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Methods in Enzymology 2024Terpenes constitute one of the largest family of natural products with potent applications as renewable platform chemicals and medicines. The low activity, selectivity...
Terpenes constitute one of the largest family of natural products with potent applications as renewable platform chemicals and medicines. The low activity, selectivity and stability displayed by terpene biosynthetic machineries can constitute an obstacle towards achieving expedient biosynthesis of terpenoids in processes that adhere to the 12 principles of green chemistry. Accordingly, engineering of terpene synthase enzymes is a prerequisite for industrial biotechnology applications, but obstructed by their complex catalysis that depend on reactive carbocationic intermediates that are prone to undergo bifurcation mechanisms. Rational redesign of terpene synthases can be tedious and requires high-resolution structural information, which is not always available. Furthermore, it has proven difficult to link sequence space of terpene synthase enzymes to specific product profiles. Herein, the author shows how ancestral sequence reconstruction (ASR) can favorably be used as a protein engineering tool in the redesign of terpene synthases without the need of a structure, and without excessive screening. A detailed workflow of ASR is presented along with associated limitations, with a focus on applying this methodology on terpene synthases. From selected examples of both class I and II enzymes, the author advocates that ancestral terpene cyclases constitute valuable assets to shed light on terpene-synthase catalysis and in enabling accelerated biosynthesis.
Topics: Alkyl and Aryl Transferases; Terpenes; Protein Engineering; Evolution, Molecular
PubMed: 38942509
DOI: 10.1016/bs.mie.2024.04.025 -
The European Respiratory Journal Jun 2024
Topics: Humans; Epoprostenol; Hypertension, Pulmonary; Pulmonary Disease, Chronic Obstructive; Administration, Inhalation; Antihypertensive Agents
PubMed: 38942439
DOI: 10.1183/13993003.E6306-2024 -
Urology Jun 2024To determine whether early vs. delayed autotransplantation are associated with adverse outcomes in patients undergoing renal autotransplantation.
OBJECTIVE
To determine whether early vs. delayed autotransplantation are associated with adverse outcomes in patients undergoing renal autotransplantation.
METHODS
Patients who underwent renal autotransplantation from June 2012 to September 2022 were divided into two groups based on timing of autotransplant in relation to initial intervention or diagnosis (early cohort: ≤1-year; delayed cohort: >1-year). Primary outcomes were perioperative complications, aborted surgery, renal function (glomerular filtration rate [GFR]), and postoperative complications at most recent follow-up.
RESULTS
Autotransplantation patients (N=72) were predominantly female (68%) and White (54%), with a median age of 49 years. 90% of patients had undergone previous interventions, including stenting (40%) and nephrostomy tubes (49%), primarily for obstruction (64%). Early vs. delayed cohorts had median preoperative disease durations of 143 (IQR 83-222) vs. 673 days (IQR 529-1,703, p<0.001), with similar median follow-up times (879 vs. 818 days, p=0.8). Groups were similar in demographics and comorbidities. There were no significant differences in rates of aborted surgery (15% vs. 4.2%, p=0.3), perioperative complications (15% vs. 17%, p>0.9), long-term complications (49% vs. 48%, p>0.9), or changes in GFR (median change +3 vs. +4, p=0.7). Outcomes were comparable across preoperative disease durations ranging from 6 to 24 months. These findings were confirmed following adjustments for sex, body mass index, American Society of Anesthesiologists classification, race, preoperative creatinine levels, laterality, gastroesophageal reflux disease, diabetes, hypertension, nephrolithiasis, hyperlipidemia, history of colon surgery, urologic surgery, abdominal surgery, and prior interventions in separate logistic models.
CONCLUSIONS
Disease duration before autotransplantation does not influence outcomes, offering reassurance for clinical decision-making in complex cases.
PubMed: 38942394
DOI: 10.1016/j.urology.2024.06.050 -
Annals of Vascular Surgery Jun 2024To examine the efficacy of antegrade and retrograde approaches with the AngioJet thrombectomy device for the treatment of acute lower limb deep vein thrombosis (DVT) and...
OBJECTIVE
To examine the efficacy of antegrade and retrograde approaches with the AngioJet thrombectomy device for the treatment of acute lower limb deep vein thrombosis (DVT) and to evaluate the necessity of filter placement.
METHODS
The clinical data of patients with acute lower limb DVT treated with the AngioJet device from January 2021 to June 2023 were retrospectively analyzed. The patients were divided into the antegrade and retrograde treatment groups according to the surgical approach and the direction of valve opening. The thrombosis interception rate of the filter, incidence of pulmonary embolism (PE), thrombectomy effectiveness, venous obstruction rate, and thrombosis recurrence rate of each treatment group were evaluated. In addition, factors affecting patency were analyzed.
RESULTS
AngioJet was employed for 84 patients with acute lower limb DVT, treating a total of 88 limbs. The thrombosis interception rate of the filter was 35.7% (30 patients). The incidence of new PE or PE exacerbation was 6.0% (5 patients), and a filter retrieval rate of 97.6% (82 patients) was detected. Thrombus removal of grade III occurred in 35 (64.8%) of the 54 limbs (61.4%) in the antegrade treatment group, versus 13 (38.2%) of the 34 limbs (38.6%) in the retrograde treatment group (P<0.05). At 3 months, venous patency and bleeding events involved 52 (96.3%) and 4 (7.4%) limbs in the antegrade treatment group, respectively, versus 29 (85.3%) and 2 (5.9%) in the retrograde treatment group, respectively (P>0.05). Regression analysis was performed to determine factors that may affect 3-month patency in both groups. Statistically significant linear relationships were found between 3-month patency and thrombus removal rate [OR=0.546 (0.326, 0.916)], thrombus formation time [OR=1.018 (1.002, 1.036)], and preoperative thrombosis score [OR=1.012 (1.002, 1.022)] in the antegrade treatment group, as well as thrombus removal rate [0.473 (0.229, 0.977)] in the retrograde treatment group. In regression analysis of factors affecting patency in both groups and VCSS/Villalta score, a statistically significant linear relationship was found between thrombus formation time and VCSS score in the antegrade treatment group [0.576 (0.467, 0.710)].
CONCLUSION
Both antegrade and retrograde approaches are safe and effective for the treatment of acute lower limb DVT. There are no differences in 3-month deep vein patency and post-thrombotic syndrome (PTS) incidence rates. Individuals with acute lower limb DVT are at high risk of thrombus shedding after treatment with AngioJet thrombectomy, and placement of a vena cava filter (VCF) is recommended for effective interception.
PubMed: 38942376
DOI: 10.1016/j.avsg.2024.04.014 -
Life Sciences Jun 2024Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals... (Review)
Review
Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality globally and the risk of developing lung cancer is six times greater in individuals with COPD who smoke compared to those who do not smoke. Matrix metalloproteinases (MMPs) play a crucial role in the pathophysiology of respiratory diseases by promoting inflammation and tissue degradation. Furthermore, MMPs are involved in key processes like epithelial-to-mesenchymal transition (EMT), metastasis, and invasion in lung cancer. While EMT has traditionally been associated with the progression of lung cancer, recent research highlights its active involvement in individuals with COPD. Current evidence underscores its role in orchestrating airway remodeling, fostering airway fibrosis, and contributing to the potential for malignant transformation in the complex pathophysiology of COPD. The precise regulatory roles of diverse MMPs in steering EMT during COPD progression needs to be elucidated. Additionally, the less-understood aspect involves how these MMPs bi-directionally activate or regulate various EMT-associated signaling cascades during COPD progression. This review article explores recent advancements in understanding MMPs' role in EMT during COPD progression and various pharmacological approaches to target MMPs. It also delves into the limitations of current MMP inhibitors and explores novel, advanced strategies for inhibiting MMPs, potentially offering new avenues for treating respiratory diseases.
PubMed: 38942362
DOI: 10.1016/j.lfs.2024.122874 -
Journal of Minimally Invasive Gynecology Jun 2024To estimate the risk of bowel obstruction after hysterectomy for benign indications depending on the surgical method (abdominal, vaginal, or laparoscopic) and identify...
STUDY OBJECTIVE
To estimate the risk of bowel obstruction after hysterectomy for benign indications depending on the surgical method (abdominal, vaginal, or laparoscopic) and identify risk factors for adhesive bowel obstruction.
DESIGN
A national registry-based cohort.
SETTING
Danish hospitals during the period 1984-2013.
PATIENTS
Danish women who underwent hysterectomy for benign indications (N=125,568).
INTERVENTIONS
Abdominal hysterectomies were compared with vaginal hysterectomies, laparoscopic hysterectomies, and minimally invasive (vaginal and laparoscopic) hysterectomies.
MEASUREMENTS AND MAIN RESULTS
The incidence of bowel obstruction according to the surgical method was compared using Cox proportional hazard regression. The covariates included were the time period, age, concomitant operations, prior abdominal surgery or disease, and socioeconomic factors. In a sub-analysis (n=35,712 women) of the period 2004-2013, detailed information from the Danish Hysterectomy Database enabled the inclusion of patient-related, surgery-related, and complication-related covariates. The overall crude incidence of bowel obstruction was 17.4/1000 hysterectomies (2196 incident cases). The 10-year cumulative incidence of bowel obstruction differed between the surgical routes (abdominal, 1.7%; laparoscopic, 1.4%; and vaginal, 0.9%). In multiple adjusted analyses, the risk of bowel obstruction was higher after abdominal hysterectomy than after vaginal (HR 1.64 [95% CI 1.39-1.93]) and minimally invasive (vaginal or laparoscopic) hysterectomy (HR 1.54 [1.33-1.79]). Additional pre-existing risk factors for bowel obstruction at the time of hysterectomy were increased age, low education, low income, smoking, high ASA comorbidity score, history of infertility, abdominal infection, and prior abdominal surgery (apart from cesarean section),penetrating lesions in abdominal organs, or operative adhesiolysis. Perioperative risk factors at the time of hysterectomy included concomitant removal of the ovaries, adhesiolysis, blood transfusion, readmission, and overall presence of perioperative complications.
CONCLUSION
Abdominal hysterectomy is associated with a 54% higher risk of bowel obstruction than minimally invasive (laparoscopic or vaginal) hysterectomy.
PubMed: 38942232
DOI: 10.1016/j.jmig.2024.06.010 -
The Lancet. Neurology Jun 2024Sleep disorders are common in people with Parkinson's disease. These disorders, which increase in frequency throughout the course of the neurodegenerative disease and... (Review)
Review
Sleep disorders are common in people with Parkinson's disease. These disorders, which increase in frequency throughout the course of the neurodegenerative disease and impair quality of life, include insomnia, excessive daytime sleepiness, circadian disorders, obstructive sleep apnoea, restless legs syndrome, and rapid eye movement (REM) sleep behaviour disorder. The causes of these sleep disorders are complex and multifactorial, including the degeneration of the neural structures that modulate sleep, the detrimental effect of some medications on sleep, the parkinsonian symptoms that interfere with mobility and comfort in bed, and comorbidities that disrupt sleep quality and quantity. The clinical evaluation of sleep disorders include both subjective (eg, questionnaires or diaries) and objective (eg, actigraphy or video polysomnography) assessments. The management of patients with Parkinson's disease and a sleep disorder is challenging and should be individualised. Treatment can include education aiming at changes in behaviour (ie, sleep hygiene), cognitive behavioural therapy, continuous dopaminergic stimulation at night, and specific medications. REM sleep behaviour disorder can occur several years before the onset of parkinsonism, suggesting that the implementation of trials of neuroprotective therapies should focus on people with this sleep disorder.
PubMed: 38942041
DOI: 10.1016/S1474-4422(24)00170-4 -
Sleep Medicine Jun 2024Over the past few years, there has been a surge in interest regarding the connection between sleep duration and quality, sleep disorders, mainly Obstructive sleep apnoea... (Review)
Review
Over the past few years, there has been a surge in interest regarding the connection between sleep duration and quality, sleep disorders, mainly Obstructive sleep apnoea (OSA) and Vitamin D. There is growing evidence to support a new role of Vitamin D in the maintenance and regulation of optimal sleep. Furthermore, a notable link has been identified between OSA and a decrease in serum Vitamin D levels, which appears to intensify as the severity of sleep apnea worsens. Vitamin D status could also potentially serve as a mediator or provide an explanation for the association between OSA and cardiometabolic morbidity, but the current state of research in this area is inadequate. Studies have indicated that the supplementation of Vitamin D can optimize sleep quality, presenting more proof of the connection between insufficient vitamin D levels and sleep disorders. However, it is unclear whether low serum Vitamin D levels are a contributing factor to OSA development or if OSA predisposes individuals to Vitamin D deficiency. As a result, various studies have endeavored to examine the complex relationship between OSA and Vitamin D deficiency. In children and adolescents, while data is limited, there seems also to be a link between sleep disorders and Vitamin D levels. Therefore, the objective of this review is to provide a comprehensive overview of the current evidence on the association between Vitamin D and sleep disorders in both adults and children.
PubMed: 38941960
DOI: 10.1016/j.sleep.2024.06.023 -
Heart & Lung : the Journal of Critical... Jun 2024Aeorobic exercise is an essential component of the pulmonary rehabilitation program for patients with chronic obstructive pulmonary disease (COPD). Single-limb exercises... (Review)
Review
BACKGROUND
Aeorobic exercise is an essential component of the pulmonary rehabilitation program for patients with chronic obstructive pulmonary disease (COPD). Single-limb exercises are a type of aeorobic exercise that aims to increase patient tolerance by reducing the workload of the respiratory system.
OBJEKTIVES
The aim of our systematic review was to determine the effects of single-limb exercises on pulmonary function, dyspnea, fatigue, and muscle dysfunction in patients with COPD.
METHODS
Searches were performed using PubMed, Pedro, Google Scholar, MEDLINE, EMBASE, Scopus, Cochrane Library, Web of Science databases. Publications from the beginning to 2023 searched. Studies were selected by two authors by scanning the title, Mesh terms abstract in Rayyan QCRI software. Selected studies were subjected to full-text screening by applying selection criteria. Randomized controlled, case-control, cohort studies were included.
RESULTS
In the first screening according to mesh terms, 1011 articles were identified. After the screening criteria and duplicate articles were evaluated, 10 articles were included. This systematic review includes seven case-control, one randomized control trial (RCT), one cross-sectional, and one non-randomized study. A total of 157 patients with COPD received treatment in these studies. According to the Bakker scale, single-limb exercises have been shown to improve pulmonary function with strong evidence. There is strong evidence that single-limb exercises have no effect on dyspnea and fatigue in COPD patients. There is limited evidence that single-limb exercises have an effect on functional exercise capacity.
CONCLUSION
Single-limb exercise can advised in terms of improving pulmonary function in patients with COPD. Current systematic review has found single limb exercise has no effect on dyspnea and fatigue perception. No side effects were reported in the studies and these exercises can be considered safe.
PubMed: 38941773
DOI: 10.1016/j.hrtlng.2024.06.004 -
Respiratory Investigation Jun 2024Gastroesophageal reflux disease (GERD) is one of the most common comorbidities of chronic obstructive pulmonary disease (COPD). Decreased lower and upper esophageal... (Review)
Review
Gastroesophageal reflux disease (GERD) is one of the most common comorbidities of chronic obstructive pulmonary disease (COPD). Decreased lower and upper esophageal sphincter pressures, esophageal dysmotility, high transdiaphragmatic pressure, and decreased saliva secretion have been implicated as mechanisms leading to the development of GERD in COPD. Clinically, comorbid GERD in COPD is reportedly associated with worse symptoms, quality of life, and lung function, as well as a high risk of exacerbations. Aspiration of regurgitation and the cholinergic-mediated esophagobronchial reflex play a significant role in the pathophysiology. Abnormal swallowing reflexes and discoordination of swallowing can worsen aspiration. The diagnosis of GERD is not based on a single criterion; however, various approaches, including questionnaires and endoscopic evaluations, can be widely applied in clinical settings. Due to the increased risk of esophageal and gastric cancers in patients with COPD, the threshold for endoscopic examination should be low. Acid inhibitory agents, such as proton pump inhibitors and histamine H2 receptor antagonists, and prokinetic agents, including mosapride and itopride, are clinically used to treat GERD. Endoscopic fundoplication can be performed in patients with GERD refractory to medical treatment. There is still insufficient evidence, but an increasing number of studies have suggested the clinical efficacy of treatment in patients with COPD and GERD. As GERD is an evaluative and treatable common disease, and access to evaluation and treatment is relatively easy, clinicians should provide adequate care for GERD in the management of COPD.
PubMed: 38941760
DOI: 10.1016/j.resinv.2024.06.004