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Background: The TYRX (Medtronic) absorbable antibacterial envelope has been shown to stabilize implantable cardiac devices and reduce infection. A third-generation envelope was developed to reduce surface roughness with a redesigned multifilament mesh and enhanced form factor but identical polymer coating and antibiotic concentrations as the currently available second-generation envelope., Objective: The purpose of this study was to compare drug elution, bacterial challenge efficacy, stabilization, and absorption of second- vs third-generation envelopes., Methods: Antibiotic elution was assessed in vitro and in vivo. For efficacy against gram-positive/gram-negative bacteria, 40 rabbits underwent device insertions with or without third-generation envelopes. For stabilization (migration, rotation), 5 sheep were implanted with 6 devices each in second- or third-generation envelopes. Prespecified acceptance criteria were <83-mm migration and <90° rotation. Absorption was assessed via gross pathology., Results: Elution curves were equivalent (similarity factors ≥50 per Food and Drug Administration guidance). Third-generation envelopes eluted antibiotics above minimal inhibitory concentration (MIC) in vivo at 2 hours postimplant through 7 days, consistent with second-generation envelopes. Bacterial challenge showed reductions (P <.05) in infection with second- and third-generation envelopes. Device migration was 5.5 ± 3.5 mm (third-generation) vs 9. 9 ±7.9 mm (second-generation) (P <.05). Device rotation was 18.9° ± 11.4° (third-generation) vs 17.6° ± 15.1° (second-generation) and did not differ (P = .79). Gross pathology confirmed the absence of luminal mesh remainders and no differences in peridevice fibrosis at 9 or 12 weeks., Conclusion: The third-generation TYRX absorbable antibacterial envelope demonstrated equivalent preclinical performance to the second-generation envelope. Antibiotic elution curves were similar, elution was above MIC for 7 days, infections were reduced compared to no envelope, and acceptance criteria for migration, rotation, and absorption were met., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The Molecular Pathology Section, Cleveland Clinic (Cleveland, OH), has undergone enhancement of its testing portfolio and processes. An Excel 2013- and paper-based data-management system was replaced with a commercially available laboratory information-management system (LIMS) software application, a separate bioinformatics platform, customized test-interpretation applications, a dedicated sample-accessioning service, and a results-releasing software application. The customized LIMS solution manages complex workflows, large-scale data packets, and process automation. A customized approach was required because, in a survey of commercially available off-the-shelf software products, none met the diverse and complex needs of this molecular diagnostics service. The project utilized the expertise of clinical laboratorians, pathologists, genetics counselors, bioinformaticians, and systems analysts in partnering with software-engineering consultants to design and implement a solution. Concurrently, Agile software-building best practices were formulated, which may be emulated for scalable and cost-effective laboratory-authored software., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare rates of ocular hypertension (OHT) in eyes receiving 40 mg sub-Tenon triamcinolone (STT), 0.7 mg dexamethasone implant (DEX), and 2 mg intravitreal triamcinolone (IVT)., Methods: This study is a single-centre, retrospective case series. All patients receiving STT and DEX between 4/1/2014 and 3/1/2017 and IVT between 3/1/2012 and 3/1/2017 with a minimum of 3 months' follow-up were included. OHT was defined as an intraocular pressure (IOP) >24 mm Hg. Patients receiving any other form of topical, oral, or intravitreal steroid were excluded., Results: 113 eyes from 104 patients in the STT group, 122 eyes from 109 patients in the DEX group, and 109 eyes from 103 patients in the IVT group were included. The mean number of injections for each eye was 1.7 in the STT group, 2.6 for the DEX group, and 2.8 for the IVT group (p < 0.001). Twenty eyes (17.7%) developed OHT in the STT group, 19 eyes (15.6%) developed OHT in the DEX group, and 14 eyes (12.8%) developed OHT in the IVT group (p = 0.60). IOP was controlled in all eyes with observation, topical IOP-lowering medication, or surgical intervention. The rate of incisional glaucoma surgery was 1.7% in the STT group, 1.6% in the DEX group, and 0% in the IVT group (p = 0.55)., Conclusions: The rate of OHT was similar across treatment groups. The proportion of OHT in patients with a history of glaucoma was no different from that in patients without a history of glaucoma. All cases were successfully managed with observation, medical treatment, or incisional surgery., (Copyright © 2020 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: Papillary glioneuronal tumors (PGNTs) are rare World Health Organization grade I neoplasms that are characterized by a benign course and excellent response to surgical resection. A few reports exist of tumors with more aggressive clinical and histologic features. In this report we detail the case of an unusually aggressive PGNT in a 67-year-old woman., Case Description: The patient had a 3-year history of seizures and was diagnosed with a frontoparietal mass on imaging. She underwent subtotal resection with a histologic diagnosis of PGNT. Less than a year after surgery, the patient experienced recurrence of disease and underwent reresection and adjuvant radiation treatment. The patient's disease continued to progress despite radiation treatment, so adjuvant temozolomide was initiated. Molecular testing was performed and revealed a TERT promotor mutation, an FGFR3-TACC3 oncogenic fusion, and a copy number loss in CDKN2A/CDKN2B., Conclusions: PGNTs, while typically benign, can rarely recur after surgery. Molecular testing should be performed on all PGNTs to help possibly identify more aggressive tumors and potentially reveal novel treatment options., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Intranasal vaccination of pigs with poly lactic-co-glycolic acid and polyanhydride nanoparticles delivered inactivated influenza virus provides cross-reactive T-cell response, but not antibody response, resulting in incomplete protection and no reduction in nasal virus shedding. Expression of BAFF and Th2 transcription factor GATA-3 were downregulated in lungs of pigs vaccinated with influenza nanovaccine, but in mice it upregulated the expression of BAFF and cytokine TGFβ in cervical lymph nodes. However, the intranasal iNKT cell adjuvant, α-Galctosylceramide upregulates the expression of BAFF in pig lungs. In conclusion, expression of BAFF is differentially regulated by intranasal nanovaccine and α-Galctosylceramide in pig respiratory tract., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The American Shoulder and Elbow Surgeons (ASES) score is composed of a patient-reported portion and a physician assessment. Although the patient-reported score is frequently used to assess postoperative outcomes after shoulder arthroplasty, no previous studies have used the physician-assessment component. This study evaluated the relationship of the ASES physician-assessment measurements with patient-reported shoulder and general health outcomes., Methods: A retrospective review of a prospectively collected multicenter database was used to analyze patients who underwent primary reverse total shoulder arthroplasty (RTSA) from 2012 to 2015 with a minimum 2-year follow-up. ASES physician-assessment and patient-reported components and 12-Item Short Form Health Survey (SF-12) general health questionnaires were obtained preoperatively and 2 years postoperatively. The relationship between ASES physician measurements with ASES patient-reported outcome (PRO) scores and SF-12 Physical and Mental domain scores was assessed with Pearson correlation coefficients., Results: Included were 74 patients (32 men; mean age, 69.2 years; body mass index, 29.4 kg/m 2 ). Preoperative physician measurements and PRO scores were not significantly correlated. Postoperatively, only the ASES physician-measured active ( R  = 0.54, P  < .01) and passive forward flexion ( R  = 0.53, P  < .01) demonstrated moderate correlation with ASES patient scores. The remaining clinical measurements had no significant correlations with ASES patient or SF-12 scores. During the 2-year period, only improvements in active forward flexion correlated with improvements in ASES patient scores ( R  = 0.36, P  < .01)., Conclusions: Little correlation exists between clinical measurements from the ASES physician component and PROs, including the ASES patient-reported and SF-12 general health surveys, in RTSA patients. Improvement in active forward flexion is the only clinical measurement correlated with PRO improvement at 2 years.

Background: Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis that typically occurs in middle-aged patients. It is usually characterized by multifocal osteosclerotic lesions of the long-bones, however many cases have extraskeletal involvement. Central nervous system (CNS) involvement is common, but isolated CNS involvement at presentation has rarely been reported., Case Description: Here we report two cases of dural-based ECD mimicking meningioma on imaging with no other identified sites of disease., Conclusion: ECD is a rare disease, with isolated CNS involvement reported only a few times in the literature. The significance of this presentation requires additional study and long-term follow up., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor-alpha (PPARα), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities. Implications for quantitative risk assessment approaches were discussed, as were implications of not considering MOA and dose in hazard characterization and labeling schemes. Most, but not all, participants considered the CAR and PPARα MOAs as not relevant to humans based on quantitative and qualitative differences. In contrast, cytotoxicity is clearly relevant to humans, but a threshold applies. Questions remain for all three MOAs concerning what data are necessary to determine the MOA and to what extent it is necessary to exclude other MOAs., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Diet manipulation and genetic selection are two important mitigation strategies for reducing enteric methane (CH4) emissions from ruminant livestock. The aim of this study was to assess whether the diurnal pattern of CH4 emissions from individual dairy cows changes over time when cows are fed on diets varying in forage composition. Emissions of CH4 from 36 cows were measured during milking in an automatic (robotic) milking station in three consecutive feeding periods, for a total of 84 days. In Periods 1 and 2, the 36 cows were fed a high-forage partial mixed ration (PMR) containing 75% forage, with either a high grass silage or high maize silage content. In Period 3, cows were fed a commercial PMR containing 69% forage. Cows were offered PMR ad libitum plus concentrates during milking and CH4 emitted by individual cows was sampled during 8662 milkings. A linear mixed model was used to assess differences among cows, feeding periods and time of day. Considerable variation was observed among cows in daily mean and diurnal patterns of CH4 emissions. On average, cows produced less CH4 when fed on the commercial PMR in feeding Period 3 than when the same cows were fed on high-forage diets in feeding Periods 1 and 2. The average diurnal pattern for CH4 emissions did not significantly change between feeding periods and as lactation progressed. Emissions of CH4 were positively associated with dry matter (DM) intake and forage DM intake. It is concluded that if the management of feed allocation remains constant then the diurnal pattern of CH4 emissions from dairy cows will not necessarily alter over time. A change in diet composition may bring about an increase or decrease in absolute emissions over a 24-h period without significantly changing the diurnal pattern unless management of feed allocation changes. These findings are important for CH4 monitoring techniques that involve taking measurements over short periods within a day rather than complete 24-h observations.

The current acceptable daily intake (ADI) for benzoic acid and its salts as food additives is 0-5 mg/kg body weight. This accounts for a total uncertainty factor (UF) of 100, which includes a default factor of 10 for interspecies differences. Based on pharmacokinetic data in rodents and humans, we derived a chemical-specific adjustment factor (CSAF) of 2 for the pharmacokinetic component of the interspecies UF. Additional analyses indicate that this CSAF is conservative and interspecies differences between rats and humans are likely closer to unity. Human clinical studies indicate that the pharmacokinetics of benzoic acid and its salts are similar in children and adults, and that there is a lack of adverse events in humans at doses comparable to the no observed adverse effect level (NOAEL) in rodents; this suggests that the pharmacokinetic UF for intraspecies variability, as well as the pharmacodynamic components of the UFs, may also be reduced, although we did not calculate to what degree. In conclusion, the total UF can be reduced to 50 (2 for interspecies differences in pharmacokinetics, 2.5 for interspecies differences in pharmacodynamics, and 10 for intraspecies variability), which would increase the ADI to 0-10 mg/kg body weight., (Copyright © 2017 Gradient. Published by Elsevier Inc. All rights reserved.)

Essentials MEDI2452 is a specific antidote of the platelet P2Y 12 receptor antagonist ticagrelor. Hemostatic effects of MEDI2452 were evaluated in pigs treated with ticagrelor and aspirin. MEDI2452 eliminated free ticagrelor within 5 min and gradually normalized platelet aggregation. Improvements in blood pressure (significant) and in blood-loss and survival (non-significant) were observed., Summary: Background Ticagrelor, a P2Y 12 antagonist, is approved for the prevention of thromboembolic events. However, antiplatelet therapies carry a risk of bleeding. Objective To explore the hemostatic effects of MEDI2452, an antidote for ticagrelor. Methods Pigs, pre-treated with aspirin, were given an intravenous infusion of ticagrelor or vehicle. At the end of the infusion, a piece of a liver lobe was cut off and a bolus of MEDI2452 or vehicle was administered intravenously. Blood was collected to monitor blood loss, mean arterial blood pressure (MAP) was recorded and survival time was observed over 4 h. Blood samples for drug plasma exposures and platelet aggregation were collected. Results MEDI2452 eliminated the free concentrations of ticagrelor and its active metabolite AR-C124910XX within 5 min. ADP-induced platelet aggregation was close to normal at 60 min, which was not significantly different from aspirin alone. MEDI2452 numerically reduced ticagrelor-mediated effects: body-weight-adjusted blood loss in the 15- to 90-min interval, 12 (confidence interval [CI] 95% 7-28] vs. 17 (CI 95% 5-31) (ticagrelor and aspirin) vs. 5 (CI 95% 3-9) mL kg -1 (aspirin alone), survival 70% (CI 95% 47-100) vs. 45% (CI 95% 21-92) (ticagrelor and aspirin) vs. 100% (CI 95% 100-100) (aspirin alone), and median survival time, 240 (CI 95% 180-240) vs. 169 (CI 95% 64-240) (ticagrelor and aspirin) vs. 240 (CI 95% 240-240) min (aspirin alone). Finally, MEDI2452 significantly attenuated the decline in MAP, 0.08 (CI 95% 0.07-0.09) vs. 0.141 (CI 95% 0.135-0.148) (ticagrelor and aspirin) vs. 0.04 (CI 95% 0.03-0.05) mmHg per min (aspirin alone) and maintained MAP at a significantly higher level, 73 (CI 95% 51-95) vs. 48 (CI 95% 25-70) (ticagrelor and aspirin) vs. 115 (CI 95% 94-136) mmHg (aspirin alone). Conclusion MEDI2452 eliminated free ticagrelor and AR-C124910XX within 5 min. This translated into a gradual normalization of ADP-induced platelet aggregation and significant improvement in blood pressure and numerical but non-significant improvements in blood-loss and survival., (© 2017 International Society on Thrombosis and Haemostasis.)

Research suggests that exposure to ambient particulate matter (PM) may be associated with lung cancer; however, no mode of action (MoA) for this has been established. We applied a weight-of-evidence (WoE) approach to evaluate recent evidence from four realms of research (controlled human exposure, epidemiology, animal, and in vitro) to determine whether the overall evidence supports one or more MoAs by which PM could cause lung cancer. We evaluated three general MoAs: DNA damage and repair; other genotoxic effects, including mutagenicity and clastogenicity; and gene expression, protein expression, and DNA methylation. After assessing individual study quality, we evaluated the strength of the evidence within as well as across disciplines using a modified set of Bradford Hill considerations. We conclude that the overall WoE indicates it is plausible that PM of various size fractions may cause direct DNA damage, but the evidence is insufficient regarding the alternative MoAs we evaluated. More research is needed to determine whether DNA damage can lead to downstream events and, ultimately, lung cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Methane (CH4) emissions by dairy cows vary with feed intake and diet composition. Even when fed on the same diet at the same intake, however, variation between cows in CH4 emissions can be substantial. The extent of variation in CH4 emissions among dairy cows on commercial farms is unknown, but developments in methodology now permit quantification of CH4 emissions by individual cows under commercial conditions. The aim of this research was to assess variation among cows in emissions of eructed CH4 during milking on commercial dairy farms. Enteric CH4 emissions from 1964 individual cows across 21 farms were measured for at least 7 days/cow using CH4 analysers at robotic milking stations. Cows were predominantly of Holstein Friesian breed and remained on the same feeding systems during sampling. Effects of explanatory variables on average CH4 emissions per individual cow were assessed by fitting a linear mixed model. Significant effects were found for week of lactation, daily milk yield and farm. The effect of milk yield on CH4 emissions varied among farms. Considerable variation in CH4 emissions was observed among cows after adjusting for fixed and random effects, with the CV ranging from 22% to 67% within farms. This study confirms that enteric CH4 emissions vary among cows on commercial farms, suggesting that there is considerable scope for selecting individual cows and management systems with reduced emissions.

Background: The current effective treatment options for posttraumatic stress disorder (PTSD) are limited, and therefore the need to explore new treatment strategies is critical. Pharmacological inhibition of the renin-angiotensin system is a common approach to treat hypertension, and emerging evidence highlights the importance of this pathway in stress and anxiety. A recent clinical study from our laboratory provides evidence supporting a role for the renin-angiotensin system in the regulation of the stress response in patients diagnosed with PTSD., Methods: With an animal model of PTSD and the selective angiotensin receptor type 1 (AT1) antagonist losartan, we investigated the acute and long-term effects of AT1 receptor inhibition on fear memory and baseline anxiety. After losartan treatment, we performed classical Pavlovian fear conditioning pairing auditory cues with footshocks and examined extinction behavior, gene expression changes in the brain, as well as neuroendocrine and cardiovascular responses., Results: After cued fear conditioning, both acute and 2-week administration of losartan enhanced the consolidation of extinction memory but had no effect on fear acquisition, baseline anxiety, blood pressure, and neuroendocrine stress measures. Gene expression changes in the brain were also altered in mice treated with losartan for 2 weeks, in particular reduced amygdala AT1 receptor and bed nucleus of the stria terminalis c-Fos messenger RNA levels., Conclusions: These data suggest that AT1 receptor antagonism enhances the extinction of fear memory and therefore might be a beneficial therapy for PTSD patients who have impairments in extinction of aversive memories., (Published by Elsevier Inc.)

Background: Understanding sudden cardiac death in the young may inform prevention strategies., Objective: To determine the scope and nature of sudden death in a geographically defined population., Methods: We performed a retrospective population-based cohort study in Ontario, Canada, of all sudden cardiac death cases involving persons aged 2-40 years identified from the 2008 comprehensive Coroner database. Of 1741 Coroner's cases, 376 were considered potential sudden cardiac death cases and underwent review., Results: There were 174 cases of adjudicated sudden cardiac death from a population of 6,602,680 persons aged 2-40 years. Structural heart disease was present in 126 cases (72%), 78% of which was unrecognized. There was no identifiable cause of death in 48 cases (28%), representing primary arrhythmia syndromes. The majority of decedents were men (76%) over the age of 18 (90%). The overall incidence of sudden cardiac death increased with age from 0.7/100,000 (2-18 years) to 2.4/100,000 (19-29 years) to 5.3/100,000 (30-40 years) person-years. Persons experiencing sudden cardiac death before age 30 were more likely to have a primary arrhythmia syndrome (odds ratio 2.97; P<.001). The majority of events occurred in the home (72%); 33% of the events in children/adolescents and 9% of the events in adults occurred during reported moderate or vigorous exercise (P = .002). There were no pediatric deaths during organized competitive sports., Conclusions: The incidence of sudden cardiac death increases with age, typically occurring in a man at rest in the home with unrecognized underlying heart disease or a primary arrhythmia syndrome. Prevention strategies should consider targeting identification of unrecognized structural heart disease and primary arrhythmia syndromes., (Copyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the relationships between the time spent on sedentary activities (computer usage, video game playing, television viewing, and reading) and physical inactivity in a sample of youth (aged 12-19 years) from the 2000-2001 Canadian Community Health Survey., Methods: The study sample included 7982 youth (4034 males, 3948 females) across Canada (mean age: 15.61 years, SD: 2.23 years). Weekly time spent on computers, video games, television, and reading during leisure-time was obtained through self-reported questionnaires. Physical inactivity was determined by respondents' daily energy expenditure assessed through a physical activity questionnaire. Multivariate logistic regression analysis was conducted to examine the relationship between sedentary activities and physical inactivity respectively by gender. Sociodemographic variables, health status, and overweight status were controlled in the analysis., Results: A substantial proportion of Canadian youth was inactive: 50.3% of males and 67.8% of females. Controlling for sociodemographic variables, health status, and body mass index, television viewing was significantly associated with physical inactivity for both males and females regardless of their overweight status. However, computer usage was associated with physical activity among males, and reading was associated with physical activity among females., Conclusions: There is a complex inter-relationship between sedentary behaviors and physical inactivity, highlighting the need for targeted interventions addressing patterns of sedentary behavior engagement. Reducing time spent on television viewing may be one plausible strategy within such interventions in reducing physical inactivity among youth.

Purpose: Adolescents spend considerable time at school and thus it is important to understand their opportunities for school-based physical activity. This study surveyed Ontario secondary schools to identify the range of structured opportunities and their engagement by students., Methods: A questionnaire was mailed to key informants in 600 randomly selected secondary schools in Ontario, for which 474 respondents (79%) returned completed questionnaires., Results: Curriculum-based physical education (PE) classes in grade nine were reported to be offered in all schools and these classes in grades 10, 11 and 12 were offered in almost all schools. Student enrollment in PE decreased from grades 9 to 12 (97.9%, 49.6%, 43.3% and 35.9%, respectively). Respondents reported that funding, timetable, facilities and resources made it somewhat difficult to implement the health and physical education curriculum in their schools. About two-thirds (65.5%) of the schools had an intramural program and 15.0% of students participated in it, whereas 97.2% of the schools had an inter-school sports program and 25.0% of students participated in it. Supervision issues made it difficult to provide intramural programs and funding made it difficult to provide inter-school sports programs., Conclusions: Although provision of physical activity opportunities in Ontario appears satisfactory, actual engagement by students is low. The results suggest that strategies to increase student participation in PE, intramural programs, and inter-school sports programs need further consideration.

This article examines the relationship between vigorous physical activity and psychologic distress (by using the General Health Questionnaire-12) among a sample of 2,104 adolescents. Multiple regression analysis revealed a differential relationship between physical activity and dimensions of the General Health Questionnaire-12. Specifically, vigorous physical activity was related significantly to problems with social functioning but not to depression or anxiety.

Natural flavour complexes (NFCs) are chemical mixtures obtained by applying physical separation methods to botanical sources. Many NFCs are derived from foods. In the present paper, a 12-step procedure for the safety evaluation of NFCs, 'the naturals paradigm', is discussed. This procedure, which is not intended to be viewed as a rigid check list, begins with a description of the chemical composition of the commercial product, followed by a review of the data on the history of dietary use. Next, each constituent of an NFC is assigned to one of 33 congeneric groups of structurally related substances and to one of three classes of toxic potential, each with its own exposure threshold of toxicological concern. The group of substances of unknown structure is placed in the class of greatest toxic potential. In subsequent steps, for each congeneric group the procedure determines the per capita intake, considers metabolic pathways and explores the need and availability of toxicological data. Additional toxicological and analytical data may be required for a comprehensive safety evaluation. The procedure concludes with an evaluation of the NFC in its entirety, also considering combined exposure to congeneric groups. The first experiences with the use of this procedure are very promising. Future safety evaluations of larger numbers of NFCs will indicate the usefulness of the system, either in its present form or in a form modified on the basis of experience.

The rejection of xenografts is characterized by infiltration of monocytes and natural killer (NK) cells into the graft, suggesting an important role for the innate immune system in xenorecognition. In this study, purified human NK or T cells were cocultured with porcine endothelial cells, and cytokines were analyzed by ELISA and intracellular FACS. We demonstrated a vigorous human anti-porcine xenoresponse that was associated with a strong T-cell proliferation against porcine endothelial cells. Limiting dilution cloning and T-cell receptor (TCR) Vbeta gene usage revealed a low number of xenoreactive T-cell precursors. We demonstrated that xenogeneic porcine but not allogeneic human endothelial cells induced the early production of interferon (IFN)-gamma by human NK cells but not by CD3+ T cells. Porcine xenoantigen-induced IFN-gamma production was only partially dependent on IL-12. Blocking IL-12 with neutralizing antibodies or by depletion of human macrophages partially decreased IFN-gamma production by CD56+ NK cells. Three-color flow cytometry revealed that IL-12 was produced through a species-specific activation of human macrophages by porcine endothelial cells. Our results indicate that the direct activation of NK cells and macrophages by porcine endothelial cells provides a unique pathway of xenorecognition that augments downstream specific T-cell immunity and represents a powerful effector mechanism in xenograft rejection.

Voltage-gated calcium channels (VGCCs) within sensory neurones are believed to perform an important role in neuropathic pain. In the present study we examine the changes in VGCC mRNA which occur following streptozocin- (STZ) induced diabetic neuropathy using in situ hybridization. STZ caused a significant increase in alpha(2)delta(1), alpha(2)delta(2), and alpha(2)delta(3) mRNA levels in all neuronal cell types. Similarly, mRNA levels of alpha(1F), alpha(1I), and alpha(1S) were increased in all cell types studied whilst alpha(1A) and alpha(1G) mRNAs were specifically upregulated in medium and large diameter neurones. In conclusion, we demonstrate that the induction of diabetic neuropathy is associated with dramatic changes in the expression of VGCCs.

The extent to which a bacterial cocktail containing equal numbers of Pseudomonas fragi NCTC 10689, Listeria monocytogenes BL5/2, Salmonella Typhimurium LT2, and Escherichia coli JM 109 attached to loin surface cuts (7 by 5 cm) derived from steam-pasteurized beef carcasses has been evaluated. The extent of attachment was categorized as loosely attached (removed by rinsing), firmly attached (released by stomaching), and irreversibly bound. No significant difference (P > 0.10) in the attachment of bacteria to steam-pasteurized carcasses was found compared with control loin samples that had received no treatment. No significant difference (P > 0.05) was also found in the attachment strength between the different bacterial species tested. Most bacteria inoculated onto the loin cuts were reversibly bound, since they had been removed by rinsing and stomaching. The irreversible attachment of bacteria to loin cuts was found to vary significantly (P < 0.01) among the different carcass sets used but was independent of whether the carcass had undergone steam pasteurization treatment. Use of a bioluminescent strain of E. coli showed that cells bound preferentially to cut edges and convoluted areas on the loin surface and could not be removed by rinsing. The possible mechanisms of bacterial attachment and the suitability of steam pasteurization to remove contamination incurred during slaughter are discussed.

The amplitude of protein backbone NH group motions on a time-scale faster than molecular tumbling may be determined by analysis of (15)N NMR relaxation data according to the Lipari-Szabo model free formalism. An internet-accessible database has been compiled containing 1855 order parameters from 20 independent NMR relaxation studies on proteins whose three-dimensional structures are known. A series of statistical analyses has been performed to identify relationships between the structural features and backbone dynamics of these proteins. Comparison of average order parameters for different amino acid types indicates that amino acids with small side-chains tend to have greater backbone flexibility than those with large side-chains. In addition, the motions of a given NH group are also related to the sizes of the neighboring amino acids in the primary sequence. The secondary structural environment appears to influence backbone dynamics relatively weakly, with only subtle differences between the order parameter distributions of loop structures and regular hydrogen bonded secondary structure elements. However, NH groups near helix termini are more mobile on average than those in the central regions of helices. Tertiary structure influences are also relatively weak but in the expected direction, with more exposed residues being more flexible on average than residues that are relatively inaccessible to solvent., (Copyright 2000 Academic Press.)

Background: Schizophrenia is characterized by subcortical and cortical brain abnormalities. Evidence indicates that some nonpsychotic relatives of schizophrenic patients manifest biobehavioral abnormalities, including brain abnormalities. The goal of this study was to determine whether amygdala-hippocampal and thalamic abnormalities are present in relatives of schizophrenic patients., Methods: Subjects were 28 nonpsychotic, and nonschizotypal, first-degree adult relatives of schizophrenics and 26 normal control subjects. Sixty contiguous 3 mm coronal, T1-weighted 3D magnetic resonance images of the brain were acquired on a 1.5 Tesla magnet. Cortical and subcortical gray and white matter and cerebrospinal fluid (CSF) were segmented using a semi-automated intensity contour mapping algorithm. Analyses of covariance of the volumes of brain regions, controlling for expected intellectual (i.e., reading) ability and diagnosis, were used to compare groups., Results: The main findings were that relatives had significant volume reductions bilaterally in the amygdala-hippocampal region and thalamus compared to control subjects. Marginal differences were noted in the pallidum, putamen, cerebellum, and third and fourth ventricles., Conclusions: Results support the hypothesis that core components of the vulnerability to schizophrenia include structural abnormalities in the thalamus and amygdala-hippocampus. These findings require further work to determine if the abnormalities are an expression of the genetic liability to schizophrenia.

The objective was to determine the relationships between eye tracking disorder (ETD) in schizophrenia, specific ocular motor measures, and the deficit syndrome. Twenty-five normal comparison subjects and 53 schizophrenic patients had eye movements tested with infrared oculography using a sinusoidal target. Patients were assessed with the Schedule for the Deficit Syndrome. For the patients, the distribution of position root mean square error (a global measure of pursuit) was best fit by a mixture of two normal distributions. This information was used to divide the patients into two subgroups, those with and those without ETD. ETD was almost completely accounted for by several specific ocular motor measures and was significantly associated with the deficit syndrome. The finding that ETD was almost completely accounted for by specific measures bridges a gap of interpretation in this field. ETD and the deficit syndrome of schizophrenia may share a common pathophysiology of cerebral cortical-subcortical circuits.

We investigated the hypothesis that different prefrontal brain systems (i.e., dorsal vs. ventral) and sex contribute differentially to cognitive deficit in schizophrenia. Performance was assessed among clinically stable, chronic schizophrenic outpatients and matched normal control subjects on olfactory identification [on the University of Pennsylvania Smell Identification Test (UPSIT)] and on executive functions [using the Wisconsin Card Sorting Test (WCST)]. Patients were impaired on both tests compared to controls, and male schizophrenics were impaired on the WCST compared to female schizophrenics. The pattern of results suggests that gender differences on the UPSIT are mildly accentuated in schizophrenia. The data support our previous study indicating that UPSIT performance is largely independent of the executive or attentional deficits typically associated with schizophrenia, with the exception of verbal ability. Further research with larger samples is required to test the hypothesis that there is a severely impaired subgroup of male patients with diffuse prefrontal dysfunctions.

Paraganglioma arising in the thoracic extradural space is an uncommon tumor, with only four cases previously reported. The authors review the clinical and pathological features of thoracic paraganglioma and compare them to the more common paraganglioma of the cauda equina.

There is an abundant amount of information on the mechanisms of action of genotoxic chemicals that act as carcinogens and the role that mutations play in carcinogenesis. However, carcinogenesis is more than mutagenesis and many carcinogens are not mutagens. Thus, there is a need to consider nongenotoxic mechanisms that may be involved in carcinogenesis. In this paper, we review our working hypothesis that hypomethylation of DNA is an epigenetic, nongenotoxic mechanism that plays a role in tumor promotion by facilitating aberrant gene expression. The utility of employing experimental models that focus on relevant comparisons between sensitive and resistant strains of mice is emphasized. Additionally, aspects of DNA methylation in rodents and humans are compared and contrasted. We discuss hypomethylation of DNA as a secondary mechanism, that is expected to be threshold-exhibiting, and conclude by describing how this information may facilitate a rational approach towards risk assessment when dealing with nongenotoxic compounds that are carcinogenic in a bioassay.

The purpose of the bioassay is not to simply find chemicals that can be labeled as carcinogens. On the contrary, the overall goal is to provide a reasonable assessment of the possible hazard that a chemical might pose to people under realistic conditions of exposure. This paper focuses upon the doses commonly used in the bioassay within the context that dose influences mechanism and, over a wide range of doses, mechanism changes with changing dose. Thus, a carcinogenic effect observed at a high dose is not necessarily expected to occur at lower doses. A variety of examples are provided to illustrate the points that (a) any high dose, no matter how high, that permits test animals to live long enough to develop tumors is not an appropriate criterion for defining an acceptable high dose to employ in a carcinogen bioassay; and (b) emphasis should be placed upon research that may discern probable thresholds for the carcinogenic effect of chemicals, especially nongenotoxic chemicals.

The NTP toxicology and carcinogenicity studies of nonasbestiform, cosmetic-grade talc (the NTP Talc Report) were conducted by exposing male and female F344/N rats and B6C3F1 mice to target aerosol concentrations of 0, 6, and 18 mg/m3 talc for 6 hr daily, 5 days per week. Based on results of the high dose, the Report concluded that talc caused lung tumors in female rats and pheochromocytomas in male and female rats, and there was no evidence of carcinogenic activity in mice. A thorough evaluation of lung toxicity revealed that talc-induced lung tumors occurred only in the group of animals that exhibited the most profound degree of chronic toxicity. However, these data were presented as empirical observations rather than discussed in a manner that would relate them to the risk assessment implications of the bioassay, i.e., relevant data were collected but not "used." In addition, the evaluation of the pheochromocytomas was inadequate because it failed to place sufficient emphasis on the spontaneous incidence of this tumor in rats. These deficiencies caused the author to vote against the conclusions presented in the Talc Report when it was reviewed by the NTP Board of Scientific Counselors. The appropriate conclusions are (1) the data do not indicate that the pheochromocytomas were treatment-related; (2) the maximum tolerated dose (MTD) was exceeded in the female rats exposed to the high dose; and (3) talc is not expected to cause lung tumors under conditions of exposure that fail to result in marked chronic lung toxicity.

Purpose: This study examined the 6-month prevalence of depression and suicidal probability among new referrals to an adolescent health clinic., Methods: All subjects (n = 104) completed the Beck Depression Inventory (BDI) and the Suicide Probability Scale (SPS) prior to being seen by a physician and were categorized according to presenting problem (physical complaints only, psychological complaints only, and physical and psychological complaints combined)., Results: Fifty-nine percent of the sample was depressed with 21% falling in the moderate range and 21% falling within the severe range of depression. Almost 23% of the sample demonstrated significant suicidal probability. The BDI and SPS were highly correlated (r = .73, p < .001) and 22% of the sample met criteria for both moderate to severe depression and suicidal probability. A significantly greater proportion of patients presenting with physical and psychological complaints combined (60%) met BDI criteria for depression than was found for the other two groups. Suicidal probability was most prevalent in patients presenting with psychological complaints only (26%) and moderate to severe depression and significant suicidal probability also coexisted to a greater extent within this group (26%)., Conclusions: Results suggest that depression and suicidal probability represent significant mental health problems within the adolescent clinic and the identification of high-risk individuals can be achieved through comprehensive screening practices.

DNA was isolated from the liver of young B6C3F1, C3H/He and C57BL/6 mice, 6-9 weeks old. A portion of exon 2 of Ha-ras was amplified by PCR allele-specific amplification. The PCR product was identified by (a) size, (b) presence of a diagnostic restriction site, and (c) direct sequencing. Our results indicate that nascent mouse liver bears a subpopulation of cells which contain a mutation in codon 61 of Ha-ras, specifically an A to G transition at position 2. Therefore, the detection of this mutation in chemically induced mouse liver tumors does not demonstrate that the chemical in question acts as a mutagen. It might act by a nongenotoxic mechanism, i.e., by facilitating a clonal expression of cells bearing this spontaneous mutation.

The National Toxicology Program (NTP) Board of Scientific Counselors met on April 14 and 15, 1992 to review the NTP. This paper provides an overview of the Board's Report with an emphasis on the recommendations made by the Carcinogenesis Working Group. The prime overall recommendation is that the NTP should move from a focus on hazard identification to an emphasis on providing the type of biological information that needs to be incorporated into the risk assessment process. This would involve a hypothesis-driven mechanism of action approach aimed at understanding the basis for the actions of the chemicals of interest. Relevant examples are provided. Scientists from the National Institute of Environmental Health Sciences' (NIEHS) intramural program and those outside of NIEHS should be included in the research effort. This strategy would permit a more rational approach toward both test development and design (e.g., selection of the high dose to be employed), and the interpretation of test results (e.g., addressing questions pertaining to dose-response relationships and species to species extrapolation). The overall goal would be to provide a reasonable assessment of the possible hazard that a chemical might pose to people in light of realistic conditions of exposure.