HIV Protease: Historical Perspective and Current Research

The retroviral protease of human immunodeficiency virus (HIV) is an excellent target for antiviral inhibitors for treating HIV/AIDS. Despite the efficacy of therapy, current efforts to control the disease are undermined by the growing threat posed by drug resistance. This review covers the historical background of studies on the structure and function of HIV protease, the subsequent development of antiviral inhibitors, and recent studies on drug-resistant protease variants. We highlight the important contributions of Dr. Stephen Oroszlan to fundamental knowledge about the function of the HIV protease and other retroviral proteases. These studies, along with those of his colleagues, laid the foundations for the design of clinical inhibitors of HIV protease. The drug-resistant protease variants also provide an excellent model for investigating the molecular mechanisms and evolution of resistance.     

Measuring the appropriateness of carbamazepine and valproic acid prescribing and utilization using a newly implemented online system in the Tabuk Region of Saudi Arabia

Epilepsy is a common neurologic disorder, which is efficiently treated with carbamazepine and valproic acid. Moreover, Saudi Ministry of Health implemented a new E-system for Poison Control Centers called Awtar to enhance technology utilization in ensuring patients’ satisfaction and to improve treatment outcomes. Therefore, we conducted this study to assess appropriateness of indication of requests and therapeutic levels of carbamazepine and valproic acid in Tabuk area, North West Saudi Arabia. This is a retrospective observational study conducted in Poison Control & Forensic Chemistry Center, Tabuk, Saudi Arabia. Patients’ data were obtained for years 2018 and 2019. The blood levels of carbamazepine and valproic acid were measured by Therapeutic Drug Monitoring (TDM) Unit. We selected patients treated with either valproic acid or carbamazepine alone without any history of drug allergy. Data of 264 patients were extracted from Awtar E-system. Serum carbamazepine levels were within therapeutic range in 114 patients (75.50%), above-therapeutic range in 13 patients (8.61%) and sub-therapeutic levels in 24 patients (15.89%). Regarding serum valproic acid, it is within therapeutic range in 62 patients (54.87%), above-therapeutic range in 11 patients (9.73%) and sub-therapeutic levels in 40 patients (35.40%). In conclusion, this study gives information about partial appropriateness of usage of carbamazepine and low level of appropriateness of valproic acid. However, more efforts are needed to improve results of appropriateness of indication of antiepileptic drugs.     

直丝弓矫治器和Begg矫治器治疗安氏Ⅱ类1分类错[牙合]畸形疗效比较

目的:对比不同矫治器对错[牙合]畸形患者面高度及前后牙咬合关系的影响。方法:选取于笔者医院接受矫治的83例错[牙合]畸形患者,根据患者矫治器类型分为直丝弓组和Begg组,分别为42例和41例。比较并分析两组患者治疗前后牙咬合关系、硬组织、磨牙及面高度的变化情况。结果:矫治后,两组患者OJ-PPV、OB-PP、LMA-MPV、LMA-MPV均降低,Begg矫治组OJ-PPV水平显著高于直丝弓矫治组,OB-PP、LMA-MPV、LMA-MPV水平显著低于直丝弓矫治组,差异均具有统计学意义(P<0.05);两组患者LAFH、LAFH/TAFH、PFH/TAFH水平均升高,其中Begg矫治组患者LAFH水平显著低于直丝弓矫治组,差异均具有统计学意义(P<0.05);两组患者LMA-MP、LMC-MP水平均升高,差异具有统计学意义(P<0.05);矫治前后,两组患者SNA、SNA、ANB水平均无统计学差异(P>0.05)。结论:两种矫治器对错[牙合]畸形患者硬组织变化均无明显影响,其中Begg矫治对患者前后牙咬合关系改善作用更强,直丝弓对患者面高度的改善能力更强。     

Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery: Diagnoses and Surgical Results in 12 Pediatric Patients

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital condition. It responds well to early diagnosis and treatment, but otherwise the prognosis is poor. We present our case series of 12 patients (mean age, 2 ± 2.58 yr; age range, 2 mo–8 yr), emphasizing the diagnostic process and discussing our surgical results. The diagnosis of ALCAPA should be suspected in infants who have dilated cardiomyopathy with electrocardiographic changes that suggest ischemia, and in older children who have isolated mitral regurgitation. When clinical suspicion is high, the results of 2-dimensional echocardiography combined with color-flow Doppler studies in expert hands can establish the diagnosis, thus avoiding angiography in critically ill infants. The treatment of choice in our patients was transfer and reimplantation of the left coronary artery onto the ascending aorta. There were 2 deaths: both were infants in extremis who underwent emergency surgery. An older child with severe ventricular dysfunction was given mechanical ventricular assistance and then heart transplantation. As of this report, all 10 survivors remained well and asymptomatic.     

Reduced nontarget embolization and increased targeted delivery with a reflux-control microcatheter in a swine model

PurposeTo evaluate the potential differences in non-target embolization and vessel microsphere filling of a reflux-control microcatheter (RCM) compared to a standard end-hole microcatheter (SEHM) in a swine model.Materials and methodsRadiopaque microspheres were injected with both RCM and SEHM (2.4-Fr and 2.7-Fr) in the kidneys of a preclinical swine model. Transarterial renal embolization procedures with RCM or SEHM were performed in both kidneys of 14 pigs. Renal arteries were selectively embolized with an automated injection protocol of radio-opaque microspheres. Ex-vivo X-ray microtomography images of the kidneys were utilized to evaluate the embolization by quantification of the deposition of injected microspheres in the target vs. the non-target area of injection. X-ray microtomography images were blindly analyzed by five interventional radiologists. The degree of vessel filling and the non-target embolization were quantified using a scale from 1 to 5 for each parameter. An analysis of variance was used to compare the paired scores.ResultsTotal volumes of radio-opaque microspheres injected were similar for RCM (11.5 ± 3.6 [SD] mL; range: 6–17 mL) and SEHM (10.6 ± 5.2 [SD] mL; range: 4–19 mL) (P = 0.38). The voxels enhanced ratio in the target (T) vs. non-target (NT) areas was greater with RCM (T = 98.3% vs. NT = 1.7%) than with SEHM (T = 89% vs. NT = 11%) but the difference was not significant (P = 0.30). The total score blindly given by the five interventional radiologists was significantly different between RCM (12.3 ± 2.1 [SD]; range: 6–15) and the standard catheter (11.3 ± 2.5 [SD]; range: 4–15) (P = 0.0073), with a significant decrease of non-target embolization for RCM (3.8 ± 1.3 [SD]; range: 3.5–4.2) compared to SEHM (3.2 ± 1.5 [SD]; range: 2.9–3.5) (P = 0.014).ConclusionIn an animal model, RCM microcatheters reduce the risk of non-target embolization from 11% to 1.7%, increasing the delivery of microspheres of 98% to the target vessels, compared to SEHM microcatheters.     

盆筋膜解剖及其与直肠固有筋膜关系研究

目的 探讨盆筋膜的结构、范围及其与直肠固有筋膜的层次关系。方法 2020年12月至2021年3月对由广东药科大学生命与生物制药学院人体解剖与胚胎学系及中山大学中山医学院人体解剖学教研室提供的12具（男性5具、女性7具）骨盆标本进行大体观察，并对Denonvilliers筋膜进行组织学观察。结合2019年12月至2021年3月中山大学附属第三医院胃肠外科收治的20例直肠癌病人（男性10例、女性10例）的盆腔磁共振图像和手术视频进行解剖学印证。结果 12具骨盆大体标本显示，盆筋膜与Gerota筋膜相延续，部分纤维于S4水平构成直肠骶骨筋膜，向下与直肠固有筋膜融合终止于联合纵肌；部分纤维与后方骶前筋膜融合构成肛提肌上筋膜及肌间纤维。Denonvilliers筋膜在盆腔前外侧约2点、10点处与盆筋膜相延续构成完整筒状结构，包绕内层由直肠固有筋膜封套的直肠系膜；除“侧韧带”处有盆腔自主神经直肠支、淋巴管、直肠中动脉相连外，两层筋膜形成完整的双筒状结构，横断面呈同心圆状。除直肠支进入直肠固有筋膜外，盆腔自主神经主要分支均位于盆筋膜内层及Denonvilliers筋膜以外，沿直肠固有筋膜轮廓游离能够避免损伤盆腔自主神经。在7具女性骨盆标本中均能见到菲薄的Denonvilliers筋膜结构。直肠癌病人的横断面磁共振图像能够看到直肠固有筋膜与外侧盆筋膜、Denonvilliers筋膜的轮廓和间隙，手术视频资料也可见到完整盆壁筋膜和Denonvilliers筋膜的轮廓。结论 直肠癌手术中，在盆筋膜、Denonvilliers筋膜与直肠固有筋膜两层结构的间隙进行分离，并保持两层筋膜的完整性，对于保证肿瘤根治性和保护排尿及性功能至关重要。     

Sudden Cardiac Death in Patients With Type 1 Versus Type 2 Diabetes

ObjectiveTo investigate the association between type 1 diabetes mellitus (T1D) and type 2 diabetes mellitus (T2D) with risk of sudden cardiac arrest (SCA).MethodsIn a prospective community-based study of SCA from February 1, 2002, through November 30, 2019, we ascertained 2771 cases age 18 years of age or older and matched them to 8313 controls based on geography, age, sex, and race/ethnicity. We used logistic regression to evaluate the independent association between diabetes, T1D, T2D, and SCA.ResultsPatients had a mean age of 64.5±15.9 years, were 33.3% female and 23.9% non-White race. Overall, 36.7% (n=1016) of cases and 23.8% (n=1981) of controls had diabetes. Among individuals with diabetes, the proportion of T1D was 6.5% (n=66) among cases and 2.0% among controls (n=40). Diabetes was associated with 1.5-times higher odds of SCA. Compared with those without diabetes, the odds ratio and 95% CI for SCA was 4.36 (95% CI, 2.81 to 6.75; P<.001) in T1D and 1.45 (95% CI, 1.30 to 1.63; P<.001) in T2D after multivariable adjustment. Among those with diabetes, the odds of having SCA were 2.41 times higher in T1D than in T2D (95% CI, 1.53 to 3.80; P<.001). Cases of SCA with T1D were more likely to have an unwitnessed arrest, less likely to receive resuscitation, and less likely to survive compared with those with T2D.ConclusionType 1 diabetes was more strongly associated with SCA compared with T2D and had less favorable outcomes following resuscitation. Diabetes type could influence the approach to risk stratification and prevention of SCA.     

肝细胞癌中miR-942-5p的表达及其与患者恶性特征及不良预后的关系

目的:探讨微小RNA-942-5p(miR-942-5p)在肝细胞癌(HCC)组织中的表达及其功能。方法:用实时定量PCR检测西安交通大学第一附属医院样本库保存的73例HCC组织和对应癌旁组织中miR-942-5p的表达。分析miR-942-5p表达与HCC患者临床病理资料的关系,同时分析TCGA数据库中miR-942-5p表达与HCC患者总生存率的关系。Transwell小室检测干扰miR-942-5p表达后HCC细胞迁移和侵袭能力的变化,StarBase V3.0网站和荧光素酶报告基因质粒预测分析miR-942-5p的下游靶点,并用Western blot验证。结果:miR-942-5p表达量在HCC组织中明显高于对应癌旁组织(2.390 vs. 1.764,P0.05)。miR-942-5p表达量与HCC患者肿瘤数目、血管浸润和临床分期明显有关(均P0.05)。miR-942-5p高表达HCC患者总生存率明显低于miR-942-5p低表达HCC患者(19.535%vs. 53.873%,P0.05)。沉默miR-942-5p表达后,肝癌HCCLM3和MHCC97H细胞迁移和侵袭能力明显减弱(均P0.05)。预测与分析结果显示,扣针蛋白5(FBLN5)是miR-942-5p的直接下游靶点(P0.05),沉默miR-942-5p表达导致HCCLM3和MHCC97H细胞中FBLN5表达增加。结论:miR-942-5p在HCC组织中表达异常升高并与恶性临床特征和不良预后密切相关,机制可能与miR-942-5p抑制FBLN5表达促进HCC细胞迁移和侵袭有关。