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Competing Interests: WCH is Principal Investigator of the Family Language Planning and Language Acquisition Among Deaf and Hard of Hearing Children project (1R01DC021839–01) funded by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health. JLH serves on the Advisory Board of the American Academy of Pediatrics Early Hearing Detection and Intervention Provider Education Center and is contracted with Language First to provide educational materials. In the recent past, she has contracted with the New Mexico Department of Health and has owned stock in Pfizer.

Childhood trauma and adverse childhood experiences have a strong relationship with health disparities across the lifespan. Despite experiencing approximately doubled rates of trauma, Adverse Childhood Experiences (ACEs) are poorly characterized in deaf populations. We sought to characterize deaf-specific demographic factors and their association with multiple experiences of ACEs before the age of 18 years old. An analytical cross-sectional approach was used to ascertain associations of deaf-specific demographic factors and experiences with ACEs. The complete dataset included 520 participants for a total response rate of 56%. After adjusting for confounding effects, less severe hearing loss of 16-55 dB (2+ OR: 5.2, 4+ OR: 4.7), having a cochlear implant (2+ OR: 2.1, 4+ OR: 2.6), and not attending at least one school with signing access (2+ OR: 2.4, 4+ OR: 3.7) were significantly and independently associated with reported experiences of multiple ACEs. We conclude that factors associated with childhood hearing loss and language experiences increase risk of experiencing ACEs. Given the strong relationship between ACEs and poor social outcomes, early intervention clinical practice and health policies should consider interventions to support healthy home environments for deaf children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hall et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Numerous health disparities are documented in deaf population research, but few empirical sleep assessments exist for this under-served population, despite knowledge that sleep contributes to physical and mental health disparities. We sought to document subjective and objective sleep in deaf adults with cross-sectional and prospective measures., Methods: Twenty deaf participants completed validated sleep and mental health questionnaires, 2-weeks of nightly sleep diaries and continuous wrist-worn actigraphy monitoring, and 1-week of nightly, reduced-montage EEG recordings., Results: Questionnaire data suggest high prevalence of insomnia (70%), poor sleep (75%), daytime sleepiness (25%) and nightmares (20%) among participants. Strong correlations were found between depression and sleep quality, fear of sleep, and insomnia severity (p's < .005). Objective sleep assessments suggest elevated wake after sleep onset and low sleep efficiency and sleep duration., Conclusions: The prevalence of sleep disturbance recorded from self-report and objective sleep measures provides preliminary evidence of sleep health disparity among deaf adults., (Copyright © 2022 National Sleep Foundation. All rights reserved.)

Background: Disparities in COVID-19 information and vaccine access have emerged during the pandemic. Individuals from historically excluded communities (eg, Black and Latin American) experience disproportionately negative health outcomes related to COVID-19. Community gaps in COVID-19 education, social, and health care services (including vaccines) should be prioritized as a critical effort to end the pandemic. Misinformation created by the politicization of COVID-19 and related public health measures has magnified the pandemic's challenges, including access to health care, vaccination and testing efforts, as well as personal protective equipment. Information and Communication Technology (ICT) has been demonstrated to reduce the gaps of marginalization in education and access among communities. Chatbots are an increasingly present example of ICTs, particularly in health care and in relation to the COVID-19 pandemic., Objective: This project aimed to (1) follow an inclusive and theoretically driven design process to develop and test a COVID-19 information ICT bilingual (English and Spanish) chatbot tool named "Ana" and (2) characterize and evaluate user experiences of these innovative technologies., Methods: Ana was developed following a multitheoretical framework, and the project team was comprised of public health experts, behavioral scientists, community members, and medical team. A total of 7 iterations of ß chatbots were tested, and a total of 22 ß testers participated in this process. Content was curated primarily to provide users with factual answers to common questions about COVID-19. To ensure relevance of the content, topics were driven by community concerns and questions, as ascertained through research. Ana's repository of educational content was based on national and international organizations as well as interdisciplinary experts. In the context of this development and pilot project, we identified an evaluation framework to explore reach, engagement, and satisfaction., Results: A total of 626 community members used Ana from August 2021 to March 2022. Among those participants, 346 used the English version, with an average of 43 users per month; and 280 participants used the Spanish version, with an average of 40 users monthly. Across all users, 63.87% (n=221) of English users and 22.14% (n=62) of Spanish users returned to use Ana at least once; 18.49% (n=64) among the English version users and 18.57% (n=52) among the Spanish version users reported their ranking. Positive ranking comprised the "smiley" and "loved" emojis, and negative ranking comprised the "neutral," "sad," and "mad" emojis. When comparing negative and positive experiences, the latter was higher across Ana's platforms (English: n=41, 64.06%; Spanish: n=41, 77.35%) versus the former (English: n=23, 35.93%; Spanish: n=12, 22.64%)., Conclusions: This pilot project demonstrated the feasibility and capacity of an innovative ICT to share COVID-19 information within diverse communities. Creating a chatbot like Ana with bilingual content contributed to an equitable approach to address the lack of accessible COVID-19-related information., (©Jose G Perez-Ramos, Mariela Leon-Thomas, Sabrina L Smith, Laura Silverman, Claudia Perez-Torres, Wyatte C Hall, Suzannah Iadarola. Originally published in JMIR Formative Research (https://formative.jmir.org), 25.01.2023.)

In this concluding article of an American Annals of the Deaf Special Issue, we draw on Vygotsky's Fundamentals of Defectology to argue that the essence of deaf pedagogy is not centered on constructing deaf students' hearing abilities but on a biosocial orientation that considers the whole multimodal child with unfettered access to natural signed languages. In alignment with this biosocial view, we recognize and resist the overarching influence of biomedical professionals and systems on deaf education. Such biomedical influence comes with convenient detachment from accountability in education systems while arguably causing at least significant, if not maximal, harm to the optimal developmental outcomes of deaf children. The article ties together the articles of the Annals Special Issue, along with additional Vygotskian perspectives, to bring forth the emergence and exploration of biosocial accountability in deaf education.

Minority faculty and trainees experience unique factors that can hinder their success in academic medicine-collectively referred to as "minority tax." The authors argue that a similar "deaf tax" of unique barriers, experiences, and responsibilities disproportionately burdens deaf trainees and faculty. The cumulative effects of these deaf tax experiences represent a significant disadvantage for deaf professionals in academic medicine. Through a combination of relevant literature and the authors' personal experiences as deaf professionals, several causative domains of deaf tax are outlined, including the fight for reasonable accommodations, prejudice and discrimination, training and diversity barriers, and a lack of deaf mentorship. In addition, a number of practical steps are offered for institutional leaders to consider implementing to improve equity and inclusion in academic medicine, including facilitating language equity and communication access, implementing deaf awareness training, fostering effective deaf mentorship, and promoting deaf professionals into leadership positions. Addressing these issues would help remove the obstacles that create the high deaf tax burden and lower the near-insurmountable barrier of entry, advancement, and retention in academic medicine for deaf professionals., (Copyright © 2022 by the Association of American Medical Colleges.)

Neurite degeneration is associated with early stages of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease (PD), and amyotrophic lateral sclerosis. One method that is commonly used to analyze neurite degeneration involves calculation of a Degeneration Index (DI) following utilization of the Analyze Particles tool of ImageJ to detect neurite fragments in micrographs of cultured cells. However, DI analyses are prone to several types of measurement error, can be time consuming to perform, and are limited in application. Here, we describe an improved method for performing DI analyses. Accuracy of measurements was enhanced through modification of selection criteria for detecting neurite fragments, removal of image artifacts and non-neurite materials from images, and optimization of image contrast. Such enhancements were implemented into an ImageJ macro that enables rapid and fully automated DI analysis of multiple images. The macro features operations for automated removal of cell bodies from micrographs, thus expanding the application of DI analyses to use in experiments involving dissociated cultures. We present experimental findings supporting that, compared with the conventional method, the enhanced analysis method yields measurements with increased accuracy and requires significantly less time to perform. Furthermore, we demonstrate the utility of the method to investigate neurite degeneration in a cell culture model of PD by conducting an experiment revealing the effects of c-Jun N-terminal kinase (JNK) on neurite degeneration induced by oxidative stress in human mesencephalic cells. This improved analysis method may be used to gain novel insight into factors underlying neurite degeneration and the progression of neurodegenerative disorders., (Copyright © 2022 Clements et al.)

The p75 neurotrophin receptor (p75 NTR ) is a multifunctional protein that regulates cellular responses to pathological conditions in specific regions of the nervous system. Activation of p75 NTR in certain neuronal populations induces proteolytic processing of the receptor, thereby generating p75 NTR fragments that facilitate downstream signaling. Expression of p75 NTR has been reported in neurons of the ventral midbrain, but p75 NTR signaling mechanisms in such cells are poorly understood. Here, we used Lund Human Mesencephalic cells, a population of neuronal cells derived from the ventral mesencephalon, to evaluate the effects of oxidative stress on p75 NTR signaling. Subjection of the cells to oxidative stress resulted in decreased cell-surface localization of p75 NTR and intracellular accumulation of p75 NTR fragments. Oxidative stress-induced p75 NTR processing was reduced by pharmacological inhibition of metalloproteases or γ-secretase, but was unaltered by blockade of the ligand-binding domain of p75 NTR . Furthermore, inhibition of c-Jun N-terminal Kinase (JNK) decreased p75 NTR cleavage induced by oxidative damage. Altogether, these results support a mechanism of p75 NTR activation in which oxidative stress stimulates JNK signaling, thereby facilitating p75 NTR processing via a ligand-independent mechanism involving induction of metalloprotease and γ-secretase activity. These findings reveal a novel role for JNK in ligand-independent p75 NTR signaling, and, considering the susceptibility of mesencephalic neurons to oxidative damage associated with Parkinson's disease (PD), merit further investigation into the effects of p75 NTR on PD-related neurodegeneration., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: Many deaf children have limited access to language, spoken or signed, during early childhood - which has damaging effects on many aspects of development. There has been a recent shift to consider deafness and language deprivation as separate but related conditions. As such, educational plans should differentiate between services related to deafness and services related to language deprivation., Description: Many deaf children attend mainstream public schools, and the primary service offered to students who use American Sign Language (ASL) is generally a sign language interpreter., Assessment: We argue that while sign language interpreters can be an effective accommodation for deafness (i.e., students who are deaf and not language-deprived), there is no reason to believe they are an effective accommodation for language deprivation (i.e., students who are deaf and language-deprived)., Conclusion: Using interpreters instead of appropriate educational supports may exacerbate symptoms of language deprivation by prolonging the period of time a child goes with limited access to language.

Medical and educational interventions for children with hearing loss often adopt a single approach of spoken language acquisition through the use of technology, such as cochlear implants. These approaches generally ignore signed languages, despite no guarantees that the child will acquire fluency in a spoken language. Research with children who have a cochlear implant and do not use a signed language indicates that language outcomes are very variable and generally worse than their non-deaf peers. In contrast, signing children with cochlear implants have timely language development similar to their non-deaf peers that also exceeds their non-signing peers with cochlear implants. Natural signed languages have been shown to have the same neurocognitive benefits as natural spoken language while being fully accessible to deaf children. However, it is estimated less than 2% of the 34 million deaf children worldwide receive early childhood exposure to a signed language. Most deaf children are, therefore, at risk for language deprivation during the critical period of language acquisition in the first five years of life. Language deprivation has negative consequences for developmental domains, which rely on timely language acquisition. Beyond the adverse effects on a child's education, language deprivation also affects deaf people's mental and physical health and access to health care, among others. Therefore, policies in accordance with the United Nations Convention on the rights of persons with disabilities are needed. Such policies would ensure early intervention and education services include signed languages and bilingual programmes where the signed language is the language of instruction., ((c) 2019 The authors; licensee World Health Organization.)

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative changes in rats and mice. The purpose of this publication is to provide a standardized nomenclature for classifying changes observed in the hematolymphoid organs, including the bone marrow, thymus, spleen, lymph nodes, mucosa-associated lymphoid tissues, and other lymphoid tissues (serosa-associated lymphoid clusters and tertiary lymphoid structures) with color photomicrographs illustrating examples of the lesions. Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. The nomenclature for these organs is divided into 3 terminologies: descriptive, conventional, and enhanced. Three terms are listed for each diagnosis. The rationale for this approach and guidance for its application to toxicologic pathology are described in detail below.

Problem: Deaf professionals who use American Sign Language (ASL) are a growing population in academic medicine. Reasonable accommodations for this group include providing an ASL interpreter. Many institutions contract with external agencies to provide ad hoc interpreters, but this model has hidden costs for deaf professionals and institutions., Approach: The University of Rochester School of Medicine and Dentistry (URSMD) uses the designated interpreter model in which interpreters are on staff and embedded with deaf professionals so they can learn both the work environment and the deaf professionals' specialized science and medicine content. This model addresses many of the limitations of the external agency approach and better facilitates the inclusion of deaf professionals in the institution., Outcomes: This model has been in use at URSMD since 1990 but has seen exponential growth recently (increasing from 3 deaf professionals with designated interpreters in 2011 to a peak of 17 in 2016). Designated interpreters have worked in different research and clinical settings from dentistry and nursing to community and global health. This growth highlights the increasing number of deaf professionals in medicine and the need to train more designated interpreters., Next Steps: In response to this growing demand, URSMD is developing an ASL Interpreting in Medicine and Science program, a master's degree-level program to train interpreters who are bilingual in ASL and English to be designated interpreters. The designated interpreter model is one step toward creating an environment that is fully inclusive of deaf professionals to the benefit of the whole institution.

The influence of early language and communication experiences on lifelong health outcomes is receiving increased public health attention. Most deaf children have non-signing hearing parents, and are at risk for not experiencing fully accessible language environments, a possible factor underlying known deaf population health disparities. Childhood indirect family communication-such as spontaneous conversations and listening in the routine family environment (e.g. family meals, recreation, car rides)-is an important source of health-related contextual learning opportunities. The goal of this study was to assess the influence of parental hearing status on deaf people's recalled access to childhood indirect family communication. We analyzed data from the Rochester Deaf Health Survey-2013 (n = 211 deaf adults) for associations between sociodemographic factors including parental hearing status, and recalled access to childhood indirect family communication. Parental hearing status predicted deaf adults' recalled access to childhood indirect family communication (χ2 = 31.939, p < .001). The likelihood of deaf adults reporting "sometimes to never" for recalled comprehension of childhood family indirect communication increased by 17.6 times for those with hearing parents. No other sociodemographic or deaf-specific factors in this study predicted deaf adults' access to childhood indirect family communication. This study finds that deaf people who have hearing parents were more likely to report limited access to contextual learning opportunities during childhood. Parental hearing status and early childhood language experiences, therefore, require further investigation as possible social determinants of health to develop interventions that improve lifelong health and social outcomes of the underserved deaf population., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To assess the influence of hearing loss on child behavioral diagnoses, and socioemotional and behavior status., Methods: We analyzed US National Health Interview Survey (NHIS) child data, years 2011 to 2015, for associations between reported hearing loss and relevant NHIS items., Results: Compared with hearing children, NHIS respondents with a deaf child were more likely to report developmental delays (adjusted odds ratio [AOR] = 11.1; 95% confidence interval [CI] = 3.8, 32.4), attention-deficit disorder (AOR = 3.1; 95% CI = 2.5, 3.9), autism diagnoses (AOR = 2.9; 95% CI = 1.8, 4.9), and minor to severe socioemotional difficulties (AOR = 3.9; 95% CI = 3.2, 4.7). When asked if their child was well behaved, respondents were more likely to reply "somewhat true" or "not true" (AOR = 2.7; 95% CI = 2.2, 3.4)., Conclusions: Hearing loss increases likelihood of reporting child behavioral diagnoses, behavior issues, and socioemotional difficulties. Although etiology and professional misdiagnoses likely contribute to elevated prevalence, lack of attention toward language deprivation as a public health issue prevents any further epidemiological insights. Public Health Implications. Despite widespread use of cochlear implants, concerns about deaf children's well-being remain significant. Language deprivation requires investigation and awareness as a social determinant of health.

Purpose: There is a need to better understand the epidemiological relationship between language development and psychiatric symptomatology. Language development can be particularly impacted by social factors-as seen in the developmental choices made for deaf children, which can create language deprivation. A possible mental health syndrome may be present in deaf patients with severe language deprivation., Methods: Electronic databases were searched to identify publications focusing on language development and mental health in the deaf population. Screening of relevant publications narrowed the search results to 35 publications., Results: Although there is very limited empirical evidence, there appears to be suggestions of a mental health syndrome by clinicians working with deaf patients. Possible features include language dysfluency, fund of knowledge deficits, and disruptions in thinking, mood, and/or behavior., Conclusion: The clinical specialty of deaf mental health appears to be struggling with a clinically observed phenomenon that has yet to be empirically investigated and defined within the DSM. Descriptions of patients within the clinical setting suggest a language deprivation syndrome. Language development experiences have an epidemiological relationship with psychiatric outcomes in deaf people. This requires more empirical attention and has implications for other populations with behavioral health disparities as well.

A long-standing belief is that sign language interferes with spoken language development in deaf children, despite a chronic lack of evidence supporting this belief. This deserves discussion as poor life outcomes continue to be seen in the deaf population. This commentary synthesizes research outcomes with signing and non-signing children and highlights fully accessible language as a protective factor for healthy development. Brain changes associated with language deprivation may be misrepresented as sign language interfering with spoken language outcomes of cochlear implants. This may lead to professionals and organizations advocating for preventing sign language exposure before implantation and spreading misinformation. The existence of one-time-sensitive-language acquisition window means a strong possibility of permanent brain changes when spoken language is not fully accessible to the deaf child and sign language exposure is delayed, as is often standard practice. There is no empirical evidence for the harm of sign language exposure but there is some evidence for its benefits, and there is growing evidence that lack of language access has negative implications. This includes cognitive delays, mental health difficulties, lower quality of life, higher trauma, and limited health literacy. Claims of cochlear implant- and spoken language-only approaches being more effective than sign language-inclusive approaches are not empirically supported. Cochlear implants are an unreliable standalone first-language intervention for deaf children. Priorities of deaf child development should focus on healthy growth of all developmental domains through a fully-accessible first language foundation such as sign language, rather than auditory deprivation and speech skills.

Conducting semi-structured American Sign Language interviews with 17 Deaf trauma survivors, this pilot study explored Deaf individuals' trauma experiences and whether these experiences generally align with trauma in the hearing population. Most commonly reported traumas were physical assault, sudden unexpected deaths, and "other" very stressful events. Although some "other" events overlap with traumas in the general population, many are unique to Deaf people (e.g., corporal punishment at oral/aural school if caught using sign language, utter lack of communication with hearing parents). These findings suggest that Deaf individuals may experience developmental traumas distinct to being raised in a hearing world. Such traumas are not captured by available trauma assessments, nor are they considered in evidence-based trauma treatments.

Objectives: Stimulants may worsen psychotic symptoms but there is limited evidence about the impact of stimulant abuse in people with schizophrenia. This study examined the prevalence and correlates of stimulant and other drug disorders in a population-based sample of people with schizophrenia, examining associations with frequent service use, physical health comorbidities and accommodation instability., Methods: New South Wales (NSW) hospital, community mental health and emergency department data were used to examine health service contact over 5 years in 13,624 people with a diagnosis of schizophrenia. Associations of stimulant disorders were examined with multinomial logistic regression, comparing people with no substance disorders to those with cannabis disorders, stimulant disorders or both., Results: Of people with schizophrenia, 51% had substance disorders, including 14% with stimulant disorders. Stimulant disorders were more common in young adults and in urban areas, less common in migrants, and unrelated to initial social disadvantage. More than 80% of those with stimulant disorders also had cannabis disorders. Service use and harms were most common in this group, including frequent mental health admissions (59%), frequent emergency department presentations (52%), admissions with injury or self-harm (44%), infectious disease diagnoses (22%), multiple changes of residence (61%), movement to more disadvantaged locations (42%) and periods of homelessness (18%). People with stimulant disorders alone had higher rates of self-harm, infectious disease and non-mental health admissions than people with cannabis disorders alone., Conclusions: Stimulant disorders occur in people with schizophrenia and in first-episode psychosis at rates more than 10 times that of the broader population. Stimulant disorders are likely to worsen the burden of psychosis, and strategies are needed to engage and support the highly disadvantaged group of people with schizophrenia who have cannabis and stimulant disorders., (© The Royal Australian and New Zealand College of Psychiatrists 2014.)

Background: Few studies have examined the impact of stimulant use on outcome in early psychosis. Ceasing substance use may lead to positive outcomes in psychosis., Aims: To examine whether baseline cannabis or stimulant disorders and ongoing drug use predict readmission within 2 years of a first psychosis admission., Method: Predictors of readmission were examined with Cox regression in 7269 people aged 15-29 years with a first psychosis admission., Results: Baseline cannabis and stimulant disorders did not predict readmission. A stimulant disorder diagnosis prior to index psychosis admission predicted readmission, but a prior cannabis disorder diagnosis did not. Ongoing problem drug use predicted readmission. The lowest rate of readmission occurred in people whose baseline drug problems were discontinued., Conclusions: Prior admissions with stimulant disorder may be a negative prognostic sign in first-episode psychosis. Drug use diagnoses at baseline may be a good prognostic sign if they are identified and controlled., (Royal College of Psychiatrists.)

Background: Substance abuse adds to diagnostic uncertainty in psychosis and may increase the risk of transition from brief and affective psychoses to schizophrenia. This study examined whether comorbid substance disorder was associated with diagnostic instability and progression from other psychosis diagnoses to schizophrenia and whether effects differed for cannabis and stimulant-related disorders., Method: We identified 24,306 individuals admitted to hospital with an ICD-10 psychosis diagnosis between 2000 and 2011. We examined agreement between initial diagnosis and final diagnosis over 2-5 years and predictors of diagnostic change toward and away from a final diagnosis of schizophrenia., Results: Nearly half (46%) of participants with initial brief, atypical, or drug-induced psychoses were later diagnosed with schizophrenia. Persisting illicit drug disorders did not increase the likelihood of progression to schizophrenia (OR = 0.97; 95% CI, 0.89-1.04) but increased the likelihood of revision of index psychosis diagnosis away from schizophrenia (OR = 1.55; 95% CI, 1.40-1.71). Cannabis disorders predicted an increased likelihood of progression to schizophrenia (OR =1.12; 95% CI, 1.01-1.24), while stimulant disorders predicted a reduced likelihood (OR = 0.81; 95% CI, 0.67-0.97). Stimulant disorders were associated with greater overall diagnostic instability., Conclusions: Many people with initial diagnoses of brief and affective psychoses are later diagnosed with schizophrenia. Cannabis disorders are associated with diagnostic instability and greater likelihood of progression to schizophrenia. By contrast, comorbid stimulant disorders may be associated with better prognosis in psychosis, and it may be important to avoid premature closure on a diagnosis of schizophrenia when stimulant disorders are present., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

The 2-year rodent carcinogenicity test has been the regulatory standard for the prediction of human outcomes for exposure to industrial and agro-chemicals, food additives, pharmaceuticals and environmental pollutants for over 50 years. The extensive experience and data accumulated over that time has spurred a vigorous debate and assessment, particularly over the last 10 years, of the usefulness of this test in terms of cost and time for the information obtained. With renewed interest in the United States and globally, plus new regulations in the European Union, to reduce, refine and replace sentinel animals, this review offers the recommendation that reliance on information obtained from detailed shorter-term, 6 months rodent studies, combined with genotoxicity and chemical mode of action can realize effective prediction of human carcinogenicity instead of the classical two year rodent bioassay. The aim of carcinogenicity studies should not be on the length of time, and by obligation, number of animals expended but on the combined systemic pathophysiologic influence of a suspected chemical in determining disease. This perspective is in coordination with progressive regulatory standards and goals globally to utilize effectively resources of animal usage, time and cost for the goal of human disease predictability., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A 90-day feeding study in Han/Wistar rats with calcium lignosulphonate was evaluated by the EFSA. The study was considered to be inadequate due to potentially impaired health status of the animals based upon a high incidence of minimal lymphoid hyperplasia in mesenteric/mandibular lymph nodes and Peyer's patches, and minimal lymphoid cell infiltration in the liver in all animals. The EFSA Panel further disagreed with the conclusion that the treatment-related observation of foamy histiocytosis in mesenteric lymph nodes was non-adverse and asked whether this observation would progress to something more adverse over time. A PWG was convened to assess the sections of lymph nodes, Peyer's patches and liver. In addition, all lymphoid tissues were re-examined. The clinical pathology and animal colony health screening data were re-evaluated. The question whether the foamy histiocytosis could progress to an adverse finding with increasing exposure duration was addressed by read-across. In conclusion, the animals on the 90-day feeding study were in good health, the study was adequate for safety evaluation, and the foamy histiocytes in the mesenteric lymph nodes were not considered adverse, but rather an adaptive response that was considered unlikely to progress to an adverse condition with time. The NOAEL was re-affirmed to be 2000 mg/kgbw/d., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A thirteen week feeding study was conducted by feeding young adult male and female Sprague Dawley [Crl:CD®(SD)] rats diets containing grain from genetically modified (GM) DP-ØØ4114-3 maize that was either untreated (4114) or treated in the field with glufosinate ammonium (4114GLU). Control rats were fed diets containing the same concentration of near isogenic, non-GM maize grain (091) or one of three types of commercially available non-GM maize grain. At the end of the in-life phase, renal tubule tumors were reported in two male rats consuming diets containing 4114 maize grain. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded kidney histology sections from control (091) and treated (4114 and 4114GLU) male rats. The objectives were for the panel to characterize the histopathologic findings and to interpret their relationship to consumption of the indicated diet. The PWG concluded unanimously that the kidney tumors were characteristic of amphophilic-vacuolar (AV) tumors and AV atypical tubular hyperplasia which represent a distinctive phenotype that has been reported to occur sporadically in young Sprague Dawley Rats. The PWG determined that the neoplasms and atypical tubular hyperplasias were multicentric and bilateral which typifies tumors of familial origin. Degenerative/regenerative or cytotoxic changes consistent with nephrotoxicity leading to tumor induction were not observed in these rats and thus supports the conclusion that tumors were unrelated to consumption of the test diet. It was the unanimous opinion of the PWG that the proliferative renal tubule cell lesions were spontaneous and not related to consumption of diets containing 4114 maize grain.

Objectives: To obtain a suitable conduit from the lesser (short) saphenous system for use in coronary artery bypass surgery. We wanted to perform this while the patient was in the supine position as to not disrupt the standard operation, and at the same time, utilizing the endoscopic vein harvest technique with its obvious abilities to decrease vein harvest morbidity. We also theorized that through endoscopic techniques instead of the open technique we could harvest greater lengths of conduit, thus providing quality vein segments for additional grafts if needed., Methods: We were able to perform endoscopic vein harvest while in the supine position with one unique centrally located incision that has not been previously described., Results: The lesser saphenous vein harvested in the described technique provided excellent conduit for our patients that were conduit poor. The endoscopic technique allowed increased length of harvested segments, by giving us the ability to travel under the gastrocnemius muscle with minimal morbidity as opposed to the open technique, where the traditional endpoint is the aforementioned muscle. Conduits were harvested successfully from 14 of 16 candidates. No wound infections or healing problems were experienced. Neurovascular integrity was maintained in all patients., Conclusions: Endoscopic vein harvest of the lesser saphenous vein with the patient in the supine position is safe, effective and affords conduits for a unique subset of patients undergoing coronary artery bypass grafting.

Extensive experience in conducting long term cancer bioassays has been gained over the past 50 years of animal testing on drugs, pesticides, industrial chemicals, food additives and consumer products. Testing protocols for the conduct of carcinogenicity studies in rodents have been developed in Guidelines promulgated by regulatory agencies, including the US EPA (Environmental Protection Agency), the US FDA (Food and Drug Administration), the OECD (Organization for Economic Co-operation and Development) for the EU member states and the MAFF (Ministries of Agriculture, Forestries and Fisheries) and MHW (Ministry of Health and Welfare) in Japan. The basis of critical elements of the study design that lead to an accepted identification of the carcinogenic hazard of substances in food and beverages is the focus of this review. The approaches used by entities well-known for carcinogenicity testing and/or guideline development are discussed. Particular focus is placed on comparison of testing programs used by the US National Toxicology Program (NTP) and advocated in OECD guidelines to the testing programs of the European Ramazzini Foundation (ERF), an organization with numerous published carcinogenicity studies. This focus allows for a good comparison of differences in approaches to carcinogenicity testing and allows for a critical consideration of elements important to appropriate carcinogenicity study designs and practices. OECD protocols serve as good standard models for carcinogenicity testing protocol design. Additionally, the detailed design of any protocol should include attention to the rationale for inclusion of particular elements, including the impact of those elements on study interpretations. Appropriate interpretation of study results is dependent on rigorous evaluation of the study design and conduct, including differences from standard practices. Important considerations are differences in the strain of animal used, diet and housing practices, rigorousness of test procedures, dose selection, histopathology procedures, application of historical control data, statistical evaluations and whether statistical extrapolations are supported by, or are beyond the limits of, the data generated. Without due consideration, there can be result conflicting data interpretations and uncertainty about the relevance of a study's results to human risk. This paper discusses the critical elements of rodent (rat) carcinogenicity studies, particularly with respect to the study of food ingredients. It also highlights study practices and procedures that can detract from the appropriate evaluation of human relevance of results, indicating the importance of adherence to international consensus protocols, such as those detailed by OECD., (Copyright © 2010. Published by Elsevier Inc.)

Attenuation of visual activity in the superficial layers (SLs), stratum griseum superficiale and stratum opticum, of the superior colliculus during saccades may contribute to reducing perceptual blur during saccades and also may help prevent subsequent unwanted saccades. GABAergic neurons in the intermediate, premotor, layer (SGI), stratum griseum intermedium, send an inhibitory input to SL. This pathway provided the basis for a model proposing that the SGI premotor cells that project to brainstem gaze centers and discharge before saccades also activate neighboring GABAergic neurons that suppress saccade-induced visual activity in SL. The in vitro method allowed us to test this model. We made whole-cell patch-clamp recordings in collicular slices from either rats or GAD67-GFP knock-in mice, in which GABAergic neurons could be identified by their expression of green fluorescence protein (GFP). Antidromic electrical stimulation of SGI premotor cells was produced by applying pulse currents in which their axons congregate after exiting the superior colliculus. The stimulation evoked monosynaptic EPSCs in SGI GABAergic neurons that project to SL, as would be predicted if these neurons receive excitatory input from the premotor cells. Second, IPSCs were evoked in SL neurons, some of which project to the visual thalamus. These IPSCs were polysynaptically mediated by the GABAergic neurons that were excited by the antidromically activated SGI neurons. These results support the hypothesis that collaterals of premotor neuron axons excite GABAergic neurons that inhibit SL visuosensory cells.

Highly refined mineral hydrocarbons (MHCs) such as low melting point paraffin wax (LMPW) and low viscosity white oils can cause inflammatory changes in the liver and mesenteric lymph nodes (MLNs) of the Fischer-344 (F-344) rat. In contrast, only minimal MLN changes are seen in the Sprague-Dawley (S-D) rat with no changes in the liver. In this study, the response of female F-344 and S-D rats was compared after 90days dietary treatment with 0%, 0.2% or 2% LMPW. Effects in the F-344 rats were significantly greater than in the S-D rats: increased liver and splenic weights and inflammatory changes (hepatic microgranulomas) in these tissues were observed only in the F-344 rats. Microgranulomas in the MLNs were observed in both strains but the effects were substantially greater in the F-344 rats. Cellular markers of inflammation were examined in a subset of rats from each group using immunohistochemical staining. An increase in staining for CD3 (T-cells), CD8a (suppresser/cytotoxic T-cells) and CD4 (helper T-cells) correlated with an increase in lymphoid cells in the livers of treated F-344 rats. The majority of macrophages in the hepatic microgranulomas of treated F-344 rats were negative for the ED2 marker, indicating a likely origin from non-resident macrophages. Electron microscopy showed Kupffer cell hypertrophy and hyperplasia in treated F-344 rats. However, lysozyme staining (indicating activation of epithelioid macrophages) decreased with increasing granuloma size. Non-ED2 expressing cells may have been recruited but not sufficiently activated to be lysozyme positive. Inflammatory changes in the cardiac mitral valve noted in previous studies of LMPW were also seen in the F-344 rats in this study but not in the S-D rats. Chemical analysis showed that MHC accumulated in livers from treated F-344 but not S-D rats and the concentration was more than 2-fold greater in MLNs from the F-344 than from the S-D rats. The F-344 appears to be more immunologically sensitive to a number of agents than other rat strains and the results of this study suggest that this may contribute, along with pharmacokinetic differences, to the inflammatory response of F-344 rats to dietary MHCs., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The superior colliculus plays an important role in the translation of sensory signals that encode the location of objects in space into motor signals that encode vectors of the shifts in gaze direction called saccades. Since the late 1990s, our two laboratories have been applying whole cell patch-clamp techniques to in vitro slice preparations of rodent superior colliculus to analyze the structure and function of its circuitry at the cellular level. This review describes the results of these experiments and discusses their contributions to our understanding of the mechanisms responsible for sensorimotor integration in the superior colliculus. The experiments analyze vertical interactions between its superficial visuosensory and intermediate premotor layers and propose how they might contribute to express saccades and to saccadic suppression. They also compare and contrast the circuitry within each of these layers and propose how this circuitry might contribute to the selection of the targets for saccades and to the build-up of the premotor commands that precede saccades. Experiments also explore in vitro the roles of extrinsic inputs to the superior colliculus, including cholinergic inputs from the parabigeminal and parabrachial nuclei and GABAergic inputs from the substantia nigra pars reticulata, in modulating the activity of the collicular circuitry. The results extend and clarify our understanding of the multiple roles the superior colliculus plays in sensorimotor integration.

Here we survey a molecular genetic approach for imaging synaptic inhibition. This approach is based on measuring intracellular chloride concentration ([Cl(-)](i)) with the fluorescent chloride indicator protein, Clomeleon. We first describe several different ways to express Clomeleon in selected populations of neurons in the mouse brain. These methods include targeted viral gene transfer, conditional expression controlled by Cre recombination, and transgenesis based on the neuron-specific promoter, thy1. Next, we evaluate the feasibility of using different lines of thy1::Clomeleon transgenic mice to image synaptic inhibition in several different brain regions: the hippocampus, the deep cerebellar nuclei (DCN), the basolateral nucleus of the amygdala, and the superior colliculus (SC). Activation of hippocampal interneurons caused [Cl(-)](i) to rise transiently in individual postsynaptic CA1 pyramidal neurons. [Cl(-)](i) increased linearly with the number of electrical stimuli in a train, with peak changes as large as 4 mM. These responses were largely mediated by GABA receptors because they were blocked by antagonists of GABA receptors, such as GABAzine and bicuculline. Similar responses to synaptic activity were observed in DCN neurons, amygdalar principal cells, and collicular premotor neurons. However, in contrast to the hippocampus, the responses in these three regions were largely insensitive to antagonists of inhibitory neurotransmitter receptors. This indicates that synaptic activity can also cause Cl(-) influx through alternate pathways that remain to be identified. We conclude that Clomeleon imaging permits non-invasive, spatiotemporally precise recordings of [Cl(-)](i) in a large variety of neurons, and provides new opportunities for imaging synaptic inhibition and other forms of neuronal chloride signaling.

Rats were fed diets containing 0%, 1%, 3%, or 5% mixed tocopheryl phosphates for 90 days. No abnormal clinical signs related to treatment appeared. Some statistically significant changes in hematology and clinical chemistry parameters appeared, but the majority were not dose dependent, occurred in only one sex or group, and/or remained within the historical control range for this strain of rat. A statistically significant apparent reduction in blood protein was observed in animals treated with the tocopheryl phosphates, but further investigation showed that the test substance interfered with the protein assay. Repeat analysis using a method unaffected by plasma test substance levels showed no difference in plasma proteins among all groups. Gross necropsy revealed no abnormalities; reduced relative heart and epididymal weights were observed, but were not dose dependent and were considered incidental. Histopathological changes occurred only in the mesenteric lymph node and small intestine. Foreign material in a crystal-like form appeared in macrophages in both organs, and increased in a dose-related fashion. In the lymph node, sinus histiocytosis increased with dose, but the severity was similar between the control and low-dose groups. Foreign-body granulomatous inflammation, associated with Maltese cross birefringence of the crystals was seen in the mid- and high-dose animals, but not the low-dose group. Similarly, the small intestine showed increasing amounts of foreign material and inflammation in the mid- and high-dose but not in the 1% diet. The 1% diet (equivalent to 587 and 643 mg mixed tocopheryl phosphates/kg body weight/day for male and female rats, respectively) was considered the no observed adverse effect level.

To permit rapid optical control of brain activity, we have engineered multiple lines of transgenic mice that express the light-activated cation channel Channelrhodopsin-2 (ChR2) in subsets of neurons. Illumination of ChR2-positive neurons in brain slices produced photocurrents that generated action potentials within milliseconds and with precisely timed latencies. The number of light-evoked action potentials could be controlled by varying either the amplitude or duration of illumination. Furthermore, the frequency of light-evoked action potentials could be precisely controlled up to 30 Hz. Photostimulation also could evoke synaptic transmission between neurons, and, by scanning with a small laser light spot, we were able to map the spatial distribution of synaptic circuits connecting neurons within living cerebral cortex. We conclude that ChR2 is a genetically based photostimulation technology that permits analysis of neural circuits with high spatial and temporal resolution in transgenic mammals.

The nucleus of the optic tract (NOT) has been implicated in the initiation of the optokinetic reflex (OKR) and in the modulation of visual activity during saccades. The present experiments demonstrate that these two functions are served by separate cell populations that can be distinguished by differences in both their cellular physiology and their efferent projections. We compared the response properties of NOT cells in rats using target-directed whole cell patch-clamp recording in vitro. To identify the cells at the time of the recording experiments, they were prelabeled by retrograde axonal transport of WGA-apo-HRP-gold (15 nm), which was injected into their primary projection targets, either the ipsilateral superior colliculus (iSC), or the contralateral NOT (cNOT), or the ipsilateral inferior olive (iIO). Retrograde labeling after injections in single animals of either WGA-apo-HRP-gold with different particle sizes (10 and 20 nm) or two different fluorescent dyes distinguished two NOT cell populations. One projects to both the iSC and cNOT. These cells are spontaneously active in vitro and respond to intracellular depolarizations with temporally regular tonic firing. The other population projects to the iIO and consists of cells that show no spontaneous activity, respond phasically to intracellular depolarization, and show irregular firing patterns. We propose that the spontaneously active pathway to iSC and cNOT is involved in modulating the level of visual activity during saccades and that the phasically active pathway to iIO provides a short-latency relay from the retina to premotor mechanisms involved in reducing retinal slip.

Neurons in the superficial gray layer (SGS) of the superior colliculus receive visual input and excite intermediate layer (SGI) neurons that play a critical role in initiating rapid orienting movements of the eyes, called saccades. In the present study, two types of experiments demonstrate that a population of SGI neurons gives rise to a reciprocal pathway that inhibits neurons in SGS. First, in GAD67-GFP knockin mice, GABAergic SGI neurons that expressed GFP fluorescence were injected with the tracer biocytin to reveal their axonal projections. Axons arising from GFP-positive neurons in SGI terminated densely in SGS. Next, SGI neurons in rats and mice were stimulated by using the photolysis of caged glutamate, and in vitro whole-cell patch-clamp recordings were used to measure the responses evoked in SGS cells. Large, synaptically mediated outward currents were evoked in SGS neurons. These currents were blocked by gabazine, confirming that they were GABA(A) receptor-mediated inhibitory postsynaptic currents. This inhibitory pathway from SGI transiently suppresses visual activity in SGS, which in turn could have multiple effects. These effects could include reduction of perceptual blurring during saccades as well as prevention of eye movements that might be spuriously triggered by the sweep of the visual field across the retina.

Multiple renal tubular cell adenomas and atypical tubular hyperplasia were diagnosed in 2 high-dose and 1 mid-dose female Sprague-Dawley (Crl:CD (SD)IGS BR) rats from a 90-day toxicity study of an amino acid found in green tea. The tumors were bilateral multicentric adenomas accompanied by atypical foci of renal tubular hyperplasia in both kidneys of the 3 animals. Toxic tubular changes that typically accompany renal carcinogenesis were not seen in any of the other animals of the study, suggesting rather, an underlying germline mutation of a tumor suppressor gene in these three rats. The histological appearance of these tumors and short latency was reminiscent of the spontaneous lesions reported to arise in Sprague-Dawley rats in the Nihon rat model. Nihon rats develop kidney tumors as a result of a spontaneous mutation in the rat homologue of the Birt-Hogg-Dubé gene (Bhd). Frozen samples of liver from two tumor-bearing rats were assayed for germline alterations in the Bhd gene. The entire coding region (exons 3-13) of the Bhd gene was sequenced, and a guanine (nt106G) to adenine (nt106A) polymorphism was detected resulting in a glycine to arginine (G36R) substitution in both tumor-bearing animals. In the study animals, the frequency of the A-allele (adenine) was determined to be 27% (19/70). Interestingly, rats obtained from two other sources (n = 17) only carried the nt106G-allele, consistent with the published rat sequence for this gene. Genetic fingerprinting of microsatellite loci indicated that the rats had a shared genetic background. Laser capture microdissection (LCM) of the tumor cells demonstrated a loss of heterozygosity in the Bhd gene in neoplastic cells of one of the two animals. Taken together, these data suggest that the tumors observed in these animals arose spontaneously as a result of a shared genetic susceptibility leading to the development of renal tubular neoplasms.

Some models propose that the spatial and temporal distributions of premotor activity in the intermediate layer of the superior colliculus are shaped by neuronal ensembles that give rise to local excitatory and distant inhibitory connections. One function proposed for these connections is to mediate a "winner-take-all" network; the short-range excitatory connections build up the activity of neighboring cells that command orienting movements in one direction, whereas the wide-ranging inhibitory projections attenuate the activity of remote cells that command incompatible movements. We used in vitro photostimulation and whole-cell patch-clamp recording to test these models by measuring the spatial extent of synaptic interactions within the rat intermediate layer. Uncaging glutamate over whole-cell patch-clamped cells in the intermediate layer elicited long-lasting inward currents, resulting from direct activation of glutamate receptors expressed by the cells, and brief synaptic currents evoked by activation of presynaptic neurons. The synaptic responses comprised clusters of excitatory and inhibitory currents. The size of these responses depended on the location of the stimulus with respect to the clamped cell. Large responses were commonly evoked by stimuli within 200 microm of the soma in the intermediate layer; smaller responses could occasionally be evoked from sites as distant as 500 microm. Responses evoked by stimulation beyond this distance were rare. Although the results demonstrated powerful local excitatory and inhibitory connections, they did not support the pattern of short-range excitation and widespread inhibition predicted by the winner-take-all hypothesis.

Objectives: To examine the relationship between maternal infant-feeding style and adiposity in childhood and to determine whether feeding style explains any of the association between maternal obesity and childhood adiposity., Design: Prospective cohort study., Setting: Cincinnati metropolitan area., Participants: A total of 313 preschool children; 80% were white and 20% were black., Main Outcome Measures: Seven factors describing maternal infant-feeding style derived from the Infant Feeding Questionnaire administered at age 3 years; maternal obesity, defined as a body mass index of 30 or higher before pregnancy; and adiposity at 5 years of age as assessed by dual-energy x-ray absorptiometry., Results: The mean +/- SD fat mass was 4.55 +/- 1.64 kg. Seventeen percent of the mothers were obese before pregnancy. Children whose mothers had high concern about the infant overeating or becoming overweight (the highest tertile of the "overeating" factor) had 0.67 kg (95% confidence interval, 0.31-1.03 kg) higher fat mass than children whose mothers did not have high concern (the other 2 tertiles). None of the other 6 feeding factors were related to childhood adiposity. Children of obese mothers had 0.54 kg (95% confidence interval, 0.10-0.98 kg) higher fat mass than children of nonobese mothers. High concern about the infant overeating, which was more common in obese mothers, accounted for 15% of this 0.54-kg difference., Conclusion: High maternal concern about an infant overeating or becoming overweight was associated with higher adiposity at 5 years of age and explained some of the association between maternal obesity and child adiposity.

Background: Although dual-energy X-ray absorptiometry (DXA) is considered the most accurate measure of adiposity in children, it has rarely been used to examine the relation between infant feeding and adiposity during childhood., Objective: The objective was to ascertain whether adiposity at age 5 y was related to breastfeeding, to the timing of the introduction of complementary foods during infancy, or to both., Design: Body composition was measured in 313 children at age 5 y by using DXA. Data on breastfeeding, formula feeding, and the timing of the introduction of complementary foods were obtained from the mothers when the children were 3 y old. Regression analysis was used to examine the relation between infant feeding and fat mass after adjustment for lean body mass, sex, birth weight, maternal obesity, race, and other sociodemographic variables., Results: Fifty-three percent of the children were boys, 80% were white, and 20% were black. There was no significant difference in adjusted fat mass between those ever breastfed and those never breastfed (x +/- SE: 4.48 +/- 0.09 and 4.76 +/- 0.17 kg, respectively; P = 0.17). Children who were breastfed for a longer duration and those who were breastfed without concurrent formula feeding did not have significantly lower fat mass than did those children who were never breastfed. Children did not differ significantly in fat mass if they were introduced to complementary foods before or after 4 mo of age (4.49 +/- 0.12 and 4.63 +/- 0.12 kg, respectively; P = 0.42)., Conclusion: Neither breastfeeding nor the timing of the introduction of complementary foods was associated with adiposity at age 5 y.

A pathway from the superficial visual layers to the intermediate premotor layers of the superior colliculus has been proposed to mediate visually guided orienting movements. In these experiments, we combined photostimulation using "caged" glutamate with in vitro whole cell patch-clamp recording to demonstrate this pathway in the rat. Photostimulation in the superficial gray and optic layers (SGS and SO, respectively) evoked synaptic responses in intermediate gray layer (SGI) cells. The responses comprised individual excitatory postsynaptic currents (EPSCs) or EPSC clusters. Blockade of these EPSCs by TTX confirmed that they were synaptically mediated. Stimulation within a column (approximately 500 microm diam) extending superficially from the recorded cell evoked the largest and most reliable responses, but off-axis stimuli were effective as well. The EPSCs could be evoked by stimuli 1,000 microm off-axis from the postsynaptic neuron. The dimensions of this wider region (approximately 2 mm diam) corresponded to those of the dendrites of superficial layer wide-field neurons. SGI neurons differed in their input from SGS and SO; neurons in the middle of the intermediate layer (SGIb) were less likely to respond to visual layer photostimulation than were those in sublayers just above and below them. However, focal stimulation within SGIa did evoke responses within SGIb, indicating that SGIb neurons may receive input from the visual layers indirectly. These results demonstrate a columnar pathway that may mediate visually guided orienting movements, but the results also reveal spatial attributes of the pathway which imply that it also plays a more complex role in visuomotor integration.

The goal of this study was to identify age-related changes in the expression of estrogen target genes in mouse uterus. We developed a novel 'estrogen response element (ERE) Chip' microarray bearing 297 genes including both known estrogen target genes and genes identified by searching the mouse genome database to have EREs, AP-1 sites, and Sp1 sites, all targets of estrogen receptor (ER) regulation. 400-500 bp PCR products of these 297 genes were printed onto nylon membranes creating the 'ERE Chip' microarray. This microarray is unique because it is the first estrogen-responsive gene-specific microarray to identify changes in uterine gene expression in young versus old mice. Using this ERE microarray we identified 10 uterine genes whose expression was up-regulated in old mice, e.g. beta-actin, calcium binding protein 45a, Sp1, and COUP-TFII. In contrast, the expression of only 4 uterine genes, i.e., complement C3, lactoferrin, Muc-1, and 17-beta-hydroxysteroid dehydrogenase 8 (H2-Ke6) was down-regulated in old mice. These changes may reflect an increase in stromal and a decrease in glandular epithelial gene expression, and may be associated with age-related changes in these tissue compartments within the uterus, possibly leading to the decline in reproductive function in C57Bl/6 mice.

Purpose: To evaluate the ability of the EmulSiv filter (EF) to remove extrinsic microbial contaminants from propofol., Methods: Aliquots of Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), Klebsiella pneumoniae (K. pneumoniae), Moraxella osloensis (M. osloensis), Enterobacter agglomerans (E. agglomerans), Escherichia coli (E. coli), Serratia marcescens (S. marcescens), Moraxella catarrhalis (M. catarrhalis), Haemophilus influenzae (H. influenzae) and Campylobacter jejuni (C. jejuni) were inoculated into vials containing 20 mL of sterile propofol. The unfiltered inoculated propofol solutions served as controls. Ten millilitres and 20 mL samples of the inoculated propofol were filtered through the EF. All solutions were then subplated onto three culture plates using a precision 1 micro L calibrated platinum loop and incubated. The number of colony forming units (CFU) were counted. Data were analyzed using a one-sample t test, and a P value of less than 0.05 was selected as the level of statistical significance., Results: The EF was able to completely remove CFU of S. aureus, C. albicans, K. pneumoniae, M. osloensis, E. agglomerans, E. coli, S. marcescens, and M. catarrhalis (P < 0.05). A small number of H. influenzae CFU were able to evade filtration in both the 10 mL and 20 mL samples. C. jejuni CFU were able to evade filtration in only the 10 mL sample., Conclusions: The EF removes the majority of microbial contaminates from propofol with the exception of H. influenzae and C. jejuni. Although the EF is capable of removing most of the microbial contamination produced by H. influenzae and C. jejuni, a few CFU are capable of evading filtration. Consequently, even the use of a filter capable of removing microbial contaminants is not a substitute for meticulous aseptic technique and prompt administration when propofol is used.

Background: Current trends show that patients referred for coronary artery bypass grafting (CABG) are significantly older, sicker, and at higher risk for complications than ever before. Eliminating leg wound complications would significantly benefit these patients and reduce the consumption of health care time and dollars. Endoscopic vein harvesting (EVH) decreases the risk of wound complications in patients following CABG and may decrease costly long-term wound-related problems., Methods: In this retrospective study, the cases of 1909 Medicare patients who had undergone EVH or open vein harvesting (OVH) for CABG were reviewed. The risk factors of these patients were examined and compared with those of 1485 non- Medicare patients. Readmissions, home health care costs, and office lengths of service were reviewed and analyzed., Results: The results of univariate analyses of the Medicare versus non-Medicare populations indicated significant differences for peripheral vascular disease (25.4% versus 17.2%; P <.0001), renal failure (6.0% versus 2.8%; P <.0001), hypertension (75.4% versus 71.5%; P =.011), female sex (31.1% versus 22.4%; P <.0001), mean age (69.8 years versus 57.1 years; P <.0001), and mortality risk (4.6% versus 2.2%; P <.0001). The wound rates in the Medicare group were 1.1% for EVH (n = 741) versus 2.8% for OVH (n = 1168), and this difference was significant (P =.0163) despite a higher frequency of morbid obesity in the EVH population (P <.0001). No significant differences were found in readmission frequency, home health care costs, or office length of service., Conclusion: EVH benefits Medicare patients. Although this study is the largest to date to use disposable instruments, there is a lack of statistical power in the analysis of cost comparisons due to the small sample size of wound complications. However, there appears to be a general trend toward a lower treatment cost per patient and less resource use with EVH.

The humanized monoclonal antibody Hu1D10 (Remitogen, Protein Design Labs, Fremont, CA) recognizes a polymorphic determinant of human leukocyte antigen-DR expressed on the majority of B-cell lymphomas and on normal B cells of most individuals. Hu1D10 mediates complement-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and apoptosis of 1D10 antigen (Ag)-positive B cells in vitro. The 1D10 Ag is expressed on a variety of tissues but is restricted primarily to lymphocytes, macrophages, and mesenchymal dendritic cells. The safety and pharmacology of Hu1D10 were investigated in rhesus macaques. Animals were prescreened for 1D10 Ag expression on circulating B cells. Sixteen animals received either placebo (4 Ag+ animals), 1 mg/kg Hu1D10 (4 Ag+ animals), or 10 mg/kg Hu1D10 (4 Ag+ animals and 4 Ag- animals) daily via intravenous (i.v.) bolus-injection for 5 consecutive days, and 4 Ag+ animals received 10 mg/kg Hu1D10 via 90 min i.v. infusion x 5 days. Bolus-injection of Hu1D10 resulted in type 1 hypersensitivity reactions in the majority of Ag+ animals and one death due to anaphylaxis. Slow infusion of Hu1D10 was associated with only mild hypersensitivity reactions after the first dose but not subsequent doses. In animals treated with 10 mg/kg Hu1D10 via bolus-injection, the median terminal elimination half-life of Hu1D10 was 2.6 and 8.4 days in Ag+ and Ag- animals, respectively. Administration of Hu1D10 to Ag+ animals resulted in rapid and profound depletion of circulating B cells for 7-10 days following the last dose. No B-cell depletion was observed in Ag- animals, despite slower elimination of Hu1D10. These studies demonstrate that Hu1D10 reacts with antigen-presenting cells in rhesus macaques. It can be safely administered as a slow i.v. infusion but causes severe toxicity when given as a bolus. This study provides the foundation for testing Hu1D10 for the treatment of B-cell malignancies in humans.

Stratum griseum superficiale (SGS) of the superior colliculus receives a dense cholinergic input from the parabigeminal nucleus. In this study, we examined in vitro the modulatory influence of acetylcholine (ACh) on the responses of SGS neurons that project to the visual thalamus in the rat. We used whole-cell patch-clamp recording to measure the responses of these projection neurons to electrical stimulation of their afferents in the stratum opticum (SO) before and during local pressure injections of ACh. These colliculothalamic projection neurons (CTNs) were identified during the in vitro experiments by prelabeling them from the thalamus with the retrograde axonal tracer wheat germ agglutinin-apo-HRP-gold. In a group of cells that included the prelabeled neurons, EPSCs evoked by SO stimulation were significantly reduced by the application of ACh, whereas IPSC amplitudes were significantly enhanced. Similar effects were observed when the nicotinic ACh receptor agonist lobeline was used. Application of the selective GABA(B) receptor antagonist 3-[[(3,4-dichlorophenyl)-methyl]amino]propyl](diethoxymethyl)phosphinic acid blocked ACh-induced reduction in the evoked response. In contrast, the ACh-induced reduction was insensitive to application of the GABA(A) receptor antagonist bicuculline. The ACh-induced reduction was also diminished by bath application of muscimol at the low concentrations that selectively activate GABA(C) receptors. Because GABA(C) receptors may be specifically expressed by GABAergic SGS interneurons (Schmidt et al., 2001), our results support the hypothesis that ACh reduces CTN activity by nicotinic receptor-mediated excitation of local GABAergic interneurons. These interneurons in turn use GABA(B) receptors to inhibit the CTNs.

1D10 is a previously described antibody that binds to cells from a majority of B-cell malignancies. The current studies were designed to further evaluate the antigen specificity of 1D10 and its potential as an immunotherapeutic agent. Studies with transfectants and immunoprecipitation demonstrated that 1D10 recognizes some, but not all, of the human HLA-DR beta chains. Both normal and malignant B cells can express the 1D10 antigen. A humanized version of 1D10 was produced using CDR grafting. The resulting antibody has an affinity that is similar to that of the parental murine antibody. In addition, the humanized antibody is capable of inducing complement-mediated cytotoxicity, antibody-dependent cell cytotoxicity, and direct apoptosis of 1D10-expressing B cells. Based on these in vitro anti-tumor activities, we conclude humanized 1D10 deserves further evaluation as an immunotherapeutic agent., (Copyright 2001 Wiley-Liss, Inc.)

Surgical biopsies of the liver were obtained from woodchuck hepatitis virus (WHV)-infected neonatal woodchucks at 2 time points before the self-limited or chronic outcomes became obvious by serologic criteria. Following segregation of outcomes, livers were analyzed for intrahepatic type 1 cytokine messenger RNAs (mRNAs) (interleukin 2 [IL-2], interferon gamma [IFN-gamma], tumor necrosis factor-alpha [TNF-alpha]) and leukocyte inflammatory phenotype (IgG+ plasma cells, lysozyme+ macrophages, CD3+ T cells). Baselines were assessed using age-matched uninfected control livers. At week 8 (early acute phase), intrahepatic type 1 cytokine mRNAs were similarly low in both outcome settings and no different from age-matched uninfected controls. This was consistent with the minimal initial viral loads and lack of histologic inflammation at this time. At week 14 (mid-acute phase), changes in viral load between outcome groups related inversely to the intrahepatic inflammatory responses. Animals that eventually became resolved had increased intrahepatic expression of IFN-gamma and TNF-alpha mRNAs and robust inflammation by CD3+ T cells, plasma cells, and macrophages. At the same time point of infection, animals that eventually became chronic carriers had an acute hepatitis involving the same cell types, but at diminished levels, and markedly deficient intrahepatic expression of IFN-gamma and TNF-alpha mRNAs. IL-2 mRNA remained at baseline control levels in both outcome groups. These cotemporal comparisons map a critical deviation in host response to the acute stage of an evolving chronic infection. They strongly suggest that increasing viral load and chronicity as an outcome of neonatal WHV infection result from a temporal deficiency in the acute intrahepatic effector mechanisms mediated by IFN-gamma and TNF-alpha.