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Of the six elements incorporated into the major polymers of life, phosphorus is the least abundant on a global scale [E. Anders, M. Ebihara, Geochim. Cosmochim. Acta 46, 2363-2380 (1982)] and has been described as the "ultimate limiting nutrient" [T. Tyrrell, Nature 400, 525-531 (1999)]. In the modern ocean, the supply of dissolved phosphorus is predominantly sustained by the oxidative remineralization/recycling of organic phosphorus in seawater. However, in the Archean Eon (4 to 2.5 Ga), surface waters were anoxic and reducing. Here, we conducted photochemical experiments to test whether photodegradation of ubiquitous dissolved organic phosphorus could facilitate phosphorus recycling under the simulated Archean conditions. Our results strongly suggest that organic phosphorus compounds, which were produced by marine biota (e.g., adenosine monophosphate and phosphatidylserine) or delivered by meteorites (e.g., methyl phosphonate) can undergo rapid photodegradation and release inorganic phosphate into solution under anoxic conditions. Our experimental results and theoretical calculations indicate that photodegradation of organic phosphorus could have been a significant source of bioavailable phosphorus in the early ocean and would have fueled primary production during the Archean eon.
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BACKGROUND: Plasma microbial cell-free DNA sequencing (mcfDNA-Seq) is a noninvasive test for microbial diagnosis of invasive mold infection (IMI). The utility of mcfDNA-Seq for predicting IMI onset and the clinical implications of mcfDNA concentrations are unknown. METHODS: We retrospectively tested plasma from hematopoietic cell transplant (HCT) recipients with pulmonary IMI and ≥1 mold identified by mcfDNA-Seq in plasma collected within 14 days of clinical diagnosis. Samples collected from up to 4 weeks before and 4 weeks after IMI diagnosis were evaluated using mcfDNA-Seq. RESULTS: Thirty-five HCT recipients with 39 IMIs (16 Aspergillus and 23 non-Aspergillus infections) were included. Pathogenic molds were detected in 38%, 26%, 11%, and 0% of samples collected during the first, second, third, and fourth week before clinical diagnosis, respectively. In non-Aspergillus infections, median mcfDNA concentrations in samples collected within 3 days of clinical diagnosis were higher in infections with versus without extrapulmonary spread (4.3 vs 3.3 log10 molecules per microliter [mpm], P = .02), and all patients (8/8) with mcfDNA concentrations >4.0 log10 mpm died within 42 days after clinical diagnosis. CONCLUSIONS: Plasma mcfDNA-Seq can identify pathogenic molds up to 3 weeks before clinical diagnosis of pulmonary IMI. Plasma mcfDNA concentrations may correlate with extrapulmonary spread and mortality in non-Aspergillus IMI.
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Ácidos Nucleicos Livres , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Retrospectivos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Fungos , Pulmão , Aspergillus/genéticaRESUMO
Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis and clinical trials are ongoing to study their effectiveness in OI adults. Additionally, novel bone-protective agents are in preclinical studies and various phases of OI clinical trials. This review summarizes current knowledge on available pharmacologic agents and current drug trials involving OI participants. A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in August 2022. Articles screened were restricted to adults. A ClinicalTrials.gov database search of all studies involving "osteogenesis imperfecta" was performed in August 2023. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving bone mineral density. As of yet, no clinical trials are available that adequately evaluate the usefulness of current therapies in reducing fracture risk. Several therapeutics, including teriparatide, setrusumab, anti-TGF-ß antibodies, and allogeneic stem cells, are being studied in clinical trials. Preclinical studies involving Dickkopf-1 antagonists present promising data in non-OI bone disease, and could be useful in OI. Research is ongoing to improve therapeutic options for adults with OI and clinical trials involving gene-editing may be possible in the coming decade.
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Kidney transplantation is preferred for end-stage renal disease. The current gold standard for kidney preservation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal graft damage through ischemia-reperfusion injury (IRI). We previously reported renal graft protection after SCS with a hydrogen sulfide donor, sodium thiosulfate (STS), at 4 °C. Therefore, this study aims to investigate whether SCS at 10 °C with STS and Hemopure (blood substitute), will provide similar protection. Using in vitro model of IRI, we subjected rat renal proximal tubular epithelial cells to hypoxia-reoxygenation for 24 h at 10 °C with or without STS and measured cell viability. In vivo, we preserved 36 donor kidneys of Lewis rats for 24 h in a preservation solution at 10 °C supplemented with STS, Hemopure, or both followed by transplantation. Tissue damage and recipient graft function parameters, including serum creatinine, blood urea nitrogen, urine osmolality, and glomerular filtration rate (GFR), were evaluated. STS-treated proximal tubular epithelial cells exhibited enhanced viability at 10 °C compared with untreated control cells (p < 0.05). Also, STS and Hemopure improved renal graft function compared with control grafts (p < 0.05) in the early time period after the transplant, but long-term function did not reach significance. Overall, renal graft preservation at 10 °C with STS and Hemopure supplementation has the potential to enhance graft function and reduce kidney damage, suggesting a novel approach to reducing IRI and post-transplant complications.
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Hemoglobinas , Transplante de Rim , Traumatismo por Reperfusão , Tiossulfatos , Ratos , Animais , Preservação de Órgãos , Sobrevivência de Enxerto , Ratos Endogâmicos Lew , Rim , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controleRESUMO
Antibodies against foreign human leukocyte antigen (HLA) molecules are barriers to successful organ transplantation. B cell-depleting treatments are used to reduce anti-HLA antibodies but have limited efficacy. We hypothesized that the primary source for anti-HLA antibodies is long-lived plasma cells, which are ineffectively targeted by B cell depletion. To study this, we screened for anti-HLA antibodies in a prospectively enrolled cohort of 49 patients who received chimeric antigen receptor T-cell therapy (CARTx), targeting naïve and memory B cells (CD19-targeted, n = 21) or plasma cells (BCMA-targeted, n = 28) for hematologic malignancies. Longitudinal samples were collected before and up to 1 year after CARTx. All individuals were in sustained remission. We identified 4 participants with anti-HLA antibodies before CD19-CARTx. Despite B cell depletion, anti-HLA antibodies and calculated panel reactive antibody scores were stable for 1 year after CD19-CARTx. Only 1 BCMA-CARTx recipient had pre-CARTx low-level anti-HLA antibodies, with no follow-up samples available. These data implicate CD19neg long-lived plasma cells as an important source for anti-HLA antibodies, a model supported by infrequent HLA sensitization in BCMA-CARTx subjects receiving previous plasma cell-targeted therapies. Thus, plasma cell-targeted therapies may be more effective against HLA antibodies, thereby enabling improved access to organ transplantation and rejection management.
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Neoplasias Hematológicas , Imunoterapia Adotiva , Humanos , Antígeno de Maturação de Linfócitos B , Antígenos CD19 , Linfócitos BRESUMO
The oxidation states of manganese minerals in the geological record have been interpreted as proxies for the evolution of molecular oxygen in the Archean eon. Here we report that an Archean manganese mineral, rhodochrosite (MnCO3), can be photochemically oxidized by light under anoxic, abiotic conditions. Rhodochrosite has a calculated bandgap of about 5.4 eV, corresponding to light energy centering around 230 nm. Light at that wavelength would have been present on Earth's surface in the Archean, prior to the formation of stratospheric ozone. We show experimentally that the photooxidation of rhodochrosite in suspension with light centered at 230 nm produced H2 gas and manganite (γ-MnOOH) with an apparent quantum yield of 1.37 × 10-3 moles hydrogen per moles incident photons. Our results suggest that manganese oxides could have formed abiotically on the surface in shallow waters and on continents during the Archean eon in the absence of molecular oxygen.
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The global donor kidney shortage crisis has necessitated the use of suboptimal kidneys from donors-after-cardiac-death (DCD). Using an ex vivo porcine model of DCD kidney transplantation, the present study investigates whether the addition of hydrogen sulfide donor, AP39, to University of Wisconsin (UW) solution improves graft quality. Renal pedicles of male pigs were clamped in situ for 30 min and the ureters and arteries were cannulated to mimic DCD. Next, both donor kidneys were nephrectomized and preserved by static cold storage in UW solution with or without AP39 (200 nM) at 4 °C for 4 h followed by reperfusion with stressed autologous blood for 4 h at 37 °C using ex vivo pulsatile perfusion apparatus. Urine and arterial blood samples were collected hourly during reperfusion. After 4 h of reperfusion, kidneys were collected for histopathological analysis. Compared to the UW-only group, UW+AP39 group showed significantly higher pO2 (p < 0.01) and tissue oxygenation (p < 0.05). Also, there were significant increases in urine production and blood flow rate, and reduced levels of urine protein, serum creatinine, blood urea nitrogen, plasma Na+ and K+, as well as reduced intrarenal resistance in the UW+AP39 group compared to the UW-only group. Histologically, AP39 preserved renal structure by reducing the apoptosis of renal tubular cells and immune cell infiltration. Our finding could lay the foundation for improved graft preservation and reduce the increasingly poor outcomes associated with DCD kidney transplantation.
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Sulfeto de Hidrogênio , Transplante de Rim , Humanos , Masculino , Suínos , Animais , Sulfeto de Hidrogênio/farmacologia , Criopreservação , MitocôndriasRESUMO
Inflammation posttransplant is directly linked to cell death programs including apoptosis and necrosis. Cell death leads to the release of cellular contents which can promote inflammation. Targeting of these pathways should be an effective strategy to prevent transplant rejection. Toll-like receptor 3 (TLR3) is emerging as a major endogenous sensor of inflammation. In this study, we assessed the role of TLR3 on cell death and transplant rejection. We showed that TLR3 is highly expressed on mouse microvascular endothelial cell (ECs) and the endothelium of cardiac grafts. We demonstrated that TLR3 interacting with dsRNA or self-RNA triggered apoptosis and necroptosis in ECs. Interestingly, TLR3-induced necroptosis led mitochondrial damage. Inhibition of the mitochondrial membrane permeability molecule Cyclophilin D prevented necroptosis in ECs. In vivo, endothelium damage and activities of caspase-3 and mixed lineage kinase domain-like protein were inhibited in TLR3-/- cardiac grafts compared with C57BL/6 grafts posttransplant (n = 5, p < .001). Importantly, TLR3-/- cardiac grafts had prolonged survival in allogeneic BALB/c mice (mean survival = 121 ± 67 vs. 31 ± 6 days of C57BL/6 grafts, n = 7, p = .002). In summary, our study suggests that TLR3 is an important cell death inducer in ECs and cardiac grafts and thus a potential therapeutic target in preventing cardiac transplant rejection.
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Transplante de Coração , Receptor 3 Toll-Like , Animais , Apoptose , Morte Celular , Transplante de Coração/efeitos adversos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Doadores de Tecidos , Receptor 3 Toll-Like/metabolismoRESUMO
Transplantation is invariably associated with programmed cell death including apoptosis and necrosis, resulting in delayed graft function and organ rejection. We have demonstrated the contribution of necroptosis to mouse microvascular endothelial cell (MVEC) death and transplant rejection. Organ injury results in the opening of mitochondrial permeability transition pores (mPTPs), which can trigger apoptotic molecules release that ultimately results in cell death. The effect of mPTPs in the necroptotic pathway remains controversial; importantly, their role in transplant rejection is not clear. In this study, tumor necrosis factor-α triggered MVECs to undergo receptor-interacting protein kinase family (RIPK1/3)-dependent necroptosis. Interestingly, inhibition of mPTP opening could also inhibit necroptotic cell death. Cyclophilin-D (Cyp-D) is a key regulator of the mPTPs. Both inhibition and deficiency of Cyp-D protected MVECs from necroptosis (n = 3, P < .00001). Additionally, inhibition of Cyp-D attenuated RIPK3-downstream mixed-lineage kinase domain-like protein phosphorylation. In vivo, Cyp-D-deficient cardiac grafts showed prolonged survival in allogeneic BALB/c mice posttransplant compared with wild-type grafts (n = 7, P < .0001). Our study results suggest that the mPTPs may be important mechanistic mediators of necroptosis in cardiac grafts. There is therapeutic potential in targeting cell death via inhibition of the mPTP-regulating molecule Cyp-D to prevent cardiac graft rejection.
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Permeabilidade da Membrana Celular , Células Endoteliais/patologia , Rejeição de Enxerto/etiologia , Transplante de Coração/efeitos adversos , Mitocôndrias/patologia , Necroptose , Peptidil-Prolil Isomerase F/metabolismo , Aloenxertos , Animais , Peptidil-Prolil Isomerase F/genética , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Doadores de Tecidos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
PURPOSE: Lactotroph adenomas (LA) are the most frequently encountered pituitary tumors. Although more frequently observed in women, LAs in men were recently included in a more aggressive category regardless of histological grading, by the WHO. We aimed to perform a rigorous retrospective review of a single center's pre-operative evaluation, patient characteristics and outcomes of male LAs patients requiring pituitary surgery. METHODS: A retrospective review, over 11 years, of patients who underwent resection of a pituitary adenoma at a single center was conducted. Predictors of persistent disease in male LAs patients along with a comparison to predictors of silent corticotroph adenomas (SCAs) patients who also underwent surgery at the center was also conducted. RESULTS: Thirty-one male patients with LAs were identified. When compared to SCAs patients, LAs male patients were younger (41 vs. 50 years of age, p = 0.01). Men with LAs had more invasive tumors (75% vs. 44.7% p = 0.02). More LAs in men had residual tumor after surgery than patients with SCA (92.6% vs. 42.1%, p < 0.001). Male patients with LAs and patients with SCA had similar rates of requiring additional surgery (28.9% vs. 24.1%, p = NS) and radiation therapy (18.4% vs. 19.4%, p = NS). CONCLUSIONS: High rates of DA resistance, invasive tumors and postoperative residual disease in male patients with LA who required surgery are shown. Surgery improved optic chiasm compression, PRL level and central hypogonadism but, not surprisingly, failed to normalize other pituitary hormones and/or eliminate need for DA therapy.
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Hipófise/patologia , Prolactinoma/cirurgia , Prolactinoma/terapia , Adenoma Hipofisário Secretor de ACT/tratamento farmacológico , Adenoma Hipofisário Secretor de ACT/patologia , Adenoma Hipofisário Secretor de ACT/cirurgia , Adulto , Agonistas de Dopamina/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Hipófise/efeitos dos fármacos , Hipófise/cirurgia , Prolactinoma/tratamento farmacológico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A new catalytic system based on the readily available Zn, (i)PrI, H8BINOL, and Ti(O(i)Pr)4 has been developed which avoids the use of pyrophoric ZnEt2. It can effectively catalyze the reaction of various terminal alkynes with aromatic, aliphatic, and vinyl aldehydes to generate chiral propargylic alcohols at room temperature with up to 98% yield and 98% enantiomeric excess. This new system signifciantly expands the substrate scope of the previously reported system using Zn, EtI, BINOL, and Ti(O(i)Pr)4.
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Background and Aims: Maxillofacial surgeries, including procedures to the face, oral cavity, jaw, and head and neck, are common in adults. However, they impose a risk of adverse cardiac events (ACEs). While ACEs are well understood for other non-cardiac surgeries, there is a paucity of data about maxillofacial surgeries. This systematic review and meta-analysis report the incidence and presentation of perioperative ACEs during maxillofacial surgery. Methods: We included primary studies that reported on perioperative ACEs in adults. To standardise reporting, ACEs were categorised as 1. heart rate and rhythm disturbances, 2. blood pressure disturbances, 3. ischaemic heart disease and 4. heart failure and other complications. The primary outcome was ACE presentation and incidence during the perioperative period. Secondary outcomes included the surgical outcome according to the Clavien-Dindo classification and trigeminocardiac reflex involvement. STATA version 17.0 and MetaProp were used to delineate proportion as effect size with a 95% confidence interval (CI). Results: Twelve studies (34,227 patients) were included. The incidence of perioperative ACEs was 2.58% (95% CI 1.70, 3.45, I2 = 96.17%, P = 0.001). Heart rate and rhythm disturbances resulted in the greatest incidence at 3.84% among the four categories. Most commonly, these ACEs resulted in intensive care unit admission (i.e. Clavien-Dindo score of 4). Conclusion: Despite an incidence of 2.58%, ACEs can disproportionately impact surgical outcomes. Future research should include large-scale prospective studies that may provide a better understanding of the contributory factors and long-term effects of ACEs in patients during maxillofacial surgery.
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Background: Reverse total shoulder arthroplasty (RTSA) has evolved beyond its initial indication for elderly patients with rotator cuff arthropathy and is now performed in younger patients for various shoulder pathologies. This surgical procedure has recently gained popularity and has been shown to result in similar functional improvements and complication rates compared to anatomical total shoulder arthroplasty. Scapular posture and sagittal spine alignment (SSPA) have recently emerged as factors potentially influencing RTSA outcomes. This scoping review aimed to assess the existing body of evidence on this topic. Methods: A systematic search was conducted on MEDLINE, Embase, and CENTRAL databases to evaluate the impact of scapular posture and SSPA on RTSA outcomes. Results: A total of 6 studies (616 shoulders) were included in this review. Scapular posture was found to influence RTSA outcomes, with studies reporting correlations between scapular posture with postoperative range of motion and functional scores. Suboptimal scapular posture, particularly type C (kyphotic posture with protracted scapulae), appeared to be associated with reduced external rotation. However, findings among the included studies regarding SSPA were varied. Some studies suggested that SSPA, notably thoracic kyphosis, might impact RTSA outcomes by influencing scapular posture, while others did not find a clear relationship. Conclusion: Scapular posture was implicated as a potential factor affecting RTSA outcomes; however, the role of SSPA remains inconclusive. There is currently a lack of high-quality evidence in the literature to draw definitive conclusions regarding the impact of scapular posture and SSPA on RTSA outcomes. More research is warranted to investigate these relationships more comprehensively.
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Neurological and cardiovascular disorders are the leading causes of morbidity and mortality worldwide. While the effects of cardiovascular disease (CD) on the nervous system are well understood, understanding of the reciprocal relationship has only recently become clearer. Based on disability-adjusted life years, this systematic review and meta-analysis present the pooled incidence and association of CD in 4 selected common, noncommunicable neurological disorders: (1) migraine, (2) Alzheimer disease and other dementias, (3) epilepsy, and (4) head injury. Sixty-five studies, including over 4 and a half million patients, were identified for inclusion in this review. Among the 4 neurological disorders, the majority of patients (89.4%) had epilepsy, 9.6% had migraine, and 0.97% had head injury. Alzheimer disease and other dementias were reported in only 0.02% of patients. The pooled effect estimates (incidence and association) of CD in the 4 neurological disorders was 10% (95% CI: 5.8%-16.9%; I2 = 99.94%). When stratified by the neurological disorder, head injury was associated with the highest incidence of CD (28%). The 4 neurological disorders were associated with a 2-fold increased odds for developing CD in comparison to patients without neurological disorders. Epilepsy was associated with the greatest increased odds of developing CD (odds ratio: 2.25; 95% CI: 1.82-2.79; P = 0.04). In studies that reported this variable, the pooled hazard ratio was 1.64 (95% CI: 1.38-1.94), with head injury having the highest hazard ratio (2.17; 95% CI: 1.30-3.61). Large prospective database studies are required to understand the long-term consequences of CD in patients with neurological disorders.
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Multimorbidity (multiple conditions) and polypharmacy (multiple medications) are increasingly common, yet there is a need to better understand the prevalence of co-occurrence. In this systematic review, we examined the prevalence of multimorbidity and polypharmacy among adults (≥18 years) and older adults (≥65 years) in clinical and community settings. Six electronic databases were searched, and 87 studies were retained after two levels of screening. Most studies focused on adults 65 years and older and were done in population-based community settings. Although the operational definitions of multimorbidity and polypharmacy varied across studies, consistent cut-points (two or more conditions and five or more medications) were used across most studies. In older adult samples, the prevalence of multimorbidity ranged from 4·8% to 93·1%, while the prevalence of polypharmacy ranged from 2·6% to 86·6%. High heterogeneity between studies indicates the need for more consistent reporting of specific lists of conditions and medications used in operational definitions.
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Multimorbidade , Polimedicação , Humanos , Prevalência , Idoso , Adulto , Idoso de 80 Anos ou maisRESUMO
CONTEXT: Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility largely caused by defects in structure, synthesis, or post-translational processing of type I collagen. The effectiveness of medications used for fracture reduction in adults with OI is understudied and practice recommendations are not well established. Drugs currently used to improve skeletal health in OI were initially developed to treat osteoporosis. Oral and intravenous bisphosphonates have been shown to improve bone mineral density (BMD) in adults with OI and are commonly used; however, conclusive data confirming fracture protection are lacking. Similarly, teriparatide appears to increase BMD, an effect that seems to be limited to individuals with type I OI. The role of denosumab, abaloparatide, romosozumab, and estradiol/testosterone in adult OI have not been systematically studied. Anti-sclerostin agents and transforming growth factor-beta antagonists are under investigation in clinical trials. OBJECTIVE: This review summarizes current knowledge on pharmacologic treatment options for reducing fracture risk in adults with OI. METHODS: A PubMed online database search of all study types published in the English language using the terms "osteogenesis imperfecta," "OI," and "brittle bone disease" was performed in June 2022. Articles screened were restricted to adults. Additional sources were identified through manual searches of reference lists. CONCLUSION: Fracture rates are elevated in adults with OI. Although clinical trial data are limited, bisphosphonates and teriparatide may be useful in improving BMD. Further research is needed to develop medications for adults with OI that will lead to definite fracture rate reduction.
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Conservadores da Densidade Óssea , Fraturas Ósseas , Osteogênese Imperfeita , Adulto , Humanos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/tratamento farmacológico , Teriparatida/uso terapêutico , Teriparatida/farmacologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Difosfonatos/uso terapêutico , Densidade Óssea , Fixação de Fratura/efeitos adversosRESUMO
OBJECTIVES: Letermovir for cytomegalovirus (CMV) prophylaxis in allogeneic haematopoietic cell transplant (HCT) recipients has decreased anti-CMV therapy use. Contrary to letermovir, anti-CMV antivirals are also active against human herpesvirus-6 (HHV-6). We assessed changes in HHV-6 epidemiology in the post-letermovir era. METHODS: We conducted a retrospective cohort study of CMV-seropositive allogeneic HCT recipients comparing time periods before and after routine use of prophylactic letermovir. HHV-6 testing was at the discretion of clinicians. We computed the cumulative incidence of broad-spectrum antiviral initiation (foscarnet, (val)ganciclovir, and/or cidofovir), HHV-6 testing, and HHV-6 detection in blood and cerebrospinal fluid within 100 days after HCT. We used Cox proportional-hazards models with stabilized inverse probability of treatment weights to compare outcomes between cohorts balanced for baseline factors. RESULTS: We analysed 738 patients, 376 in the pre-letermovir and 362 in the post-letermovir cohort. Broad-spectrum antiviral initiation incidence decreased from 65% (95% CI, 60-70%) pre-letermovir to 21% (95% CI, 17-25%) post-letermovir. The cumulative incidence of HHV-6 testing (17% [95% CI, 13-21%] pre-letermovir versus 13% [95% CI, 10-16%] post-letermovir), detection (3% [95% CI, 1-5%] in both cohorts), and HHV-6 encephalitis (0.5% [95% CI, 0.1-1.8%] pre-letermovir and 0.6% [95% CI, 0.1-1.9%] post-letermovir) were similar between cohorts. First HHV-6 detection occurred at a median of 37 days (interquartile range, 18-58) in the pre-letermovir cohort and 27 (interquartile range, 25-34) in the post-letermovir cohort. In a weighted model, there was no association between the pre-versus post-letermovir cohort and HHV-6 detection (adjusted hazard ratio, 1.08; 95% CI, 0.44-2.62). DISCUSSION: Despite a large decrease in broad-spectrum antivirals after the introduction of letermovir prophylaxis in CMV-seropositive allogeneic HCT recipients, there was no evidence for increased clinically detected HHV-6 reactivation and disease.
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Sulfur is an essential element of life that is assimilated by Earth's biosphere through the chemical breakdown of pyrite. On the early Earth, pyrite weathering by atmospheric oxygen was severely limited, and low marine sulfate concentrations persisted for much of the Archean eon. Here, we show an anoxic photochemical mechanism of pyrite weathering that could have provided substantial amounts of sulfate to the oceans as continents formed in the late Archean. Pyrite grains suspended in anoxic ferrous iron solutions produced millimolar sulfate concentrations when irradiated with ultraviolet light. The Fe2+(aq) was photooxidized, which, in turn, led to the chemical oxidation of pyritic sulfur. Additional experiments conducted with 2.68 Ga shale demonstrated that photochemically derived ferric iron oxidizes and dissolves sedimentary pyrite during chemical weathering. The results suggest that before the rise of atmospheric oxygen, oxidative pyrite weathering on Archean continents was controlled by the exposure of land to sunlight.
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INTRODUCTION: Cold ischemia-reperfusion injury (IRI) is an inevitable event that increases post-transplant complications. We have previously demonstrated that supplementation of University of Wisconsin (UW) solution with non-FDA-approved hydrogen sulfide (H2S) donor molecules minimizes cold IRI and improves renal graft function after transplantation. The present study investigates whether an FDA-approved H2S donor molecule, sodium thiosulfate (STS), will have the same or superior effect in a clinically relevant rat model of syngeneic orthotopic kidney transplantation. METHOD: Thirty Lewis rats underwent bilateral nephrectomy followed by syngeneic orthotopic transplantation of the left kidney after 24-hour preservation in either UW or UW+STS solution at 4 °C. Rats were monitored to post-transplant day 14 and sacrificed to assess renal function (urine output, serum creatinine and blood urea nitrogen). Kidney sections were stained with H&E, TUNEL, CD68, and myeloperoxidase (MPO) to detect acute tubular necrosis (ATN), apoptosis, macrophage infiltration, and neutrophil infiltration. RESULT: UW+STS grafts showed significantly improved graft function immediately after transplantation, with improved recipient survival compared to UW grafts (p < 0.05). Histopathological examination revealed significantly reduced ATN, apoptosis, macrophage and neutrophil infiltration and downregulation of pro-inflammatory and pro-apoptotic genes in UW+STS grafts compared to UW grafts (p < 0.05). CONCLUSION: We show for the first time that preservation of renal grafts in STS-supplemented UW solution protects against prolonged cold IRI by suppressing apoptotic and inflammatory pathways, and thereby improving graft function and prolonging recipient survival. This could represent a novel clinically applicable therapeutic strategy to minimize the detrimental clinical outcome of prolonged cold IRI in kidney transplantation.
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Transplante de Rim/métodos , Soluções para Preservação de Órgãos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Tiossulfatos/farmacologia , Adenosina/administração & dosagem , Adenosina/farmacologia , Alopurinol/administração & dosagem , Alopurinol/farmacologia , Animais , Apoptose/fisiologia , Nitrogênio da Ureia Sanguínea , Isquemia Fria/efeitos adversos , Creatinina/sangue , Glutationa/administração & dosagem , Glutationa/farmacologia , Insulina/administração & dosagem , Insulina/farmacologia , Testes de Função Renal , Masculino , Soluções para Preservação de Órgãos/administração & dosagem , Rafinose/administração & dosagem , Rafinose/farmacologia , Ratos , Ratos Endogâmicos Lew , Taxa de Sobrevida , Tiossulfatos/administração & dosagemRESUMO
A crucial step towards engineering biological systems is the ability to precisely tune the genetic response to environmental stimuli. In the case of Escherichia coli inducible promoters, our incomplete understanding of the relationship between sequence composition and gene expression hinders our ability to predictably control transcriptional responses. Here, we profile the expression dynamics of 8269 rationally designed, IPTG-inducible promoters that collectively explore the individual and combinatorial effects of RNA polymerase and LacI repressor binding site strengths. We then fit a statistical mechanics model to measured expression that accurately models gene expression and reveals properties of theoretically optimal inducible promoters. Furthermore, we characterize three alternative promoter architectures and show that repositioning binding sites within promoters influences the types of combinatorial effects observed between promoter elements. In total, this approach enables us to deconstruct relationships between inducible promoter elements and discover practical insights for engineering inducible promoters with desirable characteristics.