Enantioselective α-Boryl Carbene Transformations.

Carbenes, recognized as potent intermediates, enable unique chemical transformations, and organoborons are pivotal in diverse chemical applications. As a hybrid of carbene and the boryl group, α-boryl carbenes are promising intermediates for the construction of organoborons; unfortunately, such carbenes are hard to access and have low structural diversity with their asymmetric transformations largely uncharted. In this research, we utilized boryl cyclopropenes as precursors for the swift synthesis of α-boryl metal carbenes, a powerful category of intermediates for chiral organoboron synthesis. These α-boryl carbenes undergo a series of highly enantioselective transfer reactions, including B-H and Si-H insertion, cyclopropanation, and cyclopropanation/Cope rearrangement, catalyzed by a singular chiral copper complex. This approach opens paths to previously unattainable but easily transformable chiral organoborons, expanding both carbene and organoboron chemistry.

A comparison of Atlas and Leo Baby stents-assisted coiling of intracranial aneurysms with small parent vessels.

Some studies have reported the efficacy and safety of the Atlas stent and the Leo Baby stent-assisted coiling (SAC) of intracranial aneurysms arising from small cerebral vessels. The authors aimed to compare the clinical performance of the Atlas and the Leo Baby stents in small parent arteries. Methods and materials: Between January 2019 and November 2022, 56 patients at our centre were treated using either Atlas or Leo Baby SAC of intracranial aneurysms arising from small parent vessels (<2 mm). The clinical and angiographic imaging data of the two cohorts were retrospectively collected and comparatively analyzed. Results: A total of 56 patients were included in this study. Thirty-two patients were treated with the Atlas SAC, and 24 patients were treated with the Leo Baby SAC. The mean age of the Atlas stent cohort was older, and the mean aneurysm size was smaller than the Leo Baby stent. The immediate complete occlusion rate was 68.6% in the Atlas stent cohort and 62.5% in the Leo Baby stent cohort. The mean angiographic follow-up time for Atlas stent cohort was 8.9±2.5 months, and the final aneurysm complete occlusion rate was 81.0%. The mean follow-up time for Leo Baby stent cohort was 18.9±6.0 months, and the final aneurysm complete occlusion rate was 83.3%. Conclusions: At the final follow-up, the Atlas or the Leo baby stent SAC of intracranial aneurysms with small parent vessels resulted in favourable angiographic results and clinical outcomes, with a low rate of associated complications.

Tubridge flow diverter alone vs. Tubridge flow diverter and coils for the treatment of intracranial aneurysms: A propensity score matching analysis.

Background: The study was designed to assess the clinical performance of a tubridge flow diverter (TFD) in the treatment of intracranial aneurysms and to compare the efficacy and safety between intracranial aneurysms treated with TFD alone and TFD combined with coiling. Methods: In this retrospective study, patients treated with the TFD alone or TFD combined with coiling between June 2018 to November 2022 were included. The patient demographics, the characteristics of the aneurysm, and the treatment outcomes between the two groups were compared. Propensity score matching was performed to match the variables with a significant difference between groups. Results: In the current study, data from 93 consecutive patients including 104 aneurysms treated with TFD were analyzed. In total, 43 patients with 49 aneurysms were treated with TFD alone, and 50 patients with 55 aneurysms were treated with TFD combined with coiling. Aneurysms in the TFD combined with the coiling group were larger (12.9 ± 8.6 vs. 8.7 ± 8.8 mm, P = 0.016) and more likely to be saccular (92.7% vs. 75.5%, P = 0.027) than in the TFD alone group. No significant difference was observed between the two groups in terms of perioperative complication rate. During the follow-up period, the complete occlusion rate in the TFD combined with the coiling group was higher (80.0% vs. 43.8%, P = 0.001) than in the TFD alone group. These results were further confirmed using a propensity score matching analysis. Conclusion: TFD combined with coiling can be a safe and effective alternative option for the treatment of complex aneurysms. Given the potential risks of these therapeutic modalities, thus very careful consideration is required on an individual patient basis.

Highly Regio-, Stereo-, and Enantioselective Copper-Catalyzed B-H Bond Insertion of α-Silylcarbenes: Efficient Access to Chiral Allylic gem-Silylboranes.

Herein, we report the development of a method for highly regio-, stereo-, and enantioselective B-H bond insertion reactions of α-silylcarbenes generated from 1-silylcyclopropenes in the presence of a chiral copper(I)/bisoxazoline catalyst for the construction of chiral γ,γ-disubstituted allylic gem-silylboranes, which cannot be prepared by any other known methods. This reaction is the first highly enantioselective carbene insertion reaction of α-silylcarbenes ever to be reported. The method shows general applicability for various 3,3-disubstituted silylcyclopropenes and exclusively affords E-products. The novel chiral γ,γ-disubstituted allylic gem-silylborane products are versatile allylic bimetallic reagents with high stability and have great synthetic potential, especially for the construction of complex molecules with continuous chiral centers.

Validation, Optimization, and Application of the Zebrafish Developmental Toxicity Assay for Pharmaceuticals Under the ICH S5(R3) Guideline.

The zebrafish as an alternative animal model for developmental toxicity testing has been extensively investigated, but its assay protocol was not harmonized yet. This study has validated and optimized the zebrafish developmental toxicity assay previously reported by multiple inter-laboratory studies in the United States and Europe. In this study, using this classical protocol, of 31 ICH-positive compounds, 23 compounds (74.2%) were teratogenic in zebrafish, five had false-negative results, and three were neither teratogenic nor non-teratogenic according to the protocol standard; of 14 ICH-negative compounds, 12 compounds (85.7%) were non-teratogenic in zebrafish and two had false-positive results. After we added an additional TI value in the zebrafish treated with testing compounds at 2 dpf along with the original 5 dpf, proposed a new category as the uncategorized compounds for those TI values smaller than the cutoff both at 2 dpf and 5 dpf but inducing toxic phenotypes, refined the testing concentration ranges, and optimized the TI cut-off value from ≥ 10 to ≥ 3 for compounds with refined testing concentrations, this optimized zebrafish developmental assay reached 90.3% sensitivity (28/31 positive compounds were teratogenic in zebrafish) and 88.9% (40/45) overall predictability. Our results from this study strongly support the use of zebrafish as an alternative in vivo method for screening and assessing the teratogenicity of candidate drugs for regulatory acceptance.

Evidences for the mechanism of Shenmai injection antagonizing doxorubicin-induced cardiotoxicity.

BACKGROUND: Doxorubicin (DOX) is a widely used antitumor drug. However, its clinical application is limited for its serious cardiotoxicity. The mechanism of DOX-induced cardiotoxicity is attributed to the increasing of cell stress in cardiomyocytes, then following autophagic and apoptotic responses. Our previous studies have demonstrated the protective effect of Shenmai injection (SMI) on DOX-induced cardiotoxicity via regulation of inflammatory mediators for releasing cell stress. PURPOSE: To further investigate whether SMI attenuates the DOX-induced cell stress in cardiomyocytes, we explored the mechanism underlying cell stress as related to Jun N-terminal kinase (JNK) activity and the regulation of autophagic flux to determine the mechanism by which SMI antagonizes DOX-induced cardiotoxicity. STUDY DESIGN: The DOX-induced cardiotoxicity model of autophagic cell death was established in vitro to disclose the protected effects of SMI on oxidative stress, autophagic flux and JNK signaling pathway. Then the autophagic mechanism of SMI antagonizing DOX cardiotoxicity was validated in vivo. RESULTS: SMI was able to reduce the DOX-induced cardiomyocyte apoptosis associated with inhibition of activation of the JNK pathway and the accumulation of reactive oxygen species (ROS). Besides, SMI antagonized DOX cardiotoxicity, regulated cardiomyocytes homeostasis by restoring DOX-induced cardiomyocytes autophagy. Under specific circumstances, SMI depressed autophagic process by reducing the Beclin 1-Bcl-2 complex dissociation which was activated by DOX via stimulating the JNK signaling pathway. At the same time, SMI regulated lysosomal pH to restore the autophagic flux which was blocked by DOX in cardiomyocytes. CONCLUSION: SMI regulates cardiomyocytes apoptosis and autophagy by controlling JNK signaling pathway, blocking DOX-induced apoptotic pathway and autophagy formation. SMI was also found to play a key role in restoring autophagic flux for counteracting DOX-damaged cardiomyocyte homeostasis.

Management of imported malaria cases and healthcare institutions in central China, 2012-2017: application of decision tree analysis.

BACKGROUND: Imported malaria has been an important challenge for China. Fatality rates from malaria increased in China, particularly in Henan Province, primarily due to malpractice and misdiagnoses in healthcare institutions, and the level of imported malaria. This study aims to investigate the relationship between the state of diagnosis and subsequent complications among imported malaria cases at healthcare institutions, based on malaria surveillance data in Henan Province from 2012 to 2017. METHODS: A retrospective descriptive analysis was performed using data from the Centre for Disease Control and Prevention, Zhengzhou City, the capital of Henan Province. A decision tree method was exploited to provide valuable insight into the correlation between imported malaria cases and healthcare institutions. RESULTS: From 2012 to 2017, there were 371 imported malaria cases, mostly in males aged between 20 and 50 years, including 319 Plasmodium falciparum cases. First visits of 32.3%, 19.9% and 15.9% malaria cases for treatment were to provincial, municipal and county healthcare institutions, respectively. The time interval between onset and initial diagnosis of 284 cases (76.5%) and the time interval between initial diagnosis and final diagnosis of 197 cases (53.1%) was no more than 72 h. An apparent trend was found that there were notably fewer patients misdiagnosed at first visit to healthcare institutions of a higher administrative level; 12.5% of cases were misdiagnosed in provincial healthcare institutions compared to 98.2% in private clinics, leading to fewer complications at healthcare institutions of higher administrative level due to correct initial diagnosis. In the tree model, the rank of healthcare facilities for initial diagnosis, and number of days between onset and initial diagnosis, made a major contribution to the classification of initial diagnosis, which subsequently became the most significant factor influencing complications developed in the second tree model. The classification accuracy were 82.2 and 74.1%, respectively for the tree models of initial diagnosis and complications developed. CONCLUSION: Inadequate seeking medical care by imported malaria patients, and insufficient capacity to diagnose malaria by healthcare institutions of lower administrative level were identified as major factors influencing complications of imported malaria cases in Henan Province. The lack of connection between uncommon imported malaria cases and superior medical resources was found to be the crucial challenge. A web-based system combined with WeChat to target imported malaria cases was proposed to cope with the challenge.

Adipose tissue-derived stem cell therapy for erectile dysfunction in rats: a systematic review and meta-analysis.

OBJECTIVE: We aimed to systematically assess the effect of adipose tissue-derived stem cell (ADSC) therapy and its influential factors on the treatment of erectile dysfunction (ED) in rats. METHODS: Two authors independently searched for published studies through PubMed and EMBASE from study inception until August 31, 2016. A meta-analysis was used to combine the effect estimate from the published studies. A subgroup analysis was performed to identify the effect of some influential factors. The pooled standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated by a fixed-effects or random-effects model analysis. RESULTS: Twenty studies with a total of 248 rats were included in this meta-analysis. The pooled analysis showed that ADSC therapy significantly increased the ratio of intracavernous pressure and mean arterial pressure (ICP/MAP; SMD 3.46, 95% CI 2.85-4.06; P < 0.001) compared to control therapy. The levels of neuronal nitric oxide synthase (nNOS; SMD 6.37, 95% CI 4.35-8.39; P < 0.001), the cavernous smooth muscle content (CSMC; SMD 3.65, 95% CI 2.65-4.65; P < 0.001), the ratio of cavernous smooth muscle and collagen (CSM/collagen; SMD 4.16, 95% CI 2.59-5.72; P < 0.001), and the cyclic guanosine monophosphate (cGMP; SMD 7.12, 95% CI 2.76-11.48; P = 0.001) were higher following ADSC therapy than following control therapy. Subgroup analysis showed that ADSCs modified by growth or neurotrophic factors significantly recovered erectile function (P < 0.001) compared with ADSC therapy. CONCLUSION: The adequate data indicated that ADSC therapy recovered erectile function and regenerated cavernous structures in ED rats, and ADSCs modified by some growth and neurotrophic factors accelerated the recovery of erectile function and cavernous structures in ED rats.