ABSTRACT
AIMS: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS: This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS: ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. CONCLUSION: These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.
Subject(s)
Esterases , Histone Deacetylase Inhibitors , Humans , Animals , Mice , Histone Deacetylase Inhibitors/pharmacology , Macrophage Colony-Stimulating Factor , CytokinesABSTRACT
Three trials were conducted to evaluate the performances of red snapper, Lutjanus campechanus, in low salinities. The median lethal concentration (96 h LC50) of salinity was determined by trimmed Spearman-Karber method using survival data of fish (18.9 ± 0.2 g) collected after 96 h from acclimation to 2, 4, 8, and 32 ppt salinities in 800 L tanks (n = 3), while the serum osmolality of fish (74.1 ± 3.9 g) was determined after 48 h from acclimation to 6, 8, 16, 24, and 32 ppt salinities in 150 L tanks (n = 3). The growth trial was conducted for 6 weeks in 800 L tanks to determine the growth and survival of fish (18.8 ± 0.2 g) at 8 ppt salinity compared to the control (32 ppt salinity). At the conclusion, the isosmotic point of fish was estimated as 357.2 mmol/kg (correspond to 11.0 ppt salinity), while the 96 h LC50 was estimated as 5.65 ppt salinity. No significant differences were noted for survival and FCR of fish reared in 8 and 32 ppt salinities. However, growth was significantly lower in fish reared in 8 ppt salinity compared to the fish reared in 32 ppt salinity. The reduced growth could be, at least partially, due to the increased osmoregulatory energy expenditure at lower salinities.
Subject(s)
Osmoregulation , Perciformes , Salinity , Animals , Fishes , SeafoodABSTRACT
Naïve T cell activation requires antigen presentation combined with costimulation through CD28, both of which optimally occur in secondary lymphoid tissues such as lymph nodes and the spleen. Belatacept impairs CD28 costimulation by binding its ligands, CD80 and CD86, and in doing so, impairs de novo alloimmune responses. However, in most patients belatacept is ineffective in preventing allograft rejection when used as a monotherapy, and adjuvant therapy is required for control of costimulation-blockade resistant rejection (CoBRR). In rodent models, impaired access to secondary lymphoid tissues has been demonstrated to reduce alloimmune responses to vascularized allografts. Here we show that surgical maneuvers, lymphatic ligation, and splenectomy, designed to anatomically limit access to secondary lymphoid tissues, control CoBRR and facilitate belatacept monotherapy in a nonhuman primate model of kidney transplantation without adjuvant immunotherapy. We further demonstrate that animals sustained on belatacept monotherapy progressively develop an increasingly naïve T and B cell repertoire, an effect that is accelerated by splenectomy and lost at the time of belatacept withdrawal and rejection. These pilot data inform the role of secondary lymphoid tissues on the development of CoBRR and the use of costimulation molecule-focused therapies.
Subject(s)
Abatacept/therapeutic use , CD28 Antigens/antagonists & inhibitors , Graft Rejection/prevention & control , Graft Survival/immunology , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/mortality , Lymphoid Tissue/immunology , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Graft Rejection/etiology , Graft Rejection/pathology , Graft Survival/drug effects , Immunologic Memory , Immunotherapy , Kidney Transplantation/adverse effects , Lymphoid Tissue/drug effects , Primates , Splenectomy , Survival Rate , Transplantation, HomologousABSTRACT
OBJECTIVE: To investigate trends in long-term graft and patient outcomes following liver transplantation using grafts from donors ≥60 years old. SUMMARY BACKGROUND DATA: The scarcity of donor livers has led to increased utilization of organs from donors ≥60 years old. However, few studies have examined how long-term transplant outcomes from older donors have evolved over time. METHODS: The OPTN/UNOS database was queried for all first-time isolated adult liver transplants. We identified 14,796 adult liver transplant using donors â§60-year-old suitable for analysis from 1990 to 2014. Cohorts were then developed based on 5-year intervals of transplant date. Kaplan-Meier analysis was used to compare graft and patient survival for recipients from older donor across each 5-year era. RESULTS: Utilization of donor grafts ≥60 years old increased steadily for the first 15 years of the study, but has leveled off over the last 10 years. Comparison of the earliest and latest eras in the study was notable for an increase in median recipient age (51 vs. 59, P < 0.001) and reduction in median cold ischemic time (10 vs. 6âh, P = 0.001). Unadjusted 5-year graft and patient survival has improved significantly over time (P < 0.0001). More importantly, the discrepancy in survival between older and younger grafts has narrowed substantially over time (P < 0.0001). CONCLUSIONS: This study demonstrates significant improvement in transplant outcomes with donor grafts ≥60-years old and supports increased but judicious use of extended criteria donors liver grafts. Improved patient selection and reduction in cold ischemia time appear to be contributing factors.
Subject(s)
Liver Diseases/surgery , Liver Transplantation/methods , Patient Selection , Registries , Tissue Donors , Tissue and Organ Procurement/methods , Age Factors , Aged , Female , Follow-Up Studies , Graft Survival , Humans , Liver Diseases/mortality , Male , Middle Aged , Retrospective Studies , Survival Rate/trends , United States/epidemiologyABSTRACT
Machine preservation (MP) has emerged as a promising technology in liver transplantation, but the cellular processes occurring during MP have not been characterized. Recent studies have noted the presence of inflammatory molecules generated during MP. We hypothesized that there is a metabolism-dependent accumulation of damage-associated molecular patterns (DAMPs) and inflammatory cytokines during MP and that these molecules provoke inflammation in the graft. To stratify groups by metabolic rate, MP was performed on rat livers from standard donors at 3 different temperatures: room temperature (RT), subnormothermic (30°C), and normothermic (37°C). Static cold storage at 4°C was included as a reference group. Following a 4-hour preservation period, graft reperfusion was performed ex vivo at 37°C (n = 6 for all groups). Levels of DAMPs and inflammatory cytokines were measured, and their biological activity was assessed by determining toll-like receptor (TLR) stimulation, inflammatory gene expression, and activation of cell death pathways. There was a time-dependent increase in levels of DAMPs during MP with high-mobility group box 1 and extracellular DNA levels increasing for all groups (P < 0.05, 30 versus 240 minutes). Tumor necrosis factor α levels in the perfusate also increased during MP for all groups (P < 0.05, 30 minutes versus 240 minutes). Levels of inflammatory molecules correlated with increased activation of TLRs (TLR3, P = 0.02, normothermic machine preservation [MP37] versus machine preservation at room temperature [MPRT]; TLR9, P = 0.02, MP37 versus MPRT). Priming of the NLRP3 inflammasome and activation of cell death pathways were reduced in grafts preserved by MP at room temperature. In conclusion, inflammatory molecules produced during MP have a biological impact on the graft. Therapies to attenuate DAMP-mediated inflammation during MP may further enhance this promising technology.
Subject(s)
Alarmins/metabolism , Liver Transplantation , Organ Preservation/adverse effects , Perfusion/adverse effects , Reperfusion Injury/immunology , Alarmins/immunology , Allografts/blood supply , Allografts/immunology , Allografts/pathology , Animals , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Humans , Inflammasomes/immunology , Inflammasomes/metabolism , Liver/blood supply , Liver/immunology , Liver/pathology , Male , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Organ Preservation/instrumentation , Organ Preservation/methods , Perfusion/instrumentation , Perfusion/methods , Rats , Reperfusion Injury/etiology , Reperfusion Injury/pathology , Signal Transduction/immunology , Temperature , Toll-Like Receptors/immunology , Toll-Like Receptors/metabolismABSTRACT
Recipients of liver allografts from diabetic donors have decreased graft survival. However, limited data exist on the effects of donor HbA1c. We hypothesized that allografts from nondiabetic donors with elevated HbA1c would be associated with decreased survival. Liver transplant recipients from the UNOS database from nondiabetic donors were stratified into two groups: euglycemic (HbA1c<6.5) and hyperglycemic (HbA1c≥6.5). Propensity score matching (10:1) was used to adjust for donor and recipient characteristics. Kaplan-Meier analysis was used to assess survival. Donors of hyperglycemic allografts were older (49 vs 36, P<.001), were more likely to be non-white, had a higher BMI (29.8 vs 26.2, P<.001), were more likely to engage in heavy cigarette use (1.5% vs 1.3%, P=.004), had higher serum creatinine levels (1.3 vs 1.0, P=.002), and were more likely to be an expanded-criteria donor (35.8% vs 14.4%, P<.001). After propensity matching to account for these differences, allograft survival was significantly decreased in the recipients of hyperglycemic allografts (P=.049), and patient survival showed a trend toward reduction (P=.082). These findings suggest that HbA1c may be a simple and inexpensive test with potential utility for better organ risk stratification.
Subject(s)
Glycated Hemoglobin/metabolism , Graft Survival , Hyperglycemia/complications , Liver Transplantation , Tissue Donors , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Female , Humans , Hyperglycemia/blood , Hyperglycemia/diagnosis , Kaplan-Meier Estimate , Liver Transplantation/mortality , Male , Middle Aged , Outcome Assessment, Health Care , Propensity Score , Registries , Risk Factors , Young AdultABSTRACT
Harvest in walleye Sander vitreus fisheries is size-selective and could influence phenotypic traits of spawners; however, contributions of individual spawners to recruitment are unknown. We used parentage analyses using single nucleotide polymorphisms to test whether parental traits were related to the probability of offspring survival in Escanaba Lake, Wisconsin. From 2017 to 2020, 1339 adults and 1138 juveniles were genotyped and 66% of the offspring were assigned to at least one parent. Logistic regression indicated the probability of reproductive success (survival of age-0 to first fall) was positively (but weakly) related to total length and growth rate in females, but not age. No traits analyzed were related to reproductive success for males. Our analysis identified the model with the predictors' growth rate and year for females and the models with year and age and year for males as the most likely models to explain variation in reproductive success. Our findings indicate that interannual variation (i.e., environmental conditions) likely plays a key role in determining the probability of reproductive success in this population and provide limited support that female age, length, and growth rate influence recruitment.
ABSTRACT
The bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized.
Subject(s)
Administration, Intravenous , Animals , Administration, Oral , Mice , Structure-Activity Relationship , Humans , Transcription Factors/antagonists & inhibitors , Transcription Factors/metabolism , Molecular StructureABSTRACT
This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/pharmacokinetics , Dogs , Half-Life , Haplorhini , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Male , Microsomes, Liver/metabolism , Niacinamide/analogs & derivatives , Niacinamide/chemistry , Niacinamide/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.
Subject(s)
Benzazepines/chemistry , Histamine H3 Antagonists/chemistry , Receptors, Histamine H3/chemistry , Animals , Benzazepines/chemical synthesis , Benzazepines/pharmacokinetics , Cytochrome P-450 CYP2D6/chemistry , Cytochrome P-450 CYP2D6/metabolism , Drug Evaluation, Preclinical , Half-Life , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacokinetics , Humans , Microsomes, Liver/metabolism , Protein Binding , Rats , Receptors, Histamine H3/genetics , Receptors, Histamine H3/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Structure-Activity RelationshipABSTRACT
As the field of mechanical circulatory support (MCS) continues to advance and resuscitation protocols are being refined, elderly patients previously not considered for MCS are now being supported. MCS devices can broadly be classified based on the duration of support into temporary or durable devices. Although mortality is higher in the elderly, carefully selected patients, MCS support can be valuable and lead to excellent recovery. Age itself should not preclude patients from being candidates for MCS because we must not restrict the progress of science in medicine for any age.
Subject(s)
Extracorporeal Membrane Oxygenation , Heart-Assist Devices , Humans , Aged , Shock, Cardiogenic/etiology , Heart-Assist Devices/adverse effects , Intra-Aortic Balloon Pumping/methods , Extracorporeal Membrane Oxygenation/methods , Resuscitation , Treatment OutcomeABSTRACT
The zinc finger protein ZFYVE21 is involved in immune signaling. Using humanized mouse models, primary human cells, and patient samples, we identified a T cell-autonomous role for ZFYVE21 in promoting chronic vascular inflammation associated with allograft vasculopathy. Ischemia-reperfusion injury (IRI) stimulated endothelial cells to produce Hedgehog (Hh) ligands, which in turn induced the production of ZFYVE21 in a population of T memory cells with high amounts of the Hh receptor PTCH1 (PTCHhi cells, CD3+CD4+CD45RO+PTCH1hiPD-1hi), vigorous recruitment to injured endothelia, and increased effector responses in vivo. After priming by interferon-γ (IFN-γ), Hh-induced ZFYVE21 activated NLRP3 inflammasome activity in T cells, which potentiated IFN-γ responses. Hh-induced NLRP3 inflammasomes and T cell-specific ZFYVE21 augmented the vascular sequelae of chronic inflammation in mice engrafted with human endothelial cells or coronary arteries that had been subjected to IRI before engraftment. Moreover, the population of PTCHhi T cells producing high amounts of ZFYVE21 was expanded in patients with renal transplant-associated IRI, and sera from these patients expanded this population in control T cells in a manner that depended on Hh signaling. We conclude that Hh-induced ZFYVE21 activates NLRP3 inflammasomes in T cells, thereby promoting chronic inflammation.
Subject(s)
Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Humans , Mice , Endothelial Cells/metabolism , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Inflammasomes/genetics , Inflammasomes/metabolism , Inflammation/genetics , Inflammation/metabolism , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , T-Lymphocytes/metabolism , Membrane Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolismABSTRACT
The contribution of aquatic animal protein to the global, animal-source protein supply and the relative importance of aquaculture to capture fisheries in supplying this protein is relevant in assessments and decisions related to the future of aquatic food production and its security. Meat of terrestrial animals, milk, and eggs resulted in 76,966 Kt crude protein compared with 13,950 Kt or 15.3% from aquatic animals in 2018.While aquaculture produced a greater tonnage of aquatic animals, capture fisheries resulted in 7,135 Kt crude protein while aquaculture yielded 6,815 Kt. Capture fisheries production has not increased in the past two decades, and aquaculture production must increase to assure the growing demand for fisheries products by a larger and more affluent population. We estimated based on status quo consumption, that aquaculture production would need to increase from 82,087 Kt in 2018 to 129,000 Kt by 2050 to meet the demand of the greater population. About two-thirds of finfish and crustacean production by aquaculture is feed-based, and feeds for these species include fishmeal and fish oil as ingredients. Aquaculture feeds require a major portion of the global supply of fishmeal and fish oil. An estimated 71.0% of fishmeal and 73.9% of fish oil are made from the catch with the rest coming from aquatic animal processing waste. The catch of small, pelagic fish from the ocean is not predicted to increase in the future. Aquaculture should reduce its fishmeal and oil use to lessen its dependency on small wild fish important to the integrity of marine food webs and food security for the poor in many coastal areas. Fishmeal and fish oil shortages for use in aquaculture feed will result in a limit on production in the future if goals to lessen their use in feeds are not met.
ABSTRACT
OBJECTIVE: Ex vivo lung perfusion has emerged as a novel technique to safely preserve lungs before transplantation. Recent studies have demonstrated an accumulation of inflammatory molecules in the perfusate during ex vivo lung perfusion. These proinflammatory molecules, including damage-associated molecular patterns and inflammatory cytokines, may contribute to acute and chronic allograft dysfunction. At present, ex vivo lung perfusion is performed clinically at normothermic temperature (37°C). The effect of lowering temperature to the subnormothermic range during ex vivo lung perfusion has not been reported. In this study, we hypothesized that lower ex vivo lung perfusion temperature will lead to a reduction in allograft inflammation and result in improved post-transplant graft function. METHODS: Lewis rat heart-lung blocs underwent 4 hours of ex vivo lung perfusion in 3 temperature groups: 37°C (MP37), 30°C (MP30), and 25°C (MP25). In the control group, lung grafts were preserved by static cold storage before transplantation. After ex vivo lung perfusion or static cold storage, the left lung was transplanted for 2 hours before the animal was killed. Sera and tissue were collected and analyzed. RESULTS: There were no differences in partial pressure of arterial oxygenation to fraction of inspired oxygen ratios during 4 hours of ex vivo lung perfusion between temperature groups. Tumor necrosis factor α significantly increased in the MP37 group during ex vivo lung perfusion, whereas this was not seen at lower temperatures. Extracellular DNA and high-mobility group box 1 perfusate concentrations increased significantly during ex vivo lung perfusion in all groups, but the rate of increase was diminished at lower temperature. Two hours post-transplant, there were no significant differences in partial pressure of arterial oxygenation to fraction of inspired oxygen ratios of the lung graft or serum damage-associated molecular pattern levels among groups. On histologic grading after transplantation, greater injury was observed in the MP30 and MP37 groups, but not MP25, when compared with static cold storage. CONCLUSIONS: Subnormothermic ex vivo lung perfusion at 25°C reduces the production of inflammatory mediators during ex vivo lung perfusion and is associated with reduced histologic graft injury after transplantation.
Subject(s)
Lung Transplantation , Reperfusion Injury , Animals , Inflammation/etiology , Inflammation/prevention & control , Lung , Lung Transplantation/adverse effects , Lung Transplantation/methods , Organ Preservation/methods , Oxygen , Perfusion/methods , Rats , Rats, Inbred Lew , Reperfusion Injury/pathologyABSTRACT
BACKGROUND: Allosteric modulation of γ-secretase is an attractive therapeutic approach for the treatment of Alzheimer's disease. We recently identified a novel γ-secretase modulator, GSM-10h, which effectively lowers Aß42 production in cells and in amyloid precursor protein transgenic mice. OBJECTIVE: Here, we describe the in vivo characterization of GSM-10h in a model of endogenous Aß production. METHODS: Rats were administered orally with GSM-10h, and the effect on Aß levels in peripheral and central compartments was determined. In addition, the effect of GSM-10h on Notch processing was assessed. RESULTS: Acute administration of GSM-10h to rats causes a dose-dependent decrease in the level of Aß42 in plasma, CSF and brain, with little effect on the level of Aß40 in these compartments. The magnitude of Aß42 lowering in the CSF and brain was further enhanced upon sub-chronic administration of GSM-10h. No deleterious effect on Notch processing was evident in either of these studies. To further explore the dynamics of Aß42 reduction in peripheral and CNS compartments, a time course study was conducted. In all compartments, the decrease in Aß42 was greatest at 6 h after administration of GSM-10h. This decrease in Aß42 was maintained for 9-15 h, after which time Aß42 levels returned to baseline levels. Encouragingly, no rebound in Aß42 levels beyond baseline levels was observed. CONCLUSIONS: These findings support the γ-secretase modulator profile of GSM-10h, and highlight the utility of the rat for assessing the pre-clinical efficacy of γ-secretase modulators.
Subject(s)
Acetates/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Brain Chemistry/drug effects , Enzyme Inhibitors/pharmacology , Peptide Fragments/metabolism , Piperidines/pharmacology , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Basic Helix-Loop-Helix Transcription Factors/biosynthesis , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Count , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Homeodomain Proteins/biosynthesis , Homeodomain Proteins/genetics , Male , Neurons/metabolism , Peptide Fragments/blood , Peptide Fragments/cerebrospinal fluid , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Receptors, Notch/drug effects , Signal Transduction/drug effects , Thymus Gland/cytology , Thymus Gland/drug effects , Transcription Factor HES-1ABSTRACT
Shrimp are an important and valuable commodity for aquaculture that are widely traded internationally. Widespread antibiotic use has been documented in shrimp farming and is a common source of criticism of aquaculture products. Additionally, previous reports have found some evidence of antibiotic residues in shrimp samples obtained from retail stores in the United States, which is a concern for consumers. To further understand the prevalence of antibiotics in retail shrimp in the United States, shrimp samples obtained from grocery stores across 16 states were analyzed for 74 antibiotic compounds/metabolites at a commercial laboratory. 68 samples were analyzed for a multiclass antibiotic panel which included 66 antibiotics while a subset of 15 samples were analyzed for ß-lactam antibiotics, Nitrofurans, and Oxytetracycline. Samples were obtained that were labeled as being from major production countries, including India, Indonesia, Thailand, and Vietnam. No detectable antibiotic residues were found in this survey in any samples. This is contrary to previous findings in frozen shrimp analyzed for antibiotics, which typically report low levels of the prevalence of antibiotics.
ABSTRACT
Background Because of discrepancies between donor supply and recipient demand, the cardiac transplantation process aims to prioritize the most medically urgent patients. It remains unknown how recipients with the lowest medical urgency compare to others in the allocation process. We aimed to examine differences in clinical characteristics, organ allocation patterns, and outcomes between cardiac transplantation candidates with the lowest and highest medical urgency. Methods and Results We performed a retrospective analysis of the United Network for Organ Sharing database. Patients listed for cardiac transplantation between January 2011 and May 2020 were stratified according to status at time of transplantation. Baseline recipient and donor characteristics, waitlist survival, and posttransplantation outcomes were compared in the years before and after the 2018 allocation system change. Lower urgency patients in the old system were older (58.5 versus 56 years) and more likely female (54.4% versus 23.8%) compared with the highest urgency patients, and these trends persisted in the new system (P<0.001, all). Donors for the lowest urgency patients were more likely older, female, or have a history of cytomegalovirus, hepatitis C, or diabetes (P<0.01, all). The lowest urgency patients had longer waitlist times and under the new allocation system received organs from shorter distances with decreased ischemic times (178 miles versus 269 miles, 3.1 versus 3.5 hours; P<0.001, all). There was no difference in posttransplantation survival (P<0.01, all). Conclusions Patients transplanted as lower urgency receive hearts from donors with additional comorbidities compared with higher urgency patients, but outcomes are similar at 1 year.
Subject(s)
Heart Transplantation , Databases, Factual , Female , Heart Transplantation/trends , Humans , Male , Retrospective Studies , Survival Analysis , Tissue Donors/statistics & numerical data , Tissue Donors/supply & distribution , Treatment Outcome , Waiting ListsABSTRACT
Reactive oxygen species play an important role in the pathogenesis of hypertension, disease in which reactive oxygen species levels and markers of oxidative stress are increased. Xanthine oxidase (XO) is a reactive oxygen species-producing enzyme the activity of which may increase during hypertension. Studies on XO inhibition effects on blood pressure have yielded controversial results. We hypothesized that XO inhibition would decrease blood pressure or attenuate the development of deoxycorticosterone acetate (DOCA)-salt hypertension. We administered the XO inhibitor, allopurinol (50 mg/kg per day, orally) or its vehicle to rats during the established or development stages of DOCA-salt hypertension. We validated XO inhibition by high-performance liquid chromatography measurements of XO metabolites in urine, serum, and tissues demonstrating a decrease in products, increase in substrates, and detection of the active metabolite of allopurinol, oxypurinol. We monitored blood pressure continuously through radiotelemetry and performed gross evaluations of target organs of hypertension. Allopurinol treatment did not impact the course of DOCA-salt hypertension regardless of the timing of administration. Aside from a significant decrease in pulse pressure in allopurinol-treated rats, no positive differences were observed between the allopurinol and the vehicle-treated rats. We conclude that XO does not play an important role in the development or maintenance of hypertension in the rat DOCA-salt hypertension model.
Subject(s)
Allopurinol/therapeutic use , Blood Pressure/drug effects , Desoxycorticosterone/toxicity , Disease Models, Animal , Hypertension/prevention & control , Allopurinol/pharmacology , Animals , Blood Pressure/physiology , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/toxicity , Hypertension/chemically induced , Hypertension/enzymology , Male , Rats , Rats, Sprague-Dawley , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/metabolismABSTRACT
BACKGROUND: While ex vivo lung perfusion (EVLP) has become established in lung transplantation, the cellular processes occurring during this period are not yet fully understood. Prior studies demonstrated that donor leukocytes (DLs) migrate from the graft into the perfusate during EVLP, but the distribution of DLs in graft and perfusate compartments has not been characterized. Moreover, cell death of DLs has been implicated in mediating graft injury during EVLP, but the underlying mechanisms have not been elucidated. We hypothesized the following: (1) there is a nonspecific migration of DLs from the graft into perfusate and (2) cell death of DLs releases damage-associated molecular patterns (DAMPs) that contribute to the inflammatory milieu during EVLP. METHODS: EVLP was performed on rat lungs for 3 hours (N = 6). At the end of EVLP, flow cytometry was used to quantify the distribution of different DL cell types in both the graft and perfusate compartments. During EVLP, the perfusate was also sampled hourly to measure levels of DAMPs and downstream inflammatory cytokines generated during EVLP. RESULTS: At the conclusion of EVLP, there was a significantly higher proportion of T and B cells present in the perfusate compartment compared with the graft compartment. There was a time-dependent increase in extracellular DNA and tumor necrosis factor α in the perfusate during EVLP. CONCLUSIONS: T cells and B cells are enriched in the perfusate compartment during EVLP. Cell death of DLs contributes to an accumulation of DAMPs during EVLP.
ABSTRACT
The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.