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Clinical laboratory quality improvement (QI) efforts can include population test utilization. The authors used a health care organization's Medical Data Warehouse (MDW) to characterize a gap in guideline-concordant laboratory testing recommended for safe use of antirheumatic agents, then tested the effectiveness of laboratory-led, technology-enabled outreach to patients at reducing this gap. Data linkages available through the Kaiser Permanente Colorado MDW and electronic health record were used to identify ambulatory adults taking antirheumatic agents who were due/overdue for alanine aminotransferase (ALT), aspartate aminotransferase (AST), complete blood count (CBC), or serum creatinine (SCr) testing. Outreach was implemented using an interactive voice response system to send patients text or phone call reminders. Interrupted time series analysis was used to estimate reminder effectiveness. Rates of guideline-concordant testing and testing timeliness in baseline vs. intervention periods were determined using generalized linear models for repeated measures. Results revealed a decrease in percentage of 3763 patients taking antirheumatic agents due/overdue for testing at any given time: baseline 24.3% vs. intervention 17.5% (P < 0.001). Among 3205 patients taking conventional antirheumatic agents, concordance for all ALT testing was baseline 52.8% vs. intervention 65.4% (P < 0.001) among patients chronically using these agents and baseline 20.6% vs. intervention 26.1% (P < 0.001) among patients newly starting these agents. The 95th percentiles for days to ALT testing were baseline 149 vs. intervention 117 among chronic users and baseline 134 vs. intervention 92 among new starts. AST, CBC, and SCr findings were similar. Technology-enabled outreach reminding patients to obtain laboratory testing improves health care system outcomes.

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Chemical warfare nerve agents (CWNAs) present a global threat to both military and civilian populations. The acute toxicity of CWNAs stems from their ability to effectively inhibit acetylcholinesterase (AChE). This inhibition can lead to uncontrolled cholinergic cellular signaling, resulting in cholinergic crisis and, ultimately, death. Although the current FDA-approved standard of care is moderately effective when administered early, development of novel treatment strategies is necessary. Butyrylcholinesterase (BChE) is an enzyme which displays a high degree of structural homology to AChE. Unlike AChE, the roles of BChE are uncertain and possibilities are still being explored. However, BChE appears to primarily serve as a bioscavenger of toxic esters due to its ability to accommodate a wide variety of substrates within its active site. Like AChE, BChE is also readily inhibited by CWNAs. Due to its high affinity for binding CWNAs, and that null-BChE yields no apparent health effects, exogenous BChE has been explored as a candidate therapeutic for CWNA intoxication. Despite years of research, minimal strides have been made to develop a catalytic bioscavenger. Furthermore, BChE is only in early clinical trials as a stoichiometric bioscavenger of CWNAs, and large quantities must be administered to treat CWNA toxicity. Here, we describe previously unidentified mutations to residues within and adjacent to the acyl binding pocket (positions 282-285 were mutagenized from YGTP to NHML) of BChE that confer catalytic degradation of the CWNA, sarin. These mutations, along with corresponding future efforts, may finally lead to a novel therapeutic to combat CWNA intoxication.

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Organophosphorus (OP) compounds, which include insecticides and chemical warfare nerve agents (CWNAs) such as sarin (GB) and VX, continue to be a global threat to both civilian and military populations. It is widely accepted that cholinesterase inhibition is the primary mechanism for acute OP toxicity. Disruption of cholinergic function through the inhibition of acetylcholinesterase (AChE) leads to the accumulation of the neurotransmitter acetylcholine. Excess acetylcholine at the synapse results in an overstimulation of cholinergic neurons which manifests in the common signs and symptoms of OP intoxication (miosis, increased secretions, seizures, convulsions, and respiratory failure). The primary therapeutic strategy employed in the United States to treat OP intoxication includes reactivation of inhibited AChE with the oxime pralidoxime (2-PAM) along with the muscarinic acetylcholine receptor antagonist atropine and the benzodiazepine, diazepam. CWNAs are also known to inhibit butyrylcholinesterase (BChE) without any apparent toxic effects. Therefore, BChE may be viewed as a "bioscavenger" that stoichiometrically binds CWNAs and removes them from circulation. The degree of inhibition of AChE and BChE and the effectiveness of 2-PAM are known to vary among species. Animal models are imperative for evaluating the efficacy of CWNA medical countermeasures, and a thorough characterization of available animal models is important for translating results to humans. Thus, the objective of this study was to compare the circulating levels of each of the cholinesterases as well as multiple kinetic properties (inhibition, reactivation, and aging rates) of both AChE and BChE derived from humans to AChE and BChE derived from commonly used large animal models.

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BACKGROUND: Dual diagnosis covers a broad spectrum of mental health and substance misuse conditions occurring concurrently (NICE, 2016 ). Its manifestation is complex and, as such, the disorder is recognized as influencing adherence to prescribed medication and service engagement and has a worse prognosis than substance use and mental health conditions occurring independently. AIMS: To determine the effectiveness of psychoeducational group therapy in a sample of dual diagnosis patients. METHODS: Patients who met the Diagnostic and Statistical Manual of Mental Disorders-IV Axis 1 criteria for serious mental illness and current substance misuse were approached to take part in a psychoeducational program. Those who consented were assessed at baseline and end point using measures of psychiatric syptomatology, psychological well-being, and substance use patterns with the following scales: the Brief Psychiatric Rating Scale, the Hospital Anxiety and Depression Scale, the Maudsley Addiction Profile, and the Warwick-Edinburgh Mental Wellbeing Scale. RESULTS: Fifty-one patients completed the program, while 29 dropped out after initial assessment. Between baseline and follow-up, there was a decline in the number of participants using alcohol, cannabis, cocaine, amphetamine, illicit benzodiazepines and methadone. However, the number of participants using heroin remained constant. The mean amount of substances used was not reduced over the study period except in the case of alcohol. Overall improvements in syptomatology and psychological well-being were observed. DISCUSSION: Mental health services should focus on integrated approaches via multimodal treatment interventions that encapsulate harm reduction and educational initiatives. Despite the modest sample, the findings have emphasized the importance of a broad range of treatment approaches delivered within a unitary delivery system.

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Campylobacter jejuni is a leading cause of human foodborne gastroenteritis worldwide. The interactions between this pathogen and the intestinal microbiome within a host are of interest as endogenous intestinal microbiota mediates a form of resistance to the pathogen. This resistance, termed colonization resistance, is the ability of commensal microbiota to prevent colonization by exogenous pathogens or opportunistic commensals. Although mice normally demonstrate colonization resistance to C. jejuni, we found that mice treated with ampicillin are colonized by C. jejuni, with recovery of Campylobacter from the colon, mesenteric lymph nodes, and spleen. Furthermore, there was a significant reduction in recovery of C. jejuni from ampicillin-treated mice inoculated with a C. jejuni virulence mutant (ΔflgL strain) compared to recovery of mice inoculated with the C. jejuni wild-type strain or the C. jejuni complemented isolate (ΔflgL/flgL). Comparative analysis of the microbiota from nontreated and ampicillin-treated CBA/J mice led to the identification of a lactic acid-fermenting isolate of Enterococcus faecalis that prevented C. jejuni growth in vitro and limited C. jejuni colonization of mice. Next-generation sequencing of DNA from fecal pellets that were collected from ampicillin-treated CBA/J mice revealed a significant decrease in diversity of operational taxonomic units (OTUs) compared to that in control (nontreated) mice. Taken together, we have demonstrated that treatment of mice with ampicillin alters the intestinal microbiota and permits C. jejuni colonization. These findings provide valuable insights for researchers using mice to investigate C. jejuni colonization factors, virulence determinants, or the mechanistic basis of probiotics.

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Campylobacter jejuni is a leading bacterial cause of human gastroenteritis. The goal of this study was to analyze the C. jejuni F38011 strain, recovered from an individual with severe enteritis, at a genomic and proteomic level to gain insight into microbial processes. The C. jejuni F38011 genome is comprised of 1,691,939 bp, with a mol.% (G+C) content of 30.5%. PacBio sequencing coupled with REBASE analysis was used to predict C. jejuni F38011 genomic sites and enzymes that may be involved in DNA restriction-modification. A total of five putative methylation motifs were identified as well as the C. jejuni enzymes that could be responsible for the modifications. Peptides corresponding to the deduced amino acid sequence of the C. jejuni enzymes were identified using proteomics. This work sets the stage for studies to dissect the precise functions of the C. jejuni putative restriction-modification enzymes. Taken together, the data generated in this study contributes to our knowledge of the genomic content, methylation profile, and encoding capacity of C. jejuni.

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Campylobacter jejuni is a leading bacterial cause of human gastrointestinal disease worldwide. While C. jejuni is a commensal organism in chickens, case-studies have demonstrated a link between infection with C. jejuni and the consumption of foods that have been cross-contaminated with raw or undercooked poultry. We hypothesized that vaccination of chickens with C. jejuni surface-exposed colonization proteins (SECPs) would reduce the ability of C. jejuni to colonize chickens, thereby reducing the contamination of poultry products at the retail level and potentially providing a safer food product for consumers. To test our hypothesis, we injected chickens with recombinant C. jejuni peptides from CadF, FlaA, FlpA, CmeC, and a CadF-FlaA-FlpA fusion protein. Seven days following challenge, chickens were necropsied and cecal contents were serially diluted and plated to determine the number of C. jejuni per gram of material. The sera from the chickens were also analyzed to determine the concentration and specificity of antibodies reactive against the C. jejuni SECPs. Vaccination of chickens with the CadF, FlaA, and FlpA peptides resulted in a reduction in the number of C. jejuni in the ceca compared to the non-vaccinated C. jejuni-challenged group. The greatest reduction in C. jejuni colonization was observed in chickens injected with the FlaA, FlpA, or CadF-FlaA-FlpA fusion proteins. Vaccination of chickens with different SECPs resulted in the production of C. jejuni-specific IgY antibodies. In summary, we show that the vaccination of poultry with individual C. jejuni SECPs or a combination of SECPs provides protection of chickens from C. jejuni colonization.

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Bacterial pathogens can induce an inflammatory response from epithelial tissues due to secretion of the pro-inflammatory chemokine interleukin-8 (IL-8). Many bacterial pathogens manipulate components of the focal complex (FC) to induce signalling events in host cells. We examined the interaction of several bacterial pathogens with host cells, including Campylobacter jejuni, to determine if the FC is required for induction of chemokine signalling in response to bacterial pathogens. Our data indicate that secretion of IL-8 is triggered by C. jejuni, Helicobacter pylori and Salmonella enterica serovar Typhimurium in response to engagement of ß1 integrins. Additionally, we found that the secretion of IL-8 from C. jejuni infected epithelial cells requires FAK, Src and paxillin, which in turn are necessary for Erk 1/2 recruitment and activation. Targeting the FC component paxillin with siRNA prevented IL-8 secretion from cells infected with several bacterial pathogens, including C. jejuni, Helicobacter pylori, Salmonella enterica serovar Typhimurium, Staphylococcus aureus, Pseudomonas aeruginosa, and Vibrio parahaemolyticus. Our findings indicate that maximal IL-8 secretion from epithelial cells in response to bacterial infection is dependent on the FC. Based on the commonality of the host response to bacterial pathogens, we propose that the FC is a signalling platform for an epithelial cell response to pathogenic organisms.

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We present the results of a study using high-throughput whole-transcriptome sequencing (RNA-seq) and vibrational spectroscopy to characterize and fingerprint pathogenic-bacterium injury under conditions of unfavorable stress. Two garlic-derived organosulfur compounds were found to be highly effective antimicrobial compounds against Cronobacter sakazakii, a leading pathogen associated with invasive infection of infants and causing meningitis, necrotizing entercolitis, and bacteremia. RNA-seq shows changes in gene expression patterns and transcriptomic response, while confocal micro-Raman spectroscopy characterizes macromolecular changes in the bacterial cell resulting from this chemical stress. RNA-seq analyses showed that the bacterial response to ajoene differed from the response to diallyl sulfide. Specifically, ajoene caused downregulation of motility-related genes, while diallyl sulfide treatment caused an increased expression of cell wall synthesis genes. Confocal micro-Raman spectroscopy revealed that the two compounds appear to have the same phase I antimicrobial mechanism of binding to thiol-containing proteins/enzymes in bacterial cells generating a disulfide stretching band but different phase II antimicrobial mechanisms, showing alterations in the secondary structures of proteins in two different ways. Diallyl sulfide primarily altered the α-helix and ß-sheet, as reflected in changes in amide I, while ajoene altered the structures containing phenylalanine and tyrosine. Bayesian probability analysis validated the ability of principal component analysis to differentiate treated and control C. sakazakii cells. Scanning electron microscopy confirmed cell injury, showing significant morphological variations in cells following treatments by these two compounds. Findings from this study aid in the development of effective intervention strategies to reduce the risk of C. sakazakii contamination in the food production environment and on food contact surfaces, reducing the risks to susceptible consumers.

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Caveolae are 25-100 nm flask-like membrane structures enriched in cholesterol and glycosphingolipids. Researchers have proposed that Campylobacter jejuni require caveolae for cell invasion based on the finding that treatment of cells with the cholesterol-depleting compounds filipin III or methyl-ß-cyclodextrin (MßCD) block bacterial internalization in a dose-dependent manner. The purpose of this study was to determine the role of caveolae and caveolin-1, a principal component of caveolae, in C. jejuni internalization. Consistent with previous work, we found that the treatment of HeLa cells with MßCD inhibited C. jejuni internalization. However, we also found that the treatment of HeLa cells with caveolin-1 siRNA, which resulted in greater than a 90% knockdown in caveolin-1 protein levels, had no effect on C. jejuni internalization. Based on this observation we performed a series of experiments that demonstrate that MßCD acts broadly, disrupting host cell lipid rafts and C. jejuni-induced cell signaling. More specifically, we found that MßCD inhibits the cellular events necessary for C. jejuni internalization, including membrane ruffling and Rac1 GTPase activation. We also demonstrate that MßCD disrupted the association of the ß1 integrin and EGF receptor, which are required for the maximal invasion of epithelial cells. In agreement with these findings, C. jejuni were able to invade human Caco-2 cells, which are devoid of caveolae, at a level equal to that of HeLa cells. Taken together, the results of our study demonstrate that C. jejuni internalization occurs in a caveolae-independent manner.

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BACKGROUND: Enteric pathogens utilize a distinct set of proteins to modulate host cell signaling events that promote host cell invasion, induction of the inflammatory response, and intracellular survival. Human infection with Campylobacter jejuni, the causative agent of campylobacteriosis, is characterized by diarrhea containing blood and leukocytes. The clinical presentation of acute disease, which is consistent with cellular invasion, requires the delivery of the Campylobacter invasion antigens (Cia) to the cytosol of host cells via a flagellar Type III Secretion System (T3SS). We identified a novel T3SS effector protein, which we termed CiaD that is exported from the C. jejuni flagellum and delivered to the cytosol of host cells. RESULTS: We show that the host cell kinases p38 and Erk 1/2 are activated by CiaD, resulting in the secretion of interleukin-8 (IL-8) from host cells. Additional experiments revealed that CiaD-mediated activation of p38 and Erk 1/2 are required for maximal invasion of host cells by C. jejuni. CiaD contributes to disease, as evidenced by infection of IL-10 knockout mice. Noteworthy is that CiaD contains a Mitogen-activated protein (MAP) kinase-docking site that is found within effector proteins produced by other enteric pathogens. These findings indicate that C. jejuni activates the MAP kinase signaling pathways Erk 1/2 and p38 to promote cellular invasion and the release of the IL-8 pro-inflammatory chemokine. CONCLUSIONS: The identification of a novel T3SS effector protein from C. jejuni significantly expands the knowledge of virulence proteins associated with C. jejuni pathogenesis and provides greater insight into the mechanism utilized by C. jejuni to invade host cells.

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Mental Health Service Users (MHSU) are becoming increasingly recognized as very valuable contributors to the research process. The current study originated from the idea of a group of MHSU within a service user and carer research group. They wanted to investigate the attitudes of mental health staff towards clients in an acute mental health setting, as well as their attitudes towards certain aspects of service. An amended version of the 'Attitudes Towards Acute Mental Health Scale' was sent to nursing and allied staff at an acute psychiatric unit within the Gloucestershire 2gether NHS Foundation Trust. Fifty-seven of the 200 anonymous questionnaires were returned. Generally positive opinions of MHSU were obtained, but there were divided opinions on questions regarding the aetiology of mental health problems (e.g. social vs. genetic determinants). Opinions on aspects of the admissions process, therapeutic aspects of care, the use of medication and the use of control and restraint techniques were also obtained. Demographic variables of staff age, status and years of experience in mental health were found to be associated with attitudes and opinions. This MHSU-initiated study has extended the literature on mental health staff attitudes towards clients and services in an acute mental health setting. This study is split into two parts, Part A is focused on the process of involving MHSU in this project, Part B is concerned with the empirical investigation.

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Campylobacter jejuni is a gram-negative, curved and rod-shaped bacterium that causes human gastroenteritis. Acute disease is associated with C. jejuni invasion of the intestinal epithelium. Epithelial cells infected with C. jejuni strains containing mutations in the FlpA and CadF fibronectin (Fn)-binding proteins exhibit reduced invasion of host cells and a C. jejuni CadF FlpA double mutant is impaired in the activation of epidermal growth factor receptor (EGFR) and Rho GTPase Rac1. Although these observations establish a role for Fn-binding proteins during C. jejuni invasion, their mechanistic contributions to invasion-associated signaling are unclear. We examined FlpA, a C. jejuni Fn-binding protein composed of three FNIII-like repeats D1, D2 and D3, to identify the interactions required for cellular adherence on pathogen-induced host cell signaling. We report that FlpA binds the Fn gelatin-binding domain via a motif within the D2 repeat. Epithelial cells infected with a flpA mutant exhibited decreased Rac1 activation and reduced membrane ruffling that coincided with impaired delivery of the secreted Cia proteins and reduced cell association. Phosphorylation of the Erk1/2 kinase, a downstream effector of EGFR signaling, was specifically associated with FlpA-mediated activation of ß1-integrin and EGFR signaling. In vivo experiments revealed that FlpA is necessary for C. jejuni disease based on bacterial dissemination to the spleen of IL-10(-/-) germ-free mice. Thus, a novel Fn-binding motif within FlpA potentiates activation of Erk1/2 signaling via ß1-integrin during C. jejuni infection.

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This study was performed to elucidate the host cell scaffolding and signalling molecules that Campylobacter jejuni utilizes to invade epithelial cells. We hypothesized that the C. jejuni fibronectin-binding proteins and secreted proteins are required for cell signalling and maximal invasion of host cells. C. jejuni binding to host cells via the CadF and FlpA fibronectin-binding proteins activated the epidermal growth factor (EGF) pathway, as evidenced by inhibitor studies and immunoprecipitation coupled with immunoblot analysis using antibodies reactive against total and active EGF receptor. Inhibitor studies revealed maximal C. jejuni host cell invasion was dependent upon PI3-Kinase, c-Src and focal adhesion kinase (FAK), all of which are known to participate in cytoskeletal rearrangements. Knockdown of endogenous Dock180, which is a Rac1-specific guanine nucleotide exchange factor, using siRNA revealed that C. jejuni invasion was significantly reduced compared with cells treated with scrambled siRNA. We further demonstrated that the C. jejuni Cia proteins are, in part, responsible for Rho GTPase Rac1 recruitment and activation, as judged by immunofluorescence microscopy and Rac1 activation. Based on these data, we present a model that illustrates that C. jejuni utilizes a coordinated mechanism involving both adhesins and secreted proteins to promote membrane ruffling and host cell invasion.

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BACKGROUND: Utilization of arthroplasty is increasing, but there are little data exploring the causes of this increase. The objective of this study was to examine the relationship between new programs for arthroplasty of the lower extremity joints and the utilization of arthroplasty. METHODS: We identified twenty-four markets (hospital referral regions) that experienced the entry of new physician-owned specialty hospitals, using 1991 to 2005 Medicare data. We matched each market with a new specialty hospital to two different control markets (one market with a new arthroplasty program in a general hospital and one market without a new arthroplasty program), using a propensity score that accounted for market supply and demand for orthopaedic surgery and the regulatory environment. We compared the utilization of arthroplasty of the lower extremity joints (total hip arthroplasty and total knee arthroplasty) in each group of markets over a five-year window, extending from two years before to three years after the entry of new orthopaedic surgery programs. RESULTS: The twenty-four markets with new specialty orthopaedic hospitals had higher utilization of arthroplasty at baseline (10.9 arthroplasties per 1000 Medicare beneficiaries per year) and follow-up (12.7 per 1000 beneficiaries) compared with the twenty-four markets with new arthroplasty programs in general hospitals (9.7 and 11.4, respectively) and the twenty-four markets with no new programs (9.9 and 11.3), although the differences were not significant (p > 0.05). Growth in the utilization of arthroplasty was similar in markets with new specialty hospitals before (an increase of 0.63 procedure per 1000 beneficiaries per year) and after the entry of new specialty hospitals (an increase of 0.39) compared with markets with new surgery programs in general hospitals (an increase of 0.24 before and 0.43 after) and markets with no new programs (an increase of 0.38 before and 0.33 after the entry of new specialty hospitals) (p > 0.05 for all comparisons). CONCLUSIONS: The utilization of arthroplasty is increasing at similar rates in markets with and without new arthroplasty programs.

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OBJECTIVE: To explore the relation between hospital orthopaedic specialisation and postoperative outcomes after total hip or knee replacement surgery. DESIGN: Retrospective analysis of US Medicare data, 2001-5. SETTING: 3818 US hospitals carrying out total joint replacement. Population 1 273 081 Medicare beneficiaries age 65 and older who underwent primary or revision hip or knee replacement. MAIN OUTCOME MEASURES: Hospitals were stratified into fifths on the basis of their degree of orthopaedic specialisation (lowest fifth, least specialised; highest fifth, most specialised). The primary outcome was defined as a composite representing the occurrence of one or more of pulmonary embolism, deep vein thrombosis, haemorrhage, infection, myocardial infarction, or death within 90 days of the index surgery. RESULTS: As hospital orthopaedic specialisation increased from the lowest fifth to highest fifth, the proportion of people admitted who were women or black, or who had diabetes or heart failure progressively decreased (P<0.001), whereas procedural volume increased. Compared with the most specialised hospitals (highest fifth), after adjustment for patient characteristics and hospital volume, the odds of adverse outcomes increased progressively with decreased hospital specialisation: lowest fifth (odds ratio 1.59, 95% confidence interval 1.53 to 1.65), second fifth (1.32, 1.28 to 1.36), third fifth (1.24, 1.21 to 1.28), and fourth fifth (1.10, 1.07 to 1.13). CONCLUSIONS: Increased hospital orthopaedic specialisation is associated with improved patient outcomes after adjusting for both patient characteristics and hospital procedural volume. These results should be interpreted with caution because the possibility that other unmeasured confounders related to socioeconomic status or different factors are responsible for the improved patient outcomes rather than hospital specialisation can not be excluded. The findings suggest that hospital specialisation may capture different components of hospital quality than the components captured by hospital volume.

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Published studies of physician-owned specialty hospitals have typically examined the impact of these hospitals on disparities, quality, and utilization at a national level. Our objective was to examine the impact of newly opened physician-owned specialty orthopaedic hospitals on individual competing general hospitals. We used Medicare Part A administrative data to identify all physician-owned specialty orthopaedic hospitals performing total hip arthroplasty (THA) and total knee arthroplasty (TKA) between 1991 and 2005. We identified newly opened specialty hospitals in three representative markets (Durham, NC, Kansas City, and Oklahoma City) and assessed their impact on surgical volume and patient case complexity for the five competing general hospitals located closest to each specialty hospital. The average general hospital maintained THA and TKA volume following the opening of the specialty hospitals. The average general hospital also did not experience an increase in patient case complexity. Thus, based on these three markets, we found no clear evidence that entry of physician-owned specialty orthopaedic hospitals resulted in declines in THA or TKA volume or increases in patient case complexity for the average competing general hospital.

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Viral haemorrhagic septicaemia (VHS) was diagnosed in rainbow trout in the UK in May 2006. VHS virus (VHSV) was isolated from fingerlings showing typical histopathological lesions at a single rainbow trout farm site experiencing high mortality. The virus was confirmed as VHSV by serological and molecular biological tests. Phylogenetic analysis based on the complete glycoprotein gene sequence revealed that the isolate was closely related (99% nucleotide identity) to several Danish isolates from 1991 to 2000 and was assigned to VHSV genogroup Ia. The pathogenicity of the isolate was determined in infection experiments using rainbow trout fry. Following waterborne challenge, cumulative mortalities reached 96.67-100% by 12 days post-infection. This represents the first isolation of a pathogenic freshwater VHSV in the UK.

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The allometric scaling of metabolic rate with organism body mass can be partially accounted for by differences in cellular metabolic rates. For example, hepatocytes isolated from horses consume almost 10-fold less oxygen per unit time as mouse hepatocytes [Porter and Brand, Am J Physiol Regul Integr Comp Physiol 269: R226-R228, 1995]. This could reflect a genetically programmed, species-specific, intrinsic metabolic rate set point, or simply the adaptation of individual cells to their particular in situ environment (i.e., within the organism). We studied cultured cell lines derived from 10 mammalian species with donor body masses ranging from 5 to 600,000 g to determine whether cells propagated in an identical environment (media) exhibited metabolic rate scaling. Neither metabolic rate nor the maximal activities of key enzymes of oxidative or anaerobic metabolism scaled significantly with donor body mass in cultured cells, indicating the absence of intrinsic, species-specific, cellular metabolic rate set points. Furthermore, we suggest that changes in the metabolic rates of isolated cells probably occur within 24 h and involve a reduction of cellular metabolism toward values observed in lower metabolic rate organisms. The rate of oxygen delivery has been proposed to limit cellular metabolic rates in larger organisms. To examine the effect of oxygen on steady-state cellular respiration rates, we grew cells under a variety of physiologically relevant oxygen regimens. Long-term exposure to higher medium oxygen levels increased respiration rates of all cells, consistent with the hypothesis that higher rates of oxygen delivery in smaller mammals might increase cellular metabolic rates.

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