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Background: Postoperative pain management is particularly challenging in patients using opioids preoperatively, but previous studies have not stratified patients not using opioids at the time of surgery according to history of opioid use. This study was designed to test the hypothesis that history of opioid use among patients not reporting opioid use at the time of surgery was independently associated with new persistent opioid use after surgery., Methods: Using prospective perioperative data from the Analgesic Outcomes Study, we assessed outcomes of patients 18 years of age or older who underwent elective surgery between December 2015 and January 2019 and were not using opioids at the time of surgery. Patient self-reported outcome measures were collected on the day of surgery and at 2 weeks, 1 month, and 3 months postoperatively. The primary outcome was new persistent opioid use, defined as continued opioid use 3 months after surgery. The primary explanatory variable was history of opioid use, which was categorized as no history of opioid use, history of non-continuous opioid use, or history of continuous opioid use (defined as daily or almost every day for 3 months or longer). Other covariates included demographics, validated measures (pain, mood), surgery type and approach, comorbidities, and use of tobacco, alcohol, cannabis, and benzodiazepines. Backward stepwise logistic regression models were used to determine patient factors associated with new persistent opioid use and refill after surgery., Results: A total of 1,249 patients not taking opioids preoperatively were included in the study cohort for new persistent opioid use. A total of 54 (4.3%) patients had continued use 3 months after surgery. New persistent opioid use after surgery was independently associated with non-continuous opioid use history (adjusted odds ratio 2.9, [95% confidence interval, 1.21 to 6.94]), continuous opioid use history (adjusted odds ratio 5.0, [95% confidence interval, 1.48 to 16.76]), and moderate to high alcohol use (adjusted odds ratio 2.5, [95% confidence interval, 1.24 to 4.93]). Similarly, opioid prescription refill at 1 month after surgery was independently associated with history of non-continuous opioid use (adjusted odds ratio 1.6, [95% confidence interval, 1.12 to 2.24]), history of continuous opioid use (adjusted odds ratio 2.2, [95% confidence interval, 1.15 to 4.06]), and moderate to high alcohol use (adjusted odds ratio 1.7, [95% confidence interval, 1.18 to 2.48])., Conclusion: Among patients not using opioids preoperatively, a history of opioid use was independently associated with new persistent opioid use after surgery, especially those with a history of continuous opioid use., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Previous studies have demonstrated that weight loss has been shown to improve pain in weight-bearing joints, and more recent studies suggest that weight loss may be accompanied by improvements in pain in non-weight-bearing regions. In previous work, we demonstrated that these symptoms improve substantially in patients with obesity undergoing 12 weeks of a very low-energy diet (VLED) restricted to 800 kcal as part of a weight-loss program. Preclinical models also have shown analgesic effects of calorie restriction. The purpose of the current observational study was to determine the time course and trajectory of improvement in pain and other symptoms, especially during the early phase of a VLED intervention, prior to major weight loss., Methods: Participants were 195 individuals with obesity who had elevated levels of pain and associated symptoms at baseline (score of ≥4 on Fibromyalgia Survey Criteria) and completed a minimum of 3 weeks of a VLED intervention. The primary outcome was improvement in Fibromyalgia Survey Criteria at week 3. In secondary analyses, we created groups of those showing little/no improvement, moderate improvement, and high improvement (little/no improvement mean, 2.21; SD, 1.02; moderate improvement mean, 2.25; SD, 0.81; high improvement mean, 2.42; SD, 0.95; F 2,189  = 1.01, P = 0.37), then compared baseline characteristics., Results: A large proportion of study participants (72%) experienced symptom reductions of 30% or greater by week 3, but there were no differences in the amount of weight lost at this time point. Those who showed little or no improvement (less than 30%) had a higher body mass index at baseline and were more likely to report a diagnosis of depression (both P < 0.05)., Conclusion: This degree of improvement after 3 weeks of a VLED is encouraging. These findings help establish the temporal pattern of symptom improvement associated with caloric restriction and suggest that the palliative effects of this diet are at least partly due to the diet itself, rather than the weight loss that ensues., (© 2022 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Purpose: Cannabis use is increasing among emerging adults (ages 18-25), necessitating the need for prevention interventions. Using a novel platform - social media - we developed an 8-week motivational interviewing and cognitive-behavioral intervention targeting cannabis use among emerging adults. Herein, we report on the feasibility and acceptability of the intervention in a pilot trial., Procedures: For NCT04187989 we recruited N = 149 emerging adults who used cannabis (at least 3 times/week for the past month) using social media advertising. Their mean age was 21.0 years (SD = 2.2); 55.7% were female. Most were White (70.5%; 20.1% Black/African American, 9.4% Other races), with 20.1% identifying as Hispanic/Latinx. Participants were randomized to the 8-week intervention or an 8-week attention-placebo control condition, both delivered in secret Facebook groups by electronic health coaches (e-coaches). Follow-up assessments occurred at 3- and 6-months., Results: The intervention was well-received and follow-up rates were high; fidelity was good. Intervention participants rated e-coaches significantly higher in terms of helpfulness, warmth, etc., compared to control participants. Intervention participants were more likely to engage with and recommend the group. In terms of percentage reductions in cannabis outcomes, the intervention group evidenced absolute reductions over time in several measures of cannabis consumption across modalities. In an adjusted model, reductions in vaping days in the intervention group, relative to attention-control, reached statistical significance (p = .020, D =.40)., Conclusions: This social media intervention for emerging adults' cannabis use was feasible and acceptable in the target population warranting future testing in a fully powered trial., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The wide heterogeneity of available cannabis products makes it difficult for physicians to appropriately guide patients. In the current study, our objective was to characterize naturalistic cannabis use routines and explore associations between routines and reported benefits from consuming cannabis., Methods: We performed a mixed methods analysis of n=1087 cross-sectional survey responses from adults with self-reported chronic pain using cannabis for symptom management in the USA and Canada. First, we qualitatively analyzed responses to an open-ended question that assessed typical cannabis use routines, including administration routes, cannabinoid content, and timing. We then sub-grouped responses into categories based on inhalation (smoking, vaporizing) vs. non-inhalation (e.g., edibles). Finally, we investigated subgroups perceptions of how cannabis affected pain, overall health, and use of medications (e.g., substituting for opioids, benzodiazepines). Substitutions were treated as a count of medication classes, while responses for both pain and health were analyzed continuously, with - 2 indicating health declining a lot or pain increasing a lot and 2 indicating that health improved a lot or pain decreased a lot., Results: Routines varied widely in terms of administration routes, cannabinoid content, and use timing. Overall, 18.8%, 36.2%, and 45% used non-inhalation, inhalation, and non-inhalation + inhalation routes, respectively. Those who used inhalation routes were younger (mean age 46.5 [inhalation] and 49.2 [non-inhalation + inhalation] vs. 56.3 [inhalation], F=36.1, p<0.001), while a higher proportion of those who used non-inhalation routes were female (72.5% non-inhalation vs. 48.3% inhalation and 65.3% non-inhalation + inhalation, X 2 =59.6, p<0.001). THC-rich products were typically used at night, while CBD-rich products were more often used during the day. While all participants reported similarly decreased pain, participants using non-inhalation + inhalation administration routes reported larger improvements in health than the non-inhalation (mean difference = 0.32, 95% CI: 0.07-0.37, p<0.001) and inhalation subgroups (mean difference = 0.22, 95% CI: 0.07-0.37, p=0.001). Similarly, the non-inhalation + inhalation group had significantly more medication substitutions than those using non-inhalation (mean difference = 0.62, 95% CI: 0.33-0.90, p<0.001) and inhalation administration routes (mean difference = 0.45, 95% CI: 0.22-0.69, p<0.001), respectively., Conclusions: Subgrouping medical cannabis patients based on administration route profile may provide useful categories for future studies examining the risks and benefits of medical cannabis., (© 2022. The Author(s).)

Objective: Most studies on preoperative opioid use only describe whether or not patients use opioids without characterizing reasons for use. Knowing why patients use opioids can help inform perioperative opioid management. The objective of this study was to explore pain specific reasons for preoperative opioid use prior to total hip and knee arthroplasty (THA and TKA) and their association with persistent use., Methods: This is a prospective study of 197 patients undergoing THA (n = 99) or TKA (n = 98) enrolled in the Analgesic Outcomes Study between December 2015 and November 2018. All participants reported preoperative opioid use., Results: Reasons for preoperative opioid use were categorized as surgical site pain only (81 [41.1%]); pain in other body areas only (22 [11.2%]); and combined pain (94 [47.7%]). Compared to patients taking opioids for surgical site pain, those with combined reasons for use had 1.24 (P = .40) and 2.28 (P = .16) greater odds of persistent use at 3 and 6 months postoperatively, adjusting for relevant covariates., Conclusions: This study provides novel insights into the heterogeneity of reasons for presurgical opioid use in patients undergoing a THA or TKA. One key take away is that not all preoperative opioid use is the same and many patients are taking opioids preoperatively for more than just pain at the surgical site. Combined reasons for use was associated with long-term use, suggesting nonsurgical pain, in part, drives persistent opioid use after surgery. Future directions in perioperative care should focus on pain and non-pain reasons for presurgical opioid use to create tailored postoperative opioid weaning plans., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase pathway activation has recently been found to be associated with almost all Langerhans cell histiocytosis cases. In BRAF V600E mutation-positive cases, this activation is seen as a downstream activation. In addition, cyclin D1 is a downstream target of the MAPK pathway. Recent studies have argued in favor of using cyclin D1 as a potential neoplastic marker to differentiate Langerhans cell histiocytosis from other reactive Langerhans cell proliferations in the skin and lymph nodes. Therefore, we chose to study the immunohistochemical expression of cyclin D1 in cutaneous xanthogranuloma (XG) cases. Fifteen XG cases were retrieved and stained for cyclin D1, BRAF (v-raf murine sarcoma viral oncogene homolog B1), CD1a, and langerin (CD207). Twelve cases showed strong and diffuse nuclear positivity for cyclin D1, both in the XG cells and in the multinucleated osteoclast-like giant cells. Three cases showed focal weak nuclear staining for cyclin D1. All 15 cases showed negative immunoreactivity for BRAF, CD1a, and CD207. Although limited by small sample size, we conclude that most cases of cutaneous XG should show at least weak nuclear staining with cyclin D1. The histogenesis of XG is still largely unknown, and the finding of cyclin D1 positivity in a majority of cases may indicate a role for the MAPK/extracellular signal-regulated kinase pathway in cutaneous XG., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Childhood trauma and adversity have been linked to chronic pain and pain sensitivity, particularly centralized pain. Yet, there remain numerous gaps in our understanding of this link., Purpose: We explored the association between nonviolent and violent childhood trauma and a component of centralized pain (i.e., generalized sensory sensitivity) and pain sensitivity using self-report measures of centralized pain and quantitative sensory testing (QST)., Methods: Patients scheduled for a total knee arthroplasty (n = 129) completed questionnaires and QST prior to surgery., Results: We found that self-report measures of centralized pain (i.e., widespread pain, somatic awareness, and sensory sensitivity) displayed a graded relationship across trauma groups, with patients with a history of violent trauma reporting the highest scores. Univariable multinomial logistic regression analyses showed that higher sensory sensitivity was associated with increased risk of being in the nonviolent trauma group compared to the no trauma group. Furthermore, higher widespread pain, higher somatic awareness, and higher sensory sensitivity distinguished the violent trauma group from the no trauma group. In multivariable analyses, sensory sensitivity is uniquely distinguished between the violent trauma group and the no trauma group. QST did not distinguish between groups., Conclusions: The findings highlight the need for future research and interventions that reduce sensory sensitivity for chronic pain patients with a history of violent childhood trauma., (© Society of Behavioral Medicine 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cannabis-using youth are a large epidemiologic subgroup whose age and smoking-related risks underscore the importance of examining the impact of the COVID-19 pandemic in this population. Within a clinical trial (n = 36 received an intervention prior to data collection reported herein), we surveyed cannabis-using emerging adults (ages 18-25) about perceived COVID-19 impacts. Participants (n = 141) reporting weekly cannabis use (M = 18.6 use days in the past 30) were enrolled and completed online surveys as part of either their baseline or 3 month assessment. COVID-19-related measures included symptoms, substance use, mood, etc. Participants were 57% female (mean age = 21, standard deviation = 2.2), with 21% Hispanic/Latinx, 70% White, 20% Black/African American, and 10% of other races. Most participants (86%) reported quarantine/self-isolation (M = 59 days). Several had COVID-19 symptoms (16%), but none reported testing COVID-19 positive. Many respondents felt their cannabis use (35%-50%, across consumption methods) and negative emotions (e.g., loneliness, stress, and depression; 69.5%, 69.5%, and 61.8%, respectively) increased. They reported decreased in-person socialization (90.8%) and job losses (23.4%). Reports of increased cannabis smoking were associated with increased negative emotions. On an open-response item, employment/finances and social isolation were frequently named negative impacts (33.3% and 29.4%, respectively). Although cannabis-using emerging adults' reports of increases in cannabis use, coupled with mental health symptoms and social isolation, are concerning, the full impact of the pandemic on their health and well-being remains unknown. Future studies examining the relationship between social isolation, mental health, and cannabis use among young people are needed., (© Society of Behavioral Medicine 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The ongoing COVID-19 pandemic strains the medical system, limiting access to healthcare services. Many people use cannabis medically for chronic health conditions and as a substitute for other medications. As such, changes in cannabis access associated with COVID-19 may result in increased non-cannabis drug use., Methods: We recruited N = 353 individuals through Amazon Mechanical Turk who reported current medical cannabis use in April and May of 2020. We assessed the effects of the COVID-19 pandemic on patterns of medication and substance use, as well as on cannabis use patterns., Results: Over half of participants either started using or increased use of medications or substances because of the COVID-19 pandemic, most commonly alcohol and sleep aids. Over a third of participants increased cannabis use while 25% decreased cannabis use. Approximately 40% of participants who increased or started use of medications/substances (other than cannabis) reported doing so because of changed access to medical cannabis., Conclusion: The reported increase in drug use among people using medical cannabis is concerning. Because the pandemic will likely continue for months (or even years), having a better understanding of why this is occurring is critical for developing effective harm-reduction strategies in this population., Competing Interests: Declarations of Interest Drs. McAfee, Ackerman, and Kruger declare no conflicts of interest. Dr. Boehnke currently sits on a data safety monitoring board for an ongoing study with Vireo Health (unpaid). The cost of this research was covered by discretionary funds from the Chronic Pain and Fatigue Research Center., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Despite increases in cannabis use generally and for pain management, data regarding cannabis use in patients undergoing surgery are lacking. This study examined the prevalence of cannabis use among patients undergoing elective surgery and explored differences in clinical characteristics and surgical outcomes between cannabis users and non-cannabis users., Methods: This prospective study included 1335 adults undergoing elective surgery. Participants completed self-report questionnaires preoperative and at 3-month and 6-month postsurgery to assess clinical characteristics and surgical outcomes., Results: Overall, 5.9% (n=79) of patients reported cannabis use (53.2% medical, 19.0% recreational and 25.3% medical and recreational). On the day of surgery, cannabis users reported worse pain, more centralized pain symptoms, greater functional impairment, higher fatigue, greater sleep disturbances and more symptoms of anxiety and depression versus non-cannabis users (all p<0.01). Additionally, a larger proportion of cannabis users reported opioid (27.9%) and benzodiazepine use (19.0%) compared with non-cannabis users (17.5% and 9.2%, respectively). At 3 and 6 months, cannabis users continued to report worse clinical symptoms; however, both groups showed improvement across most domains (p≤0.05). At 6 months, the groups did not differ on surgical outcomes, including surgical site pain (p=0.93) or treatment efficacy (p=0.88)., Conclusions: Cannabis use is relatively low in this surgical population, yet cannabis users have higher clinical pain, poorer scores on quality of life indicators, and higher opioid use before and after surgery. Cannabis users reported similar surgical outcomes, suggesting that cannabis use did not impede recovery., Competing Interests: Competing interests: CMB is a consultant for Heron Therapeutics (San Diego, California, USA), not related to this work. KB sits on a data safety and monitoring committee (unpaid) for an ongoing study with Vireo Health (New York, New York, USA)., (© American Society of Regional Anesthesia & Pain Medicine 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Enterohemorrhagic Escherichia coli O157:H7 has been linked to both waterborne and foodborne illnesses, and remains a threat despite the food- and water-screening methods used currently. While conventional bacterial detection methods, such as polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays (ELISA) can specifically detect pathogenic contaminants, they require extensive sample preparation and lengthy waiting periods. In addition, these practices demand sophisticated laboratory instruments and settings, and must be executed by trained professionals. Herein, a protocol is proposed for a simpler diagnostic technique that features the unique combination of magnetic and fluorescent parameters in a nanoparticle-based platform. The proposed multiparametric magneto-fluorescent nanosensors (MFnS) can detect E. coli O157:H7 contamination with as little as 1 colony-forming unit present in solution within less than 1 h. Furthermore, the ability of MFnS to remain highly functional in complex media such as milk and lake water has been verified. Additional specificity assays were also used to demonstrate the ability of MFnS to only detect the specific target bacteria, even in the presence of similar bacterial species. The pairing of magnetic and fluorescent modalities allows for the detection and quantification of pathogen contamination in a wide range of concentrations, exhibiting its high performance in both early- and late-stage contamination detection. The effectiveness, affordability, and portability of the MFnS make them an ideal candidate for point-of-care screening for bacterial contaminants in a wide range of settings, from aquatic reservoirs to commercially packaged foods.

Objective: To integrate multiple sources of clinical information with patient feedback to build evidence-based decision support model to facilitate treatment selection for patients suffering from vestibular schwannomas (VS)., Methods: This was a mixed methods study utilizing focus group and survey methodology to solicit feedback on factors important for making treatment decisions among patients. Two 90-minute focus groups were conducted by an experienced facilitator. Previously diagnosed VS patients were recruited by clinical investigators at the University of Pittsburgh Medical Center (UPMC). Classical content analysis was used for focus group data analysis. Providers were recruited from practices within the UPMC system and were surveyed using Delphi methods. This information can provide a basis for multi-criteria decision analysis (MCDA) framework to develop a treatment decision support system for patients with VS., Results: Eight themes were derived from these data (focus group + surveys): doctor/health care system, side effects, effectiveness of treatment, anxiety, mortality, family/other people, quality of life, and post-operative symptoms. These data, as well as feedback from physicians were utilized in building a multi-criteria decision model., Discussion: The study illustrated steps involved in the development of a decision support model that integrates evidence-based data and patient values to select treatment alternatives., Conclusions: Studies focusing on the actual development of the decision support technology for this group of patients are needed, as decisions are highly multifactorial. Such tools have the potential to improve decision making for complex medical problems with alternate treatment pathways., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Enterohemorrhagic Escherichia coli O157:H7 presents a serious threat to human health and sanitation and is a leading cause in many food- and waterborne ailments. While conventional bacterial detection methods such as PCR, fluorescent immunoassays and ELISA exhibit high sensitivity and specificity, they are relatively laborious and require sophisticated instruments. In addition, these methods often demand extensive sample preparation and have lengthy readout times. We propose a simpler and more sensitive diagnostic technique featuring multiparametric magneto-fluorescent nanosensors (MFnS). Through a combination of magnetic relaxation and fluorescence measurements, our nanosensors are able to detect bacterial contamination with concentrations as little as 1 colony-forming unit (CFU). The magnetic relaxation property of our MFnS allow for sensitive screening at low target CFU, which is complemented by fluorescence measurements of higher CFU samples. Together, these qualities allow for the detection and quantification of broad-spectrum contaminations in samples ranging from aquatic reservoirs to commercially produced food.

Eye reduction occurs in many troglobitic, fossorial, and deep-sea animals but there is no clear consensus on its evolutionary mechanism. Given the highly conserved and pleiotropic nature of many genes instrumental to eye development, degeneration might be expected to follow consistent evolutionary trajectories in closely related animals. We tested this in a comparative study of ocular anatomy in solariellid snails from deep and shallow marine habitats using morphological, histological, and tomographic techniques, contextualized phylogenetically. Of 67 species studied, 15 lack retinal pigmentation and at least seven have eyes enveloped by surrounding epithelium. Independent instances of reduction follow numerous different morphological trajectories. We estimate eye loss has evolved at least seven times within Solariellidae, in at least three different ways: characters such as pigmentation loss, obstruction of eye aperture, and "lens" degeneration can occur in any order. In one instance, two morphologically distinct reduction pathways appear within a single genus, Bathymophila. Even amongst closely related animals living at similar depths and presumably with similar selective pressures, the processes leading to eye loss have more evolutionary plasticity than previously realized. Although there is selective pressure driving eye reduction, it is clearly not morphologically or developmentally constrained as has been suggested by previous studies., (© 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.)

Combination antiviral therapy involving sofosbuvir (SOF) and simeprevir (SIM) is a treatment option in patients with genotype 1 chronic hepatitis C; however, the safety of this regimen in patients with decompensated cirrhosis is not established. Data from a combined treatment cohort of 2 large hepatology referral centers were evaluated to assess for safety and efficacy of SIM plus SOF with or without ribavirin (RBV) in patients with Child B or C cirrhosis. All (n = 42) patients included in the analysis had Child B (n = 35) or C (n = 7) cirrhosis and received 400 mg daily of SOF plus 150 mg daily of SIM, with (n = 7) or without (n = 35) RBV, for 12 weeks. Of the 42 patients in this cohort, 31 (74%) were male, 22 (52%) had failed prior treatments, and 28 (67%) were genotype 1a. Prior decompensating events included encephalopathy (57%), fluid overload (88%), or variceal hemorrhage (24%). Median Model for End-Stage Liver Disease score was 12 (range, 6-25). Treatment was well tolerated overall with more than one-half (57%) reporting no adverse events. In those reporting adverse events, the most common were fatigue (n = 6), insomnia (n = 4), headache (n = 5), nausea (n = 4), and grade 1 rash (n = 1). One patient developed chemical pancreatitis that did not require treatment discontinuation. Three of 7 patients who received RBV developed anemia, with 2 requiring blood transfusions and 1 requiring a dose reduction. No episodes of decompensation requiring hospitalization or deaths occurred on treatment. Of 42 patients, 38 (90%) patients had negative viral load at end of treatment (EOT), and 31 of 42 patients (74%) achieved sustained virological response 12 weeks after EOT; 10 of 10 patients (100%) with HCV genotype 1b achieved sustained virological response for 12 weeks (SVR12). In conclusion, SOF plus SIM was very well tolerated in patients with advanced Child B/C decompensated cirrhosis. Overall, 74% of patients achieved SVR12; 100% of patients with genotype 1b decompensated cirrhosis achieved SVR12., (© 2015 American Association for the Study of Liver Diseases.)

Study Objective: Develop a Pediatric and Adolescent Gynecology (PAG) curriculum, appropriate pelvic model for teaching examination skills, and an objective structured clinical examination (OSCE) for evaluation. Compare OSCE performance between residents with clinical training in PAG vs those that completed the curriculum vs those without either experience., Design: Prospective cohort study., Setting: Obstetrics and Gynecology (Ob/Gyn) residency program in an urban academic center., Participants: Senior Ob/Gyn residents., Interventions: A simulation-based teaching curriculum was created to teach PAG skills. A pediatric mannequin with anatomic pre-pubertal genitalia was developed for teaching and assessment of skills., Main Outcome Measures: Performance on a PAG-based OSCE as assessed by 2 observers using a 40 point checklist., Results: 17 residents participated in the OSCE; 5 completed the curriculum, 6 completed a clinical rotation, and 6 were controls. The teaching curriculum group had the highest median composite OSCE score (75.0%) compared to the clinical group (73.1%) and control group (55.3%). There was no statistical difference between the scores of the teaching and clinical groups, but the teaching group scored statistically higher than controls (P = .0331). Scores for each OSCE component were compared. The teaching and clinical groups outperformed controls on assessment and procedures. There was no difference in scores on history taking or physical examination., Conclusion: An interactive teaching curriculum incorporating simulation and a realistic pediatric pelvic model can be used to teach PAG clinical skills. Using an OSCE to evaluate skills shows that residents completing the curriculum perform as well as those with clinical experience and better than controls., (Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

The explosive expansion of knowledge in immunology in recent decades has already affected the research and practice of nuclear medicine in several ways. New hematopoietic cells have been isolated and their functions discovered, including hematopoietic stem cells and dendritic cells (DCs). Many new humeral factors have been found that have potent effects on cells, including cytokines, growth factors, and specialized proteins. Radiolabeled compounds are needed to follow the pharmacodynamics of the humeral factors and to follow the migration of mobile cells in animals and humans. In this article, only DCs, cytokines, and growth factors used clinically are discussed. DCs are essential for defense against infectious diseases. Autologous DCs cultured for a week and pulsed with tumor antigens have already proved highly immunogenic compared with other methods for activating cytotoxic T cells, and preliminary studies suggest that DCs are more potent for tumor cell killing than monoclonal antibodies. DCs, unfortunately, also play an important role in causing certain human diseases. In allograft transplants, residual donor DCs are responsible for the cellular rejection; if they could be eliminated, rejection could be prevented. These cells are also detrimental in rheumatoid arthritis, other autoimmune diseases, asthma, and chronic obstructive pulmonary disease. Cytokines such as interleukin-2 and such growth factors as granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor, administered to patients with malignancies to alleviate the leukopenia of chemotherapy agents, frequently alter the tissue distribution of radiopharmaceuticals; these alterations may be confused with disease.

The hnRNP C protein tetramer cooperatively binds 230 nt increments of pre-mRNA in vitro in a salt-resistant manner and is located along the length of vertebrate transcripts in vivo. Based on these and other findings it has been suggested that hnRNP C functions as a chaperonin to maintain long lengths of RNA topologically single-stranded and accessible to splicing factors. We report here that human C protein is lethal when expressed in the yeast Saccharomyces cerevisiae. Through a series of fluorescent immunolocalization studies, lethality was observed to be associated with the rapid nuclear accumulation of both C protein and yeast pre-mRNA. Studies using various protein constructs and the two hybrid assay reveal that these events are dependent on the basic 40 residue high-affinity RNA binding domain and its contiguous leucine zipper-like motif (the bZLM, residues 140-214). Additionally, equilibrium binding studies have shown that the bZLM is the determinant of C protein's salt-resistant RNA binding mode. Taken together, these findings further distinguish the bZIP-like domain as the major determinant of C protein's high-affinity interaction with RNA, oligomerization, and its highly cooperative RNA binding activity. Finally, these findings indicate that yeast and vertebrates may possess a conserved mechanism for general import of RNP although a true homolog to vertebrate C protein appears not to exist in yeast. Lethality is likely due to the absence in yeast of specific mechanisms for the removal of human C protein from nascent transcripts., (Copyright 2001 Academic Press.)

Unlabelled: This study evaluated the biodistribution and tumor targeting ability of radiolabeled insulinlike growth factor (IGF)-I. Because IGF binding proteins (IGFBPs) play a critical role in modulating IGF activity, the binding properties of 125I-labeled IGF-I to IGFBPs were investigated in vitro and in vivo. Because a large amount of the IGF-I was catabolized in vivo, we also studied the catabolism of IGF-I by tumor cells in vitro., Methods: 125I-labeled-IGF-I was prepared using the chloramine T method. The biodistribution of 125I-labeled-IGF-I in tumor-bearing nude mice was compared between groups injected with 125I-labeled IGF-I alone or coinjected with unlabeled peptide. In vitro and in vivo chromatography studies were performed to evaluate the binding profile to IGFBPs and the degree of catabolites in serum as well as urine., Results: Data indicated that the binding of radiolabeled IGF-I to IGFBPs in vitro was dose dependent. However, there was a difference in complex formation between the serum and the heparinized plasma. In heparinized plasma, the radioactivity shifted from a 30- to 50-kDa complex to a 150-kDa complex and to a free ligand, because the binding of heparin with IGFBPs decreased its affinity for IGF-I. In plasma prepared with acid citrate dextrose a binding pattern identical to that of serum was observed. Moreover, there was a binding difference between mouse and rat. The 125I-labeled IGF-I catabolized very quickly when incubated at 37 degrees C but not at all at 4 degrees C. In tumor-bearing nude mice, the uptake of radioactivity in normal tissues decreased quickly, particularly in the kidneys. In mice coinjected with unlabeled carrier, the radioactivity in most normal tissues was lower and the tumor uptake higher than in the mice without carrier., Conclusion: These data confirm that 125I-labeled IGF-I is avidly bound to IGFBPs, both in vitro and in vivo. By partially saturating this binding with unlabeled peptides, a favorable biodistribution was achieved, including faster clearance from normal tissue and higher tumor uptake, which resulted in better tumor-to-nontumor ratios. Nevertheless, the rapid catabolism and release of the radiolabel from tumor tissue result in a suboptimal targeting agent.

To examine current practices in the use of psychoeducational evaluations for service delivery, we surveyed 91 service providers to college students with learning disabilities. The three purposes of the survey were to determine (a) whether service delivery decisions are based on information from psychoeducational evaluations, (b) which sections of the psychoeducational report are most useful in making service delivery decisions, and (c) the respondents' satisfaction with the tests and measurements for service delivery. The findings supported the common belief that data from psychoeducational evaluations serve as the primary basis for both eligibility and specific accommodation determinations. Respondents reported that all sections of the psychoeducational evaluation written report were useful, with the least useful section being test scores and the most useful being the summary of cognitive strengths and weaknesses. However, the section used most often for service delivery decisions was the professional's recommendations.

The preclinical evaluation of a sigma receptor-specific radiopharmaceutical that binds to human prostate tumor cells with a high affinity is described. We have synthesized and radioiodinated 2-[125I]-N-(N-benzylpiperidin-4-yl)-2-iodobenzamide (2-[125I]BP) that possesses high affinity for both sigma-1 and sigma-2 receptor subtypes that are expressed on a variety of tumor cells. 2-IBP was synthesized, purified and characterized by routine spectroscopic and analytical methods. Radioiodination was accomplished using an oxidative iododestannylation reaction in the presence of chloramine T in high yields (76%-93%) with a very high-specific activity (1700-1900 Ci/mmol). The in vitro competition binding studies of 2-[125I]BP with various sigma receptor ligands in LnCAP human prostate tumor cells showed a dose-dependent saturable binding. The inhibition constants (Ki, nM) for binding of 2-[125I]BP to human prostate tumor cells for 4-IBP, haloperidol and 2-IBP were 4.09, 6.34 and 1.6 nM, respectively. The clearance of 2-[125I]BP, in Sprague-Dawley rats, was rapid from the blood pool, other normal tissues and the total body. Tissue distribution studies in nude mice bearing human prostate tumor (DU-145) also showed a fast clearance from normal organs. The tumor had the highest percentage of injected dose per gram (%ID/g) of all tissues at 4 h as well as 24 h (2.0 +/- 0.05 and 0.147 +/- 0.038 ID/g, respectively) postinjection. The in vivo receptor binding specificity was demonstrated using haloperidol (a known high-affinity sigma receptor ligand). A significant decrease (> 50%, p = 0.001) was observed in tumor concentration when haloperidol was used as a blocking agent. The high affinity of 2-[125I]BP for sgma receptor-binding sites, its fast in vivo clearance from normal organs and its high uptake and retention in tumor implies that 2-[123I]BP or 2-[131I]BP may be a promising tracer for noninvasive imaging of human prostate tumors.

Polypyrimidine tract binding protein (PTB) is a 57 kD hnRNP protein (hnRNP I) that binds to the pyrimidine tract typically found near the 3' end of introns. Primary sequence analysis suggests that PTB contains four RNA recognition motifs (RRMs). Data from comparative structural and deletional analysis of PTB are consistent with the presence of a four reiterated domain structure. Since PTB exists in solution as a homodimer, it contains an oligomeric array of eight RRMs. Though the function of RRMs in a monomeric context has been addressed, the significance of their presence in an oligomeric context has not been investigated. To correlate structural motifs with function, we have analyzed the RNA binding properties of wild-type and deletion constructs of PTB that contain RRMs in both an oligomeric and monomeric context. These studies indicate that there is not a strong correlation between the RNA binding affinity and specificity upon oligomerization. However, the mode of RNA interaction and dimerization is linked. We have also found that the primary contributor to the free energy of PTB binding and the primary determinant for RNA binding specificity resides in RRM 3, while the primary contributor to dimer stabilization coincides with residues in RRM 2.

Insulin-like growth factor I (IGF-I) is a potent mitogen for many tumor cell lines, and IGF-I receptors are overexpressed in many tumors. Specific IGF-binding proteins (IGFBPs) modulate the interaction of IGF and its receptors. Consequently, radiolabeled IGF-I has been considered for tumor imaging. In the present study, we investigated the biodistribution of 125I-labeled des(1-3)IGF-I, a truncated analogue of IGF-I, in tumor-bearing nude mice. Additional studies included its catabolism by tumor cells in vitro and its binding to serum IGFBPs in vivo in nude mice. We also compared groups that were and were not injected with unlabeled peptide analogue. Our data showed that 125I-labeled des(1-3)IGF-I catabolized very fast, with a rapid appearance of nonprecipitable iodine, when incubated at 37 degrees C, but it was not catabolized at 4 degrees C incubation. 125I-labeled des(1-3)IGF-I was bound to serum-binding proteins, mainly in a complex with a molecular weight of M(r) 150,000. The uptake of radioactivity in normal tissues decreased quickly with time, particularly in the kidneys. In mice receiving higher doses of des(1-3)IGF-I, the radioactivity in all normal tissues was lower than in the mice with no carrier-added des(1-3)IGF-I, except in the stomach and spleen. These data suggest that 125I-labeled des(1-3)IGF-I is rapidly internalized after binding to the IGF receptor and is rapidly catabolized with release of breakdown products. Lower specific activity of 125I-labeled des(1-3)IGF-I resulted in altered biodistribution, including faster blood clearance and higher tumor uptake, by decreasing the formation of complexes with IGFBPs.

Alternative splicing of pre-mRNA is a commonly used mechanism to regulate gene expression in higher eukaryotes. However, with the exception of regulated cascades in Drosophila, the cis-acting elements and the trans-acting factors that control tissue- and/or developmentally regulated splicing remain largely unidentified. Cis-acting elements that control smooth muscle-specific repression of exon 3 of alpha-tropomyosin (alpha-TM) have been identified recently and consist of two regions that flank this exon. Deletion of either element causes misregulated splicing of alpha-TM in transfected smooth muscle cells. In experiments designed to characterize essential sequences within each element and the factors that interact with these sequences, we have identified two overlapping sequences within the downstream regulatory element (DRE) that are identical to binding sites for polypyrimidine tract binding protein (PTB) that were identified using iterative selection techniques. Mutation of these sites caused aberrant splicing regulation in transfected smooth muscle cells. In addition, sequences identical to high-affinity PTB binding sites were also detected upstream of exon 3 and mutation of these sites also resulted in misregulation of splicing in vivo, suggesting that PTB binding to specific sequences flanking exon 3 is responsible, in part, for the repression of exon 3. Consistent with this hypothesis, UV crosslinking and equilibrium binding assays confirm that the same mutations that cause misregulated splicing also disrupt PTB binding to RNA.

The C protein tetramer of hnRNP complexes binds approximately 150-230 nt of RNA with high cooperativity (McAfee J et al., 1996, Biochemistry 35:1212-1222). Three contiguously bound tetramers fold 700-nt lengths of RNA into a 19S triangular intermediate that nucleates 40S hnRNP assembly in vitro (Huang M et al., 1994, Mol Cell Biol 14:518-533). Although it has been assumed that the consensus RNA recognition motif (RRM) of C protein (residues 8-87) is the primary determinant of RNA binding, we report here that a recombinant construct containing residues 1-115 has very low affinity for RNA at physiological ionic strength (100 mM NaCl). Moreover, we demonstrate that an N-terminal deletion construct lacking the consensus RRM but containing residues 140-290 binds RNA with an affinity sufficient to account for the total free energy change observed for the binding of intact protein. Like native C protein, the 140-290 construct is a tetramer in solution and binds RNA stoichiometrically in a salt-resistant manner in 100-300 mM NaCl. Residues 140-179 of the N-terminal truncated variant contain 11 basic and 2 acidic residues, whereas residues 180-207 specify a leucine zipper motif that directs dimer assembly. Elements within the 50-residue carboxy terminus of C protein are required for tetramer assembly. A basic region followed by a leucine zipper is identical to the domain organization of the basic-leucine zipper (bZIP) class of DNA binding proteins. Sequence homologies with other proteins containing RRMs and the bZIP motif suggest that residues 140-207 represent a conserved bZIP-like RNA binding motif (designated bZLM). The steric orientation of four high-affinity RNA binding sites about rigid leucine zipper domains may explain in part C protein's asymmetry, its large occluded site size, and its RNA folding activity.

The thermodynamics of the binding of the Sac7d protein of Sulfolobus acidocaldarius to double-stranded DNA has been characterized using spectroscopic signals arising from both the protein and the DNA. Ligand binding density function analysis has been used to demonstrate that the fractional change in protein intrinsic tryptophan fluorescence quenching that occurs upon DNA binding is equal to the fraction of protein bound. Reverse titration data have been fit directly to the McGhee-von Hippel model [McGhee, J., & von Hippel, P. (1974) J. Mol. Biol. 86, 469-489] using nonlinear regression. Sac7d binds noncooperatively to poly(dGdC) x poly(dGdC) with an intrinsic affinity of 6.5 x 10(6) M(-1) and a site size of 4 base pairs in 1 mM KH2PO4 and 50 mM KC1 (pH 6.8). Some binding sequence preference is noted, with the binding to poly(dIdC) x poly(dIdC) over 10-fold stronger than to poly(DAdT) x poly(dAdT). The binding is largely driven by the polyelectrolyte effect and is consistent with a release of 4.4 monovalent cations from DNA upon complex formation or the formation of 5 ion pairs at the protein-DNA interface. Extrapolation of salt back-titration data to 1 M KC1 indicates a -2.2 kcal/mol nonelectrostatic contribution to the binding free energy. A van't Hoff analysis of poly(dGdC) x poly(dGdC) binding shows that the binding enthalpy is approximately zero and the process is entropically driven. The affinity decreases slightly between pH 5.4 and 8.0. There is no significant difference between the binding parameters of recombinant Sac7d and native Sac7 proteins, indicating that methylation of the native protein has no effect on the DNA binding function. The binding of Sac7d to various DNAs leads to a significant increase in the DNA long-wavelength circular dichroism (CD) band, the intensity of which shows a sigmoidal dependence on Sac7d concentration. The sigmoidal CD binding isotherm can be quantitatively modeled by a conformational transition in the DNA that is cooperatively induced when protein monomers are bound within a given number of base pairs, ranging from zero for poly(dIdC) x poly(dIdC) to 8 or less for poly(dAdG) x poly(dCdT).

Proteins C1 and C2 together comprise about one-third the protein mass of mammalian core 40S heterogeneous nuclear ribonucleoprotein particles (40S hnRNP) and exist as heterotetramers of (C1)3C2. On the basis of nonequilibrium binding studies, it has been suggested that the C proteins specifically bind oligo(U)- and poly(U)-rich sequences, and preferentially associate with uridine-rich regions near the 3' termini of many introns. We describe here a more quantitative characterization of the equilibrium binding properties of native and recombinant C protein to homoribopolymers using fluorescence spectroscopy. Like C protein from HeLa cells, the recombinant proteins spontaneously oligomerize to form tetramers with the same hydrodynamic properties as native protein. Near-stoichiometric binding titrations of the fluorescent homoribopolymer polyethenoadenosine (poly[r(epsilon A)]) with recombinant (C1)4 and (C2)4 homotetramers along with competition binding assays with poly(A) and poly(C) indicate that the binding site size (n) is between 150 and 230 nucleotides. This site size range is in close agreement with that previously determined for native C protein through hydrodynamic and ultrastructural studies (approximately 230 nucleotides). (C1)4 and (C2)4 bind poly(G) with intrinsic affinities (Ki) of 10(9) M-1, which are a hundredfold higher than their affinities for poly(U). In opposition to reports that C protein does not bind poly(A) and poly(C), we find that the C proteins bind these substrates with moderate Ki, but with high cooperativity (omega). The overall affinity (K omega) for the binding of both proteins to poly(A) and poly(C) is 10-fold higher (> 10(8) but < 10(9) M-1) than their affinities for poly(U). The highly cooperative binding of C protein to these substrates provides a mechanistic basis for the distribution of C protein along the length of nucleic acid substrates.

The genes for two Sac7 DNA-binding proteins, Sac7d and Sac7e, from the extremely thermophilic archaeon Sulfolobus acidocaldarius have been cloned into Escherichia coli and sequenced. The sac7d and sac7e open reading frames encode 66 amino acid (7608 Da) and 65 amino acid (7469 Da) proteins, respectively. Southern blots indicate that these are the only two Sac7 protein genes in S. acidocaldarius, each present as a single copy. Sac7a, b, and c proteins appear to be carboxy-terminal modified Sac7d species. The transcription initiation and termination regions of the sac7d and sac7e genes have been identified along with the promoter elements. Potential ribosome binding sites have been identified downstream of the initiator codons. The sac7d gene has been expressed in E. coli, and various physical properties of the recombinant protein have been compared with those of native Sac7. The UV absorbance spectra and extinction coefficients, the fluorescence excitation and emission spectra, the circular dichroism, and the two-dimensional double-quantum filtered 1H NMR spectra of the native and recombinant species are essentially identical, indicating essentially identical local and global folds. The recombinant and native proteins bind and stabilize double-stranded DNA with a site size of 3.5 base pairs and an intrinsic binding constant of 2 x 10(7) M-1 for poly[dGdC].poly[dGdC] in 0.01 M KH2PO4 at pH 7.0. The availability of the recombinant protein permits a direct comparison of the thermal stabilities of the methylated and unmethylated forms of the protein. Differential scanning calorimetry demonstrates that the native protein is extremely thermostable and unfolds reversibly at pH 6.0 with a Tm of approximately 100 degrees C, while the recombinant protein unfolds at 92.7 degrees C.

The efficacy of two new tiny snares has been evaluated for removal of diminutive (7 mm or less) colorectal polyps. The small size of the snares facilitates direct placement over a polyp, after which resection can be performed using monopolar current. Data were prospectively collected on 183 polyps, 2 to 7 mm in diameter, encountered in 90 patients. Polyp diameter, location relative to the splenic flexure, and histologic characteristics were noted, as were retrieval rate and complications. Ninety-four percent of the polyps could be removed with a tiny snare, and 88% of these were recovered. Forty percent of the polyps were located proximal to the splenic flexure, and 69% were neoplastic. The only complication was major hemorrhage in 1 patient (0.5%), in whom snare polypectomy without current application was used. Tiny snares can effectively and safely be used to remove diminutive colorectal polyps, and they may make "hot biopsy" forceps obsolete.

This study investigates the activities and interactions of elderly patients in an acute medical geriatric unit and a psychiatric unit. The Clifton Assessment Procedures for the Elderly were used to measure cognitive and behavioural functioning, and the 24 subjects studied were divided into three groups: lucid, confused, and demented. Information about subjects' activities and interactions with nursing staff was gained from time sampling by non-participant direct observation. The results reveal very low levels of staff-patient interaction outside of expected routines of patient care. At no time during the observation periods did staff engage patients in social activities or prolonged informal conversations. Yet 306 nurses, of various grades, completed a questionnaire in which they ranked talking to patients as 'enjoyable', 'important', 'rewarding', and an 'objective' for themselves and the unit.

To improve the radiolabeling yield and the specific activity of [125I]N-(2-diethylaminoethyl)-4-iodobenzamide (DAB), the aryltributyltin precursor was synthesized from the N-(2-diethylaminoethyl)-4-bromobenzamide derivative by palladium catalyzed stannylation using bis(tributyltin). The radiolabeled product, [125I]DAB, was obtained by an iododestannylation reaction in high radiochemical yields (85-94%, radiochemical purity, > 98%) using chloramine-T as an oxidizing agent. The specific activity was greater than 1600 Ci/mmol. The biodistribution studies in nude mice implanted with human malignant melanoma xenograft showed a good tumor uptake (6.14% ID/g at 1 h, 2.81% ID/g at 6 h and 0.42% ID/g at 24 h) of [125I]DAB. Unfortunately, a high uptake in the non-target organs, such as liver and lung, was found. At 1 h post-injection the activity level in liver and lung was 11.76 and 7.58% ID/g, respectively. A slow clearance of activity from liver and lung was observed at 6 h (3.43 and 0.49% ID/g). These results demonstrate that iodinated IDAB is a potential radiopharmaceutical for the management of patients with malignant melanoma.

Although transjugular liver biopsy requires the availability of trained personnel, takes more time than percutaneous biopsy and is moderately expensive, it is a safe alternative technique for obtaining adequate liver tissue for diagnosis in special clinical situations. The usual indications for transjugular rather than percutaneous liver biopsy are (a) coagulation disorder (prothrombin time greater than 3 sec over control value and/or platelet count less than 60,000/cm3), (b) massive ascites and (c) desire to perform ancillary procedures, such as measurement of pressures or opacification of the hepatic veins and inferior vena cava. Less common indications for transjugular liver biopsy include failed percutaneous biopsy, massive obesity, small cirrhotic liver (increased risk and lower success rate) and suspected vascular tumor or peliosis hepatis. Results from several centers indicate that adequate or diagnostic liver tissue is obtained in 81% to 97% of cases. The typical length of the biopsy core ranges from 0.3 cm to 2.0 cm. Modification of the classic technique, particularly the adaptation of a Tru-Cut needle, shows promise in yielding longer cores of tissue with less fragmentation. Transjugular liver biopsy is performed with an acceptable complication rate that ranges 0% to 20%. The reported mortality of transjugular liver biopsy was 0 in three major centers and ranged from 0.1% to 0.5% in three other centers. Transjugular liver biopsy may be useful in obtaining diagnostic liver tissue not only in advanced chronic liver disease with coagulopathy, ascites or both, but also in patients with fulminant hepatic failure to better determine prognosis and the need for liver transplantation.

A variety of radioactive agents, injected directly intravenously have demonstrated foci of inflammation by gamma camera imaging, avoiding the in vitro preparation of labeled leukocytes. This study sought to find out if any of these agents mimicked the biodistribution in abscesses and non-target organs of labeled mixed leukocyte suspensions. Eight different agents were compared with 111In-oxine labeled leukocytes in an acute soft tissue E. coli abscess and an acute arthritic lesion in 24 dogs one day after intravenous administration. These included 67Ga-citrate, human and canine polyclonal immunoglobulin (IgG), rabbit anti-dog polyclonal IgG, serum albumin, monoclonal antibody TNT-1 F(ab')2 against nuclear antigens, 57Co-porphyrin and serum albumin nanocolloid. None of these agents achieved abscess concentrations approaching those obtained with labeled leukocytes, and their abscess/blood and abscess/muscle concentration ratios were considerably lower. No statistically significant differences were found between the different radiolabeled proteins evaluated. The abscess concentration of 99mTc-nanocolloid was much lower than that of other agents, and the results with the oldest agent, 67Ga-citrate, were disappointing in these acute experiments.

Polyclonal human IgG (IgG), antinuclear antibody (TNT-1), and human serum albumin (HSA), were labeled with 99mTc by a method recently developed in our laboratory, and administered i.v., each to a separate group of five mice, bearing inflammatory foci induced by an i.m. injection of 40 microL turpentine or 5 x 10(8) E. coli and 5 x 10(8) Entercocci. TNT-1 labeled with 125I served as a control and 67Ga-citrate as a "gold standard". At 4 or 24 h post injection, animals were imaged and sacrificed for tissue distribution studies. At 4 h in the turpentine group, the abscess-to-muscle ratios were: 67Ga, 4.8 +/- 2.1, 125I-TNT-1, 4.3 +/- 1; 99mTc-TNT-1, 3.5 +/- 1.8; 99mTc-IgG, 3.9 +/- 0.6; and 99mTc-HSA, 4.3 +/- 1. In the microorganism group, these ratios were 2.6 +/- 0.6, 3.3 +/- 0.5, 3.4 +/- 0.08, 3 +/- 1.1 and 4.1 +/- 0.6, respectively. Autoradiographic examination of infected tissues indicated that leakage of labeled proteins into interstitial space due to increased capillary permeability may be one of the major mechanisms of uptake.

Radioimmunoimaging of experimentally-induced canine thrombi has previously been achieved with iodine-131- and indium-111-labeled (131I and 111In) anti-fibrin T2G1s monoclonal antibody (MAb). We now compare T2G1s to another anti-fibrin MAb, designated GC4, for imaging fresh and aged canine thrombi. GC4 is specific for a neoepitope exposed on fibrin later in the thrombolytic process after plasmin digestion. Femoral venous thrombi were induced in six groups of dogs, each containing three dogs. In two groups, the MAbs were compared when the thrombi were 3-hr or 3-days old at the time of injection, and the dogs were killed at 48 hr. In thrombi 3-hr-old, the GC4/T2G1s concentration ratio averaged 0.53 compared to 1.9 in 3-day-old thrombi. Two groups of dogs with thrombi 1- or 3-days-old were heparinized before MAb injection and were killed at 24 hr. The heparinized dogs with thrombi 1- or 3-days-old had GC4/T2G1s mean ratios of 2.3 and 2.9, respectively. In the unheparinized groups, the corresponding ratios were 1.1 and 1.9. GC4 may be more useful for clinical thrombus imaging than T2G1s because spontaneous venous thrombi are usually several days old at the time of presentation and patients are often heparinized immediately.

The effect of rapid converting enzyme inhibition (CEI) with intravenous enalaprilat on technetium-99m-(99mTc) diethylenetriaminepentaacetic acid (DTPA) and 99mTc-dimercaptosuccinic acid (DMSA) renograms was evaluated in rats with two-kidney, one-clip renovascular hypertension. Rapid sequential DTPA renograms, performed immediately before and five minutes after enalaprilat injection (30 micrograms/kg), demonstrated a selective decrease in clipped kidney DTPA plasma clearance following CEI and no significant effect on unclipped kidney function. Pre- and post-CEI data were obtained with a single injection of DMSA by administering enalaprilat five minutes after the radiopharmaceutical. Enalaprilat slowed the rate of DMSA accumulation in clipped relative to unclipped kidneys, and reduced the clipped/unclipped kidney ratio of absolute DMSA uptake at 10 and 30 min. DTPA and DMSA were equally effective in demonstrating the CEI effect. Enalaprilat was also compared with captopril (3 mg/kg, intraperitoneally), using sequential DTPA renograms. Clipped kidney DTPA plasma clearance was reduced to an identical degree (40%) by both converting enzyme inhibitors. Clinical renographic protocols can probably be devised to take advantage of the rapid, reliable CEI of enalaprilat, thereby shortening total procedure time.

Previous studies addressing the usefulness of pallor in anemia are deficient because of observer or spectrum bias. Three internists made individual assessments of conjunctivae, face, nails, palms, and palmar creases in 98 male and 5 female hospitalized patients at a Veterans Administration Medical Center. The true-positive rates (sensitivities) were highest for pallor at any one of three sites (ie, the conjunctivae, face, or palms; 0.65) and for pallor of the palms (0.53). True-negative rates (specificities) were best for palmar creases (1.00), for pallor at conjunctivae, face, and palms (all three in combination; 0.95), and for the face (0.90). Receiver operator characteristic curve analysis revealed that the examination of the nailbeds is inferior to all other sites or combinations. Interobserver variability K scores were negative for palmar creases but ranged from .16 to .51 for other sites. We conclude that (1) the absence of pallor does not rule out anemia, and therefore this sign is not useful for screening an asymptomatic population; (2) pallor of the conjunctivae, face, and palms together is of benefit in confirming the presence of anemia; and (3) neither the nailbeds nor palmar creases are of value in assessing the presence or absence of anemia.

For the purpose of radiation dose estimates, organ assays and excretion measurements of the Tc-99m and In-111 complexes with DTPA were conducted in dogs at various time intervals up to 24 hr, and the results compared with available human data. The peak concentration of the Tc-99m complex, at 3 min after injection, was 5% of the administered dose for one kidney, 3.5% for the liver, and 3.5% for the small bowel. No organ system except the urinary tract reached a concentration higher than that in blood for several hours after the injection. The biliary excretion of these agents was extremely low, and their elimination in the feces was negligible. In man, it appears that the residual 4-5% of an administered dose not eliminated in the urine by 24 hr is widely distributed in various tissues. The distribution of the In-111 complex is similar but not identical to that of the Tc-99m complex.