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Animals integrate sensory information from the environment and display various behaviors in response to external stimuli. In Caenorhabditis elegans hermaphrodites, 33 types of sensory neurons are responsible for chemosensation, olfaction, and mechanosensation. However, the functional roles of all sensory neurons have not been systematically studied due to the lack of facile genetic accessibility. A bipartite cGAL-UAS system has been previously developed to study tissue- or cell-specific functions in C. elegans. Here, we report a toolkit of new cGAL drivers that can facilitate the analysis of a vast majority of the 60 sensory neurons in C. elegans hermaphrodites. We generated 37 sensory neuronal cGAL drivers that drive cGAL expression by cell-specific regulatory sequences or intersection of two distinct regulatory regions with overlapping expression (split cGAL). Most cGAL-drivers exhibit expression in single types of cells. We also constructed 28 UAS effectors that allow expression of proteins to perturb or interrogate sensory neurons of choice. This cGAL-UAS sensory neuron toolkit provides a genetic platform to systematically study the functions of C. elegans sensory neurons.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Células Receptoras Sensoriais/metabolismoRESUMO
BACKGROUND: Although many pain-related smartphone apps exist, little attention has been given to understanding how these apps are used over time and what factors contribute to greater compliance and patient engagement. OBJECTIVE: This retrospective analysis was designed to help identify factors that predicted the benefits and future use of a smartphone pain app among patients with chronic pain. METHODS: An app designed for both Android and iOS devices was developed by Brigham and Women's Hospital Pain Management Center (BWH-PMC) for users with chronic pain to assess and monitor pain and communicate with their providers. The pain app offered chronic pain assessment, push notification reminders and communication, personalized goal setting, relaxation sound files, topics of interest with psychological and medical pain management strategies, and line graphs from daily assessments. BWH-PMC recruited 253 patients with chronic pain over time to use the pain app. All subjects completed baseline measures and were asked to record their progress every day using push notification daily assessments. After 3 months, participants completed follow-up questionnaires and answered satisfaction questions. We defined the number of completed daily assessments as a measure of patient engagement with the pain app. RESULTS: The average age of participants was 51.5 years (SD 13.7, range 18-92), 72.8% (182/253) were female, and 36.8% (78/212) reported the low back as their primary pain site. The number of daily assessments ranged from 1 to 426 (average 62.0, SD 49.9). The app was easy to introduce among patients, and it was well accepted. Those who completed more daily assessments (greater patient engagement) throughout the study were more likely to report higher pain intensity, more activity interference, and greater disability and were generally overweight compared with others. Patients with higher engagement with the app rated the app as offering greater benefit in coping with their pain and expressed more willingness to use the app in the future (P<.05) compared with patients showing lower engagement. Patients completing a small number of daily assessments reported less pain intensity, less daily activity interference, and less pain-related disability on average and were less likely to use the two-way messaging than those who were more engaged with the pain app (P<.05). CONCLUSIONS: Patients with chronic pain who appeared to manage their pain better were less likely to report benefits of a smartphone pain app designed for chronic pain management. They demonstrated lower patient engagement in reporting their daily progress, in part, owing to the perceived burden of regularly using an app without a perceived benefit. An intrinsically different pain app designed and targeted for individuals based on early identification of user characteristics and adapted for each individual would likely improve compliance and app-related patient engagement.
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Assistência Ambulatorial/normas , Dor Crônica/epidemiologia , Aplicativos Móveis/estatística & dados numéricos , Cooperação do Paciente/estatística & dados numéricos , Smartphone/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Both federal government and civil society organization data point to consistently rising incidents of antisemitic narratives and acts across Canada. In spite of this, antisemitic hate crime has not been the focus of any academic research here, some would argue because Jews are not typically thought to be an at-risk community. Rather, the Jewish community is thought to occupy a relatively privileged place in society which shields them from bias motivated attacks. Countering this narrative, our study, based in Ontario and Quebec, reveals that Jewish individuals and institutions are highly vulnerable to discursive, physical, and property violations. Many of those we spoke with felt embattled by the narrative attacks that rendered the community vulnerable to corollary physical attacks. Of particular significance are the enabling images of Jews that equate "Jewish privilege" with excessive power and control. We explore these themes, concluding with calls for strategies intended to counter hateful narratives.
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Ódio , Humanos , Canadá , Judeus , Crime , Ontário , QuebequeRESUMO
Background: The difficulties in defining hate crime, hate incidents and hate speech, and in finding a common conceptual basis constitute a key barrier toward operationalisation in research, policy and programming. Definitions disagree about issues such as the identities that should be protected, the types of behaviours that should be referred to as hateful, and how the 'hate element' should be assessed. The lack of solid conceptual foundations is reflected in the absence of sound data. These issues have been raised since the early 1990s (Berk, 1990; Byers & Venturelli, 1994) but they proved to be an intractable problem that continues to affect this research and policy domain. Objectives: Our systematic review has two objectives that are fundamentally connected: mapping (1) original definitions and (2) original measurement tools of hate crime, hate speech, hate incidents and surrogate terms, that is, alternative terms used for these concepts (e.g., prejudice-motivated crime, bias crime, among many others). Search Methods: We systematically searched over 19 databases to retrieve academic and grey literature, as well as legislation. In addition, we contacted 26 country experts and searched 211 websites, as well as bibliographies of published reviews of related literature, and scrutiny of annotated bibliographies of related literature. Inclusion Criteria: This review included documents published after 1990 found in academic literature, grey literature and legislation. We included academic empirical articles with any study design, as well as theoretical articles that focused specifically on defining hate crime, hate speech, hate incidents or surrogate terms. We also reviewed current criminal or civil legislation that is intended to regulate forms of hate speech, hate incidents and hate crimes. Eligible countries included Canada, USA, UK, Ireland, Germany, France, Italy, Spain, Australia and New Zealand. For documents to be included in relation to research objective (1), they had to contain at least one original definition of hate speech, hate incidents or hate crimes, or any surrogate term. For documents to be included in relation to research objective (2), they had to contain at least one original measurement tool of hate speech, hate incidents or hate crimes, or any surrogate term. Documents could be included in relation to both research objectives. Data Collection and Analysis: The systematic search covered 1 January 1990 to 31 December 2021, with searches of academic databases conducted between 8th March and 12th April 2022 yielding 35,191 references. We carried out country-specific searches for grey literature published in the same time period between 27th August and 2nd December 2021. These searches yielded a total of 2748 results. We coded characteristics of the definitions and measurement tools, including the protected characteristics, the approaches to categorise the 'hate element' and other variables. We used univariate and bivariate statistical methods for data analysis. We also carried out a social network analysis. Main Results: We provide as annex complete lists of the original definitions and measurement tools that met our inclusion criteria, for the use of researchers and policy makers worldwide. We included 423 definitions and 168 measurement tools in academic and grey literature, and 83 definitions found in legislation. To support future research and policy work in this area, we included a synthetic assessment of the (1) the operationalisability of each definition and (2) the theoretical robustness and transparency of each measurement tool. Our mapping of the definitions and measurement tools revealed numerous significant trends, clusters and differences between and within definitions and measurement tools focusing on hate crime, hate speech and hate incidents. For example, definitions and measurement tools tend to focus more on ethnic and religious identities (e.g., racism, antisemitism, Islamophobia) compared to sexual, gender and disability-related identities. This gap is greater in the definitions and measurement tools of hate speech than hate crime. Our analysis showed geographical patterns: hate crime definitions and measurement tools are more likely to originate from Anglophonic countries, especially the USA, but hate speech definitions and measurement tools are more likely to originate from continental Europe. In terms of disciplinary fragmentation, our social network analysis revealed that the collaboration and exchange of conceptual frameworks and methodological tools between social sciences and computer science is limited, with most definitions and measurement tools clustering along disciplinary lines. More detailed findings are presented in the results section of the report. Authors' Conclusions: There is an urgent need to close the research and policy gap between the protections of 'ethnic and religious identities' and other (less) protected characteristics such as gender and sexual identities, age and disability. There is also an urgent need to improve the quality of methodological and reporting standards in research examining hate behaviours, including transparency in methodology and data reporting, and discussion of limitations (e.g., bias in data). Many of the measurement tools found in the academic literature were excluded because they did not report transparently how they collected and analysed the data. Further, 41% of documents presenting research on hate behaviours did not provide a definition of what they were looking at. Given the importance of this policy domain, it is vital to raise the quality and trustworthiness of research in this area. This review found that researchers in different disciplinary areas (e.g., social sciences and computer science) rarely collaborate. Future research should attempt to build on existing definitions and measurement tools (instead of duplicating efforts), and engage in more interdisciplinary collaborations. It is our hope that that this review can provide a solid foundation for researchers, government, and other bodies to build cumulative knowledge and collaboration in this important field.
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BACKGROUND: The term "weaponized autism" is frequently used on extremist platforms. To better understand this, we conducted a discourse analysis of posts on Gab, an alt-right social media platform. METHODS: We analyzed 711 posts spanning 2018-2019 and filtered for variations on the term "weaponized autism". RESULTS: This term is used mainly by non-autistic Gab users. It refers to exploitation of perceived talents and vulnerabilities of "Weaponized autists", described as all-powerful masters-of-technology who are devoid of social skills. CONCLUSIONS: The term "weaponized autism" is simultaneously glorified and derogatory. For some autistic people, the partial acceptance offered within this community may be preferable to lack of acceptance offered in society, which speaks to improving societal acceptance as a prevention effort.
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Transtorno do Espectro Autista , Transtorno Autístico , Mídias Sociais , Humanos , Habilidades SociaisRESUMO
Osteoarthritis and rheumatoid arthritis are debilitating conditions, affecting millions of people. Both osteoarthritis and rheumatoid arthritis degrade the articular cartilage (AC) at the ends of long bones, resulting in weakened tissue prone to further damage. This degradation impairs the cartilage's mechanical properties leading to areas of thinned cartilage and exposed bone which compromises the integrity of the joint. No preventative measures exist for joint destruction. Discovering a way to slow the degradation of AC or prevent it would slow the painful progression of the disease, allowing millions to live pain-free. Recently, that the articular injection of the polyphenol epigallocatechin-gallate (EGCG) slows AC damage in an arthritis rat model. It was suggested that EGCG crosslinks AC and makes it resistant to degradation. However, direct evidence that intraarticular injection of EGCG crosslinks cartilage collagen and changes its compressive properties are not known. The aim of this study was to investigate the effects of intraarticular injection of EGCG induced biomechanical properties of AC. We hypothesize that in vivo exposure EGCG will bind and crosslink to AC collagen and alter its biomechanical properties. We developed a technique of nano-indentation to investigate articular cartilage properties by measuring cartilage compressive properties and quantifying differences due to EGCG exposure. In this study, the rat knee joint was subjected to a series of intraarticular injections of EGCG and contralateral knee joint was injected with saline. After the injections animals were sacrificed, and the knees were removed and tested in an anatomically relevant model of nanoindentation. All mechanical data was normalized to the measurements in the contralateral knee to better compare data between the animals. The data demonstrated significant increases for reduced elastic modulus (57.5%), hardness (83.2%), and stiffness (17.6%) in cartilage treated with injections of EGCG normalized to those treated with just saline solution when compared to baseline subjects without injections, with a significance level of alpha = 0.05. This data provides evidence that EGCG treated cartilage yields a strengthened cartilage matrix as compared to AC from the saline injected knees. These findings are significant because the increase in cartilage biomechanics will translate into resistance to degradation in arthritis. Furthermore, the data suggest for the first time that it is possible to strengthen the articular cartilage by intraarticular injections of polyphenols. Although this data is preliminary, it suggests that clinical applications of EGCG treated cartilage could yield strengthened tissue with the potential to resist or compensate for matrix degradation caused by arthritis.
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Artrite Reumatoide , Cartilagem Articular , Osteoartrite , Ratos , Animais , Cartilagem Articular/metabolismo , Polifenóis/farmacologia , Solução Salina/farmacologia , Injeções Intra-Articulares , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Colágeno/metabolismo , Artrite Reumatoide/tratamento farmacológicoRESUMO
The overallaim of the review is to map the definitions and measurement tools used to capture the whole spectrum of hate motivated behaviors, including hate crime, hate speech and hate incidents. This will benefit the field of hate studies by providing a baseline that can inform the building of cumulative knowledge and comparative research. The first review objective is to map definitions of hate crime, hate incidents, hate speech, and surrogate terms. Specific research questions underpinning this objective are: (a) How are hate crimes, hate speech and hate incidents defined in the academic, legal, policy, and programming literature?; (b) What are the concepts, parameters and criteria that qualify a behavior as being hate crime, hate incident or hate speech?; and (c) What are the most common concepts, parameters and criteria found across definitions? What are the differences between definitions and the elements they contain? The second review objective is to map the tools used to measure the prevalence of hate crime, hate incidents, hate speech, and surrogate terms. Specific research questions underpinning this objective are: (a) How are definitions operationalised to measure hate crimes, hate speech, and hate incidents?; and (b) How valid and reliable are these measures?
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Smoking is a prevalent behavior with severe health consequences. Various smoking cessation methods that are available to dentists include nicotine replacement therapies, other pharmacological agents, and biobehavioral therapies. This article presents a smoking cessation protocol that can be carried out as part of routine oral care.
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Assistência Odontológica , Educação de Pacientes como Assunto , Abandono do Hábito de Fumar/métodos , Protocolos Clínicos , Aconselhamento , Árvores de Decisões , Humanos , Padrões de Prática OdontológicaRESUMO
Meniscus injuries represent one of the most-common intra-articular knee injuries. The current treatment options include meniscectomy and allograft transplantation, both with poor long-term outcomes. Therefore, there is a need for regenerative techniques to restore meniscal function. To preclinically test scaffolds for meniscus replacement, large animal models need to be established and standardized. This review establishes the anatomical and compositional similarities between human and sheep menisci and provides guidance for implantation and evaluation of such devices. The ovine meniscus represents a scaled-down version of the human meniscus, with only slight structural differences that can be addressed during device fabrication. Implantation protocols in sheep remain a challenge, as the meniscus cannot be visualized with the arthroscopic-assisted procedures commonly performed in human patients. Thus, we recommend the appropriate implantation protocols for meniscus visualization, ligamentous restoration, and surgical fixation of both total and partial meniscus replacement devices. Last, due to the lack of standardization in evaluation techniques, we recommend a comprehensive battery of tests to evaluate the efficacy of meniscus replacement implants. We recommend other investigators utilize these surgical and testing techniques to establish the ovine model as the gold standard for preclinical evaluation of meniscus replacement devices.
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Menisco/anatomia & histologia , Menisco/fisiologia , Modelos Animais , Implantação de Prótese , Engenharia Tecidual/métodos , Animais , Fenômenos Biomecânicos , Articulações/patologia , Articulações/cirurgia , OvinosRESUMO
Hate crime scholars have long argued that the harms of hate crime extend beyond the immediate victim to negatively impact the victim's reference community. However, this assertion is speculative and in need of empirical support. Utilizing focus group data from 15 people who identified as lesbian, gay, bisexual, or pansexual, this pilot study explored the extent to which the harms of anti-LGB hate crime spread beyond the immediate victim to impact nonvictims in the LGB community. The findings suggest that anti-LGB hate violence can have profound and negative effects on the psychological and emotional well-being of nonvictims who are LGB and may result in dramatic behavioral change as well. The findings also indicate that hate violence negatively affected participants' decisions to disclose their sexual orientation to others. On a more positive note, however, awareness of such violence may also mobilize some people within the LGB community.
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Bissexualidade/psicologia , Crime/legislação & jurisprudência , Crime/psicologia , Ódio , Homofobia/legislação & jurisprudência , Homofobia/psicologia , Homossexualidade Feminina/psicologia , Homossexualidade Masculina/psicologia , Mudança Social , Adulto , Atitude , Canadá , Feminino , Grupos Focais , Identidade de Gênero , Heterossexualidade/psicologia , Humanos , Masculino , Valores Sociais , Violência/legislação & jurisprudência , Violência/psicologiaRESUMO
A new poly(ethylene glycol)-based copolymer containing multiple thiol (-SH) groups was cross-linked in situ to form a polymer hydrogel under mild conditions. No organic solvent, elevated temperature, or harsh pH is required in the formulation or patient administration processes, making it particularly useful for delivery of fragile therapeutics, such as proteins. The in vitro release of fluorescein-labeled bovine serum albumin and the in vivo release of the model proteins, erythropoietin, RANTES and three PEG-conjugated RANTES derivatives showed sustained release for 2-4 weeks and demonstrated prolonged biological activity of the released proteins in animals.
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Materiais Biocompatíveis/síntese química , Sistemas de Liberação de Medicamentos , Polietilenoglicóis/síntese química , Proteínas/administração & dosagem , Animais , Materiais Biocompatíveis/química , Bovinos , Quimiocina CCL5/administração & dosagem , Reagentes de Ligações Cruzadas , Preparações de Ação Retardada , Eritropoetina/administração & dosagem , Hidrogéis/síntese química , Hidrogéis/química , Técnicas In Vitro , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes , Segurança , Soroalbumina Bovina/administração & dosagemRESUMO
The current study was performed in intestinal and vascular access ported rabbits to quantify and differentiate the components of intestinal and hepatic first pass extraction (i.e., metabolism and secretion) of saquinavir (SQV) mediated by P-glycoprotein (P-gp) and CYP3A. SQV was administered i.v. (1-5 mg/kg) or into the upper small intestine (USI) (5 mg/kg). The roles of intestinal and hepatic secretion by means of P-gp and/or metabolism by CYP3A on the first pass gastrointestinal extraction of SQV were differentiated by using N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) (a P-gp inhibitor), midazolam (an inhibitor of CYP3A), or cyclosporine A (an inhibitor of P-gp and CYP3A). The bioavailability (BA) of SQV after USI dosing was 4%. In the presence of CYP3A and P-gp inhibitors, the BA of SQV increased 2- to 11-fold. Based on a relatively unchanged Cmax but prolonged Tmax and t(1/2), P-gp and CYP3A inhibition appeared to alter SQV disposition (i.e., enhanced oral bioavailability by diminishing SQV elimination and by increasing its net intestinal absorption). In conclusion, the current results substantiate the role of the liver and, for the first time, experimentally establish an important role for the intestine in the net absorption and disposition of SQV. The results also demonstrate that changes in SQV disposition due to the modulation of metabolism and secretion were important and may potentially have considerable implications on multiple drug therapeutic regimens used in the treatment of AIDS.
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Sistema Digestório/metabolismo , Inibidores da Protease de HIV/farmacocinética , Fígado/metabolismo , Saquinavir/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Feminino , Inibidores da Protease de HIV/sangue , Coelhos , Saquinavir/sangueRESUMO
OBJECTIVE: To evaluate the efficacy and safety of topiramate (TPM) for weight loss in healthy obese subjects. RESEARCH METHODS AND PROCEDURES: A randomized, double-blind, placebo-controlled, dose-ranging trial was conducted. Three hundred eighty-five subjects, 18 and 75 years of age, were randomized to receive either placebo or TPM at 64, 96, 192, or 384 mg daily. Dosing began at 16 mg once daily. In week 2, the dose was increased to 16 mg twice daily. Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until subjects reached their target dose. Twenty-four weeks after beginning treatment, all subjects were tapered off treatment by a dose reduction of 50% per week. All participants received the same lifestyle program. RESULTS: Mean percent weight loss from baseline to week 24 was -2.6% in placebo-treated patients vs. -5.0%, -4.8%, -6.3%, and -6.3% in the 64, 96, 192, and 384 mg/d TPM groups, respectively. Greater percentages of TPM-treated patients lost at least 5% or 10% of body weight compared with placebo. The most frequent adverse events were related to the central or peripheral nervous system, including paresthesia, somnolence, and difficulty with memory, concentration, and attention. Most events were dose-related, occurred early in treatment, and usually resolved spontaneously; only 21% receiving TPM withdrew due to adverse events compared with 11% on placebo. DISCUSSION: TPM produced significantly greater weight loss than placebo at all doses.
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Fármacos Antiobesidade/uso terapêutico , Frutose/análogos & derivados , Frutose/uso terapêutico , Obesidade/tratamento farmacológico , Adolescente , Adulto , Idoso , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/efeitos adversos , Pressão Sanguínea , Índice de Massa Corporal , Sistema Cardiovascular/efeitos dos fármacos , Método Duplo-Cego , Feminino , Frutose/administração & dosagem , Frutose/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Fatores de Risco , Fatores de Tempo , Topiramato , Redução de PesoRESUMO
This paper presents a case study involving a meta-analytic approach for an integrated summary of efficacy based upon four phase II and III clinical trials that comprised the basis for a Biologics License Application to the U.S. Food and Drug Administration for approval of becaplermin gel. There were substantial variations in observed response rates across the four studies that were of concern to regulatory agencies. Due to these variations and because there were various treatment combinations in the four trials, standard statistical methods for an integrated analysis of efficacy were problematic. A meta-analytic model that focused on the variations of concern was employed to permit a suitable integrated analysis. The resulting integrated analysis clarified response rate variability and provided accurate estimates of treatment effects based upon the four clinical trials. While this meta-analysis was viewed by neither regulators nor the sponsor as a confirmatory analysis, it was seen by both regulators and sponsor as strongly supportive of the efficacy of becaplermin gel.
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Anticoagulantes , Aprovação de Drogas/métodos , Metanálise como Assunto , Modelos Estatísticos , Fator de Crescimento Derivado de Plaquetas , Becaplermina , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Géis , Humanos , Modelos Logísticos , Proteínas Proto-Oncogênicas c-sis , Úlcera/tratamento farmacológico , Estados Unidos , Cicatrização/efeitos dos fármacosRESUMO
Low and varied oral bioavailability (BA) of some drugs has been attributed to extraction by the intestine and liver. However, the role of the intestine is difficult to directly assess. We recently developed an in vivo intestinal and vascular access-ported (IVAP) rabbit model that allows for a direct assessment of the contributions of the gut and the liver to the first-pass loss of drugs. The current studies validate the utility of the IVAP rabbit model using verapamil (VL). VL pharmacokinetics (PK) were determined after intravenous (i.v.), portal venous (PV), and upper small intestinal (USI) administration. In the i.v. dose range studied, VL exhibited linear PK. The PV concentration of VL was significantly lower than systemic concentrations after i.v. administration, suggesting significant intestinal second-pass extraction. The intestinal and hepatic extraction of VL, calculated directly from area under the curve measurements, were 79% and 92%, respectively, and are in contrast to our previous dog results that showed VL intestinal extraction to be negligible. Assessing the role of intestinal extraction using an "indirect" method was not predictive, further showing the utility of this direct measurement model. The BA of VL after USI administration was 1.65%, much lower than that reported for rats, dogs, or humans. However, humans and rabbits behave similarly in that the contribution of intestinal extraction for VL is high. In conclusion, the current results demonstrate the utility of the rabbit IVAP model in studying the first- and second-pass intestinal and hepatic loss of drugs and other xenobiotics.