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SUMMARYThe introduction of a centralized system for recording cattle movements in the UK has provided a framework for network-based models for disease spread. However, there are many types of non-reportable contacts between farms which may play a role in disease spread. The lack of real pathogen data with which to test network models makes it difficult to assess whether reported data adequately captures the risk-potential network between farms and improves the accuracy of disease forecasts. A novel multi-disciplinary approach is described whereby network-based models, built upon reported cattle movements and non-reportable local contacts between study farms, are parameterized using field data on bovine Staphylococcus aureus strains. Reported cattle movements were found to play a role in strain spread between farms, but other contacts via farm visitors were also correlated with strain distribution, suggesting that parameterizing contact networks using cattle-tracing data alone may not adequately capture the disease dynamics. [ABSTRACT FROM AUTHOR]

Although studies of Ames and Snell dwarf mice have suggested possible important roles of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in aging and age-related diseases, the results cannot rule out the possibility of other hormonal changes playing an important role in the life extension exhibited by these dwarf mice. Therefore, growth hormone receptor/binding protein (GHR/BP) knockout (KO) mice would be valuable animals to directly assess the roles of somatotropic axis in aging and age-related diseases because the primary hormonal change is due to GH/IGF-1 deficiency. Our pathological findings showed GHR/BP KO mice to have a lower incidence and delayed occurrence of fatal neoplastic lesions compared with their wild-type littermates. These changes of fatal neoplasms are similar to the effects observed with calorie restriction and therefore could possibly be a major contributing factor to the extended life span observed in the GHR/BP KO mice. [ABSTRACT FROM AUTHOR]

Abstract Background There is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status. Methods Fresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune-compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serial in vivo generations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection. Results Fresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity. Conclusions The preservation of the patient’s tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology.

Abstract This review article focuses on the various aspects of translational research, where research on human subjects can ultimately enhance the diagnosis and treatment of future patients. While we will use specific examples relating to the asbestos related cancer mesothelioma, it should be stressed that the general approach outlined throughout this review is readily applicable to other diseases with an underlying molecular basis. Through the integration of molecular-based technologies, systematic tissue procurement and medical informatics, we now have the ability to identify clinically applicable "genotype"-"phenotype" associations across cohorts of patients that can rapidly be translated into useful diagnostic and treatment strategies. This review will touch on the various steps in the translational pipeline, and highlight some of the most essential elements as well as possible roadblocks that can impact success of the program. Critical issues with regard to Institutional Review Board (IRB) and Health Insurance Portability and Accountability Act (HIPAA) compliance, data standardization, sample procurement, quality control (QC), quality assurance (QA), data analysis, preclinical models and clinical trials are addressed. The various facets of the translational pipeline have been incorporated into a fully integrated computational system, appropriately named Dx2Tx. This system readily allows for the identification of new diagnostic tests, the discovery of biomarkers and drugable targets, and prediction of optimal treatments based upon the underlying molecular basis of the disease.

Background: Animals can act as a reservoir and source for the emergence of novel meticillin-resistant Staphylococcus aureus (MRSA) clones in human beings. Here, we report the discovery of a strain of S aureus (LGA251) isolated from bulk milk that was phenotypically resistant to meticillin but tested negative for the mecA gene and a preliminary investigation of the extent to which such strains are present in bovine and human populations.Methods: Isolates of bovine MRSA were obtained from the Veterinary Laboratories Agency in the UK, and isolates of human MRSA were obtained from diagnostic or reference laboratories (two in the UK and one in Denmark). From these collections, we searched for mecA PCR-negative bovine and human S aureus isolates showing phenotypic meticillin resistance. We used whole-genome sequencing to establish the genetic basis for the observed antibiotic resistance.Findings: A divergent mecA homologue (mecA(LGA251)) was discovered in the LGA251 genome located in a novel staphylococcal cassette chromosome mec element, designated type-XI SCCmec. The mecA(LGA251) was 70% identical to S aureus mecA homologues and was initially detected in 15 S aureus isolates from dairy cattle in England. These isolates were from three different multilocus sequence type lineages (CC130, CC705, and ST425); spa type t843 (associated with CC130) was identified in 60% of bovine isolates. When human mecA-negative MRSA isolates were tested, the mecA(LGA251) homologue was identified in 12 of 16 isolates from Scotland, 15 of 26 from England, and 24 of 32 from Denmark. As in cows, t843 was the most common spa type detected in human beings.Interpretation: Although routine culture and antimicrobial susceptibility testing will identify S aureus isolates with this novel mecA homologue as meticillin resistant, present confirmatory methods will not identify them as MRSA. New diagnostic guidelines for the detection of MRSA should consider the inclusion of tests for mecA(LGA251).Funding: Department for Environment, Food and Rural Affairs, Higher Education Funding Council for England, Isaac Newton Trust (University of Cambridge), and the Wellcome Trust. [ABSTRACT FROM AUTHOR]

Advanced manufacturing has received considerable attention as a tool for the fabrication of cell scaffolds however, finding ideal biocompatible and biodegradable materials that fit the correct parameters for 3D printing and guide cells to align remain a challenge. Herein, a photocrosslinkable smectic-A (Sm-A) liquid crystal elastomer (LCE) designed for 3D printing is presented, that promotes cell proliferation but most importantly induces cell anisotropy. The LCE-based bio-ink allows the 3D duplication of a highly complex brain structure generated from an animal model. Vascular tissue models are generated from fluorescently stained mouse tissue spatially imaged using confocal microscopy and subsequently processed to create a digital 3D model suitable for printing. The 3D structure is reproduced using a Digital Light Processing (DLP) stereolithography (SLA) desktop 3D printer. Synchrotron Small-Angle X-ray Diffraction (SAXD) data reveal a strong alignment of the LCE layering within the struts of the printed 3D scaffold. The resultant anisotropy of the LCE struts is then shown to direct cell growth. This study offers a simple approach to produce model tissues built within hours that promote cellular alignment., (© 2022 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.)

The COVID-19 pandemic has seen infectious disease modelling at the forefront of government decision-making. Models have been widely used throughout the pandemic to estimate pathogen spread and explore the potential impact of different intervention strategies. Infectious disease modellers and policymakers have worked effectively together, but there are many avenues for progress on this interface. In this paper, we identify and discuss seven broad challenges on the interaction of models and policy for pandemic control. We then conclude with suggestions and recommendations for the future., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: This study evaluated the real-world performance of six test systems for detection of SARS-CoV-2 in 138 pediatric and 110 adult maternal patients. Materials & methods: Nasopharyngeal swabs were tested directly using the Aptima™ SARS-CoV-2 (Aptima) and Simplexa™ COVID-19 Direct (Simplexa), and with Altona RealStar ® RT-PCR and CDC RT-PCR with nucleic acid extracted on the Roche ®  MagNA Pure 96 (Altona-MP96) or bioMérieux EMAG ® (Altona-EMAG). Results/Conclusion: Overall percent-positive and percent-negative agreements among the six test systems were, respectively: Aptima: 94.8 and 100%; Altona-MP96: 96.5 and 99.3%; CDC-MP96: 100 and 99.3%; Altona-EMAG: 86.1 and 100%; CDC-EMAG: 98.2 and 100%; Simplexa: 87 and 99.2%. The six test systems showed agreement ranging from 92.7 (κ = 0.85) to 98.8% (κ = 0.98)., Competing Interests: Financial & competing interests disclosure JJ Dunn has received consultant fees and honoraria from Diasorin Molecular, Inc. and Hologic, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No funded writing assistance was used in the creation of this manuscript., (© 2021 Future Medicine Ltd.)

Despite remarkable developments in healthcare, the world was not ready to stop the spread of the novel COVID-19 pandemic almost a century after the great influenza pandemic. The explosive increase in the number of patients stalled the healthcare system, and the first and apparent issue was the shortage of personal protective equipment (PPE). Our group established a system using a hydrogen peroxide vaporization method to decontaminate and reuse N95 respirators for healthcare workers. The system decontaminated over 12,000 units of PPE to cover institutions in West Texas. This service provided support at the most needed time during the pandemic., (© 2021 The Authors.)

Objective: Recognition and reporting of vector-borne and zoonotic disease (VBZD) cases is largely dependent upon the consideration of such diseases by healthcare practitioners during the initial diagnosis and ordering of specific confirmative diagnostic tests. This study was conducted to assess the general knowledge and understanding of VBZD transmission and clinical presentation., Methods: Healthcare practitioners were surveyed to determine the extent of training and educational experiences they received relative to VBZDs, and their likelihood to consider such diseases during differential diagnoses. In addition, an assessment of their knowledge of arthropod species that may transmit VBZD pathogens was conducted., Results: Having postprofessional school training relevant to VBZDs significantly influenced diagnostic accuracy for such disease cases based on the presented clinical signs and symptoms., Conclusions: The prevalence of VBZDs in the United States likely is significantly underestimated. The authors suggest the enhancement of VBZD-focused education as an important initiative that would significantly improve timely diagnosis, treatment, and, ultimately, prevention of these diseases.

Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.

Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases and assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient's bedside, it is becoming increasingly apparent that the mouse immune system is substantially different from the human. Indeed, it is well known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation, and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system to address important human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hematolymphoid cells in mice would provide investigators with a relatively inexpensive small animal model to study clinically relevant mechanisms and facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss the use of these unique mouse models to define the human-specific immunopathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation.

Multiyear molecular epidemiological surveillance of multidrug-resistant Pseudomonas aeruginosa (MRPA) in a pediatric cystic fibrosis care center identified an endemic MRPA strain (Houston-1). Recent hospitalization was found to be a statistically significant risk factor for acquisition of the endemic strain. Multiple infection control improvements led to the reduced incidence of the Houston-1 strain in the CF population.

Primary myelofibrosis is a chronic myeloproliferative neoplasm characterized by cytopenias, leukoerythroblastosis, extramedullary hematopoiesis, hepatosplenomegaly and bone marrow fibrosis. Primary myelofibrosis is a rare disorder in adults; children are even less commonly affected by this entity, with the largest pediatric case series reporting on three patients. Most literature suggests spontaneous resolution of myelofibrosis without long term complications in the majority of affected children. We describe the clinical, pathologic, and molecular characteristics and outcomes of nineteen children with primary myelofibrosis treated in our center from 1984 to 2011. Most patients had cytopenia significant enough to require supportive therapy. No child developed malignant transformation and only five of the 19 children (26%) had spontaneous resolution of disease. Sequence analyses for JAK2V617F and MPLW515L mutations were performed on bone marrow samples from 17 and six patients, respectively, and the results were negative. In conclusion, analysis of this large series of pediatric patients with primary myelofibrosis demonstrates distinct clinical, hematologic, bone marrow, and molecular features from adult patients., (Copyright © 2012 Wiley Periodicals, Inc.)

The introduction of a centralized system for recording cattle movements in the UK has provided a framework for network-based models for disease spread. However, there are many types of non-reportable contacts between farms which may play a role in disease spread. The lack of real pathogen data with which to test network models makes it difficult to assess whether reported data adequately captures the risk-potential network between farms and improves the accuracy of disease forecasts. A novel multi-disciplinary approach is described whereby network-based models, built upon reported cattle movements and non-reportable local contacts between study farms, are parameterized using field data on bovine Staphylococcus aureus strains. Reported cattle movements were found to play a role in strain spread between farms, but other contacts via farm visitors were also correlated with strain distribution, suggesting that parameterizing contact networks using cattle-tracing data alone may not adequately capture the disease dynamics.

We examined the effects of increased levels of thioredoxin 1 (Trx1) on resistance to oxidative stress and aging in transgenic mice overexpressing Trx1 [Tg(TRX1)(+/0)]. The Tg(TRX1)(+/0) mice showed significantly higher Trx1 protein levels in all the tissues examined compared with the wild-type littermates. Oxidative damage to proteins and levels of lipid peroxidation were significantly lower in the livers of Tg(TRX1)(+/0) mice compared with wild-type littermates. The survival study demonstrated that male Tg(TRX1)(+/0) mice significantly extended the earlier part of life span compared with wild-type littermates, but no significant life extension was observed in females. Neither male nor female Tg(TRX1)(+/0) mice showed changes in maximum life span. Our findings suggested that the increased levels of Trx1 in the Tg(TRX1)(+/0) mice were correlated to increased resistance to oxidative stress, which could be beneficial in the earlier part of life span but not the maximum life span in the C57BL/6 mice.

A postal survey of all registered cattle and sheep farmers in East Anglia was carried out from July 2008 to determine bluetongue virus serotype 8 (BTV-8) vaccine uptake in the region. The vaccine was available to farmers in this region from May 2008. The survey was repeated in Cumbria and Northumberland at the beginning of 2009. In these regions, the vaccine was not available until September 1, 2008. Holding-level vaccine uptake was estimated to be 85 per cent (95 per cent confidence interval [CI] 83 to 87 per cent, n=1623) in East Anglia and 36 per cent (95 per cent CI 32 to 40 per cent, n=633) in northern England. A telephone follow-up of non-responders reduced these estimates to 79 and 29 per cent in East Anglia and northern England, respectively. In both regions, vaccine coverage was higher in sheep than in cattle, with 92 per cent of sheep in East Anglia having been vaccinated. The proportion of holdings that had applied the vaccine or were intending to apply the vaccine in 2009 in the northern region was 51 per cent (95 per cent CI 47 to 54 per cent, n=664), with a further 37 per cent undecided at the time of response.

Clostridium difficile is a major cause of nosocomial antibiotic-associated infectious diarrhea and pseudomembranous colitis. Detection of C. difficile by anaerobic bacterial culture and/or cytotoxicity assays has been largely replaced by rapid enzyme immunoassays (EIA). However, due to the lack of sensitivity of stool EIA, we developed a multiplex real-time PCR assay targeting the C. difficile toxin genes tcdA and tcdB. Stool samples from hospitalized pediatric patients suspected of having C. difficile-associated disease were prospectively cultured on cycloserine-cefoxitin-fructose agar following alcohol shock. Six testing modalities were evaluated, including stool EIA, culture EIA, and real-time PCR (tcdA and tcdB) of cultured isolates and stool samples. Real-time PCR detection was performed with tcdA and tcdB gene-specific primers and hydrolysis probes using the LightCycler platforms (Roche Diagnostics, Indianapolis, IN). A total of 157 samples from 96 pediatric patients were analyzed. The sensitivities of stool real-time PCR and stool EIA were 95% and 35%, respectively, with a specificity of 100% for both methods. The lower limit of detection of the stool real-time PCR was 30 CFU/ml of stool sample per reaction for tcdA and tcdB. This study highlights the poor performance of stool toxin EIAs in pediatric settings. Direct detection of C. difficile toxin genes in stool samples by real-time PCR showed sensitivity superior to that of stool and culture EIAs and performance comparable to that of real-time PCR assay of cultured isolates. Real-time PCR of DNA from stool samples is a rapid and cost-effective diagnostic modality for children that should facilitate appropriate patient management and halt the practice of serial testing by EIA.

The British Cattle Movement Service (BCMS) database contains an unprecedented quantity of data on the movement of cattle within the UK. These data may be used to construct models of the contact structure of the UK cattle herd, for epidemiological purposes. There are two significant potential sources of inaccuracy within such models: movements that are not reported or are reported inaccurately to the BCMS, and contacts between farms that might transmit infection, but are not animal movements. This field study addressed these issues. Cattle farmers on the Isle of Lewis were recruited with the assistance of the local veterinary surgeon, and asked to record a range of potential risk behaviours for a one-month period. They were also asked questions about husbandry practices on their farm. Comparison of the BCMS contact data with that reported by Lewis' farmers highlighted use of common grazing land as a significant source of contact, and potential disease transmission, between cattle that currently goes unreported; around half of responding holdings on Lewis use common grazing land at some point during the year, and these movements are not reported to the BCMS.

Purpose: Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O(6)-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:C-->A:T) transition mutations in KRAS and P53, and silencing of hMLH1 leads to high levels of microsatellite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist., Experimental Design: We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1, P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas., Results: We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in non-MSI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002)., Conclusions: Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors.

Background: The implementation of national systems for recording the movements of cattle between agricultural holdings in the UK has enabled the development and parameterisation of network-based models for disease spread. These data can be used to form a network in which each cattle-holding location is represented by a single node and links between nodes are formed if there is a movement of cattle between them in the time period selected. However, this approach loses information on the time sequence of events thus reducing the accuracy of model predictions. In this paper, we propose an alternative way of structuring the data which retains information on the sequence of events but which still enables analysis of the structure of the network. The fundamental feature of this network is that nodes are not individual cattle-holding locations but are instead direct movements between pairs of locations. Links are made between nodes when the second node is a subsequent movement from the location that received the first movement., Results: Two networks are constructed assuming (i) a 7-day and (ii) a 14-day infectious period using British Cattle Movement Service (BCMS) data from 2004 and 2005. During this time period there were 4,183,670 movements that could be derived from the database. In both networks over 98% of the connected nodes formed a single giant weak component. Degree distributions show scale-free behaviour over a limited range only, due to the heterogeneity of locations: farms, markets, shows, abattoirs. Simulation of the spread of disease across the networks demonstrates that this approach to restructuring the data enables efficient comparison of the impact of transmission rates on disease spread., Conclusion: The redefinition of what constitutes a node has provided a means to simulate disease spread using all the information available in the BCMS database whilst providing a network that can be described analytically. This will enable the construction of generic networks with similar properties with which to assess the impact of small changes in network structure on disease dynamics.

The mitochondrial form of thioredoxin, thioredoxin 2 (Txn2), plays an important role in redox control and protection against ROS-induced mitochondrial damage. To evaluate the effect of reduced levels of Txn2 in vivo, we measured oxidative damage and mitochondrial function using mice heterozygous for the Txn2 gene (Txn2(+/-)). The Txn2(+/-) mice showed approximately 50% decrease in Trx-2 protein expression in all tissues without upregulating the other major components of the antioxidant defense system. Reduced levels of Txn2 resulted in decreased mitochondrial function as shown by reduced ATP production by isolated mitochondria and reduced activity of electron transport chain complexes (ETCs). Mitochondria isolated from Txn2(+/-) mice also showed increased ROS production compared to wild type mice. The Txn2(+/-) mice showed increased oxidative damage to nuclear DNA, lipids, and proteins in liver. In addition, we observed an increase in apoptosis in liver from Txn2(+/-) mice compared with wild type mice after diquat treatment. Our results suggest that Txn2 plays an important role in protecting the mitochondria against oxidative stress and in sensitizing the cells to ROS-induced apoptosis.

This study examines the knowledge, attitudes, and beliefs of African-American men and their female significant others regarding prostate cancer screening. Study flyers and a television interview were used to recruit participants into the study that took place in Harrisburg, Pennsylvania. Six focus groups were conducted: four with African-American men and two with female significant others. A total of 32 people participated in the study. The groups expressed multiple apprehensions toward prostate cancer screening, including feelings of vulnerability, compromised manhood, and discomfort. They also shared motivators for screening, including female significant others, physician recommendation, early education, and church influence.

Variations in genetic mutations in pancreatic carcinoma between different populations have not been studied extensively, especially in developing countries where pancreatic cancer is rare. We studied the molecular pathology of 44 pancreatic carcinomas from patients residing in a heavily polluted region in the Nile River delta and compared the findings with tumors from 44 United States (US) patients. We evaluated K-ras mutations in codon 12, p53 mutations in exons 5-8, and Gadd45a mutations in exons 1 and 4. Overall, rates of K-ras, p53 and Gadd45 mutations were not statistically different in tumors of patients from Egypt and the US (67.4 vs. 63.4%; 27.3 vs. 36.4% and 9.1 vs. 4.5%, respectively). However, there were distinct differences in the specific types of K-ras and p53 mutations between the 2 groups. In K-ras, G --> T transversion mutation was more frequent in the tumors from Egypt than from the US (58.6 vs. 26.9%), whereas G --> C transversion was detected in 26.9% of US tumors but none from Egypt (p = 0.003). We also found a trend toward differences in the p53 exons in which mutations occurred, with higher frequency of exon 5 mutation and lower frequency of exon 6 mutation in Egyptian tumors. Logistic regression showed that K-ras G --> T transversion mutations and p53 exon 6 mutations were predicted by the country of residence of the patients. Our study identifies that there are differences in the types of mutations found in tumors from pancreatic carcinoma patients in Egypt and the US, and suggests that environmental factors may explain these differences.

In colorectal tumorigenesis, Ki-ras proto-oncogene mutation often occurs early in the adenoma-adenocarcinoma sequence, whereas mutation of the p53 gene is associated with late progression to carcinoma. We evaluated the relationship of demographic and clinicopathologic characteristics to Ki-ras mutation and p53 gene product overexpression in 1,093 baseline sporadic colorectal adenomas from 926 individuals enrolled in a phase III recurrence prevention trial. Ki-ras mutation was found in 14.7% of individuals and p53 overexpression was found in 7.0% of those tested. Multivariate analysis found older age, rectal location, and villous histology to be independently associated with Ki-ras mutation. Individuals with an advanced adenoma (>or=1 cm or high-grade dysplasia or villous histology) had a 4-fold higher likelihood of Ki-ras mutation [odds ratios (OR), 3.96; 95% confidence intervals (CI), 2.54-6.18]. Ki-ras mutations in codon 12 and of the G-to-A transition type were more frequent in older individuals, whereas G-to-T transversion was more frequent in rectal adenomas than in the colon. Multivariate analysis showed that previous history of a polyp (P = 0.03) was inversely associated with p53 overexpression. Large adenoma size (>or=1 cm), high-grade dysplasia, and villous histology were independently associated with p53 overexpression, with the strongest association for advanced adenomas (OR, 7.20; 95% CI, 3.01-17.22). Individuals with a Ki-ras mutated adenoma were more likely to overexpress p53 (OR, 2.46; 95% CI, 1.36-4.46), and 94.8% of adenomas with both alterations were classified as advanced (P

Rodent models are an invaluable resource for studying the mechanism of mammalian aging. In recent years, the availability of transgenic and knockout mouse models has facilitated the study of potential mechanisms of aging. Since 1996, aging studies with several long-lived mutant mice have been conducted. Studies with the long-lived mutant mice, Ames and Snell dwarf, and growth hormone receptor/binding protein knockout mice, are currently providing important clues regarding the role of the growth hormone/insulin like growth factor-1 axis in the aging process. Interestingly, these studies demonstrate that these long-lived mutant mice have physiological characteristics that are similar to the effects of calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, a question remains to be answered: do these long-lived mutant and calorie-restricted mice extend their lifespan through a common underlying mechanism?

Because of the risk to public health posed by the potential presence of bovine spongiform encephalopathy (BSE) in sheep, there are plans to eradicate transmissible spongiform encephalopathies (TSEs) from the British sheep population. We used a mathematical model for the spread of scrapie between sheep flocks to assess the efficacy of five control strategies at eradicating the infection from the national flock. These range from ram-genotyping schemes through whole-flock genotyping with selective culling to whole-flock slaughter. The impact of control was considered under three scenarios for the long-term dynamics of scrapie in GB: two in which scrapie is ultimately eliminated (with different median extinction times) and one in which scrapie remains endemic. Results suggested that it is feasible to eradicate scrapie from the British sheep flock, but that any national control programme will take decades to eliminate the disease and be costly. The most-effective strategy, measured in terms of the probability of eradication and time taken for eradication, was predicted to be whole-flock culling, which was effective under all three scenarios for the long-term dynamics of scrapie. Strategies involving whole-flock genotyping with selective culling were also effective, though they were predicted to take longer to eradicate scrapie than whole-flock culling. Ram-genotyping schemes were effective in some instances, but not for the scenario where scrapie remained endemic in the national flock. At low levels of reporting of clinical disease (< 20%) the probability of eradication within 100 years was predicted to be < 100% and, consequently, low levels of reporting could compromise the effectiveness of a control programme. Moreover, the predicted time taken to eradicate scrapie would increase markedly if the reporting compliance decreased.

The spatial and temporal dynamics of many farm animal diseases depend both on disease specific parameters and on the underlying contact structure between farms. Whilst many models for farm animal diseases focus on obtaining and estimating disease transmission parameters, relatively little attention has been given to modelling the underlying network of contacts. In this paper, we present an initial analysis of two relations underlying the contact network of individual sheep breeds in Great Britain. The first relation is based on geographical proximity and the second is based on attendance at agricultural shows. These relations are combined to give a risk-potential network that is based on these two levels of interaction. The structure of each network is investigated using techniques developed in graph theory and social network analysis.

Our aim was to compare the efficiency of different surveillance strategies for detecting scrapie-infected sheep flocks in the Norwegian population using simulation modelling. The dynamic Monte Carlo simulation model has the flock as the unit. The input parameters include properties of the sheep population (number of flocks, flock size, age distribution, reasons for culling, breeds, prion protein-allele distribution); properties of scrapie (genotype-dependent infection rate and incubation periods, and age- and genotype-dependent prevalence of scrapie); properties of the surveillance strategy (selection of sheep for examination, period in which infected sheep are detectable, and properties of the diagnostic tests). For simplification, the prion protein-alleles were grouped into three allele groups: VRQ, ARR, and ARQ' (ARQ' represents ARQ, ARH and AHQ). Through either abattoir surveillance or surveillance of fallen stock, 70% of the detected sheep (compared to 33% in the underlying population). The model output was sensitive to the susceptibility of infection for the genotype ARQ'/ARQ'. The effect was large for abattoir surveillance (increased susceptibility increased the efficiency of abattoir surveillance).

An accurate estimate of the prevalence of scrapie infection in the Great Britain (GB) sheep flock is essential when assessing any potential risk to human health through exposure to sheep transmissible spongiform encephalopathies (TSEs). One method for assessing the prevalence is to sample sheep intended for human consumption using a diagnostic test capable of detecting infected animals prior to the onset of clinical signs. An abattoir survey conducted in Great Britain in 1997-1998 tested brain samples from 2809 apparently healthy sheep of which none was found to be positive for scrapie by histopathology or immunohistochemistry (IHC) although 10 were positive for scrapie-associated fibrils (SAF). Subsequently, the tonsils from a subset of the animals sampled were examined using IHC, one of which tested positive. To interpret these results we use a likelihood-based approach, which accounts for the variation in the prevalence of infection with age and test sensitivity and specificity with stage of infection. Combining the results for all of the diagnostic tests yields an estimate of the prevalence of scrapie infection in the GB sheep flock of 0.22% (95% confidence interval: 0.01-0.97%). Moreover, our analysis suggests that all of the diagnostic tests used are very specific (greater than 99%). Indeed, only SAF detection yields a specificity estimate of less than 100%, which helps to account for the high number of samples found to be positive for SAF.

Susceptibility to clinical scrapie is associated with polymorphisms in the PrP gene. The 'ARR' allele of this gene reduces susceptibility to clinical disease caused by all known strains of the transmissible spongiform encephalopathy (TSE) agent. The British government proposes to use a ram-genotyping scheme to breed genetic resistance to clinical scrapie into the national sheep population. We considered how best to target limited genotyping resources to achieve the maximum rate of genotype evolution. We created a metapopulation model of the British sheep industry, which includes the major pure-breeds of sheep and the cross-breeds produced by crossing these pure-bred animals. The main criterion for assessing the efficacy of different strategies was the time taken to increase the prevalence of the ARR allele in the slaughter-lamb population. Our model predicted that the most-effective strategy would be to target genotyping to those rams used for pure-breeding (i.e. mated with the same breed of ewe). This strategy was compared to two further strategies, in which the proportion of rams genotyped in each breed depended on the prevalence of the ARR/ARR genotype in that breed. A policy in which the proportion of animals genotyped is reduced as the ARR prevalence in that breed increases is efficient. The most-effective policy was targeting the hill sector in the early years and gradually switching to genotyping more terminal-sire and longwool rams as the resistance of the hill sector increases., (Crown Copyright 2002 Published by Elsevier Science B.V.)

In 1997/1998, an abattoir survey was conducted to determine the likely exposure of the human population to transmissible spongiform encephalopathy (TSE) infection in sheep submitted for slaughter in Great Britain. The survey examined brain material from 2809 sheep processed through British abattoirs. Sampling was targeted by age: 45% of animals tested were > or =15 months old. All samples of adequate quality (98%) were tested for signs of scrapie infection using histopathology and scrapie-associated fibril (SAF) detection and 500 were tested using immunohistochemistry (IHC). No conclusive positive animals were found using either histology or IHC. Ten animals were positive by SAF. Standard statistical analyses suggest (with 95% confidence) that the prevalence of detectable (by histopathology) infection in the slaughter population was < or =0.11%. However, the incubation period of scrapie is long (usually around 2-3 years) and none of the tests used in the survey is capable of detecting scrapie infection in the early stages of infection. We present an age-structured stochastic model incorporating parameters for the incubation period of scrapie, prevalence of infection by age and test sensitivity. Using the model, we demonstrate that the negative results obtained for all samples using IHC and histopathology are consistent with a true prevalence of infection in the slaughter population of up to 11%. This suggests that up to 300 of the animals tested might have been infected but the infection was not sufficiently advanced in these animals to be detectable by IHC or histopathology. The survey was designed to detect a prevalence of 1% with a precision of +/-0.5% and a confidence level of 95% in each age group assuming that diagnostic tests were 100% specific and sensitive from a known stage in the incubation period. The results of the model demonstrate that to estimate a true prevalence of scrapie infection of 1% with an accuracy of +/-0.5% would have required a far larger sample size. An accurate estimate of the required sample size is complicated by uncertainty about test sensitivity and the underlying infection dynamics of scrapie. A pre-requisite for any future abattoir survey is validation of the diagnostic tests used in relation to both stage of incubation and genotype. Sampling in the <15-month age group was of no value in this survey because the diagnostic tests used were thought to be ineffective in most of the animals in this age group.

A randomised sample of 2,809 apparently healthy sheep, 55 per cent of them less than 15 months of age, which were slaughtered for human consumption at abattoirs in Great Britain in 1997/98, was taken to establish the prevalence of scrapie infection. The medulla oblongata of each sheep was examined histopathologically at the level of the obex, and fresh brain tissue was examined for scrapie-associated fibrils (SAF) to establish whether there was evidence of scrapie. In addition, histological sections of the medulla from 500 of the sheep were immunostained with an antiserum to PrP, and the same technique was also applied to any animal found positive or inconclusive by the histological or SAF examinations. Any sheep which was positive by any of these diagnostic methods was also examined by Western immunoblotting, for the detection of the disease-specific protein PrP(Sc). A total of 2,798 sheep (99.6 per cent) were negative by all the methods applied. Ten animals were SAF-positive but negative by all the other methods, and in one animal there was immunohistochemical staining which could not be interpreted unequivocally as disease-specific. A mathematical model was used to estimate the prevalence of scrapie infection in the national slaughtered sheep population which would be consistent with these results. By this model, the absence of unequivocally substantiated cases of scrapie in the sample was consistent with a prevalence of infection in the slaughter population of up to 11 per cent.

Models of particular epidemiological systems can rapidly become complicated by biological detail which can obscure their essential features and behaviour. In general, we wish to retain only those components and processes that contribute to the dynamics of the system. In this paper, we apply asymptotic techniques to an SEI-type model with primary and secondary infection in order to reduce it to a much simpler form. This allows the identification of parameter groupings discriminating between regions of contrasting dynamics and leads to simple approximations for the model's transient behaviour. These can be used to follow the evolution of the developing infection process. The techniques examined in this paper will be applicable to a large number of similar models.

Objective: The requirement for permanent pacemaker implantation after most initial cardiac surgical procedures generally is less than 3%. To identify the incidence and factors related to permanent pacemaker need after repeat cardiac surgery, we retrospectively studied 558 consecutive patients undergoing at least one repeat cardiac operation., Method: Univariable and multivariable analyses of comorbidity, preoperative catheterization values, and operative data were performed to identify factors related to pacemaker implantation., Results: In this group, 54 patients (9.7%) required a permanent pacemaker. A multivariable model showed a relationship between a permanent pacemaker and tricuspid valve replacement/annuloplasty associated with aortic/mitral valve replacement, preoperative endocarditis, increasing number of reoperations, the degree of hypothermia during cardiopulmonary bypass, and advanced age. Additional univariable predictors of pacemaker need included multiple valve replacement, increased cardiopulmonary bypass and aortic crossclamp times, and aortic valve replacement. Over 90% of patients who have or have not received permanent pacemaker implantation were in New York Heart Association class I to II, with a mean follow-up time of 6 years. Kaplan-Meier survival curves were statistically similar for both groups at 5 and 10 years after the operation., Conclusion: Permanent pacemaker implantation was required in 9.7% of patients undergoing repeat cardiac surgery. This represented approximately a fourfold increase compared with similar primary operations reported in other series. Factors strongly related to this need included valve replacement, preoperative endocarditis, number of reoperations, advanced age, and degree of hypothermia during cardiopulmonary bypass. The need for a permanent pacemaker after reoperations did not result in significant long-term impairment of functional status or longevity compared with those who did not require a permanent pacemaker.

Background: Atrial fibrillation (AF) after coronary bypass graft surgery may result in hypotension, heart failure symptoms, embolic complications, and prolongation in length of hospital stay (LOHS). The purpose of this study was to determine whether intravenous diltiazem is more effective than digoxin for ventricular rate control in AF after coronary artery bypass graft surgery. A secondary end point was to determine whether ventricular rate control with diltiazem reduces postoperative LOHS compared with digoxin., Methods and Results: Patients with AF and ventricular rate > 100 beats/min within 7 days after coronary artery bypass graft surgery were randomly assigned to receive intravenous therapy with diltiazem (n = 20) or digoxin (n = 20). Efficacy was measured with ambulatory electrocardiography (Holter monitoring). Safety was assessed by clinical monitoring and electrocardiographic recording. LOHS was measured from the day of surgery. Data were analyzed with the intention-to-treat principle in all randomly assigned patients. In addition, a separate intention-to-treat analysis was performed excluding patients who spontaneously converted to sinus rhythm. In the analysis of all randomly assigned patients, those who received diltiazem achieved ventricular rate control (> or = 20% decrease in pretreatment ventricular rate) in a mean of 10 +/- 20 (median 2) minutes compared with 352 +/- 312 (median 228) minutes for patients who received digoxin (p < 0.0001). At 2 hours, the proportion of patients who achieved rate control was significantly higher in patients treated with diltiazem (75% vs 35%, p = 0.03). Similarly, at 6 hours, the response rate associated with diltiazem was higher than that in the digoxin group (85% vs 45%, p = 0.02). However, response rates associated with diltiazem and digoxin at 12 and 24 hours were not significantly different. At 24 hours, conversion to sinus rhythm had occurred in 11 of 20 (55%) patients receiving diltiazem and 13 of 20 (65%) patients receiving digoxin (p = 0.75). Results of the analysis of only those patients who remained in AF were similar to those presented above. There was no difference between the diltiazem-treated and digoxin-treated groups in postoperative LOHS (8.6 +/- 2.2 vs 7.7 +/- 2.0 days, respectively, p = 0.43)., Conclusions: Ventricular rate control occurs more rapidly with intravenous diltiazem than digoxin in AF after coronary artery bypass graft surgery. However, 12- and 24-hour response rates and duration of postoperative hospital stay associated with the two drugs are similar.

Kinins acting on the B2 receptor appear to be involved in the cardioprotective effect of preconditioning on myocardial ischemia/reperfusion injury. We tested the hypothesis that in mice lacking the gene encoding for the B2 kinin receptor (B2 knockout mice; B2-KO) as well as in rats deficient in high-molecular-weight (HMW) kininogen (Brown Norway Katholiek rats; BNK), the cardioprotective effect of preconditioning is diminished or abolished. 129SvEvTac (SV129) mice and Brown Norway rats (BN) served as controls. We confirmed that plasma HMW kininogen in BNK rats was 100-fold lower than in BN and 140-fold lower than in Sprague-Dawley rats (33+/-4 versus 1814+/-253 and 2397+/-302 ng/mL, P<.01). Each strain of mice was divided into (1) controls (without preconditioning); (2) one cycle of preconditioning (3 minutes ligation and 5 minutes reperfusion); and (3) three cycles of preconditioning. Each strain of rats was divided into (1) controls; and (2) three cycles of preconditioning. All animals were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In SV129 controls, the ratio of infarct size to risk area (IS/AR) was 55.6+/-4.6%. One and three cycles of preconditioning reduced IS/AR to 38.6+/-3.2% and 31.1+/-2.3%, respectively (P<.05 and P<.01 versus control). This protective effect was absent in B2-KO mice: IS/AR was 54.8+/-2.9% in controls, 58.5+/-3.6% with one cycle of preconditioning, and 58.5+/-3.4% with three cycles. In BN rats without preconditioning, IS/AR was 84.7+/-3.9%; preconditioning reduced it to 61.6+/-3.4% (P<.01). In BNK rats, IS/AR was 87.1+/-4.8% in controls and 84.3+/-4.1% with preconditioning. Preconditioning also prevented reperfusion arrhythmias in BN but not BNK rats. Within species, risk area, mean blood pressure, and heart rate were similar between strains. We concluded that (1) preconditioning protects the heart against ischemia/reperfusion injury in mice and rats; (2) activation of prekallikrein, which in turn generates kinins from HMW kininogen, may contribute to the effect of preconditioning; and (3) an intact kallikrein-kinin system is necessary for the cardioprotective effect of preconditioning.

We determined the effect of cocaine on ventricular vulnerability to fibrillation, as measured by ventricular fibrillation threshold (VFT), and cardiac electrophysiology in 20 anesthetized dogs with normal hearts. Animals were randomized in blinded fashion to receive a continuous 3-hour infusion of cocaine 0.11 mg/kg/minute (total dose 20 mg/kg) or placebo (lactose dissolved in normal saline). The VFT, systolic and diastolic blood pressures, ventricular effective refractory period (ERP), and electrocardiographic intervals were measured at baseline and every 30 minutes during infusion. Baseline mean +/- SE VFT in cocaine and placebo groups was 57.0 +/- 7.8 and 51.8 +/- 7.6 mA, respectively (p = 0.64). Cocaine did not significantly decrease VFT, but actually increased it (i.e., reduced ventricular vulnerability to fibrillation) compared with placebo (84.6 +/- 10.4 vs 55.8 +/- 7.2 mA, respectively, at 150 minutes, p = 0.04). Cocaine prolonged ERP and PR, QRS, QT, QTc, JT, and JTc intervals. Cocaine does not increase ventricular vulnerability to fibrillation in anesthetized dogs with normal intact hearts. Its electrophysiologic effects are similar to those of class I antiarrhythmic agents in this model.

To determine and describe relationships between plasma cocaine concentrations and electrophysiologic and electrocardiographic effects, 10 anesthetized dogs with normal intact hearts received a continuous 3-hour infusion of cocaine 0.11 mg/kg/minute (total dose 20 mg/kg). Data were collected as part of a randomized, blinded, placebo-controlled study investigating the effects of cocaine on ventricular fibrillation threshold. Every 30 minutes during infusion of cocaine or placebo and for 3 hours after discontinuation of the infusion, heart rate and mean arterial pressure were determined, effective refractory period (ERP) was measured, and QRS duration and PR, QTc, and JTc intervals were recorded. At the time of each 30-minute measurement, arterial blood was obtained to determine plasma cocaine concentrations. Hysteresis curves were observed for cocaine-induced increases in ERP and PR interval. The effects of cocaine on QRS duration and QTc and JTc intervals were not well described by tested models. Pharmacodynamic modeling techniques may be used to describe relationships between plasma cocaine concentrations and specific cardiovascular effects of cocaine. Further study is required to determine applicability of this model for prediction of cocaine's cardiovascular effects in humans.

Study Objective: To determine whether breathing a blend of 70% helium:30% oxygen (heliox) would improve pulmonary function, decrease clinical score, and improve the sensation of dyspnea in children hospitalized with acute severe asthma., Design: Prospective, randomized, double-blind, crossover study., Setting: The inpatient pediatric service of a military, tertiary care, teaching hospital., Patients: Children 5 to 18 years who required hospital admission for treatment of acute asthma., Interventions: All patients received 5 mg of nebulized albuterol every 1 to 4 h, with a dose given within 30 min of the start of the study, and IV administered methylprednisolone. Patients breathed heliox and a 30% oxygen-enriched air mixture for 15 min each in random order., Measurements and Results: Clinical score, dyspnea score, oxygen saturation, heart rate, and respiratory rate, followed by FVC, FEV1, peak expiratory flow rate (PEFR), and, mean midexpiratory flow rate (FEF25-75) were obtained at study entry, 15 min after breathing the first gas mixture (heliox or air per randomization), 15 min after breathing the second mixture, and again 15 min after stopping the second gas mixture (study end values). Eleven children were enrolled, and all completed the study. There were no significant differences between study entry and study end spirometric values. Using the paired t test, we found no significant differences between mean values (SD) of FEV1 and FVC obtained while breathing heliox vs air; FEV1-heliox, 53% (18%) of the predicted value; FEV1-air, 52% (16%) of the predicted value (p = 0.36); FVC-heliox, 69% (22%) of the predicted value; and FVC-air, 70% (21%) of the predicted value (p = 0.50). The differences in values for PEFSR and FEF25-75 while breathing heliox vs air were small but did reach statistical significance in favor of heliox: PEFR-heliox, 56% (20%) of the predicted value; PEFR-air, 50% (16%) of the predicted value (p = 0.04); FEF25-75-heliox, 32% (13%) of the predicted value; and FEF25-75-heliox, 29% (11%) of the predicted value (p = 0.006). Heliox had no effect on either clinical or dyspnea scores., Conclusion: The short-term inhalation of heliox did not benefit this group of children hospitalized with acute, severe asthma.

Dosage reduction of procainamide has been recommended in patients with congestive heart failure (CHF). However, these recommendations are based primarily on studies with unmatched control groups, suboptimal blood sampling, and in patients not receiving angiotensin-converting enzyme (ACE) inhibitors. These agents increase renal blood flow, which theoretically may offset alterations in drug disposition in patients with CHF. The pharmacokinetics of procainamide in patients with chronic CHF and in matched controls were compared. A single intravenous dose of 750 mg of procainamide was administered to 9 patients with chronic New York Heart Association (NYHA) class II or III CHF (mean +/- SD left ventricular ejection fraction 22 +/- 9%) receiving medical therapy and 7 control subjects matched for age and gender. Blood and urine samples were collected at intervals over a period of 48 and 72 hours, respectively. Patients with CHF and control subjects were demographically similar, with the exception of concomitant medications, including ACE inhibitors (8/9 versus 1/7, respectively). There were no significant differences between patients with CHF and control subjects in mean +/- SD peak serum concentrations (Cmax), area under the serum concentration-time curve (AUC0-infinity), total clearance, renal clearance, half-life (t1/2), or volume of distribution (Vd) of procainamide. Similarly, there were no significant differences between patients with CHF and control subjects in the mean +/- SD Cmax, AUC0-infinity, renal clearance, or t1/2 of N-acetylprocainamide (NAPA). Procainamide dosage reduction may not be necessary in patients with chronic stable CHF who are receiving medical therapy.

Objective: To model the complex effects of demographic, psychosocial, physical, and rehabilitation variables on quality of life 2 years after hospital discharge., Design: Medical record and longitudinal survey data on traumatic brain injury (TBI) survivors who did or did not receive formal rehabilitation services after being injured were analyzed., Setting: The study sample was selected from a representative sample of hospitals in north-central Alabama., Participants: Criteria for inclusion were: (1) 18 years and older with TBI; (2) discharged after hospital stay of 3 or more days; and (3) resided and injured in Alabama. There were 293 persons eligible for the 24-month follow-up survey, 186 (63%) of whom participated; the focus was on the 116 persons (of 186) who responded to the surveys themselves., Main Outcome Measure: A causal model of hypothesized direct and indirect effects of several variables on quality of life outcomes., Results: Employment was the strongest contributor of improved quality of life. Persons unable to pay for health care showed less improvement in functional independence 12 to 24 months postinjury and reported a poorer quality of life. The psychosocial variables of self-blame and family support improved quality of life by reducing impairments and increasing the likelihood of employment. Family support also improved quality of life by increasing functional independence. Fewer physical impairments and gains in functional independence directly improved quality of life., Conclusion: The interrelationships between psychosocial and physical variables are important when examining quality of life. Interventions are recommended targeting psychosocial variables and functional independence in efforts to improve quality of life.

Intravenous inotropic agents promote increased myocardial contractility via elevation of myocyte calcium concentrations, a mechanism that is also known to promote the development of cardiac arrhythmias. The purpose of this article is to review the electrophysiologic effects and relative potential for proarrhythmia associated with dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone. Dobutamine increases sinoatrial node automaticity and decreases atrial and atrioventricular (AV) node refractoriness and AV nodal conduction time. The drug also decreases ventricular refractoriness in both healthy and ischemic myocardium. Dobutamine has been shown to increase heart rate in a dose-related fashion in animals and in humans. In humans, dobutamine has been reported to induce ventricular ectopic activity (VEA) in 3% to 15% of patients, although VEAs are often asymptomatic, requiring no intervention. Ventricular tachycardia (VT) associated with dobutamine appears to occur rarely. Patients with underlying arrhythmias or heart failure or those receiving excessive doses of dobutamine are at greatest risk for proarrhythmia. Dopamine increases automaticity in Purkinje fibers and has a biphasic effect on action potential duration. Dopamine has been reported to induce atrial or ventricular arrhythmias in animals. In humans, dopamine may be associated with dose-related sinus tachycardia but has also been reported to cause VEA, which is usually asymptomatic. Dopamine-associated VT appears to occur rarely. Dopamine produces greater elevations in heart rate or frequency of ventricular premature beats at a given value of cardiac index than does dobutamine. The phosphodiesterase inhibitors amrinone and milrinone increase conduction through the AV node and decrease atrial refractoriness. Intravenous administration of these drugs may result in sinus tachycardia in some patients and has been reported to cause VEA, which is often asymptomatic, in up to 17% of patients. VT has also been reported in association with short-term use of intravenous phosphodiesterase inhibitors. In summary, intravenous inotropic agents may be associated with proarrhythmic effects in some patients. The primary arrhythmias reported are sinus tachycardia and VEA, although other supraventricular or ventricular arrhythmias have been reported less commonly. However, clinically significant proarrhythmic effects associated with these agents appear to occur rarely, and, at conventional doses, intravenous inotropic agents are relatively safe with respect to proarrhythmic effects.

Procainamide administration often results in excessively high serum N-acetylprocainamide (NAPA) concentrations and subtherapeutic serum procainamide concentrations. Inhibition of N-acetylation of procainamide may prevent accumulation of excessive NAPA while maintaining therapeutic serum procainamide concentrations. The purpose of this randomized, two-way crossover study was to determine if para-aminobenzoic acid (PABA) inhibits N-acetylation of procainamide in healthy volunteers. Eleven (7 female, 4 male) fast acetylators of caffeine received, in random order, PABA 1.5 g orally every 6 hours for 5 days, with a single intravenous dose of procainamide 750 mg administered over 30 minutes on the third day, or intravenous procainamide alone. Blood samples were collected during a 48-hour period after initiation of the infusion. Urine was collected over a 72-hour period. Serum procainamide and NAPA concentrations were analyzed using fluorescence polarization immunoassay. Urine procainamide and NAPA concentrations were measured with high performance liquid chromatography. PABA did not significantly influence total or renal procainamide clearance, elimination rate constant, AUC0-00, amount of procainamide excreted unchanged in the urine, or volume of distribution. However, concomitant PABA administration with procainamide resulted in increases in NAPA AUC0-00 and t1/2 and reductions in NAPA Ke, procainamide acetylation (NAPA formation) clearance, and NAPA renal clearance. Although PABA inhibits metabolic conversion of procainamide to NAPA, it also impairs the renal clearance of NAPA (but not procainamide) in healthy subjects. Therefore, PABA may not be useful for optimizing the safety of efficacy of procainamide in patients.