RESUMO
CONTEXT: As the number of medical school graduates continues to outpace the available residency training positions, applying for residency in the United States has become a highly competitive process, often associated with a low rate of selection and invitation for interview. The National Resident Matching Program (NRMP) Program Director survey provides data assessing factors considered by Program Directors (PD) in selecting and inviting candidates for interview. Assessing the evolution of these factors over time is efficacious to inform and guide prospective applicants toward improving preparation for residency application. OBJECTIVES: We aim to synthesize NRMP data showing factors that PDs reported and rated as important in their decision to select and invite applicants for interview. METHODS: Data from residency PD surveys from 2008 to 2021 were accessed, but after applying inclusion/exclusion criteria, only the data from 2016 to 2020 were reviewed and analyzed. The NRMP survey reports provided two metrics that characterized PDs' evaluation of the residency factors for interview, namely, "percent citing factor" and "average rating" on a 0 to 5 Likert-type scale. These two metrics were combined into an aggregate measure of importance (AI), and another measure of relative importance (RI) was constructed from normalizing the AI of each individual factor to the sum of the AI within each survey year. RESULTS: The top ranked factors were United States Medical Licensing Examination (USMLE) Step 1/Comprehensive Osteopathic Medical Licensing Examination (COMLEX) Level 1, Letter of Recommendation (LOR) in the specialty, Medical Student Performance Evaluation (MSPE/Dean's Letter), and USMLE Step 2 Clinical Knowledge (CK)/COMLEX Level 2 Cognitive Exam (CE) score, any failed attempt in USMLE/COMLEX, and perceived commitment to specialty. Factors rising in importance were Audition Elective/Rotation Within Your Department, Personal Statement (PS), Perceived Commitment to Specialty, Perceived Interest in Program, LOR in the Specialty, Other Life Experience, and Personal Prior Knowledge of the Applicant. Factors with declining importance were Interest in Academic Career, Awards or Special Honors in Basic Sciences, Graduate of Highly Regarded US Medical School, Awards or Special Honors in Clinical Clerkships, Lack of Gaps in Medical Education, Awards or Special Honors in Clerkship in Desired Specialty, and Consistency of Grades. Compared to the 2021 PD survey, our findings show continued predictive consistency, particularly related to specialty and program commitment. CONCLUSIONS: The factors identified for the selection of medical school graduates for interview into a residency program reveal that PDs move toward a more integrated approach. Specifically, PDs are placing increasing emphasis on factors that border on subjective qualities more so than the more traditional, quantitative, and objective metrics. Medical students and educators need to continually apprise themselves of the NRMP data to inform students' preparation endeavors throughout medical school to strengthen their application portfolios and enhance their competitiveness for the matching process.
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Educação Médica , Internato e Residência , Medicina Osteopática , Estudantes de Medicina , Humanos , Estados Unidos , Inquéritos e Questionários , Medicina Osteopática/educaçãoRESUMO
The expression of nicotinic acetylcholine receptors by neurons, microglia, and astrocytes suggests possibly diverse mechanisms by which natural nicotinic cholinergic signaling and exposure to nicotine could modulate immune responses within the CNS. In this study, we show that nicotine exposure significantly delays and attenuates inflammatory and autoimmune responses to myelin Ags in the mouse experimental autoimmune encephalomyelitis model. In the periphery, nicotine exposure inhibits the proliferation of autoreactive T cells and alters the cytokine profile of helper T cells. In the CNS, nicotine exposure selectively reduces numbers of CD11c(+) dendritic and CD11b(+) infiltrating monocytes and resident microglial cells and down-regulates the expression of MHC class II, CD80, and CD86 molecules on these cells. The results underscore roles of nicotinic acetylcholine receptors and nicotinic cholinergic signaling in inflammatory and immune responses and suggest novel therapeutic options for the treatment of inflammatory and autoimmune disorders, including those that affect the CNS.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Autoimunes/imunologia , Doenças Autoimunes/prevenção & controle , Encefalomielite Aguda Disseminada/imunologia , Encefalomielite Aguda Disseminada/prevenção & controle , Imunossupressores/uso terapêutico , Nicotina/uso terapêutico , Sequência de Aminoácidos , Animais , Doenças Autoimunes/patologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Encefalomielite Aguda Disseminada/patologia , Feminino , Glicoproteínas/toxicidade , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteína Proteolipídica de Mielina/toxicidade , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos/toxicidade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
CONTEXT: Uninsured patients living in rural areas of North Carolina have been inordinately affected by the increasing prevalence of sexually transmitted diseases (STDs) in the midst of severe budget cuts to treatment programs and a shortage of rural primary care physicians. The Campbell University Community Care Clinic, a self-funded, student-run clinic, provides free health care to uninsured residents of rural Harnett County. As a relatively new clinic serving a unique population, epidemiologic research is paramount to the clinic's continued efficacy. OBJECTIVE: To determine which STDs are present in this patient population and to identify demographic groups at higher risk of contracting STDs. METHODS: This study was a retrospective analysis of patient medical records from March 1, 2015, to March 6, 2018. Records were evaluated to identify STD cases based on diagnostic information, such as primary diagnoses, positive laboratory results, and clinical indicators. RESULTS: A total of 449 patient records were analyzed, revealing an STD incidence rate of 5.3%, which represents a higher STD frequency than the national average of 2%. Our results identified human papillomavirus infection and gonorrhea as the most frequent STDs (n=7 [29.2%] and n=6 [25%], respectively), followed by chlamydia (n=4 [16.7%]), herpes simplex virus (n=4 [16.7%]), syphilis (n=2 [8.3%]), hepatitis C virus (n=2 [4.2%]), trichomoniasis (n=1 [4.2%]), and HIV (n=1 [4.2%]) infections. Among racial/ethnic groups, Hispanics had a slightly higher relative risk (RR) for STDs by a factor of 1.3 when normalized to the average frequency. Patients aged 26 to 29 and 30 to 39 years had a significantly higher RR for STDs: 2.1 and 2.0, respectively. Furthermore, female patients had an STD frequency 3 times that of male patients. CONCLUSION: This study reveals noteworthy health risks in a rural uninsured population, including a higher rate of gonorrhea compared with national rates and a higher RR for STDs in certain demographic groups. These findings form a foundation for improvements in care through earlier STD diagnoses, effective treatment, and enhanced patient education.
Assuntos
Instituições de Assistência Ambulatorial , Pessoas sem Cobertura de Seguro de Saúde/estatística & dados numéricos , Serviços de Saúde Rural , Infecções Sexualmente Transmissíveis/epidemiologia , Clínica Dirigida por Estudantes , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina , Estudos Retrospectivos , Fatores Socioeconômicos , Adulto JovemRESUMO
This is the first report, to our knowledge, of prominent, natural expression of nAChR alpha4, alpha6 and alpha9 subunits in a human, neuronally-committed cell line. We performed studies with specific reference to the expression of nicotinic acetylcholine receptors (nAChR) to further characterize a human, postmitotic, transplantable, with a neuronal phenotype, cell line called hNT (also called NT2-N). hNT cells acquire a distinctive neuronal phenotype upon differentiation from their NT2 precursors. Immunocytochemical studies showed that NT2 cells were strongly immunopositive for alpha4 or alpha7 subunits, moderately immunopositive for alpha3/alpha5 subunits, and weakly immunopositive for beta2 or beta4 subunits, whereas hNT neurons showed positive, strong-to-moderate immunostaining for all of these nAChR subunits. Reverse transcription-polymerase chain reaction (RT-PCR) mRNA analyses indicated that levels of alpha7 subunit messages were similar in both NT2 and hNT cells, whereas alpha2, alpha10, and beta3 subunit transcripts were not detected. Levels of alpha3, alpha5, and beta4 subunit messages were lower in hNT neurons than in NT2 precursors. However, alpha4 and beta2 subunit messages were present in NT2 precursors but were greatly induced in hNT neurons. Levels of alpha6 and alpha9 subunit messages, not detectable in NT2 precursors, rose to high levels in hNT neurons. hNT cell nAChR subunit message levels were comparable to (alpha4, alpha5, beta4) or higher than (alpha6, alpha9, beta2) levels in adult human brain. NT2 and hNT cells may provide an excellent model for studies of neurogenesis, roles played by nAChR in differentiation and neurodegeneration, and effects of neuronal differentiation on nAChR expression.
Assuntos
Neurônios/metabolismo , Receptores Nicotínicos/metabolismo , Southern Blotting , Linhagem Celular , Corantes , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células-Tronco/metabolismoRESUMO
Clinically important microbes, and the pathogenesis, symptoms and diagnosis of their corresponding infectious diseases were integrated into clinical schemes within a clinical presentation curriculum. Decisions on microbe placement considered a variety of factors, including spaced reinforcement of major pathogens. We report here the map of our integrated medical microbiology curriculum.
RESUMO
BACKGROUND: Diabetes is known to impair wound healing and deteriorate the periodontal condition. There is limited information about the patterns and events associated with periodontal wound repair. In this study, we evaluate the dynamics of periodontal wound repair using micro-computed tomography (microCT) and immunohistochemistry. METHODS: Thirty-six male rats were used, and diabetes was induced by streptozotocin. The maxillary first molars were extracted, and a tooth-associated osseous defect was created in the extraction area. Animals were sacrificed after 7, 14, and 21 days. Volumetry and distribution of bone trabeculae were evaluated by microCT imaging. The patterns of healing and collagen alignment were evaluated by histology. Advanced glycation end-product (AGE) deposition and expression of the receptor for AGEs (RAGE), tartrate-resistant acid phosphatase, and proliferating cell nuclear antigen were evaluated by histochemical and immunohistochemical staining. RESULTS: Diabetic animals demonstrated a significantly reduced bone volume and trabecular number as well as thinner trabeculae and more trabecular separation in osseous defects. The early stage was characterized by significantly reduced cellular proliferation and prolonged active inflammation without evident bone resorption, whereas delayed recovery of collagen realignment, matrix deposition, and bone turnover was noted in later stages. Although AGEs and RAGE were present during healing in diabetes and controls, a stronger and more persistent level of expression was observed in the group with diabetes CONCLUSIONS: Diabetes significantly delayed osseous defect healing by augmenting inflammation, impairing proliferation, and delaying bone resorption. The AGE-RAGE axis can be activated under metabolic disturbance and inflammation.
Assuntos
Perda do Osso Alveolar/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Periodontite/fisiopatologia , Cicatrização/fisiologia , Fosfatase Ácida/metabolismo , Perda do Osso Alveolar/complicações , Perda do Osso Alveolar/diagnóstico por imagem , Animais , Remodelação Óssea , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Colágenos Fibrilares/química , Produtos Finais de Glicação Avançada/análise , Imuno-Histoquímica , Isoenzimas/metabolismo , Masculino , Periodontite/complicações , Periodontite/diagnóstico por imagem , Antígeno Nuclear de Célula em Proliferação/biossíntese , Ratos , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/biossíntese , Fosfatase Ácida Resistente a Tartarato , Microtomografia por Raio-XRESUMO
Naturally expressed nicotinic acetylcholine receptors (nAChR) containing alpha4 subunits (alpha4*-nAChR) in combination with beta2 subunits (alpha4beta2-nAChR) are among the most abundant, high-affinity nicotine binding sites in the mammalian brain. beta4 subunits are also richly expressed and colocalize with alpha4 subunits in several brain regions implicated in behavioural responses to nicotine and nicotine dependence. Thus, alpha4beta4-nAChR also may exist and play important functional roles. In this study, properties were determined of human alpha4beta2- and alpha4beta4-nAChR heterologously expressed de novo in human SH-EP1 epithelial cells. Whole-cell currents mediated via human alpha4beta4-nAChR have approximately 4-fold higher amplitude than those mediated via human alpha4beta2-nAChR and exhibit much slower acute desensitization and functional rundown. Nicotinic agonists induce peak whole-cell current responses typically with higher functional potency at alpha4beta4-nAChR than at alpha4beta2-nAChR. Cytisine and lobeline serve as full agonists at alpha4beta4-nAChR but are only partial agonists at alpha4beta2-nAChR. However, nicotinic antagonists, except hexamethonium, have comparable affinities for functional alpha4beta2- and alpha4beta4-nAChR. Whole-cell current responses show stronger inward rectification for alpha4beta2-nAChR than for alpha4beta4-nAChR at a positive holding potential. Collectively, these findings demonstrate that human nAChR beta2 or beta4 subunits can combine with alpha4 subunits to generate two forms of alpha4*-nAChR with distinctive physiological and pharmacological features. Diversity in alpha4*-nAChR is of potential relevance to nervous system function, disease, and nicotine dependence.
Assuntos
Receptores Nicotínicos/análise , Receptores Nicotínicos/química , Receptores Nicotínicos/fisiologia , Acetilcolina/farmacologia , Alcaloides/farmacologia , Azocinas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Eletrofisiologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Hexametônio/farmacologia , Humanos , Lobelina/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Piridinas/farmacologia , Quinolizinas/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , TransfecçãoRESUMO
To evaluate possible physiological roles of the large cytoplasmic loops (C2) and neighboring transmembrane domains of nicotinic acetylcholine receptor (nAChR) subunits, we generated novel fusion constructs in which human nAChR alpha4, beta2, or beta4 subunit C2 or C2 and neighboring sequences were replaced by corresponding sequences from the mouse serotonin type 3A (5-HT3A) receptor subunit. Following stable expression in human SH-EP1 cells, we found that extensive sequence substitutions involving third and fourth transmembrane domains and neighboring "proximal" C2 sequences (e.g., beta2 H322-V335 and V449-R460) did not allow functional expression of nAChR containing chimeric subunits. However, expression of functional nAChR was achieved containing wild-type alpha4 subunits and chimeric beta2 (beta2chi) subunits whose "nested" C2 domain sequences K336-S448 were replaced with the corresponding 5-HT3A subunit sequences. Whereas these findings suggested indispensable roles for M3/M4 transmembrane and/or proximal C2 sequences in alpha4beta2-nAChR function, nested C2 sequences in the beta2 subunit are not essential for functional receptor expression. Ligand-binding analyses also revealed only subtle differences in pharmacological profiles of alpha4beta2-nAChR compared with alpha4beta2chi-nAChR. Nevertheless, there was heightened emergence of agonist-mediated self-inhibition of alpha4beta2chi function, greater sensitivity to functional blockade by a number of antagonists, and faster and more complete acute desensitization of alpha4beta2chi-nAChR than for alpha4beta2-nAChR. These studies are consistent with unexpected roles of nested C2 sequences in nAChR function.
Assuntos
Citoplasma/metabolismo , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/fisiologia , Sequência de Aminoácidos , Animais , Western Blotting , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Linhagem Celular , Clonagem Molecular , DNA Complementar/biossíntese , Humanos , Imunoprecipitação , Camundongos , Dados de Sequência Molecular , Nicotina/farmacologia , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Piridinas/metabolismo , RNA/biossíntese , RNA/isolamento & purificação , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Proteínas Recombinantes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Radioisótopos de Rubídio , TransfecçãoRESUMO
Amyloid-beta (Abeta) accumulation and aggregation are thought to contribute to the pathogenesis of Alzheimer's disease (AD). In AD, there is a selective decrease in the numbers of radioligand binding sites corresponding to the most abundant nicotinic acetylcholine receptor (nAChR) subtype, which contains human alpha4 and beta2 subunits (halpha4beta2-nAChR). However, the relationships between these phenomena are uncertain, and effects of Abeta on halpha4beta2-nAChR function have not been investigated in detail. We first confirmed expression of halpha4 and hbeta2 subunits as messenger RNA in transfected, human SHEP1 cells by reverse transcription-polymerase chain reaction and mRNA fluorescence in situ hybridization analyses. Immunoprecipitation Western analyses confirmed alpha4 and beta2 subunit protein expression and co-assembly. Whole cell current recording demonstrated heterologous expression in SH-EP1-halpha4beta2 cells of functional halpha4beta2-nAChRs with characteristic responses to nicotinic agonists or antagonists. Nicotine-induced whole cell currents were suppressed by Abeta(1-42) in a dose-dependent manner. Functional inhibition was selective for Abeta(1-42) compared with the functionally inactive, control peptide Abeta(40-1).Abeta(1-42)-mediated inhibition of halpha4beta2-nAChR function was non-competitive, voltage-independent, and use-independent. Pre-loading of cells with guanyl-5'-yl thiophosphate failed to prevent Abeta(1-42)-induced inhibition, suggesting that down-regulation of halpha4beta2-nAChR function by Abeta(1-42) is not mediated by nAChR internalization. Sensitivity to Abeta(1-42) antagonism at 1 nm was evident for halpha4beta2-nAChRs, but not for heterologously expressed human alpha7-nAChRs, although both nAChR subtypes were functionally inhibited by 100 nm Abeta(1-42), with the magnitude of functional block being higher for 100 nm Abeta(1-42) acting on halpha7-nAChRs. These findings suggest that halpha4beta2-nAChRs are sensitive and perhaps pathophysiologically relevant targets for Abeta neurotoxicity in AD.
Assuntos
Amiloide/fisiologia , Receptores Nicotínicos/metabolismo , Linhagem Celular , Humanos , Hibridização in Situ Fluorescente , Técnicas de Patch-Clamp , Testes de Precipitina , Receptores Nicotínicos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
alpha 7-Nicotinic acetylcholine receptors (alpha 7-nAChRs) are broadly distributed in the central nervous system, where they play important roles in chemical and electrical signaling, and perhaps in neurite outgrowth, synaptic plasticity, and neuronal death/survival. To help elucidate their normal and pathophysiological roles, we have heterologously expressed human alpha 7-nAChR in transfected SH-EP1 human epithelial cells. Reverse transcription-polymerase chain reaction and mRNA fluorescence in situ hybridization analyses demonstrate expression of human alpha 7 subunits as messenger RNA. Patch-clamp recordings exploiting a novel strategy to prevent functional rundown of whole-cell peak current responses to repeated acute challenges with nicotinic agonists show successful expression of functional alpha 7-nAChR that mediate inward currents characterized by rapid phases of activation and inactivation. Concentration-response curves show that nicotine, acetylcholine, and choline are efficacious agonists at human alpha 7-nAChRs. Current-voltage relationships show inward rectification for agonist-induced currents. Human alpha 7-nAChRs exhibit some sensitivity to alpha 7-nAChR antagonists alpha-bungarotoxin (Bgt) or methyllycaconitine (MLA) when applied coincidentally with agonist, but much higher affinity block occurs when cells and alpha 7-nAChRs are pre-exposed to antagonists for 2 min before challenge with agonist. Both Bgt and MLA are competitive inhibitors of alpha 7-nAChR function. Whole-cell current peak amplitudes and half-times for inactivation of alpha 7-nAChR functional responses to nicotine are dramatically reduced in the absence of extracellular Ca2+, suggestive of high Ca2+ permeability of the alpha 7-nAChR channel. Thus, heterologously expressed human alpha 7-nAChR in mammalian cells have properties of native alpha 7-nAChR or of alpha 7-nAChR heterologously expressed in other systems and serve as excellent models for studies of molecular bases of alpha 7-nAChR function.
Assuntos
Aconitina/análogos & derivados , Células Epiteliais/metabolismo , Receptores Nicotínicos/fisiologia , Acetilcolina/farmacologia , Aconitina/farmacologia , Bungarotoxinas/farmacologia , Cálcio/farmacologia , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Transfecção , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Naturally expressed nicotinic acetylcholine receptors composed of alpha4 and beta2 subunits (alpha4beta2-nAChR) are the predominant form of high affinity nicotine binding site in the brain implicated in nicotine reward, mediation of nicotinic cholinergic transmission, modulation of signaling through other chemical messages, and a number of neuropsychiatric disorders. To develop a model system for studies of human alpha4beta2-nAChR allowing protein chemical, functional, pharmacological, and regulation of expression studies, human alpha4 and beta2 subunits were stably introduced into the native nAChR-null human epithelial cell line SHEP1. Heterologously expressed alpha4beta2-nAChR engage in high-affinity, specific binding of 3H-labeled epibatidine (H-EBDN; macroscopic KD = 10 pM; kon = 0.74/min/nM, koff = 0.013/min). Immunofluorescence studies show alpha4 and beta2 subunit protein expression in virtually every transfected cell, and microautoradiographic studies show expression of 125I-labeled iodo-deschloroepibatidine binding sites in most cells. H-EBDN binding competition studies reveal high affinity for nicotinic agonists and lower affinity for nicotinic antagonists. Heterologously expressed alpha4beta2-nAChR functional studies using 86Rb+ efflux assays indicate full efficacy of epibatidine, nicotine, and acetylcholine; partial efficacy for 1,1-dimethyl-4-phenyl-piperazinium, cytisine, and suberyldicholine; competitive antagonism by dihydro-beta-erythroidine, decamethonium, and methyllycaconitine; noncompetitive antagonism by mecamylamine and eserine; and mixed antagonism by pancuronium, hexamethonium, and d-tubocurarine. These results demonstrate utility of transfected SH-EP1 cells as models for studies of human alpha4beta2-nAChR, and they also reveal complex relationships between apparent affinities of drugs for radioligand binding and functional sites on human alpha4beta2-nAChR.
Assuntos
Células Epiteliais/metabolismo , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/química , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/fisiologia , Humanos , Ligação Proteica/fisiologia , Piridinas/metabolismo , Receptores Nicotínicos/deficiência , Receptores Nicotínicos/genética , Transfecção/métodosRESUMO
Amyloid-Beta (Aβ) accumulation and aggregation are thought to contribute to the pathogenesis of Alzheimers disease (AD). In AD, there also is a selective decrease in numbers of radioligand binding sites corresponding to the most abundant nicotinic acetylcholine receptor (nAChR) subtype, which contains human α4 and β2 subunits (α4β2-nAChR). However, relationships between these phenomena are uncertain, and effects of Aβ on human α4β2-nAChR function have not been investigated in detail. We created SH-EP1 cells stably transfected to heterologously express human α4β2- or α7-nAChR subtypes. Whole-cell current recording confirmed heterologous expression of functional α4β2-nAChR with characteristic responses to nicotinic agonists or antagonists. Nicotine-induced whole-cell currents were suppressed by Aβ1−42 in a dose-dependent manner. Functional inhibition was selective for Aβ1−42 compared to functionally-inactive, control peptide Aβ40-1, but was mimicked by Aβ1-40. Aβ1-42-mediated inhibition of α4β2-nAChR function was non-competitive, voltage¬independent, and use-independent. Pre-loading of cells with GDP-β-S failed to prevent Aβ1-42 induced inhibition, suggesting that the down-regulation of α4β2-nAChR function by Aβ1-42 is not mediated by nAChR internalization. Sensitivity to Aβ1-42 antagonism at 1 nM was evident for α4β 2-nAChR, but not for heterologously expressed, human α7-nAChR, although both nAChR subtypes were functionally inhibited by 100 nM Aβ1-42, with the magnitude of functional block being higher for 100 nM Aβ1-42 acting at α7-nAChR. These findings suggest that α4β2-nAChR are sensitive and perhaps pathophysiologically-relevant targets for Aβ neurotoxicity in AD.