Identification of novel compounds against Tat-mediated human immunodeficiency virus-1 transcription by high-throughput functional screening assay.

Trans-activator (Tat)-mediated human immunodeficiency virus type 1 (HIV-1) transcription is essential for the replication of HIV-1 and is considered a potent therapeutic target for HIV-1 inhibition. In this study, the Library of Pharmacologically Active Compounds (LOPAC1280) was screened using our dual-reporter screening system for repositioning as Tat-inhibitory compounds. Consequently, two compounds were found to be potent, with low cytotoxicity. Of these two compounds, Roscovitine (CYC202) is already known to be a Tat inhibitor, while gemcitabine has been newly identified as an inhibitor of Tat-mediated transcription linked to viral production and replication. In an additional screening using the ribonucleoside analogues of gemcitabine, two analogues (2'-C-methylcytidine and 3-deazauridine) showed a specific Tat-inhibitory effect linked to their anti-HIV-1 activity. Interestingly, these compounds did not affect Tat protein directly, while the mechanism underlying their inhibition of Tat-mediated transcription was linked to pyrimidine biosynthesis, rather than to alteration of the dNTP pool, influenced by the inhibition of ribonucleotide reductase. Taken together, the proposed functional screening system is a useful tool for the identification of inhibitors of Tat-mediated HIV-1 transcription from among a large number of compounds, and the inhibitory effect of HIV-1 transcription by gemcitabine and its analogues may suggest a strategy for developing a new class of therapeutic anti-HIV drugs.

Favorable Outcomes of Open Surgical Repair for Blunt Aortic Injury in the Era of Endovascular Repair.

Background Long-term outcomes of open surgical repair with distal aortic perfusion for blunt aortic injury (BAI) remain undefined in this era of preferential thoracic endovascular aortic repair (TEVAR). Methods We retrospectively reviewed data from 31 consecutive patients (23 males; mean age, 46 ± 16 years) who underwent open surgical repair with distal aortic perfusion for acute BAI between 1998 and 2012 at our center and were followed up for 83 ± 47 months. Results In the 31 patients studied, BAI was most commonly secondary to traffic accidents (87%), with median accident-to-surgery time of 1 day. It was most commonly (90%) located at the isthmus. All patients had other injuries (injury severity score, 25 ± 6), 68% of which required surgery. The aorta was approached by left (84%) or bilateral (3%) thoracotomy, or median sternotomy (13%). During aortic cross-clamping (73 ± 47 minutes), distal aortic perfusion was maintained in all patients by left heart or cardiopulmonary bypass (extracorporeal circulation time, 93 ± 63 minutes). Circulatory arrest was required in 19% of patients. There was no in-hospital mortality or paraplegia. The estimated 5- and 10-year survival rates were 92 ± 6% and 80 ± 12%, respectively. One patient underwent reoperation for aortoesophageal fistula at 75 months postoperatively. Conclusion Open repair with distal aortic perfusion for BAI yielded favorable early and late outcomes, and is thus a viable option even in the era of TEVAR.

Aortic wrapping for a dilated ascending aorta in bicuspid aortic stenosis.

BACKGROUND: Ascending aorta wrapping is rarely recommended for the management of dilated aorta, because of late complications. The aim of the present study was to analyze the early and late outcomes of the aortic wrapping technique at the time of aortic valve replacement (AVR) for bicuspid aortic stenosis (BAS). METHODS AND RESULTS: Among patients who underwent primary AVR for BAS between 2002 and 2011, 79 who underwent ascending aortic wrapping (wrapping group) were compared with 144 patients who underwent AVR alone. The preoperative ascending aortic diameters were larger in the wrapping group (40.9±4.2 mm vs. 48.6±4.0 mm, P<0.001). Operative technique was to wrap the ascending aorta transversely with a semi-elliptically resected Dacron graft. The follow-up for the wrapping group was 76.5±35.5 (median 71.1) months. There were no early deaths. Early and late morbidity did not differ between groups. The 24 late deaths, including 10 cardiac-related deaths, occurred in the entire group; 3 sudden deaths occurred only in the AVR group. The 10-year overall survival in the wrapping group was higher than the AVR group (88.1±6.8% vs. 80.0±4.6%, P=0.048). No late aortic complications were detected. The aortic diameter was reduced from 49.5±4.1 mm to 45.3±5.0 mm after wrapping (P<0.001). CONCLUSIONS: The aortic wrapping technique may be an option for treating a moderately dilated ascending aorta in selected patients undergoing AVR for BAS. Longer follow-up, however, is necessary to verify later complications.

Extracorporeal membrane oxygenation saved a mother and her son from fulminant peripartum cardiomyopathy.

A 34-year-old full-term pregnant woman presented with abruptly aggravating dyspnea. A chest X-ray showed pulmonary edema, and an echocardiogram revealed a left ventricular ejection fraction of 39%. Despite conventional medical treatment for acute heart failure and mechanical ventilation, hypoxia and metabolic acidosis were aggravated, and the fetal heart rate decreased to 90 b.p.m., suggestive of fetal distress. We decided to initiate extracorporeal membrane oxygenation (ECMO) and perform a cesarean section. The infant was successfully delivered without hypoxic brain damage. The patient was weaned from ECMO 6 days after delivery and was extubated 1 day after discontinuation of ECMO. Left ventricular systolic function had completely recovered at this time. This is the first report of a patient with peripartum cardiomyopathy who had a successful delivery with the support of ECMO, demonstrating that ECMO can serve as a rescue therapy, not only treating peripartum cardiomyopathy but also permitting a safe delivery.

Migratory Azygos Lobe: A Case Report.

The azygos vein sometimes merges abnormally across the right upper lobe of the lung and it hangs at the lower edge of a membranous septum, called the meso-azygos. The septum invaginates the lobe and makes a fissure. The smaller medial part of the right upper lobe is called an azygos lobe. A 16-year-old male patient was diagnosed with right-sided pneumothorax, and a closed thoracostomy was done in the emergency room. During elective wedge resection including the bulla, the meso-azygos, abnormal azygos vein, and azygos lobe were detected. We reviewed the computed tomography images and found that the azygos lobe had re-expanded laterally, not medially, to the meso-azygos after the closed thoracostomy in the emergency room. The patient had been diagnosed with left-sided pneumothorax a year ago, and no one noticed the azygos lobe at that time. We report the intraoperative findings and comparative images of a migratory azygos lobe.

The Minimum Number of Ablation Lines for Complete Isolation of the Pulmonary Veins during Thoracoscopic Ablation for Atrial Fibrillation.

Total thoracoscopic ablation has been recommended as a class IIa indication for atrial fibrillation. However, the optimal number of ablation lines for pulmonary vein isolation has not yet been proposed. This study aimed to report the minimum number of ablation lines required to achieve an intraoperative conduction block. This study included a total of 20 patients who underwent total thoracoscopic ablation from December 2020 to July 2021. The epicardial conduction block was checked after each ablation line of pulmonary vein antral clamping. The median age was 61 years old. The median duration of atrial fibrillation since the first diagnosis was 78 months. Pulmonary vein isolation with bidirectional conduction block was confirmed in 90% of patients. A median of six ablation lines around each pulmonary vein antrum were performed according to our protocol even after the conduction block was verified. The median number of ablations to achieve an exit block was two on the right side and 3.5 on the left side. We found that most conduction blocks were achieved within three ablations around the pulmonary vein antrum. Our results may provide evidence to reduce the number of unnecessary ablation lines in the future.

Bilateral Atypical Femoral Fractures after Bisphosphonate Treatment for Osteoporosis: A Literature Review.

INTRODUCTION: This literature review aimed to investigate the incidence, anatomical concerns, etiology, symptoms, diagnostic tools, management, and prognosis of bisphosphonate (BP)-associated bilateral atypical femoral fractures (AFFs). METHODS: The PubMed, Cochrane Library, Web of Sciences, and CINAHL databases were searched up to 20 March 2022. All cases of bilateral AFFs were included, excluding those without any bisphosphonate treatment information and those in which the femoral fracture did not precisely fit into the diagnostic criteria for AFF. RESULTS: We identified 43 patients with bilateral AFFs associated with BP use and conducted a comprehensive analysis. Among 43 patients, 29 (67%) had prodromal symptoms. Regarding the simultaneity of fracture, 21 cases (49%) occurred simultaneously, and 22 cases (51%) occurred sequentially. Alendronate was the most commonly used BP treatment (59%). Regardless of the medication type, BP intake duration was more than 5 years in 77%. The initial diagnosis was performed using X-rays in all cases. A total of 53% of patients had complete fractures, and all patients underwent surgical treatment. Among the remaining patients with incomplete fractures, 18% and 29% received surgical and medical treatments, respectively. After BP discontinuation, teriparatide was most commonly used (63%). CONCLUSIONS: The careful evaluation of relevant imaging findings in patients with thigh/groin pain allows the identification of early incomplete fractures and timely management. Since the rate of contralateral side fractures is also high, imaging studies should be performed on the asymptomatic contralateral side.

Incidence and risk factors for sternal osteomyelitis after median sternotomy.

Background: Sternal osteomyelitis (OM) after median sternotomy is the rarest form of deep sternal wound infections (DSWIs). A retrospective study was implemented to evaluate the incidence and potential risk factors of sternal OM after median sternotomy. Methods: We analyzed 3,410 consecutive patients who underwent cardiothoracic surgery via median sternotomy from January 2005 to December 2019 at our institution. A sternal OM and control group without any sign of wound infections after median sternotomy were selected. Comparisons of the variables between the two groups were performed using the Student's t-test and Fisher's exact tests. The association of potential risk factors with sternal OM was tested by logistic regression analysis. Results: A total of 16 patients (0.47%) had sternal OM after median sternotomy. None of the variables were different between the sternal OM patients and the control group including body mass index (BMI), diabetes mellitus (DM), hypertension (HTN), left ventricle (LV) function, transfusion, operation time, cardiopulmonary bypass (CPB) time and intensive care unit and ventilator days. By univariate analysis, none of the variables were associated with an increased risk of sternal OM. Conclusions: The incidence of sternal OM after median sternotomy in our institution was 0.47% and there was no correlation between the known risk factors of DSWI and sternal OM in our study.

The first successful transapical aortic valve implant in Korea.

Transcatheter aortic valve implantation is an alternative to open heart surgery in high risk patients with severe aortic stenosis. High mortality and complications related to cardiopulmonary bypass for conventional open heart surgery can be avoided with this new less invasive technique. In case of concomitant severe arterial disease, the transapical approach is recommended rather than transfemoral access. An 80-yr-old man with symptomatic aortic stenosis and who had very high surgical risk factors such as diabetes mellitus, hypertension, a history of stroke, bronchial asthma including poor pulmonary function and hepatocellular carcinoma was treated with a transapical aortic valve replacement. The expected mortality in this patient was 25.4% by Euroscore if we performed the conventional aortic valve surgery. The patient was discharged and was well at the 45 follow-up days. We report the first case of successful transcatheter transapical aortic valve implantation which is available recently in Korea.

Re-dispersion of Pd-based bimetallic catalysts by hydrothermal treatment for CO oxidation.

The Pd/CeO2 catalyst, which is highly active catalyst in automobile emission control especially for CO oxidation, often suffers from severe sintering under harsh condition, specifically hydrothermal treatment. Here, we report re-dispersion of Pd-based bimetallic (Pd-Fe, Pd-Ni, and Pd-Co) catalysts deposited on ceria by hydrothermal treatment at 750 °C using 10% H2O. The re-dispersion was confirmed by various characterization techniques of transmission electron microscopy, CO chemisorption, CO-diffuse reflectance infrared Fourier transform, CO-temperature programmed desorption, and X-ray absorption spectroscopy. The dispersion of Pd increased significantly after hydrothermal treatment, resulting in improved CO oxidation activity. The presence of secondary transition metals enhanced the CO oxidation activity further, especially hydrothermally treated Pd-Fe bimetallic catalyst showed the highest activity for CO oxidation.

Identification of Aristolactam Derivatives That Act as Inhibitors of Human Immunodeficiency Virus Type 1 Infection and Replication by Targeting Tat-Mediated Viral Transcription.

Despite the success of antiretroviral therapy (ART), efforts to develop new classes of antiviral agents have been hampered by the emergence of drug resistance. Dibenzo-indole-bearing aristolactams are compounds that have been isolated from various plants species and which show several clinically relevant effects, including anti-inflammatory, antiplatelet, and anti-mycobacterial actions. However, the effect of these compounds on human immunodeficiency virus type 1 (HIV-1) infection has not yet been studied. In this study, we discovered an aristolactam derivative bearing dibenzo[cd,f]indol-4(5H)-one that had a potent anti-HIV-1 effect. A structure-activity relationship (SAR) study using nine synthetic derivatives of aristolactam identified the differing effects of residue substitutions on the inhibition of HIV-1 infection and cell viability. Among the compounds tested, 1,2,8,9-tetramethoxy-5-(2-(piperidin-1-yl)ethyl)-dibenzo[cd,f]indol-4(5H)-one (Compound 2) exhibited the most potent activity by inhibiting HIV-1 infection with a half-maximal inhibitory concentration (IC50) of 1.03 µmol/L and a half-maximal cytotoxic concentration (CC50) of 16.91 µmol/L (selectivity index, 16.45). The inhibitory effect of the compounds on HIV-1 infection was linked to inhibition of the viral replication cycle. Mode-of-action studies showed that the aristolactam derivatives did not affect reverse transcription or integration; instead, they specifically inhibited Tat-mediated viral transcription. Taken together, these findings show that several aristolactam derivatives impaired HIV-1 infection by inhibiting the activity of Tat-mediated viral transcription, and suggest that these derivatives could be antiviral drug candidates.

Mechanical Circulatory Support for Acute Heart Failure Complicated by Cardiogenic Shock.

Acute heart failure is a potentially life-threatening condition that can lead to cardiogenic shock, which is associated with hypotension and organ failure. Although there have been many studies on the treatment for cardiogenic shock, early mortality remains high at 40-50%. No new medicines for cardiogenic shock have been developed. Recently, there has been a gradual decline in the use of the intra-aortic balloon pump mainly due to a lack of adequate hemodynamic support. Extracorporeal membrane oxygenation and the percutaneous ventricular assist device have become more widely used in recent years. A thorough understanding of the mechanisms of such mechanical support devices and their hemodynamic effects, components of the devices, implantation technique, management, criteria for indications or contraindications of use, and clinical outcomes as well as multidisciplinary decision making may improve the outcomes in patients experiencing cardiogenic shock.

Arterial or venous free flaps for volar tissue defects of the proximal interphalangeal joint: A comparison of surgical outcomes.

BACKGROUND: For volar soft tissue defects of the proximal interphalangeal (PIP) joint, free flaps are technically challenging, but have more esthetic and functional advantages than local or distant flaps. In this study, we compared the long-term surgical outcomes of arterial (hypothenar, thenar, or second toe plantar) and venous free flaps for volar defects of the PIP joint. METHODS: This was a single-center retrospective review of free flap coverage of volar defects between the distal interphalangeal and metacarpophalangeal joint from July 2010 to August 2019. Patients with severe crush injuries (degloving, tendon or bone defects, or comminuted/intra-articular fractures), thumb injuries, multiple-joint and finger injuries, dorsal soft tissue defects, and defects >6 cm in length were excluded from the study, as were those lost to follow-up within 6 months. Thirteen patients received arterial (hypothenar, thenar, or second toe plantar) free flaps and 12 received venous free flaps. Patients' age, follow-up period, PIP joint active range of motion (ROM), extension lag, grip-strength ratio of the injured to the uninjured hand, and Quick Disabilities of Arm, Shoulder & Hand (QuickDASH) score were compared between the groups. RESULTS: Arterial free flaps showed significantly higher PIP joint active ROM (P=0.043) and lower extension lag (P=0.035) than venous free flaps. The differences in flexion, grip strength, and QuickDASH scores were not statistically significant. CONCLUSIONS: The surgical outcomes of arterial free flaps were superior to those of venous free flaps for volar defects of the PIP joint.

Partial second toe pulp free flaps in early childhood.

BACKGROUND: The introduction of the partial second toe pulp free flap has enabled superior aesthetic and functional results for fingertip reconstruction in adults. Children undergoing fingertip amputation for various reasons have limited options for reconstruction. Conventional treatment could shorten the finger, leading to poor cosmesis and function. We report 18 years of our experiences with fingertip reconstruction using partial second toe pulp free flaps in patients in early childhood. METHODS: Medical charts of children who had undergone fingertip reconstruction using partial second toe pulp free flaps from 2001 to 2018 were retrospectively reviewed. The surgical procedures were identical to those for adults, except for the usage of 11-0 nylon sutures. Patients' demographic data, vessel size, flap dimensions, length of the distal phalanx, and functional outcomes over the course of long-term follow-up were documented. The statistical analysis was performed with the Student t-test, the Mann-Whitney U test, and Pearson correlation analysis. RESULTS: Eighteen toe pulp flaps in 17 patients (mean age, 3.0 years) were identified. All the flaps survived without any major complications. In long-term follow-up, the flap-covered distal phalanges showed growth in line with regular development. There was no donor-site morbidity, and all children adapted to daily life without any problems. In two-point discrimination tests, the fingertip sensation recovered to almost the same level as that in the contralateral finger. CONCLUSIONS: Partial second toe pulp free flaps are an excellent option for fingertip reconstruction in young children, as well as in adults.

Usefulness of Postprocedural Electrophysiological Confirmation Upon Totally Thoracoscopic Ablation in Persistent Atrial Fibrillation.

Little information is available concerning the usefulness of electrophysiological confirmation followed by totally thoracoscopic ablation. This study aimed to examine whether postprocedural electrophysiological confirmation is always necessary after totally thoracoscopic ablation (TTA) in patients with isolated persistent atrial fibrillation. Forty-five patients with isolated persistent atrial fibrillation were randomized into 2 groups those who received routine electrophysiological confirmation and additional catheter ablation after totally thoracoscopic ablation (the hybrid group [n = 22]) and those who did not (the TTA group [n = 23]). Electrophysiological study was performed 4 or 5 days after surgery. No early or late mortality occurred. In the hybrid group, 5 patients (23%, 5/22) required additional ablation due to residual potential in the left atrium. At a year postoperatively, normal sinus rhythm was observed in 89% of patients (40/45) and similar in both groups (Odds ratio 0.80, 95% confidence interval 0.32 to 1.99). During follow-up, sinus rhythm was maintained in 16 patients (70%) in the TTA group without additional catheter ablation, which was similar (p = 0.920) to the results in the hybrid group (n = 15, 68.2%). Event-free survival rate at 12 months did not differ between groups (TTA group vs hybrid group, 78% vs 77%; p = 0.633). In simple Cox regression analysis, preoperative left atrium volume index was associated with atrial arrhythmia (p = 0.030, hazards ratio 1.087, 95% confidence interval 1.01-1.18). In conclusion, thoracoscopic ablation provided good 1-year durability in patients with isolated persistent AF irrespective of postprocedural electrophysiological confirmation. Seventy-percent of the TTA group did not need additional catheter ablation.

Clinical Pearls of Venoarterial Extracorporeal Membrane Oxygenation for Cardiogenic Shock.

Extracorporeal membrane oxygenation (ECMO) is a technique that uses a pump to drain blood from a body, circulate blood through a membrane lung, and return the oxygenated blood back into the body. Venoarterial (VA) ECMO is a simplified version of the heart-lung machine that assists native pulmonary and/or cardiac function. VA ECMO is composed of a drainage cannula in the venous system and a return cannula in the arterial system. Because VA ECMO can increase tissue perfusion by increasing the arterial blood flow, it is used to treat medically refractory cardiogenic shock or cardiac arrest. VA ECMO has a distinct physiology that is referred to as differential flows. It can cause several complications such as left ventricular distension with pulmonary edema, distal limb ischemia, bleeding, and thromboembolism. Physicians who are using this technology should be knowledgeable on the prevention and management of these complications. We review the basic physiology of VA ECMO, the mechanism of complications, and the simple management of VA ECMO.

Long-term results of radical pericardiectomy for constrictive pericarditis in Korean population.

BACKGROUND: The extent of pericardiectomy is an important issue in constrictive pericarditis but its impact on long-term outcomes has been rarely reported. We compared long-term results of radical pericardiectomy with conventional phrenic to phrenic pericardiectomy. METHODS: Ninety patients who underwent pericardiectomies between February 1995 and April 2015 were reviewed retrospectively. They were classified into conventional (n = 37) and radical (n = 53) groups according to pericardiectomy being performed anterior or posterior to the phrenic nerves, respectively. The follow-up duration at outpatient clinic was 37.6 (11.7, 86.6) months and the survival data until 91.6 (54.5, 147.0) months were obtained. The last echocardiographies were done at 22.4 (4.35, 60.85) months. RESULTS: The early mortality rate was 4.4% (4/90). They all belonged to the conventional group and died of low cardiac output syndrome. The survival rate was higher in the radical group (P = .032, 74.7 ± 9.2% versus 50.4 ± 11.9% in 20 years). NYHA class of both groups had recovered until the last follow-up but the radical group showed better recovery (P < .001). The conventional pericardiectomy (HR = 6.181; 95% CI (1.042, 36.656)), redosternotomy (HR = 6.441; 95% CI (1.224, 33.889) and preoperative grade of tricuspid regurgitation (HR = 15.003; 95% CI (1.099, 204.894) were associated with late mortality. Right ventricular systolic pressure decreased, and pericardial thickening resolved only in the radical group with significant intergroup differences as time went on. Tricuspid regurgitation worsened after the operation in both groups, but it deteriorated more in the conventional group. However, it improved over time in the radical group. CONCLUSIONS: Radical pericardiectomy led to greater improvement in right ventricular systolic pressure and lesser deterioration of tricuspid regurgitation with the passage of time than did the conventional procedure. Conventional pericardiectomy and preoperative higher grade tricuspid regurgitation were associated with long-term mortality.

Ganglioside GQ1b ameliorates cognitive impairments in an Alzheimer's disease mouse model, and causes reduction of amyloid precursor protein.

Brain-derived neurotrophic factor (BDNF) plays crucial roles in memory impairments including Alzheimer's disease (AD). Previous studies have reported that tetrasialoganglioside GQ1b is involved in long-term potentiation and cognitive functions as well as BDNF expression. However, in vitro and in vivo functions of GQ1b against AD has not investigated yet. Consequently, treatment of oligomeric Aß followed by GQ1b significantly restores Aß1-42-induced cell death through BDNF up-regulation in primary cortical neurons. Bilateral infusion of GQ1b into the hippocampus ameliorates cognitive deficits in the triple-transgenic AD mouse model (3xTg-AD). GQ1b-infused 3xTg-AD mice had substantially increased BDNF levels compared with artificial cerebrospinal fluid (aCSF)-treated 3xTg-AD mice. Interestingly, we also found that GQ1b administration into hippocampus of 3xTg-AD mice reduces Aß plaque deposition and tau phosphorylation, which correlate with APP protein reduction and phospho-GSK3ß level increase, respectively. These findings demonstrate that the tetrasialoganglioside GQ1b may contribute to a potential strategy of AD treatment.

Aorto-Uni-Iliac Stent Grafting and Femoro-Femoral Bypass in a Patient with a Failed and Catastrophic Endovascular Aortic Aneurysm Repair.

A 78-year-old man presented at Eulji University Hospital due to an abdominal aortic aneurysm with maximum diameter of 52 mm, which had been increased from 45 mm over 6 months. He underwent embolization of the left internal iliac artery with vascular plug, prior to endovascular abdominal aortic repair with a bifurcated stent graft system. Unfortunately, the inserted vascular plug was maldeployed and protruded into left external iliac artery, and caused acute limb ischemia. Because revascularization of the occluded segment was failed, emergent hybrid approach with aorto-uni-iliac stent grafting and femoro-femoral bypass was done, successfully.