromagnetic coupling between consecutive metal ions. Their application values on ischemic myocardial damage were assessed, and the detailed mechanism of the synthetic complexes was also investigated. The Elabscience Annexin V detection kit was used in this research to determine the percentage of apoptotic cardiomyocytes after different complex treatments. In addition, the relative expression of PI3K/Akt in the myocardium after the application of the compound was determined using the real-time reverse transcription polymerase chain reaction assay.

Exosomes Released from CaSR-Stimulated PMNs Reduce Ischaemia/Reperfusion Injury.

Ischemia-reperfusion (I/R) injury caused by acute myocardial infarction (AMI) can initiate a strong inflammatory response. Polymorphonuclear cells (PMNs) are the most important inflammatory cells. Our previous studies found that the calcium-sensing receptor (CaSR) regulates the proinflammatory effects of PMNs. However, the role and mechanism of CaSR-regulated PMNs in I/R injury remain uncertain. A rat AMI model was developed in this study and showed that the expression of CaSR on PMNs increased in AMI; however, the levels of Bcl-xl and SOD in myocardial tissue decreased, while Bax and MDA levels increased. Then, after coculture with CaSR-stimulated PMNs, the expression of Bcl-xl in cardiomyocytes significantly increased, Bax expression and the apoptotic rate decreased, and ROS production was significantly inhibited. At the same time, the cardiomyocyte damage caused by hypoxia-reoxygenation was reduced. Furthermore, we found that exosomes derived from PMNs could be taken up by cardiomyocytes. Additionally, the exosomes secreted by CaSR-stimulated PMNs had the same effect on cardiomyocytes as CaSR-stimulated PMNs, while the increased phosphorylation level of AKT in cardiomyocytes could be revered by AKT transduction pathway inhibitors. Subsequently, we identified the exosomes derived from CaSR-stimulated PMNs by second-generation sequencing technology, and increased expression of lncRNA ENSRNOT00000039868 was noted. The data show that this lncRNA can prevent the hypoxia-reoxygenation injury by upregulating the expression of PDGFD in cardiomyocytes. In vivo, exosomes from CaSR-stimulated PMNs played a significant role against AMI and reperfusion injury in myocardial tissue. Thus, we propose that exosomes derived from CaSR-stimulated PMNs can reduce I/R injury in AMI, and this effect may be related to the AKT signaling pathway.

Point-of-care ultrasound augments physical examination learning by undergraduate medical students.

BACKGROUND: Little is known about the impact of the provision of handheld point-of-care ultrasound (POCUS) devices on physical examination skills of medical students. METHODS: We describe an educational initiative that comprised a POCUS workshop followed by allocation of a POCUS device to medical students for use over the subsequent 8 weeks. They were encouraged to scan patients and correlate their physical examination findings. A mobile instant messaging group discussion platform was set to provide feedback from instructors. Physical examination skills were assessed by means of clinical examination. RESULTS: 210 final-year medical students from the University of Hong Kong participated in the programme. 46.3% completed the end of programme electronic survey: 74.6% enjoyed using the POCUS device, 50.0% found POCUS useful to validate physical examination findings and 47.7% agreed that POCUS increased their confidence with physical examination. 93.9% agreed that the programme should be incorporated into the medical curriculum and 81.9% would prefer keeping the device for longer time from 16 weeks (45.6%) to over 49 weeks (35.3%). Medical students who participated in the POCUS programme had a higher mean score for abdominal examination compared with those from the previous academic year with no POCUS programme (3.65±0.52 vs 3.21±0.80, p=0.014), but there was no statistically significant difference in their mean score for cardiovascular examination (3.62±0.64 vs 3.36±0.93, p=0.203). CONCLUSION: The POCUS programme that included provision of a personal handheld POCUS device improved students' attitude, confidence and ability to perform a physical examination.

TIMI risk score for secondary prevention of recurrent cardiovascular events in a real-world cohort of post-non-ST-elevation myocardial infarction patients.

BACKGROUND: Patients who survive non-ST-elevation myocardial infarction (NSTEMI) are at heightened risk of recurrent cardiovascular events. Data on long-term secondary atherothrombotic risk stratification are limited. OBJECTIVES: To stratify post-NSTEMI patients for risk of recurrent cardiovascular events to maximise benefit from aggressive secondary prevention strategies using the TIMI Risk Score for Secondary Prevention (TRS 2°P) score in a real-world cohort of NSTEMI patients. METHODS AND RESULTS: This was a single-centre observational study of 891 post-NSTEMI patients (73.7 ± 12.7 years; male: 54.2%). The TRS 2°P is a nine-point risk stratification tool to predict cardiovascular events in patients with established cardiovascular disease. The primary outcome was a composite endpoint of cardiovascular death, non-fatal MI and non-fatal ischaemic stroke. After a median follow-up of 31 months (IQR: 11.4 - 60.2), 281 patients (31.5%) had developed a primary outcome (13.3%/year) including 196 cardiovascular deaths, 94 non-fatal MIs and 22 non-fatal strokes. The TRS 2°P score was strongly associated with the primary outcome. The annual incidence of primary composite endpoint for patients with TRS 2°P score =0 was 1.6%, and increased progressively to 47.4% for those with a TRS 2°P score ≥6 (HR: 20.18, 95% CI: 4.85 to 84.05, p<0.001). Similar associations were also observed between the TRS 2°P score and cardiovascular death and MI (fatal and non-fatal), but not non-fatal ischaemic stroke. CONCLUSION: The TRS 2°P score stratified post-NSTEMI patients for risk of future cardiovascular events and potentially help guide the selection of more aggressive secondary prevention therapy.

Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention of Recurrent Cardiovascular Events in a Real-World Cohort of Post-Acute Myocardial Infarction Patients.

BACKGROUND: Patients who survive myocardial infarction (MI) are at risk of recurrent cardiovascular (CV) events. This study stratified post-MI patients for risk of recurrent CV events using the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P). Methods and Results: This was an observational study that applied TRS 2°P to a consecutive cohort of post-MI patients. The primary outcome was a composite endpoint of CV death, non-fatal MI, and non-fatal ischemic stroke. A total of 1,688 post-MI patients (70.3±13.6 years; male, 63.1%) were enrolled. After a mean follow-up of 41.5±34.4 months, 405 patients (24.0%) had developed a primary outcome (9.3%/year) consisting of 278 CV deaths, 134 non-fatal MI, and 33 non-fatal strokes. TRS 2°P was strongly associated with the primary outcome. The annual incidence of primary composite endpoint for patients with TRS 2°P 0 was 1.0%, and increased progressively to 39.9% for those with TRS 2°P ≥6 (HR, 27.6; 95% CI: 9.87-77.39, P<0.001). The diagnostic sensitivity of TRS 2°P for the primary composite endpoint was 76.3% (95% CI: 72.1-80.5%). Similar associations were also observed between TRS 2°P and CV death and non-fatal MI, but not non-fatal ischemic stroke. CONCLUSIONS: TRS 2°P reliably stratified post-MI patients for risk of future CV events.

Secular trends and etiologies of venous thromboembolism in Chinese from 2004 to 2016.

INTRODUCTION: Current epidemiological data for venous thromboembolism (VTE) are derived primarily from Caucasian populations from North America. Little is known for other ethnic groups. This study aimed to describe the incidence, etiologies, and the secular trends of VTE in a Chinese population. MATERIALS AND METHODS: This was an observational study using a hospital VTE registry. RESULTS AND CONCLUSIONS: Between 2004 and 2016, 2214 patients (mean age 66.2 ±â€¯17.4 years, 57.2% female) were hospitalized for a novel occurrence of venous thromboembolism. Of these, 1444 patients (65.2%) had deep venous thrombosis and 770 patients (34.8%) had pulmonary embolism. Over the 13-year period, there was an increasing trend in the incidence of VTE from 28.1 per 100,000 population per year in 2004 to 48.3 per 100,000 population per year in 2016. There has been a disproportional increase in the incidence of VTE among those aged 75 years or above. Etiologically, the most common cause of VTE was active malignancy with an incidence that increased from 34.8% in 2005 to 60.9% in 2014. In conclusion, the incidence of venous thromboembolism in Hong Kong appears to be lower than that in previous Caucasian series. Nonetheless there has been an increasing incidence of VTE over the past decade, primarily related to aging and malignancy.

Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study.

Current guideline-recommended screening for pulmonary hypertension in patients with systemic sclerosis has not been evaluated in systemic lupus erythematosus (SLE), which is disproportionately prevalent in Asians. This multicentre, cross-sectional screening study aims to study the prevalence of pulmonary hypertension among SLE patients using these guidelines, and identify independent predictors and develop a prediction model for pulmonary hypertension in SLE patients. SLE patients from participating centres will undergo an echocardiography- and biomarker-based pulmonary hypertension screening procedure as in the DETECT study. Standard right heart catheterisation will be provided to patients with intermediate or high echocardiographic probability of pulmonary hypertension. Those with low echocardiographic probability will rescreen within 1 year. The primary measure will be the diagnosis and types of pulmonary hypertension and prevalence of pulmonary hypertension in SLE patients. The secondary measures will be the predictors and prediction models for pulmonary hypertension in SLE patients. The estimated sample size is approximately 895 participants. The results of the SOPHIE study will be an important contribution to the literature of SLE-related pulmonary hypertension and may be immediately translatable to real clinical practice. Ultimately, this study will provide the necessary evidence for establishing universal guidelines for screening of pulmonary hypertension in SLE patients.

[Standardized investigation on medicinal nature of ethnomedicine].

This article recorded the analysis and comparison between the medicinal nature theory of traditional Chinese medicine(TCM) and ethnomedicine(EM). The vocabulary of "medicinal nature" was suggested to indicate the properties of ethnomedicine. Based on the influence of TCM medicinal nature theory on EM in China, the application of medicinal nature theory in EM was divided into 3 classes, and the standardizing principles for EM medicinal nature were proposed. It was suggested that medicinal quality, flavor, tendency, tropism, degree and efficiency can be used for the classification standard for EM medicinal nature.