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Chemistry (Weinheim An Der Bergstrasse,... May 2024Ecklonialactones, Eiseniachlorides, and Egregiachlorides are synthesized in living organisms via the lipoxygenase-mediated oxidation of polyunsaturated fatty acids....
Ecklonialactones, Eiseniachlorides, and Egregiachlorides are synthesized in living organisms via the lipoxygenase-mediated oxidation of polyunsaturated fatty acids. Originally isolated and identified from brown seaweed (Ecklonia stolonifera, Eisenia bicyclis, and Egregia menziesii), and later replicated on milligram scale through chemical synthesis, the full biological activities of these compounds remain to be elucidated. To bridge this gap in knowledge, we propose a unified methodology to synthesize the 14-membered macrocyclic structures of Ecklonialactones, Eiseniachlorides and analogs using a versatile and convergent approach. This study delineates the synthesis of Ecklonialactone A, B, C, D, and Eiseniachlorides A and B, as well as ent-Ecklonialactone B, 16-epi-Ecklonialactone B and 12,13-diepi-Ecklonialactone B.
PubMed: 38770615
DOI: 10.1002/chem.202401632 -
Protein Expression and Purification Sep 2024Protein reagents are essential resources for several stages of drug discovery projects from structural biology and assay development through lead optimization. Depending...
Protein reagents are essential resources for several stages of drug discovery projects from structural biology and assay development through lead optimization. Depending on the aim of the project different amounts of pure protein are required. Small-scale expressions are initially used to determine the reachable levels of production and quality before scaling up protein reagent supply. Commonly, amounts of several hundreds of milligrams to grams are needed for different experiments, including structural investigations and activity evaluations, which require rather large cultivation volumes. This implies that cultivation of large volumes of either transiently transfected cells or stable pools/stable cell lines is needed. Hence, a production process that is scalable, speeds up the development projects, and increases the robustness of protein reagent quality throughout scales. Here we present a protein production pipeline with high scalability. We show that our protocols for protein production in Chinese hamster ovary cells allow for a seamless and efficient scale-up with robust product quality and high performance. The flexible scale of the production process, as shown here, allows for shorter lead times in drug discovery projects where there is a reagent demand for a specific protein or a set of target proteins.
Topics: CHO Cells; Cricetulus; Animals; Bioreactors; Recombinant Proteins; Plasmids; Cricetinae
PubMed: 38768672
DOI: 10.1016/j.pep.2024.106505 -
Cureus Apr 2024Background Opioids, commonly used to control pain associated with surgery, are known to prolong the duration of mechanical ventilation and length of hospital stay. A...
Background Opioids, commonly used to control pain associated with surgery, are known to prolong the duration of mechanical ventilation and length of hospital stay. A wide range of adjunctive strategies are currently utilized to reduce postoperative pain, such as local and regional nerve blocks, nerve cryoablation, and adjunctive medications. We hypothesized that dronabinol (a synthetic cannabinoid) in conjunction with standard opioid pain management will reduce opioid requirements to manage postoperative pain. Methods Sixty-eight patients who underwent isolated first-time coronary artery bypass graft surgery were randomized to either the control group, who received only standard opioid-based analgesia, or the dronabinol group, who received dronabinol (a synthetic cannabinoid) in addition to standard opioid-based analgesia. Dronabinol was given in the preoperative unit, before extubation in the ICU, and after extubation on the first postoperative day. Preoperative, intraoperative, and postoperative parameters were compared under an IRB-approved protocol. The primary endpoints were the postoperative opioid requirement, duration of mechanical ventilation, and ICU length of stay, and the secondary endpoints were the duration of inotropic support needed, left ventricular ejection fraction (LVEF), and the change in LVEF. This study was undertaken at Northwest Medical Center, Tucson, AZ, USA. Results Sixty-eight patients were randomized to either the control group (n = 37) or the dronabinol group (n = 31). Groups were similar in terms of demographic features and comorbidities. The total postoperative opioid requirement was significantly lower in the dronabinol group [39.62 vs 23.68 morphine milligram equivalents (MMEs), p = 0.0037], representing a 40% reduction. Duration of mechanical ventilation (7.03 vs 6.03h, p = 0.5004), ICU length of stay (71.43 vs 63.77h, p = 0.4227), and inotropic support requirement (0.6757 vs 0.6129 days, p = 0.7333) were similar in the control and the dronabinol groups. However, there was a trend towards lower durations in each endpoint in the dronabinol group. Interestingly, a significantly better preoperative to postoperative LVEF change was observed in the dronabinol group (3.51% vs 6.45%, p = 0.0451). Conclusions Our study found a 40% reduction in opioid use and a significantly greater improvement in LVEF in patients treated with adjunctive dronabinol. Mechanical ventilation duration, ICU length of stay, and inotropic support requirement tended to be lower in the dronabinol group, though did not reach statistical significance. The results of this study, although limited by sample size, are very encouraging and validate our ongoing investigation.
PubMed: 38765405
DOI: 10.7759/cureus.58566 -
Environmental Science & Technology Jun 2024The presence of organic micropollutants in water and sediments motivates investigation of their biotransformation at environmentally low concentrations, usually in the...
The presence of organic micropollutants in water and sediments motivates investigation of their biotransformation at environmentally low concentrations, usually in the range of μg L. Many are biotransformed by cometabolic mechanisms; however, there is scarce information concerning their direct metabolization in this concentration range. Threshold concentrations for microbial assimilation have been reported in both pure and mixed cultures from different origins. The literature suggests a range value for bacterial growth of 1-100 μg L for isolated aerobic heterotrophs in the presence of a single substrate. We aimed to investigate, as a model case, the threshold level for sulfamethoxazole (SMX) metabolization in pure cultures of strain BR1. Previous research with this strain has covered the milligram L range. In this study, acclimated cultures were exposed to concentrations from 0.1 to 25 μg L of C-labeled SMX, and the C-CO produced was trapped and quantified over 24 h. Interestingly, SMX removal was rapid, with 98% removed within 2 h. In contrast, mineralization was slower, with a consistent percentage of 60.0 ± 0.7% found at all concentrations. Mineralization rates increased with rising concentrations. Therefore, this study shows that bacteria are capable of the direct metabolization of organic micropollutants at extremely low concentrations (sub μg L).
Topics: Sulfamethoxazole; Water Pollutants, Chemical
PubMed: 38761139
DOI: 10.1021/acs.est.4c02191 -
International Journal of Impotence... May 2024Efforts to minimize narcotic usage following inflatable penile prosthesis (IPP) implantation are vital, considering the current opioid epidemic in the United States. We...
Pudendal nerve block decreases narcotic requirements and time spent in post-anesthesia care units in patients undergoing primary inflatable penile prosthesis implantation.
Efforts to minimize narcotic usage following inflatable penile prosthesis (IPP) implantation are vital, considering the current opioid epidemic in the United States. We aimed to determine whether pudendal nerve block (PNB) utilization in a multiethnic population undergoing primary IPP implantation can decrease rates of post-operative opiate usage. A single-institution, retrospective study was conducted on patients who underwent primary IPP implantation between December 2015 and June 2022. PNB usage and intra- and post-operative outcomes were analyzed using multivariate binary logistic regression. 449 patients were included, with 373 (83.1%) in the PNB group. Median time (minutes) spent in the post-anesthesia care unit (PACU) (1499 [119-198] vs. 235 [169-322], p < 0.001) was significantly lower in the PNB group. There were no significant differences in intra-operative and PACU morphine milligram equivalents or post-operative safety outcomes between groups. However, fewer patients in the PNB group called for pain medications post-operatively (10.2% vs 19.7%, p = 0.019). Multivariate analysis revealed a significantly decreased operative time (B -6.23; 95%CI -11.28, -1.17; p = 0.016) and decreased time in recovery (B: -81.62; 95%CI: -106.49, -56.76, p < 0.001) in the PNB group. PNB decreases post-operative opioid analgesic requirements and time spent in PACU in patients undergoing a primary IPP implantation and thus may represent an attractive, non-opioid adjunct.
PubMed: 38760570
DOI: 10.1038/s41443-024-00870-1 -
Orthopaedic Journal of Sports Medicine May 2024Although several studies have noted that patients are routinely overprescribed opioids, few have reported usage after arthroscopic surgery.
BACKGROUND
Although several studies have noted that patients are routinely overprescribed opioids, few have reported usage after arthroscopic surgery.
PURPOSE
To determine opioid consumption and allocation for unused opioids after common arthroscopic surgeries.
STUDY DESIGN
Case series; Level of evidence, 4.
METHODS
Patients between the ages of 15 and 40 years who were scheduled to undergo anterior cruciate ligament reconstruction (ACLR), labral repair of the hip or shoulder, meniscectomy, or meniscal repair were prospectively enrolled. Patients were prescribed either 5 mg hydrocodone-325 mg acetaminophen or 5 mg oxycodone-325 mg acetaminophen based on surgeon preference. Patients completed a daily opioid usage survey during the 2-week postoperative period. In addition, patients completed a survey on postoperative day 21 inquiring about continued opioid use and medication disposal, if applicable. Opioid medication consumption was converted to morphine milligram equivalents (MMEs).
RESULTS
Of the 200 patients who were enrolled in the study, 176 patients had sufficient follow-up after undergoing 85 (48%) ACLR, 26 (14.8%) hip labral repair, 34 (19.3%) shoulder labral repair, 18 (10.2%) meniscectomy, and 13 (7.4%) meniscal repair procedures. Mean age was 26.1 years (SD, 7.38); surgeons prescribed a mean of 26.6 pills whereas patients reported consuming a mean of 15.5 pills. The mean MME consumption in the 14 days after each procedure was calculated: ACLR (95.7; 44% of prescription), hip labral repair (84.8; 37%), shoulder labral repair (57.2; 35%), meniscectomy (18.4; 27%), and meniscal repair (32.1; 42%). This corresponded to approximately 39% of the total opioid prescription being utilized across all procedures. Mean MME consumption was greatest on postoperative day 1 in hip, shoulder, and meniscal procedures and on postoperative day 2 in ACLR. Only 7.04% of patients reported continued opioid use in the third postoperative week. Patients had a mean of 11 unused pills or 77.7 MMEs remaining. Of the patients with remaining medication, 24.7% intended to keep their medication for future use.
CONCLUSION
The results of our study indicate that patients who undergo the aforementioned arthroscopic procedures consume <75 MMEs in the 2-week postoperative period, translating into a mean of 10 to 15 pills consumed. Approximately 60% of total opioids prescribed went unused, and one-fourth of patients intended to keep their remaining medication for future usage. We have provided general prescribing guidelines and recommend that surgeons carefully consider customizing their opioid prescriptions on the basis of procedure site to balance optimal postoperative analgesia with avoidance of dissemination of excess opioids.
PubMed: 38757068
DOI: 10.1177/23259671241249688 -
JPGN Reports May 2024Protein-losing enteropathy associated with collagenous colitis (CC) is a rare but described entity in the adult population. However, literature regarding this in the...
Protein-losing enteropathy associated with collagenous colitis (CC) is a rare but described entity in the adult population. However, literature regarding this in the pediatric population is scarce. Here we describe a 2-year-old female who presented with fevers, accompanied by nonbloody, watery diarrhea, and decreased oral intake. Work-up was significant for severe hypoalbuminemia at 1.5 grams per deciliter (g/dL), pancytopenia, and elevated fecal alpha-1-antitrypsin at 1.13 milligrams per grams (mg/g). Gastrointestinal mucosal evaluation was normal endoscopically; however, histology was consistent with CC. She responded to 12-week treatment with budesonide with resolution of symptoms and laboratory values. At this point, she has not had a recurrence 1 year later.
PubMed: 38756128
DOI: 10.1002/jpr3.12051 -
The Journal of the American Academy of... May 2024Adequate pain control and early mobilization are critical in the postoperative period after periacetabular osteotomy (PAO). Regional anesthesia can reduce postoperative...
INTRODUCTION
Adequate pain control and early mobilization are critical in the postoperative period after periacetabular osteotomy (PAO). Regional anesthesia can reduce postoperative pain, but certain techniques can increase the risk of postoperative motor block and delayed functional recovery. Continuous lumbar epidurals can provide excellent analgesia but also create challenges with early ambulation. Recently, suprainguinal fascia iliaca (SIFI) single-shot blocks have been shown to provide effective analgesia in PAO patients. The goal of this study was to compare opioid use, time to achieve inpatient physical therapy (PT) goals, and length of stay (LOS) between a cohort of patients receiving SIFI blocks and a cohort of patients receiving epidural analgesia (EA).
METHODS
This retrospective single-surgeon comparative cohort study included all patients who underwent a PAO between 2012 and 2022. Regional anesthetic technique (SIFI vs EA), length of hospital stay, intraoperative and postoperative opioid use, pain scores, and time to achievement of PT milestones before discharge were recorded. Patients were excluded if they had any preexisting neuromuscular syndrome or neurosensory deficit. All opioid use was converted to morphine-milligram equivalents using standard conversions.
RESULTS
Two hundred four surgeries were done over the study period; 164 patients received EA, and 40 received a SIFI block. The average age of our cohort was 19.5 years (±6 yrs). The SIFI cohort had a significantly shorter mean LOS than the EA cohort (2.9 vs 4.1 days, P < 0.001). Patients in the SIFI cohort achieved all PT ambulation goals significantly sooner than the lumbar epidural group (P < 0.001), with lower total opioid use on each postoperative day. No notable differences were observed in sex, race, BMI, or pain scores at inpatient PT visits before discharge.
CONCLUSION
After PAO surgery, the SIFI block is associated with shorter hospital LOS, reduced postoperative opioid use, and earlier mobilization when compared with those who were managed with an epidural.
PubMed: 38748895
DOI: 10.5435/JAAOS-D-24-00177 -
Chirality May 2024The absolute configuration of three chiral eugenol derivatives was assigned by a multi-step methodology based on enantioselective HPLC combined with spectroscopic and...
Enantioselective high-performance liquid chromatography combined with spectroscopic methods and theoretical calculations: A valid strategy to determine the absolute configuration of eugenol derivatives.
The absolute configuration of three chiral eugenol derivatives was assigned by a multi-step methodology based on enantioselective HPLC combined with spectroscopic and theoretical calculations. Milligram amounts of enantiopure forms used for stereochemical characterization were isolated by HPLC on the immobilized amylose-based chiral stationary phase Chiralpak IG using normal phase elution conditions. The absolute configuration was indirectly determined for one of the three compounds by H NMR via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (Mosher's acid). Comparison of the experimental and predicted electronic circular dichroism spectra confirmed the stereochemical assignment by Mosher's method and extended the absolute configuration assignment to two other chiral compounds.
PubMed: 38747133
DOI: 10.1002/chir.23668 -
Frontiers in Endocrinology 2024The baseline urinary albumin/creatinine ratio (uACR) has been proven to be significantly associated with the risk of major adverse cardiac events (MACE). However, data...
OBJECTIVE
The baseline urinary albumin/creatinine ratio (uACR) has been proven to be significantly associated with the risk of major adverse cardiac events (MACE). However, data on the association between the longitudinal trajectory patterns of uACR, changes in glycated hemoglobin A1c (HbA1c), and the subsequent risk of MACE in patients with diabetes are sparse.
METHODS
This is a retrospective cohort study including 601 patients with type 2 diabetes mellitus (T2DM; uACR < 300 mg/g) admitted to The First Hospital of Shanxi Medical University and The Second Hospital of Shanxi Medical University from January 2015 to December 2018. The uACR index was calculated as urinary albumin (in milligrams)/creatinine (in grams), and latent mixed modeling was used to identify the longitudinal trajectory of uACR during the exposure period (2016-2020). The deadline for follow-up was December 31, 2021. The primary outcome was the MACE [a composite outcome of cardiogenic death, hospitalization related to heart failure (HHF), non-fatal acute myocardial infarction, non-fatal stroke, and acute renal injury/dialysis indications]. The Kaplan-Meier survival analysis curve was used to compare the risk of MACE among four groups, while univariate and multivariate Cox proportional hazards models were employed to calculate the hazard ratio (HR) and 95% confidence interval (CI) for MACE risk among different uACR or HbA1c trajectory groups. The predictive performance of the model, both before and after the inclusion of changes in the uACR and HbA1c, was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC).
RESULTS
Four distinct uACR trajectories were identified, namely, the low-stable group (uACR = 5.2-38.3 mg/g, = 112), the moderate-stable group (uACR = 40.4-78.6 mg/g, = 229), the high-stable group (uACR = 86.1-153.7 mg/g, = 178), and the elevated-increasing group (uACR = 54.8-289.4 mg/g, = 82). In addition, five distinct HbA1c trajectories were also identified: the low-stable group (HbA1c = 5.5%-6.8%, = 113), the moderate-stable group (HbA1c = 6.0%-7.9%, = 169), the moderate-decreasing group (HbA1c = 7.4%-6.1%, = 67), the high-stable group (HbA1c = 7.7%-8.9%, = 158), and the elevated-increasing group (HbA1c = 8.4%-10.3%, = 94). Compared with the low-stable uACR group, patients in the high-stable and elevated-increasing uACR groups were more likely to be older, current smokers, and have a longer DM course, higher levels of 2-h plasma glucose (PG), HbA1c, N-terminal pro-B-type natriuretic peptide (NT-proBNP), uACR, and left ventricular mass index (LVMI), while featuring a higher prevalence of hypertension and a lower proportion of β-receptor blocker treatment ( < 0.05). During a median follow-up of 45 months (range, 24-57 months), 118 cases (19.6%) of MACE were identified, including 10 cases (1.7%) of cardiogenic death, 31 cases (5.2%) of HHF, 35 cases (5.8%) of non-fatal acute myocardial infarction (AMI), 18 cases (3.0%) of non-fatal stroke, and 24 cases (4.0%) of acute renal failure/dialysis. The Kaplan-Meier survival curve showed that, compared with that in the low-stable uACR group, the incidence of MACE in the high-stable (HR = 1.337, 95% CI = 1.083-1.652, = 0.007) and elevated-increasing (HR = 1.648, 95% CI = 1.139-2.387, = 0.009) uACR groups significantly increased. Similar results were observed for HHF, non-fatal AMI, and acute renal injury/dialysis indications ( < 0.05). The multivariate Cox proportional hazards models indicated that, after adjusting for potential confounders, the HRs for the risk of MACE were 1.145 ( = 0.132), 1.337 ( = 0.007), and 1.648 ( = 0.009) in the moderate-stable, high-stable, and elevated-increasing uACR groups, respectively. In addition, the HRs for the risk of MACE were 1.203 ( = 0.028), 0.872 ( = 0.024), 1.562 ( = 0.033), and 2.218 ( = 0.002) in the moderate-stable, moderate-decreasing, high-stable, and elevated-increasing groups, respectively. The ROC curve showed that, after adding uACR, HbA1c, or both, the AUCs were 0.773, 0.792, and 0.826, which all signified statistically significant improvements ( = 0.021, 0.035, and 0.019, respectively).
CONCLUSION
A long-term elevated uACR is associated with a significantly increased risk of MACE in patients with diabetes. This study implies that regular monitoring of uACR could be helpful in identifying diabetic patients with a higher risk of MACE.
Topics: Humans; Male; Female; Retrospective Studies; Diabetes Mellitus, Type 2; Middle Aged; Albuminuria; Creatinine; Aged; Glycated Hemoglobin; Longitudinal Studies; Risk Factors; Prognosis; Biomarkers; Cohort Studies; Follow-Up Studies
PubMed: 38745945
DOI: 10.3389/fendo.2024.1355149