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Background: The “chain of survival” was first systematically addressed in 1991, and its sequence still forms the cornerstone of current resuscitation guidelines. The term “chain of survival” is widely used around the world in literature, education, and awareness campaigns, but growing heterogeneity in the components of the chain has led to confusion. It is unclear which of these emerging chains is most suitable, or if adaptations are needed in particular contexts to depict key actions of resuscitation in the 21st century. This scoping review provides an overview of the variety of chains of survival described. Objectives: To identify published facets of the chain of survival, to assess views and strategies about adapting the chain, and to identify reports on how the chain of survival affects teaching, implementation, or patient outcomes. Methods, eligibility criteria, and sources of evidence: A scoping review as part of the continuous evidence evaluation process of the International Liaison Committee on Resuscitation (ILCOR) was conducted. MEDLINE(R) ALL (Ovid), Embase (Ovid), APA PsycINFO (Ovid), CINAHL (Ebscohost), ERIC (Ebscohost), Web of Science (Clarivate), Scopus (Elsevier), and Cochrane Library (Wiley Online) were searched. All publications in all languages describing chains of survival were eligible, without time restrictions. Due to the heterogeneity and publication types of the relevant studies, we did not pursue a systematic review or meta-analysis. Results: A primary search yielded 1713 studies and after screening we included 43 publications. Modified versions of the chain of survival for specific contexts were found (e.g., in-hospital cardiac arrest or paediatric resuscitation). There were also numerous versions with minor adaptations of the existing chain. Three publications suggested an impact of the use of the chain of survival on patient outcomes. No educational or implementation outcomes were reported. Conclusion: There is a vast heterogeneity of chain of survival concepts published. Future research is warranted, especially into the concept’s importance concerning educational, implementation, and clinical outcomes.

ABSTRACT: Insufficient dry matter intake (DMI) of pasture by dairy cattle is a major factor limiting growth and milk production; however, it has been hypothesized that some dairy breeds may be more efficient grazers than others. This study was conducted to determine whether dairy breed types differ in DMI and feed efficiency when grazing either grass monoculture or grass-legume mixed pastures. The experiment compared 4 different dairy breed types (Jersey, Holstein, Holstein-Jersey crossbreds, and Montbéliarde-Swedish Red-Holstein 3-breed crossbreds) and 2 levels of pasture type [grass monoculture (MONO) and grass-birdsfoot trefoil (BFT) mixture (MX)] for a total of 8 treatments. Pastures were rotationally stocked with groups of 4 prepubertal heifers for 105 d for 3 yr, and DMI was determined from herbage disappearance. Feed conversion efficiency (FCE) and residual feed intake (RFI) were then derived from DMI, and heifer body weights (BW) and normalized to animal units (AU) as 40% metabolic mature BW of the corresponding dairy breed type to account for inherent differences in size and growth rates. We observed differences in DMI and feed efficiency among breed types and between pasture types. On average, Holsteins had the greatest overall DMI (4.4 kg/AU), followed by intermediate DMI by the crossbreds (4.0 kg/AU), and Jerseys had the least DMI (3.6 kg/AU). Heifers grazing MX pastures had on average 22% greater DMI than those grazing MONO, but heifers on grass monocultures were more efficient in converting DMI to BW gain (i.e., RFI/AU of 0.27 and −0.27, respectively; more negative RFI numbers indicate less DMI to achieve the expected gains). Overall, Jerseys had the most favorable feed efficiency; however, ranking of Holsteins and crossbreds depended upon the feed efficiency metric. This study is one of the first to compare the interaction of dairy breed and pasture quality on grazing efficiency. However, the lack of a breed type × pasture type interaction for DMI, FCE, or RFI indicated that none of these dairy breed types were better adapted than another breed type to pastures with contrasting levels of nutritive value.

Coronary artery calcium scores are derived from cardiac-gated noncontrast computed tomography scans that are used in cardiac risk stratification. However, an elevated calcium score does not always translate to coronary artery luminal obstruction. Our case demonstrates an extremely high coronary artery calcium score despite nonobstructive coronaries on angiogram.

Background: Huntington's disease (HD) is characterized by motor and behavioral symptoms, and cognitive decline. HD gene carriers and their caregivers report the behavioral and cognitive symptoms as the most burdensome. Apathy is the most common behavioral symptom of HD and is related to clinical measures of disease progression, like functional capacity. However, it is unknown whether apathy is directly related to the neurodegenerative processes in HD. Objective: The aim is to investigate whether an association between atrophy of subcortical structures and apathy is present in HD, at baseline and after 2 years follow-up. Method: Volumes of 7 subcortical structures were measured using structural T1 MRI in 171 HD gene carriers of the TRACK-HD study and apathy was assessed with the Problem Behaviors Assessment-Short, at baseline and follow-up visit. At baseline, logistic regression was used to evaluate whether volumes of subcortical brain structures were associated with the presence of apathy. Linear regression was used to assess whether subcortical atrophy was associated with the degree of apathy at baseline and with an increase in severity of apathy over time. Results: At baseline, smaller volume of the thalamus showed a higher probability of the presence of apathy in HD gene carriers, but none of the subcortical structures was associated with the degree of apathy. Over time, no association between atrophy of any subcortical structures and change in degree of apathy was found. Conclusion: The presence of apathy is associated with atrophy of the thalamus in HD, suggesting that apathy has an underlying neural cause and might explain the high incidence of apathy in HD. However, no association was found between atrophy of these subcortical structures and increase in severity of apathy over a 2-year time period. Keywords: Apathy, Huntington's disease, Subcortical structures, Thalamus

New or enlarged lesions in malignant gliomas after surgery and chemoradiation can be associated with tumor recurrence or treatment effect. Due to similar radiographic characteristics, conventional-and even some advanced MRI techniques-are limited in distinguishing these two pathologies. Amide proton transfer-weighted (APTw) MRI, a protein-based molecular imaging technique that does not require the administration of any exogenous contrast agent, was recently introduced into the clinical setting. In this study, we evaluated and compared the diagnostic performances of APTw MRI with several non-contrast-enhanced MRI sequences, such as diffusion-weighted imaging, susceptibility-weighted imaging, and pseudo-continuous arterial spin labeling. Thirty-nine scans from 28 glioma patients were obtained on a 3 T MRI scanner. A histogram analysis approach was employed to extract parameters from each tumor area. Statistically significant parameters (P < 0.05) were selected to train multivariate logistic regression models to evaluate the performance of MRI sequences. Multiple histogram parameters, particularly from APTw and pseudo-continuous arterial spin labeling images, demonstrated significant differences between treatment effect and recurrent tumor. The regression model trained on the combination of all significant histogram parameters achieved the best result (area under the curve = 0.89). We found that APTw images added value to other advanced MR images for the differentiation of treatment effect and tumor recurrence., (Copyright © 2023. Published by Elsevier Inc.)

Background: Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold., Methods: To dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures., Results: In iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation., Conclusions: Our results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant., (Published by Elsevier Inc.)

Background: The US COVID-19 epidemic impacted counties differently across space and time, though large-scale transmission dynamics are unclear. The study's objective was to group counties with similar trajectories of COVID-19 cases and deaths and identify county-level correlates of the distinct trajectory groups., Methods: Daily COVID-19 cases and deaths were obtained from 3141 US counties from January through June 2020. Clusters of epidemic curve trajectories of COVID-19 cases and deaths per 100,000 people were identified with Proc Traj. We utilized polytomous logistic regression to estimate Odds Ratios for trajectory group membership in relation to county-level demographics, socioeconomic factors, school enrollment, employment and lifestyle data., Results: Six COVID-19 case trajectory groups and five death trajectory groups were identified. Younger counties, counties with a greater proportion of females, Black and Hispanic populations, and greater employment in private sectors had higher odds of being in worse case and death trajectories. Percentage of counties enrolled in grades 1-8 was associated with earlier-start case trajectories. Counties with more educated adult populations had lower odds of being in worse case trajectories but were generally not associated with worse death trajectories. Counties with higher poverty rates, higher uninsured, and more living in non-family households had lower odds of being in worse case and death trajectories. Counties with higher smoking rates had higher odds of being in worse death trajectory counties., Discussion: In the absence of clear guidelines and personal protection, smoking, racial and ethnic groups, younger populations, social, and economic factors were correlated with worse COVID-19 epidemics that may reflect population transmission dynamics during January-June 2020. After vaccination of high-risk individuals, communities with higher proportions of youth, communities of color, smokers, and workers in healthcare, service and goods industries can reduce viral spread by targeting vaccination programs to these populations and increasing access and education on non-pharmaceutical interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: We applied the actor-partner interdependence model, a method used to evaluate the relationship process between two related persons, to patient-physician data about the effect of shared decision-making behaviors on patient and physician uncertainty. We discuss measurement and interpretation problems., Study Design and Setting: The EXACKTE 2 project was a cross-sectional study of 263 unique patient-physician dyads in 17 primary care clinics in Canada. Participants independently completed self-administered questionnaires postconsultation to measure patients' and physicians' perceptions of shared decision-making behaviors and their uncertainty about whether the decision was the best one for the patient. We used the actor-partner interdependence model to explore the effect of shared decision-making behaviors on patient and physician uncertainty., Results: Application of the actor-partner interdependence model to our data showed significant actor effects only. Our exploratory analysis suggested that an appropriate dyadic pattern for this context would be the couple-oriented model., Conclusion: Each actor's perception of the physicians' shared decision-making behaviors appeared only to affect their own uncertainty (actor effects), but the questionnaire may have been inadequate for identifying partner effects. Researchers should further explore using the actor-partner interdependence model to analyze actor-partner interdependence in the physician-patient relationship, and format questions tailored precisely to the model., (Copyright © 2018 Elsevier Inc. All rights reserved.)

To many physicians and professionals, social media seems to be a risky business. However, recent literature has shown that there is potential to enhance your scholarly brand by engaging your stakeholders online. In this article, we discuss the opportunities presented to modern scholars by social media. Using case studies, we highlight two success stories around how scientists and scholars might use social media to enhance their careers. We also outline five key steps you can follow to build and manage your scholarly presence online., (Copyright © 2017 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Public-private partnerships allow many previously unavailable compounds to be screened for antiviral activity. Here a screening method was used to identify an oxindole compound, RO0504985, from a Roche kinase inhibitor library that inhibited human cytomegalovirus (HCMV) protein production. RO0504985 was previously described as an inhibitor of cyclin-dependent kinase 2 (CDK2). However, using kinase selectivity assays it was found that RO0504985 was an inhibitor of several CMGC group kinase proteins, including CDK2. Using virus yield reduction assays it was observed that RO0504985 inhibited replication of different HCMV strains at low micromolar concentrations. Western blotting was used to investigate how RO0504985 inhibited HCMV replication. Treatment of HCMV infected cells with RO0504985 inhibited production of the immediate early viral IE2 proteins and the late viral protein pp28. Thus, RO0504985 inhibited HCMV replication by preventing production of specific HCMV proteins necessary for virus replication., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Using a high throughput screening methodology we surveyed a collection of largely uncharacterized validated or suspected kinase inhibitors for anti-human cytomegalovirus (HCMV) activity. From this screen we identified three structurally related 5-aminopyrazine compounds (XMD7-1, -2 and -27) that inhibited HCMV replication in virus yield reduction assays at low micromolar concentrations. Kinase selectivity assays indicated that each compound was a kinase inhibitor capable of inhibiting a range of cellular protein kinases. Western blotting and RNA sequencing demonstrated that treatment of infected cells with XMD7 compounds resulted in a defect in the production of the major HCMV transcriptional transactivator IE2 proteins (IE2-86, IE2-60 and IE2-40) and an overall reduction in transcription from the viral genome. However, production of certain viral proteins was not compromised by treatment with XMD7 compounds. Thus, these novel anti-HCMV compounds likely inhibited transcription from the viral genome and suppressed production of a subset of viral proteins by inhibiting IE2 protein production., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (TK) that-once activated upon ligand binding-leads to receptor dimerization, recruitment of protein complexes, and activation of multiple signaling cascades. The EGFR is frequently overexpressed or mutated in various cancers leading to aberrant signaling and tumor growth. Hence, identification of interaction partners that bind to mutated EGFR can help identify novel targets for drug discovery. Here, we used a systematic approach to identify novel proteins that are involved in cancerous EGFR signaling. Using a combination of high-content imaging and a mammalian membrane two-hybrid protein-protein interaction method, we identified eight novel interaction partners of EGFR, of which half strongly interacted with oncogenic, hyperactive EGFR variants. One of these, transforming acidic coiled-coil proteins (TACC) 3, stabilizes EGFR on the cell surface, which results in an increase in downstream signaling via the mitogen-activated protein kinase and AKT pathway. Depletion of TACC3 from cells using small hairpin RNA (shRNA) knockdown or small-molecule targeting reduced mitogenic signaling in non-small cell lung cancer cell lines, suggesting that targeting TACC3 has potential as a new therapeutic approach for non-small cell lung cancer., (Copyright © 2016 AstraZeneca. Published by Elsevier Ltd.. All rights reserved.)

Shelf-stable, ready-to-eat meat and poultry products represent a large sector of the meat snack category in the meat and poultry industry. Determining the physiochemical conditions that prevent the growth of foodborne pathogens, namely, Staphylococcus aureus postprocessing, is not entirely clear. Until recently, pH and water activity (a(w)) criteria for shelf stability has been supported from the U.S. Department of Agriculture training materials. However, concern about the source and scientific validity of these critical parameters has brought their use into question. Therefore, the objective of this study was to evaluate different combinations of pH and aw that could be used for establishing scientifically supported shelf stability criteria defined as preventing S. aureus growth postprocessing. Snack sausages were manufactured with varying pH (5.6, 5.1, and 4.7) and a(w) (0.96, 0.92, and 0.88) to achieve a total of nine treatments. The treatments were inoculated with a three-strain mixture of S. aureus, with populations measured at days 0, 7, 14, and 28 during 21 °C storage. Results revealed treatments with a pH ≤ 5.1 and a(w) ≤ 0.96 did not support the growth of S. aureus and thus could be considered shelf stable for this pathogen. The results provide validated shelf stability parameters to inhibit growth of S. aureus in meat and poultry products.

The worldwide incidence of cardiovascular disease (CVD) is increasing, reflecting a combination of ongoing infective diseases and a rapid rise in traditional 'western' risk factors. It is estimated that in the next 20 years that CVD be the leading cause of death in developing nations. There are high incidences of rheumatic heart disease, coronary artery disease, cardiomyopathies, uncorrected congenital heart disease and human immunodeficiency virus (HIV) associated disease in many low-income countries. Such high levels combined with a lack of diagnostic tests and therapeutic options means mortality and morbidity rates are high. A number of charities and organizations have tried to address the discrepancy of cardiac care within developing areas although the needs remain great. However there is no one global cardiac organization that coordinates such humanitarian work. The challenges of missionary work include the need for appropriate facilities, financial constraints of clinical consumables, and lack of education of local healthcare staff, making the move away from the mission model difficult. The strategy for delivery of care in developing countries should be long term educational and technical support, so that local case volumes increase. However it must be realized that there are many different levels of local services within developing nations with different health and educational needs, including some countries with very high facilities and skills levels, yet high case loads. This paper highlights the personal experience of our organization and the types of diseases encountered in developing countries., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

To confirm the local endemicity of Schistosoma haematobium on Mafia Island, Tanzania, conjoint parasitological and malacological surveys were undertaken in July 2006 with parasitological investigations supplemented with case-history questionnaires. A total of 238 children (125 girls and 113 boys, mean age of 13.9 years) across 9 primary schools were examined. The prevalence of micro-haematuria and egg-patent infection was 18.1% (CI95=9.6-33.6) and 4.2% (CI95=1.9-7.6), respectively but a strong female bias was observed for micro-haematuria (5.6F:1M) contrasting with a strong male bias for the presence of eggs (1F:4M). All egg-patent infections were of light-intensity (<10eggs/10ml). No clear associations between infection prevalence and local water-contact, by school, were found and all 10 of the egg-positive children had a travel history to the nearby mainland or Zanzibar. Inspection of community diagnostic registers at Kilindoni Hospital revealed a low proportion (<2%) of egg-patent infection for 20,306 samples tested in the 2000-2005 period. A total of 43 freshwater sites, a third of which were previously sampled in 1999 and 2002, were surveyed and 11 species of freshwater mollusc were found. Four species of Bulinus (B. nasutus, B. forskalii, B. barthi and B. sp.) were encountered across 13 sites with B. nasutus restricted to 3 of these towards the north of the island. No collected snail was observed to shed schistosome cercariae. Further characterisation of B. nasutus and S. haematobium included infection challenge on two occasions, with miracidia obtained from egg-patent children from Mafia and Unguja islands as well as DNA barcoding of snails and schistosomes. B. nasutus was shown refractory to infection. With the substantial travel to and from Mafia, the refractory nature of local snails and evidence from DNA barcoding in schistosomes and snails, we conclude that urogenital schistosomiasis is an imported infection., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: The microtubule-associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer's disease. One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau's toxic accretion., Methods: Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the heat shock protein 70 (Hsp70) family in the brain, heat shock cognate 70 protein (Hsc70). The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures, and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured., Results: Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, overexpression of heat shock protein 40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wild-type mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in tau transgenic brain slices., Conclusions: Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in Alzheimer's disease and other tauopathies., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Evidence-based design findings are available to help inform hospital decision makers of opportunities for ensuring that quality and safety are designed into new and refurbished facilities., Framework for the Evidence: The Institute of Medicine's six quality aims of patient centeredness, safety, effectiveness, efficiency, timeliness, and equity provide an organizing framework for introducing a representative portion of the evidence. Design improvements include single-bed and variable-acuity rooms; electronic access to medical records; greater accommodation for families and visitors; handrails to prevent patient falls; standardization (room layout, equipment, and supplies for improved efficiencies); improved work process flow to reduce delays and wait times; and better assessment of changing demographics, disease conditions, and community needs for appropriately targeted health care services., The Business Case: A recent analysis of the business case suggests that a slight, one-time incremental cost for ensuring safety and quality would be paid back in two to three years in the form of operational savings and increased revenues. Hospitals leaders anticipating new construction projects should take advantage of evidence-based design findings that have the potential of raising the quality of acute care for decades to come.

The Communities That Care Youth Survey measures risk and protective factors shown in prior studies to predict adolescent problem behaviors such as drug use, delinquency, and violence. This paper describes the development and validation of cut points for the risk and protective factor scales in the Communities That Care Youth Survey that distinguish youths at higher risk for involvement in problem behaviors from those at lower risk. Using these cut points, populations surveyed with this instrument can be described in terms of the proportions of youths experiencing risk and the proportions experiencing protection on each predictor. This facilitates communities' prioritization of specific factors for attention. This paper compares different cut points, and evaluates the discriminant validity of selected cut points. Results indicate that cut points with sufficient sensitivity and selectivity can be established for each of the scales, and that risk and protective factors can be profiled as prevalence rates. Implications of these findings for prevention planning are discussed.

Background: Graduates are becoming aware of the vast changes occurring in the health care and scientific environments, which will place unprecedented demands on them., A Second Revolution: It has been suggested that the Institute of Medicine reports To Err Is Human and Crossing the Quality Chasm have alerted healthcare professionals and managers to system defects, enlisted a broad array of stakeholders in the agenda, and accelerated changes in practice needed to eliminate errors and unnecessary deaths. It is now commonplace for comparative data on the effectiveness of hospitals and medical groups to be published in this new age of transparency. Coalitions of employers are now urging the adoption of safer practices in hospitals. In addition, the science of quality improvement has flourished and become robust., Coming Changes and Possibilities: The changes over the next five years will be breathtaking. Those doctors and hospitals with the best clinical outcomes will benefit from seeing more patients and may even be paid more by Medicare, Medicaid, and insurance companies. Patients will access, via the Web, the latest quality information and make more informed choices about where to seek their care. The environment in which care is provided is also undergoing a major transformation. Hospital buildings themselves are becoming more healing, safer places. Graduates may ask themselves, "Will my residency adequately prepare me to understand and apply the science of quality improvement and evidence-based practice?"

The survival characteristics of Escherichia coli O157:H7 in silage derived from contaminated grass were investigated. The survival of other enteric bacteria was also investigated to determine if E. coli O157:H7 demonstrates enhanced acid tolerance in comparison. Samples of chopped grass were treated as follows: (i) no additive (control); (ii) inoculation with E. coli O157:H7 to a final concentration of log10 4.0 CFU g(-1); (iii) addition of an 85% solution of formic acid at 3.0 ml kg(-1) grass; and (iv) addition of both E. coli O157:H7 and formic acid, at the above concentrations. Treated 6-kg grass samples were packed into laboratory silos, sealed, and stored at 15 degrees C for up to 180 days. Individual replicate silos were removed from storage periodically and subjected to microbiological and chemical analyses. Chemical analyses of the silage samples indicated that lactic acid-dominant fermentations, with a rapid drop in pH, occurred. Numbers of enteric bacteria decreased from log10 7.0 to 8.0 CFU g(-1) to undetectable levels within 19 days' storage. E. coli O157:H7 did not survive the silage fermentation process, with numbers declining from approximately log10 4.0 CFU g(-1) to undetectable levels within 19 days of ensiling. The pattern of decline in numbers of E. coli O157:H7 was the same as that for the enteric bacteria, indicating that under the conditions tested, the acid tolerance of E. coli O157:H7 was not significantly different from the acid tolerance of other enteric bacteria. This study found that E. coli O157:H7 did not survive a good silage fermentation process, indicating that properly ensiled grass that is correctly stored is unlikely to be a vector for the transmission of the pathogen among cattle.

Viral infection is one environmental factor that has been implicated as a precipitating event that may initiate beta-cell damage during the development of diabetes. This study examines the mechanisms by which the viral replicative intermediate, double-stranded (ds) RNA impairs beta-cell function and induces beta-cell death. The synthetic dsRNA molecule polyinosinic-polycytidylic acid (poly IC) stimulates beta-cell DNA damage and apoptosis without impairing islet secretory function. In contrast, the combination of poly IC and interferon (IFN)-gamma stimulates DNA damage, apoptosis, and necrosis of islet cells, and this damage is associated with the inhibition of glucose-stimulated insulin secretion. Nitric oxide mediates the inhibitory and destructive actions of poly IC + IFN-gamma on insulin secretion and islet cell necrosis. Inhibitors of nitric oxide synthase, aminoguanidine, and N(G)-monomethyl-L-arginine, attenuate poly IC + IFN-gamma-induced DNA damage to levels observed in response to poly IC alone, prevent islet cell necrosis, and prevent the inhibitory actions on glucose-stimulated insulin secretion. N(G)-monomethyl-L-arginine fails to prevent poly IC- and poly IC + IFN-gamma-induced islet cell apoptosis. PKR, the dsRNA-dependent protein kinase that mediates the antiviral response in infected cells, is required for poly IC- and poly IC + IFN-gamma-induced islet cell apoptosis, but not nitric oxide-mediated islet cell necrosis. Alone, poly IC fails to stimulate DNA damage in islets isolated from PKR-deficient mice; however, nitric oxide-dependent DNA damage induced by the combination of poly IC + IFN-gamma is not attenuated by the genetic absence of PKR. These findings indicate that dsRNA stimulates PKR-dependent islet cell apoptosis, an event that is associated with normal islet secretory function. In contrast, poly IC + IFN-gamma-induced inhibition of glucose-stimulated insulin secretion and islet cell necrosis are events that are mediated by islet production of nitric oxide. These findings suggest that at least one IFN-gamma-induced antiviral response (islet cell necrosis) is mediated through a PKR-independent pathway.

A study was conducted to test the hypothesis that repeated low level exposures to 1,3-butadiene (BD), approaching the OSHA occupational threshold for this chemical, produce a significant mutagenic response in mice. Female B6C3F1 mice (4-5 weeks of age) were exposed by inhalation for 2 weeks (6 h/day, 5 days/week) to 0 or 3 ppm BD, and then necropsied at 4 weeks after the cessation of exposures to measure the frequency of mutations (MF) at the Hprt locus using the T-lymphocyte clonal assay. At necropsy, T cells were isolated from spleen and cultured in the presence of mitogen, growth factors, and a selection agent. Cells were scored for growth on days 8-9 after plating to determine cloning efficiencies (CEs) and Hprt MFs. There was a marginal but significant reduction in the growth of splenic T cells from mice exposed to 3 ppm (n=27) compared with control mice (n=24) (P=0.004), suggesting the occurrence of BD-induced cytotoxicity at this low exposure concentration. In addition, the average Hprt MF in mice exposed to 3 ppm BD [1.54+/-0.82 (S.D.)x10(-6)] was significantly increased by 1.6-fold over the average control value of 0.96+/-0.51 (S.D.)x10(-6) (P=0.004). Comparisons of these data to earlier Hprt mutagenicity studies of mice exposed to high concentrations of BD (where significant mutagenic but not cytotoxic effects were observed) indicate that the ability to detect the cytotoxic and mutagenic responses of T cells to low levels of BD was enhanced by using a much larger sample size than usual for both the control and treatment groups. Additional analyses of the quantitative relationships between CE and MF demonstrated that CE had no significant effect upon MF values in sham-exposed control mice or mice exposed to low-level BD. Furthermore, the approaches for assessing the impact of CE and clonality on Hprt MFs in these control and BD-exposed mice were applied with the same rigor as in in vivo Hprt mutagenicity studies in human children. The overall study results support the conclusion that short-term low-level BD exposure is mutagenic in the mouse.