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Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change ß = 0.7, false discovery rate P = 0.004; ß = 4.1, false discovery rate P = 0.03; and ß = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.
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Cardiopatias Congênitas , Criança , Feminino , Humanos , Masculino , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Córtex Cerebral/crescimento & desenvolvimento , Função Executiva/fisiologia , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/patologia , Imageamento por Ressonância Magnética , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/patologia , Adolescente , Adulto JovemRESUMO
BACKGROUND: SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described. CASES: Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities. MOLECULAR ANALYSES: The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action. CONCLUSION: Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.
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Craniossinostoses , Rádio (Anatomia)/anormalidades , Sinostose , Ulna/anormalidades , Humanos , Masculino , Craniossinostoses/diagnóstico , Craniossinostoses/genética , Rádio (Anatomia)/metabolismo , Ulna/metabolismo , Mutação de Sentido Incorreto/genética , Proteína Smad6/genética , Proteína Smad6/metabolismoRESUMO
BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. CONCLUSION: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.
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Amelogênese Imperfeita , Deficiência Intelectual , Linhagem , Humanos , Animais , Masculino , Feminino , Camundongos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Amelogênese Imperfeita/genética , Amelogênese Imperfeita/patologia , Receptores de Superfície Celular/genética , Proteínas do Tecido Nervoso/genética , Alelos , Criança , Perda Auditiva/genética , Perda Auditiva/patologia , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/patologia , Adulto , Mutação/genética , Adolescente , Pré-Escolar , FenótipoRESUMO
BACKGROUND: Biomarkers with strong predictive capacity towards transplantation outcome for livers undergoing normothermic machine perfusion (NMP) are needed. We investigated lactate clearing capacity as a basic function of liver viability during the first 6â h of NMP. METHODS: A trial conducted in 6 high-volume transplant centres in Europe. All centres applied a back-to-base NMP approach with the OrganOx metra system. Perfusate lactate levels at start, 1, 2, 4 and 6â h of NMP were assessed individually and as area under the curve (AUC) and correlated with EAD (early allograft dysfunction), MEAF (model for early allograft function) and modified L-GrAFT (liver graft assessment following transplantation) scores. RESULTS: A total of 509 livers underwent ≥6â h of NMP before transplantation in 6 centres in the UK, Germany and Austria. The donor age was 53 (40-63) years (median, i.q.r.).The total NMP time was 10.8 (7.9-15.7) h. EAD occurred in 26%, MEAF was 4.72 (3.54-6.05) and L-GrAFT10 -0.96 (-1.52--0.32). Lactate at 1, 2 and 6â h correlated with increasing robustness with MEAF. Rather than a binary assessment with a cut-off value at 2â h, the actual 2â h lactate level correlated with the MEAF (P = 0.0306 versus P = 0.0002, Pearson r = 0.01087 versus r = 0.1734). The absolute lactate concentration at 6â h, the AUC of 0-6â h and 1-6â h (P < 0.0001, r = 0.3176) were the strongest predictors of MEAF. CONCLUSION: Lactate measured 1-6â h and lactate levels at 6â h correlate strongly with risk of liver allograft dysfunction upon transplantation. The robustness of predicting MEAF by lactate increases with perfusion duration. Monitoring lactate levels should be extended to at least 6â h of NMP routinely to improve clinical outcome.
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Ácido Láctico , Transplante de Fígado , Perfusão , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Perfusão/métodos , Ácido Láctico/metabolismo , Adulto , Biomarcadores/metabolismo , Preservação de Órgãos/métodos , Sobrevivência de Enxerto , Valor Preditivo dos Testes , Resultado do TratamentoRESUMO
Since the advent of University of Wisconsin preservation solution in the 1980s, clinicians have learned to work within its confines. While affording improved outcomes, considerable limitations still exist and contribute to the large number of livers that go unused each year, often for fear they may never work. The last 10 years have seen the widespread availability of new perfusion modalities which provide an opportunity for assessing organ viability and prolonged organ storage. This review will discuss the role of in situ normothermic regional perfusion for livers donated after circulatory death. It will also describe the different modalities of ex situ perfusion, both normothermic and hypothermic, and discuss how they are thought to work and the opportunities afforded by them.
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Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.
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Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/análogos & derivados , Receptores Citoplasmáticos e Nucleares , Humanos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Animais , Ácidos e Sais Biliares/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacosRESUMO
BACKGROUND: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted. CONCLUSIONS: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.
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Fluconazol , Transplante de Fígado , Meropeném , Perfusão , Humanos , Meropeném/farmacocinética , Meropeném/administração & dosagem , Transplante de Fígado/efeitos adversos , Fluconazol/farmacocinética , Fluconazol/administração & dosagem , Incidência , Masculino , Feminino , Pessoa de Meia-Idade , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Preservação de Órgãos/métodos , Antibioticoprofilaxia/métodos , Estudos Retrospectivos , Fígado/metabolismo , Fígado/microbiologia , Fígado/efeitos dos fármacos , Candidíase/epidemiologia , Candidíase/prevenção & controle , Candidíase/tratamento farmacológico , Candidíase/diagnósticoRESUMO
BACKGROUND: Bile chemistry during normothermic ex situ liver perfusion (NESLiP) has been suggested to be an indicator of cholangiopathy. The normal range of biochemical variables in bile of livers undergoing NESLiP has not been defined, nor have published biliary viability criteria been assessed against instances of posttransplant nonanastomotic bile strictures (NASs). METHODS: The bile and perfusate chemistry of 200 livers undergoing NESLiP between February 1, 2018, and October 30, 2023, was compared. In addition, 11 livers that underwent NESLiP and later developed NAS were selected and their bile chemistry was also examined. RESULTS: In livers that did not develop cholangiopathy, concentrations of sodium, potassium, and chloride were slightly higher in bile than in perfusate, whereas the concentration of calcium was slightly lower. Bile was alkali and had a lower glucose concentration than perfusate. Cholangiocyte glucose reabsorption was shown to saturate at high perfusate concentrations and was more impaired in livers donated after circulatory death than in livers donated after brain death. Published criteria failed to identify all livers that went on to develop NASs. CONCLUSIONS: A significant false-negative rate exists with current biliary viability criteria, probably reflecting the patchy and incomplete nature of the development of NASs in the biliary tree. The data presented here provide a benchmark for future assessment of bile duct chemistry during NESLiP.
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Bile , Transplante de Fígado , Fígado , Preservação de Órgãos , Perfusão , Humanos , Transplante de Fígado/efeitos adversos , Bile/metabolismo , Bile/química , Preservação de Órgãos/métodos , Fígado/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Colestase , Adulto , Estudos Retrospectivos , Constrição PatológicaRESUMO
In recent sea level studies, discrepancies have arisen in ocean mass observations obtained from the Gravity Recovery and Climate Experiment and its successor, GRACE Follow-On, with GRACE estimates consistently appearing lower than density-corrected ocean volume observations since 2015. These disparities have raised concerns about potential systematic biases in sea-level observations, with significant implications for our understanding of this essential climate variable. Here, we reconstruct the global and regional ocean mass change through models of ice and water mass changes on land and find that it closely aligns with both GRACE and density-corrected ocean volume observations after implementing recent adjustments to the wet troposphere correction and halosteric sea level. While natural variability in terrestrial water storage is important on interannual timescales, we find that the net increase in ocean mass over 20 years can be almost entirely attributed to ice wastage and human management of water resources.
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Background: Pneumonia is the most common intensive care unit (ICU)-acquired infection and source of potential sepsis in ICU populations but can be difficult to diagnose in real-time. Despite limited data, rapid initiation of antibiotic agents is endorsed by society guidelines. We hypothesized that a post hoc analysis of a recent randomized pilot study would show no difference between two antibiotic initiation strategies. Patients and Methods: The recent Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP) was a pragmatic cluster-randomized pilot of antibiotic initiation strategies for patients with suspected ICU-acquired pneumonia. Participating ICUs were cluster-randomized to either an immediate initiation protocol or a specimen-initiated protocol where a gram stain was required for initiation of antibiotics. Patients in the study were divided into one of seven mutually exclusive outcome rankings (desirability of outcome ranking; DOOR): (1) Survival, No Pneumonia, No adverse events; (2) Survival, Pneumonia, No adverse events; (3) Survival, No Pneumonia, ventilator-free-alive days ≤14; (4) Survival, Pneumonia, ventilator-free-alive days ≤14; (5) Survival, No Pneumonia, Subsequent episode of suspected pneumonia; (6) Survival, Pneumonia, Subsequent episode of suspected pneumonia; and (7) Death. These rankings were further refined using the duration of antibiotics prescribed for pneumonia (response adjusted for antibiotic risk; RADAR). Results: There were 186 patients enrolled in the study. After applying the DOOR analysis, a randomly selected patient was equally likely to have a better outcome in specimen-initiated arm as in the immediate initiation arm (DOOR probability: 50.8%; 95% confidence interval [CI], 42.7%-58.9%). Outcome probabilities were similar after applying the RADAR analysis (52.5%; 95% CI, 44.2%-60.6%; p = 0.31). Conclusions: We found that patients for whom antibiotic agents were withheld until there was objective evidence (specimen-initiated group) had similar outcome rankings to patients for whom antibiotic agents were started immediately. This supports the findings of the TARPP pilot trial and provides further evidence for equipoise between these two treatment strategies.
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Antibacterianos , Pneumonia Associada à Ventilação Mecânica , Humanos , Antibacterianos/uso terapêutico , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Projetos Piloto , Unidades de Terapia IntensivaRESUMO
BACKGROUND: Normothermic ex situ liver perfusion (NESLiP) has the potential to increase organ utilization. Radiological evidence of localized liver injury due to compression at the time of NESLiP, termed cradle compression, is a recognized phenomenon but is poorly characterized. METHODS: A retrospective analysis of a prospectively collected database was performed of transplanted livers that underwent NESLiP and subsequently had a computed tomography performed within the first 14 d posttransplant. The primary study outcome was 1-y graft survival. RESULTS: Seventy livers (63%) were included in the analysis. Radiological evidence of cradle compression was observed in 21 of 70 (30%). There was no difference in rate of cradle compression between donor after circulatory death and donated after brain death donors ( P â =â 0.37) or with duration of NESLiP. Univariate analysis demonstrated younger (area under the receiver operating characteristic, 0.68; P = 0.008; 95% confidence interval [CI], 0.55-0.82) and heavier (area under the receiver operating characteristic, 0.80; P â <â 0.001; 95% CI, 0.69-0.91) livers to be at risk of cradle compression. Only liver weight was associated with cradle compression on multivariate analysis (odds ratio, 1.003; P â =â 0.005; 95% CI, 1.001-1.005). There was no difference in 1-y graft survival (16/17 [94.1%] versus 44/48 [91.6%]; odds ratio, 0.69; P â =â 0.75; 95% CI, 0.07-6.62). CONCLUSIONS: This is the first study assessing the impact of cradle compression on outcome. We have identified increased donor liver weight and younger age as risk factors for the development of this phenomenon. Increasing utilization of NESLiP will result in the increased incidence of cradle compression but the apparent absence of long-term sequelae is reassuring. Routine postoperative axial imaging may be warranted.
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Sobrevivência de Enxerto , Transplante de Fígado , Fígado , Perfusão , Humanos , Transplante de Fígado/efeitos adversos , Estudos Retrospectivos , Masculino , Perfusão/métodos , Perfusão/efeitos adversos , Feminino , Pessoa de Meia-Idade , Fígado/diagnóstico por imagem , Fígado/irrigação sanguínea , Fígado/patologia , Adulto , Resultado do Tratamento , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Preservação de Órgãos/métodos , Preservação de Órgãos/efeitos adversos , Análise Multivariada , Idoso , Doadores de Tecidos , Tamanho do ÓrgãoRESUMO
On June 3, 2023, the American Society of Transplant Surgeons convened a meeting in San Diego, California to (1) develop a consensus statement with supporting data on the ethical tenets of thoracoabdominal normothermic regional perfusion (NRP) and abdominal NRP; (2) provide guidelines for the standards of practice that should govern thoracoabdominal NRP and abdominal NRP; and (3) develop and implement a central database for the collection of NRP donor and recipient data in the United States. National and international leaders in the fields of neuroscience, transplantation, critical care, NRP, Organ Procurement Organizations, transplant centers, and donor families participated. The conference was designed to focus on the controversial issues of neurological flow and function in donation after circulatory death donors during NRP and propose technical standards necessary to ensure that this procedure is performed safely and effectively. This article discusses major topics and conclusions addressed at the meeting.
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Cirurgiões , Doadores de Tecidos , Humanos , Perfusão , Consenso , Cuidados CríticosRESUMO
Background: The practice of rapidly initiating antibiotic therapy for patients with suspected infection has recently been criticized yet remains commonplace. Provider comfort level has been an understudied aspect of this practice. Hypothesis: We hypothesized that there would be no significant differences in provider comfort level between the two treatment groups. Methods: We prospectively surveyed critical care intensivists who provided care for patients enrolled in the Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP), which was a multicenter cluster-randomized crossover trial that evaluated an immediate antibiotic initiation protocol compared with a protocol of specimen-initiated antibiotic initiation in ventilated patients with suspected new-onset pneumonia. At the end of each enrollment arm, physicians at each center were surveyed regarding their overall comfort level with the recently completed treatment arm, and perception of adherence. Both a paired and unpaired analysis was performed. Results: We collected 51 survey responses from 31 unique participants. Providers perceived a higher rate of adherence to the immediate initiation arm than the specimen-initiated arm (Always Adherent: 37.5% vs. 11.1%; p = 0.045). Providers were less comfortable waiting for objective evidence of infection in the specimen-initiated arm than with starting antibiotic agents immediately (Very Comfortable: 83.3% vs. 40.7%; p = 0.004). For the smaller paired analysis, there was no longer a difference in comfort level. Conclusions: There may be differences in provider comfort levels and perceptions of adherence when considering two different antibiotic initiation strategies for suspected pneumonia in ventilated patients. These findings should be considered when planning future studies.
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Médicos , Pneumonia , Humanos , Antibacterianos/uso terapêutico , Pneumonia/tratamento farmacológico , Cuidados Críticos , HospitaisRESUMO
BACKGROUND: Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes. METHODS: In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months). DISCUSSION: This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. TRIAL REGISTRATION: ISRCTN ISRCTN14957538. Registered in October 2022.
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Fígado Gorduroso , Transplante de Fígado , Perfusão , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Transplante de Fígado/métodos , Perfusão/métodos , Fígado Gorduroso/terapia , Doadores de Tecidos/provisão & distribuição , Fígado/patologia , Estudos Multicêntricos como Assunto , Preservação de Órgãos/métodos , Fatores de Tempo , Resultado do TratamentoRESUMO
Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the disease is associated with the presence of the parasite in the periphery and the second stage with the presence of the parasites in the CNS. The treatment of CNS stage HAT requires the drugs to cross the blood-brain barrier (BBB). Eflornithine is an amino acid analogue that is used to treat second stage HAT gambiense both alone and in combination with nifurtimox. Recent studies have identified that accumulation of eflornithine into the parasites (trypanosomes) involves the amino acid transporter (Trypanosoma brucei AAT6). In this study we tested the hypothesis that eflornithine uses a cationic amino acid transport system to cross the BBB. We particularly focused on system-y+ and system-B0,+. To do this we utilized specialist databases to compare the physicochemical characteristics of relevant molecules and an in vitro model of the BBB to explore the mechanisms of eflornithine delivery into the CNS. Our results confirmed that eflornithine is related to the endogenous amino acid, ornithine. At pH 7.4, eflornithine is predominately (92.39%) a zwitterionic (dipolar) amino acid and ornithine is predominately (99.08%) a cationic (tripolar) amino acid. In addition, the gross charge distribution at pH 7.4 of eflornithine is much smaller (+0.073) than that of ornithine (+0.99). Further results indicated that eflornithine utilized a saturable transport mechanism(s) to cross the hCMEC/D3 cell membranes and that transport was inhibited by the presence of other amino acids including ornithine. Eflornithine transport was also sodium-independent and sensitive to a y+-system inhibitor, but not a B0,+-system inhibitor. Eflornithine transport was also inhibited by pentamidine, suggestive of transport by organic cation transporters (OCT) which are expressed in this cell line. We confirmed expression of the y+-system protein, CAT1, and the B0,+-system protein, ATB0,+, in the hCMEC/D3 cells. We conclude that eflornithine uses the cationic amino acid transporter, system y+, and OCT to cross the BBB. This research highlights the potential of system-y+ to deliver drugs, including eflornithine, across the BBB to treat brain diseases.