RESUMO
Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.
Assuntos
Antígenos de Histocompatibilidade Classe I , Mycobacterium tuberculosis , Receptores de Antígenos de Linfócitos T , Linfócitos T , Mycobacterium tuberculosis/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Linfócitos T/imunologia , Antígenos HLA-E , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Tuberculose/imunologiaRESUMO
Naturally occurring T cells that recognize microbial peptides via HLA-E, a nonpolymorphic HLA class Ib molecule, could provide the foundation for new universal immunotherapeutics. However, confidence in the biological relevance of putative ligands is crucial, given that the mechanisms by which pathogen-derived peptides can access the HLA-E presentation pathway are poorly understood. We systematically interrogated the HIV proteome using immunopeptidomic and bioinformatic approaches, coupled with biochemical and cellular assays. No HIV HLA-E peptides were identified by tandem mass spectrometry analysis of HIV-infected cells. In addition, all bioinformatically predicted HIV peptide ligands (>80) were characterized by poor complex stability. Furthermore, infected cell elimination assays using an affinity-enhanced T cell receptor bispecific targeted to a previously reported HIV Gag HLA-E epitope demonstrated inconsistent presentation of the peptide, despite normal HLA-E expression on HIV-infected cells. This work highlights the instability of the HIV HLA-E peptidome as a major challenge for drug development.
Assuntos
Infecções por HIV , Antígenos HLA-E , Humanos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Epitopos , Infecções por HIV/terapia , Peptídeos/metabolismoRESUMO
The nonpolymorphic class Ib molecule, HLA-E, primarily presents peptides from HLA class Ia leader peptides, providing an inhibitory signal to NK cells via CD94/NKG2 interactions. Although peptides of pathogenic origin can also be presented by HLA-E to T cells, the molecular basis underpinning their role in antigen surveillance is largely unknown. Here, we solved a co-complex crystal structure of a TCR with an HLA-E presented peptide (pHLA-E) from bacterial (Mycobacterium tuberculosis) origin, and the first TCR-pHLA-E complex with a noncanonically presented peptide from viral (HIV) origin. The structures provided a molecular foundation to develop a novel method to introduce cysteine traps using non-natural amino acid chemistry that stabilized pHLA-E complexes while maintaining native interface contacts between the TCRs and different pHLA-E complexes. These pHLA-E monomers could be used to isolate pHLA-E-specific T cells, with obvious utility for studying pHLA-E restricted T cells, and for the identification of putative therapeutic TCRs.
Assuntos
Aminoácidos , Antígenos HLA , Antígenos de Histocompatibilidade Classe I , Peptídeos , Receptores de Antígenos de Linfócitos T , Antígenos HLA-ERESUMO
The molecular rules driving TCR cross-reactivity are poorly understood and, consequently, it is unclear the extent to which TCRs targeting the same Ag recognize the same off-target peptides. We determined TCR-peptide-HLA crystal structures and, using a single-chain peptide-HLA phage library, we generated peptide specificity profiles for three newly identified human TCRs specific for the cancer testis Ag NY-ESO-1157-165-HLA-A2. Two TCRs engaged the same central peptide feature, although were more permissive at peripheral peptide positions and, accordingly, possessed partially overlapping peptide specificity profiles. The third TCR engaged a flipped peptide conformation, leading to the recognition of off-target peptides sharing little similarity with the cognate peptide. These data show that TCRs specific for a cognate peptide recognize discrete peptide repertoires and reconciles how an individual's limited TCR repertoire following negative selection in the thymus is able to recognize a vastly larger antigenic pool.
Assuntos
Antígeno HLA-A2/imunologia , Antígenos de Histocompatibilidade/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linhagem Celular , Humanos , Biblioteca de PeptídeosRESUMO
BACKGROUND AND AIMS: Therapies for chronic hepatitis B virus (HBV) infection are urgently needed because of viral integration, persistence of viral antigen expression, inadequate HBV-specific immune responses, and treatment regimens that require lifelong adherence to suppress the virus. Immune mobilizing monoclonal T Cell receptors against virus (ImmTAV) molecules represent a therapeutic strategy combining an affinity-enhanced T Cell receptor with an anti-CD3 T Cell-activating moiety. This bispecific fusion protein redirects T cells to specifically lyse infected cells expressing the target virus-derived peptides presented by human leukocyte antigen (HLA). APPROACH AND RESULTS: ImmTAV molecules specific for HLA-A*02:01-restricted epitopes from HBV envelope, polymerase, and core antigens were engineered. The ability of ImmTAV-Env to activate and redirect polyclonal T cells toward cells containing integrated HBV and cells infected with HBV was assessed using cytokine secretion assays and imaging-based killing assays. Elimination of infected cells was further quantified using a modified fluorescent hybridization of viral RNA assay. Here, we demonstrate that picomolar concentrations of ImmTAV-Env can redirect T cells from healthy and HBV-infected donors toward hepatocellular carcinoma (HCC) cells containing integrated HBV DNA resulting in cytokine release, which could be suppressed by the addition of a corticosteroid in vitro. Importantly, ImmTAV-Env redirection of T cells induced cytolysis of antigen-positive HCC cells and cells infected with HBV in vitro, causing a reduction of hepatitis B e antigen and specific loss of cells expressing viral RNA. CONCLUSIONS: The ImmTAV platform has the potential to enable the elimination of infected cells by redirecting endogenous non-HBV-specific T cells, bypassing exhausted HBV-specific T cells. This represents a promising therapeutic option in the treatment of chronic hepatitis B, with our lead candidate now entering trials.
Assuntos
Vírus da Hepatite B/imunologia , Hepatite B Crônica/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Proteínas Recombinantes de Fusão/farmacologia , Linfócitos T/efeitos dos fármacos , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Complexo CD3/antagonistas & inibidores , Linhagem Celular Tumoral , Epitopos/imunologia , Antígeno HLA-A2/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Hepatócitos , Humanos , Imunoconjugados/genética , Imunoconjugados/imunologia , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Ativação Linfocitária/efeitos dos fármacos , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Linfócitos T/imunologiaRESUMO
A series of lysine-based vinyl sulfone peptidomimetics were synthesised and evaluated for anti-trypanosomal activity against bloodstream forms of T. brucei. This focused set of compounds, varying in the P3 position, were accessed in a divergent manner from a common intermediate (ammonium salt 8). Several P3 analogues exhibited sub-micromolar EC50 values, with thiourea 14, urea 15 and amide 21 representing the most potent anti-trypanosomal derivatives of the series. In order to establish an in vitro selectivity index the most active anti-trypanosomal compounds were also assessed for their impact on cell viability and cytotoxity effects in mammalian cells. Encouragingly, all compounds only reduced cellular metabolic activity in mammalian cells to a modest level and little, or no cytotoxicity, was observed with the series.
Assuntos
Sulfonas/química , Tripanossomicidas/síntese química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Humanos , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/farmacologia , Tioureia/química , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and ß with low nanomolar affinity and <20-fold selectivity for α over ß and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERß (compound 42; 170-fold selectivity).
Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Antineoplásicos/química , Benzopiranos/química , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura MolecularRESUMO
BACKGROUND: Randomized controlled trials demonstrate that timely introduction of peanut to infants reduces the risk of peanut allergy. However, much debate remains regarding how to best achieve earlier peanut introduction at the population level. Our previous study in 2007-2011 (HealthNuts, n = 5300) indicated that few infants were consuming peanut in the first year. Australian infant feeding guidelines were updated in 2016 to recommend introducing peanut before 12 months for all infants. There were no data available on the subsequent effect on peanut introduction or peanut reactions. OBJECTIVE: We sought to assess the consequences of a nonscreening approach to allergenic food introduction in a population-based sample of infants in their first year of life. METHODS: EarlyNuts is a population-based, cross-sectional study of 12-month-old infants in Melbourne, Australia, recruited by using an identical sampling frame and methods to HealthNuts (72% response rate vs 73% response rate in HealthNuts). We report here on the first 860 participants recruited between November 2016 and October 2018. RESULTS: Most infants (88.6%; 95% CI, 86.1% to 90.7%) had introduced peanut by 12 months (median age, 6 months), an increase from 28.4% (95% CI, 27.2% to 29.7%) in the HealthNuts study. By 12 months, the majority of these (76.4%) had consumed peanut more than 4 times, and 28% were eating peanut more than once per week. Preliminary results on parent-reported reactions show that 4.0% of those consuming peanut by 12 months had possible IgE-mediated reactions. CONCLUSIONS: There has been a striking shift toward earlier peanut introduction, with a 3-fold increase in peanut introduction by age 1 year in 2018 compared with 2007-2011.
Assuntos
Dietoterapia , Hipersensibilidade a Amendoim/epidemiologia , Grupos Populacionais , Alérgenos/imunologia , Arachis/imunologia , Austrália/epidemiologia , Estudos Transversais , Feminino , Humanos , Imunoglobulina E/metabolismo , Lactente , Recém-Nascido , Masculino , Hipersensibilidade a Amendoim/imunologia , Prevalência , Testes CutâneosRESUMO
Haemostatic disorders are both complex and costly in relation to both their treatment and subsequent management. As leading causes of mortality worldwide, there is an ever-increasing drive to improve the diagnosis and prevention of haemostatic disorders. The field of microfluidic and Lab on a Chip (LOC) technologies is rapidly advancing and the important role of miniaturised diagnostics is becoming more evident in the healthcare system, with particular importance in near patient testing (NPT) and point of care (POC) settings. Microfluidic technologies present innovative solutions to diagnostic and clinical challenges which have the knock-on effect of improving health care and quality of life. In this review, both advanced microfluidic devices (R&D) and commercially available devices for the diagnosis and monitoring of haemostasis-related disorders and antithrombotic therapies, respectively, are discussed. Innovative design specifications, fabrication techniques, and modes of detection in addition to the materials used in developing micro-channels are reviewed in the context of application to the field of haemostasis.
Assuntos
Técnicas Biossensoriais , Hemostasia , Transtornos Hemostáticos/diagnóstico , Microfluídica/métodos , Transtornos Hemostáticos/patologia , Humanos , Dispositivos Lab-On-A-Chip , Sistemas Automatizados de Assistência Junto ao Leito , Qualidade de VidaRESUMO
The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3' region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.
Assuntos
Amidoidrolases/antagonistas & inibidores , Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Piridazinas/farmacologia , Infecções Respiratórias/tratamento farmacológico , Dermatopatias Infecciosas/tratamento farmacológico , Amidoidrolases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/enzimologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Infecções Respiratórias/metabolismo , Dermatopatias Infecciosas/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/enzimologia , Relação Estrutura-AtividadeRESUMO
Ribosome production is an essential cellular process involving a plethora of trans-acting factors, such as nucleases, methyltransferases, RNA helicases and kinases that catalyse key maturation steps. Precise temporal and spatial regulation of such enzymes is essential to ensure accurate and efficient subunit assembly. Here, we focus on the maturation of the 3' end of the 18S rRNA in human cells. We reveal that human RIO2 is an active kinase that phosphorylates both itself and the rRNA methyltransferase DIM1 in vitro. In contrast to yeast, our data confirm that human DIM1 predominantly acts in the nucleus and we further demonstrate that the 21S pre-rRNA is the main target for DIM1-catalysed methylation. We show that the PIN domain of the endonuclease NOB1 is required for site 3 cleavage, while the zinc ribbon domain is essential for pre-40S recruitment. Furthermore, we also demonstrate that NOB1, PNO1 and DIM1 bind to a region of the pre-rRNA encompassing the 3' end of 18S and the start of ITS1, in vitro. Interestingly, NOB1 is present in the cell at higher levels than other pre-40S factors. We provide evidence that NOB1 is multimeric within the cell and show that NOB1 multimerisation is lost when ribosome biogenesis is blocked. Taken together, our data indicate a dynamic interplay of key factors associated with the 3' end of the 18S rRNA during human pre-40S biogenesis and highlight potential mechanisms by which this process can be regulated.
Assuntos
Processamento Pós-Transcricional do RNA , RNA Ribossômico 18S/genética , Técnicas de Silenciamento de Genes , Humanos , Metilação , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Conformação de Ácido Nucleico , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , RNA Ribossômico 18S/química , RNA Ribossômico 18S/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismoRESUMO
OBJECTIVE: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. METHODS: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. RESULTS: Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. SIGNIFICANCE: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.
Assuntos
Epilepsia Tipo Ausência/patologia , Epilepsia Tipo Ausência/terapia , Modelos Biológicos , Córtex Cerebral/fisiopatologia , Epilepsia Tipo Ausência/genética , Humanos , Canais Iônicos/genética , Vias Neurais/fisiopatologia , Neurônios , Receptores de GABA/genética , Tálamo/fisiopatologiaRESUMO
Background: Sarcoidosis is a multisystem inflammatory disease of unknown etiology. It is uncommon, with an incidence of approximately 16.5 per 100,000 men.1 It is characterized by noncaseating epithelioid granulomata that typically affect the chest, skin, eyes, and, much less commonly, the genital system (<0.2% of cases). Sarcoidosis can affect any of the scrotal structures, although due to its rarity, investigation of solid masses of the testes are largely targeted towards excluding either a malignant or infective etiology.² Case: We report a rare case of a 27-year-old male who presented with bilateral testicular and neck swellings. He underwent orchidectomy, and histopathology demonstrated sarcoidosis. He subsequently developed both pituitary and testicular sarcoidosis resulting in azoospermia. Through the administration of gonadotropins and surgical sperm retrieval we were able to retrieve sperm suitable for assisted reproductive technologies. Conclusion: This case illustrates the difficulties faced in managing the fertility of men who develop systemic sarcoidosis. It also highlights the diagnostic and therapeutic challenges faced by physicians when presented with a case of systemic sarcoidosis.
Assuntos
Sarcoidose/diagnóstico , Sarcoidose/terapia , Recuperação Espermática , Doenças Testiculares/diagnóstico , Doenças Testiculares/terapia , Adulto , Azoospermia/etiologia , Gonadotropinas/uso terapêutico , Humanos , Masculino , Sarcoidose/complicações , Doenças Testiculares/complicações , Testículo/patologiaRESUMO
The estrogen receptors (ERα and ERß) which are ligand inducible nuclear receptors are recognized as pharmaceutical targets for diseases such as osteoporosis and breast cancer. There is an increasing interest in the discovery of subtype Selective Estrogen Receptor Modulators (SERMs). A series of novel ß-lactam compounds with estrogen receptor modulator properties have been synthesized. The antiproliferative effects of these compounds on human MCF-7 breast tumor cells are reported, together with binding affinity for the ERα and ERß receptors. The most potent compound 15g demonstrated antiproliferative effects on MCF-7 breast tumor cells (IC50 = 186 nM) and ERα binding (IC50 = 4.3 nM) with 75-fold ERα/ß receptor binding selectivity. The effect of positioning of the characteristic amine containing substituted aryl ring (on C-4 or N-1 of the ß-lactam scaffold) on the antiproliferative activity and ER-binding properties of the ß-lactam compounds is rationalized in a molecular modeling study.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , beta-Lactamas/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Receptor Estrogênico/síntese química , Receptor beta de Estrogênio/antagonistas & inibidores , Humanos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , beta-Lactamas/síntese químicaRESUMO
A surfactant-free solution methodology, simply using water as a solvent, has been developed for the straightforward synthesis of single-phase orthorhombic SnSe nanoplates in gram quantities. Individual nanoplates are composed of {100} surfaces with {011} edge facets. Hot-pressed nanostructured compacts (Eg ≈0.85â eV) exhibit excellent electrical conductivity and thermoelectric power factors (S(2) σ) at 550â K. S(2) σ values are 8-fold higher than equivalent materials prepared using citric acid as a structure-directing agent, and electrical properties are comparable to the best-performing, extrinsically doped p-type polycrystalline tin selenides. The method offers an energy-efficient, rapid route to p-type SnSe nanostructures.
RESUMO
BACKGROUND: An ingrown toenail or onychocryptosis may occur at any age and is the mostly commonly encountered toenail problem likely to be seen in general practice. OBJECTIVE: This article will discuss the common surgical approaches available for the management of an ingrown toenail. DISCUSSION: Ingrown toenail can be a painful condition that can become infected and may require surgical treatment. The epidemiology of onychocryptosis is difficult to determine as it is often considered to be a minor medical problem and as such has been some-what neglected in the literature. The few studies that have been conducted suggest a slightly higher male-to-female ratio, particularly in the 14-25 age group,4 but it can affect patients of any age. There are multiple reasons why an ingrown toenail will develop, including improper nail cutting technique, tight-fitting footwear, trauma, anatomical factors such as thickening of the nail plate, pincer-shaped toenail, pressure from abutting digits caused by hallux valgus or lesser toe deformities, the presence of a subungual exostosis and, occasionally, the use of isotretinoin in the treatment of severe acne.
Assuntos
Medicina Geral/métodos , Unhas Encravadas/diagnóstico , Unhas Encravadas/terapia , Gerenciamento Clínico , Humanos , Dedos do PéRESUMO
An improved, Weinreb amide-based, synthesis of anti-trypanosomal lysine-containing vinyl sulfones is described incorporating, as a feature, diversity at the ε-lysine amino group. Members of this family demonstrated moderate to good efficacy as anti-trypanosomal agents and a fluorescent dansyl (19) derivative was used to investigate subcellular localisation of the compound class.
Assuntos
Dipeptídeos/química , Sulfonas/química , Sulfonas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Transporte Biológico , Técnicas de Química Sintética , Espaço Intracelular/metabolismo , Sulfonas/síntese química , Sulfonas/metabolismo , Tripanossomicidas/síntese química , Tripanossomicidas/metabolismoRESUMO
Prosopagnosia, a neurological condition affecting perception and differentiation of faces, is categorized as either acquired or developmental (present since birth). Acquired cases of prosopagnosia are usually caused by right hemisphere or bilateral damage. We present a right-handed 17-year-old male with a history of focal epilepsy and a new diagnosis of prosopagnosia due to a perinatal stroke affecting the left lingual gyrus, a structure in close proximity to the fusiform face area. In addition to showing that early acquired cases of prosopagnosia may go unrecognized, this case shows that left hemisphere lesions may also affect facial recognition. It is important to screen for prosopagnosia via comprehensive neuropsychological evaluation in patients with lesions proximal to the fusiform face area.
RESUMO
Introduction: Neonatal seizures are associated with worsened neurodevelopmental outcomes. Phenobarbital, the only US Food and Drug Administration (FDA)-approved treatment for neonatal seizures, can cause neuronal apoptosis and may worsen neurodevelopmental outcomes. Lacosamide may be an efficacious treatment for neonatal seizures. Methods: We assessed the impact of lacosamide boluses on seizure burden in a retrospective cohort of 15 neonates monitored with video electroencephalography (EEG). Medication bolus times and seizure start/end times on EEG tracings determined change in seizure burden. Results: Seven patients received lacosamide as first- or second-line treatment and 8 as third-line or later. Average 4-hour seizure burden decreased from 13% to 3% following lacosamide boluses (P = .002). Reduction in seizure burden greater than 30% followed 79% of boluses. Lacosamide was well tolerated; one patient experienced mild asymptomatic episodic bradycardia that medication taper resolved. Conclusions: Lacosamide significantly decreased seizure burden in this cohort. Prospective studies of lacosamide treatment for neonatal seizures are warranted.
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BACKGROUND: Bilateral Rasmussen encephalitis is a rare variant of a debilitating, typically unihemispheric disease with limited treatment options. Few cases with bilateral histopathology have been reported, all with poor seizure control following surgery. Here we report a favorable outcome following hemispherotomy in a four-year-old male with biopsy-confirmed bilateral disease. CASE: The patient presented with right hemispheric focal seizures with behavioral arrest and over a year progressed to left lower extremity clonic seizures, epilepsia partialis continua, and loss of ambulation, with transient response to steroids and tacrolimus. Histopathology confirmed bilateral disease. The patient developed super-refractory status epilepticus and underwent right functional hemispherotomy 4.5 years after initial presentation. In a 2.5-year follow-up period, an Engel 1D outcome classification was observed with substantially improved quality of life. CONCLUSION: Previous reports of bilateral Rasmussen encephalitis describe universally poor outcomes, and hemispherotomy is often considered contraindicated. However, hemispherotomy in a patient with bilateral Rasmussen encephalitis may have a good outcome if seizures are unihemispheric.