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Studies examining alcohol and drug education in schools of nursing were reviewed. A paucity of investigations was noted and most evaluations possessed significant methodologic shortcomings. Schools of nursing generally provided minimal exposure to important concepts in the addictions. Few classroom hours were dedicated to alcohol and drug issues and individual courses devoted to substance use disorders were uncommon. Clinical training was a particularly neglected area. Neither the scope nor intensity of clinical instruction was sufficient to ensure that graduating nurses could effectively intervene with chemically dependent patients. Other findings suggested that drug education receives less attention than alcohol education and that schools of nursing provide less chemical dependency training than medical and other professional schools. [ABSTRACT FROM AUTHOR]

Gemtuzumab-ozogamicin (GO) is an antibody-drug conjugate (ADC) in which a monoclonal antibody targeting CD33 is covalently linked to the toxin calicheamicin. GO was initially approved by the United States Food and Drug Administration (FDA) for the treatment of adult patients with CD33 + acute myeloid leukemia (AML) in 2000. However, GO was recalled from the US market due to the lack of efficacy, and higher incidence of hepatotoxicities, including hepatic veno-occlusive disease (VOD), observed in phase 3 SWOG-0106 study. Since then, several other phase 3 studies have evaluated the efficacy of GO in the frontline treatment of adult patients with AML using different GO doses and schedules. The pivotal study that led to the reconsideration of GO was the French ALFA-0701 study, which used a lower and fractionated dose of GO in combination with standard chemotherapy (SC). Patients treated with the GO combination had a significantly longer survival outcome. The modified schedule also improved the toxicity profile. A systematic review and meta-analysis of over 3000 patients treated in five phase 3 studies showed that adding GO to SC improved relapse-free and overall survival. Most importantly, 6 mg/m 2 dose of GO was associated with higher grade ⩾3 hepatoxicities and VOD than 3 mg/m 2 . The survival benefit was significant in the favorable and intermediate cytogenetic risk groups. This led to the reapproval of GO in 2017 for the treatment of patients with CD33 + AML. Currently, several clinical trials are exploring the role of GO with various combinations and in eliminating the measurable residual disease in patients with CD33 + AML., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2023.)

CPX-351 (Europe: Vyxeos ® liposomal; United States: Vyxeos ® ) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. In a phase 3 study in older adults with newly diagnosed, high-risk/secondary AML, CPX-351 improved the remission frequency, overall survival, and post-transplant survival versus 7 + 3. This post hoc analysis evaluated the final 5-year follow-up outcomes according to the European LeukemiaNet 2017 risk classification. CPX-351-treated patients had a higher remission frequency (adverse risk: 41% vs 26%; intermediate risk: 58% vs 39%) and longer median overall survival (adverse risk: 7.59 vs 5.52 months; intermediate risk: 11.86 vs 7.75 months) and post-transplant survival (adverse risk: 43.14 vs 7.08 months; intermediate risk: not reached vs 13.57 months) versus 7 + 3, with outcomes generally poorer among patients with adverse-risk AML. The safety profile of CPX-351 among patients with adverse-risk or intermediate-risk AML was consistent with that of the overall study population. Early mortality was lower, and hospitalization length of stay per patient-year was shorter with CPX-351 versus 7 + 3 within the adverse-risk and intermediate-risk subgroups. The favorable outcomes observed with CPX-351 in this post hoc analysis are consistent with results for the overall study population and further support the use of CPX-351 in these patients.ClinicalTrials.gov Identifier: NCT01696084., (© 2022. The Author(s).)

Introduction: Half of the individuals with facial acne develop truncal acne, but the impact of combined facial and truncal acne (CA) on patients' quality of life is poorly researched., Methods: A 60-min interview of 30 participants with CA was conducted that formed the basis for a cross-sectional survey of 694 adolescents and adults with CA., Results: The main themes identified from the qualitative interviews among CA subjects included acceptability to self and others, social functioning and emotional wellbeing. Feelings of embarrassment, self-consciousness and low confidence were experienced often or all the time by over 50% of participants, and were more frequent in those who perceived their acne to be out of control (P = 0.003). Half of patients reported feeling stigmatised because of their CA, and 65.4% believed that others associated their truncal acne with unhealthy or unhygienic habits. Perceived stigma was associated with more feelings of embarrassment (P = 0.005), self-consciousness (P = 0.034) and low self-confidence (P = 0.017). Overall, 64% participants reported that CA interfered with daily life, 46.4% often or always avoided social interaction, 48.6% were often concerned about talking to unfamiliar people and 47.4% were uncomfortable showing affection. Further, 32% and 24.4% participants ≥ 16 years old avoided dating or having romantic/intimate relationships because of their facial and truncal acne, respectively. Social and leisure activities were more frequently negatively impacted among those with perceived uncontrolled CA than among those with controlled CA. Avoiding undressing in front of spouse/partner/friends/relatives was more commonly reported by participants with perceived uncontrolled truncal acne than by those with controlled truncal acne (90.5% versus 80.6%, P = 0.031)., Conclusion: CA is associated with considerable psychological morbidity, with several exacerbating (e.g. perceived stigma) and attenuating factors (e.g. acne being perceived as being under control) that should be accounted for in CA management., (© 2022. The Author(s).)

The current diagnostic aids for acute vision loss are static flowcharts that do not provide dynamic, stepwise workups. We tested the diagnostic accuracy of a novel dynamic Bayesian algorithm for acute vision loss. Seventy-nine "participants" with acute vision loss in Windsor, Canada were assessed by an emergency medicine or primary care provider who completed a questionnaire about ocular symptoms/findings (without requiring fundoscopy). An ophthalmologist then attributed an independent "gold-standard diagnosis". The algorithm employed questionnaire data to produce a differential diagnosis. The referrer diagnostic accuracy was 30.4%, while the algorithm's accuracy was 70.9%, increasing to 86.1% with the algorithm's top two diagnoses included and 88.6% with the top three included. In urgent cases of vision loss ( n = 54), the referrer diagnostic accuracy was 38.9%, while the algorithm's top diagnosis was correct in 72.2% of cases, increasing to 85.2% (top two included) and 87.0% (top three included). The algorithm's sensitivity for urgent cases using the top diagnosis was 94.4% (95% CI: 85-99%), with a specificity of 76.0% (95% CI: 55-91%). This novel algorithm adjusts its workup at each step using clinical symptoms. In doing so, it successfully improves diagnostic accuracy for vision loss using clinical data collected by non-ophthalmologists.

Background: CPX-351 (United States: Vyxeos ® ; Europe: Vyxeos ® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up., Methods: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses., Results: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology., Conclusions: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete., (© 2021. The Author(s).)

Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.

Proteolytic control can govern the levels of specific regulatory factors, such as Spx, a transcriptional regulator of the oxidative stress response in Gram-positive bacteria. Under oxidative stress, Spx concentration is elevated and upregulates transcription of genes that function in the stress response. When stress is alleviated, proteolysis of Spx catalysed by ClpXP reduces Spx concentration. Proteolysis is enhanced by the substrate recognition factor YjbH, which possesses a His-Cys-rich region at its N terminus. However, mutations that generate H12A, C13A, H14A, H16A and C31/34A residue substitutions in the N terminus of Bacillus subtilis YjbH (BsYjbH) do not affect functionality in Spx proteolytic control in vivo and in vitro. Because of difficulties in obtaining soluble BsYjbH, the Geobacillus thermodenitrificans yjbH gene was cloned, which yielded soluble GtYjbH protein. Despite its lack of a His-Cys-rich region, GtYjbH complements a B. subtilis yjbH null mutant, and shows high activity in vitro when combined with ClpXP and Spx in an approximately 30 : 1 (ClpXP/Spx : GtYjbH) molar ratio. In vitro interaction experiments showed that Spx and the protease-resistant Spx(DD) (in which the last two residues of Spx are replaced with two Asp residues) bind to GtYjbH, but deletion of 12 residues from the Spx C terminus (SpxΔC) significantly diminished interaction and proteolytic degradation, indicating that the C terminus of Spx is important for YjbH recognition. These experiments also showed that Spx, but not GtYjbH, interacts with ClpX. Kinetic measurements for Spx proteolysis by ClpXP in the presence and absence of GtYjbH suggest that YjbH overcomes non-productive Spx-ClpX interaction, resulting in rapid degradation.

The Spx protein of Bacillus subtilis is a global regulator of the oxidative stress response. Spx concentration is controlled at the level of proteolysis by the ATP-dependent protease ClpXP and a substrate-binding protein, YjbH, which interacts with Spx. A yeast two-hybrid screen was carried out using yjbH as bait to uncover additional substrates or regulators of YjbH activity. Of the several genes identified in the screen, one encoded a small protein, YirB (YuzO), which elevated Spx concentration and activity in vivo when overproduced from an isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible yirB construct. Pulldown experiments using extracts of B. subtilis cells producing a His-tagged YirB showed that native YjbH interacts with YirB in B. subtilis. Pulldown experiments using affinity-tagged Spx showed that YirB inhibited YjbH interaction with Spx. In vitro, YjbH-mediated proteolysis of Spx by ClpXP was inhibited by YirB. The activity of YirB is similar to that of the antiadaptor proteins that were previously shown to reduce proteolysis of a specific ClpXP substrate by interacting with a substrate-binding protein.

Bacterial manganese(II) oxidation has a profound impact on the biogeochemical cycling of Mn and the availability of the trace metals adsorbed to the surfaces of solid Mn(III, IV) oxides. The Mn(II) oxidase enzyme was tentatively identified in Pseudomonas putida GB-1 via transposon mutagenesis: the mutant strain GB-1-007, which fails to oxidize Mn(II), harbors a transposon insertion in the gene cumA. cumA encodes a putative multicopper oxidase (MCO), a class of enzymes implicated in Mn(II) oxidation in other bacterial species. However, we show here that an in-frame deletion of cumA did not affect Mn(II) oxidation. Through complementation analysis of the oxidation defect in GB-1-007 with a cosmid library and subsequent sequencing of candidate genes we show the causative mutation to be a frameshift within the mnxS1 gene that encodes a putative sensor histidine kinase. The frameshift mutation results in a truncated protein lacking the kinase domain. Multicopy expression of mnxS1 restored Mn(II) oxidation to GB-1-007 and in-frame deletion of mnxS1 resulted in a loss of oxidation in the wild-type strain. These results clearly demonstrated that the oxidation defect of GB-1-007 is due to disruption of mnxS1, not cumA::Tn5, and that CumA is not the Mn(II) oxidase. mnxS1 is located upstream of a second sensor histidine kinase gene, mnxS2, and a response regulator gene, mnxR. In-frame deletions of each of these genes also led to the loss of Mn(II) oxidation. Therefore, we conclude that the MnxS1/MnxS2/MnxR two-component regulatory pathway is essential for Mn(II) oxidation in P. putida GB-1.

The Spx protein of Bacillus subtilis interacts with RNA polymerase (RNAP) to activate transcription initiation in response to thiol-oxidative stress. Protein-DNA cross-linking analysis of reactions containing RNAP, Spx and trxA (thioredoxin) or trxB (thioredoxin reductase) promoter DNA was undertaken to uncover the organization of the Spx-activated transcription initiation complex. Spx induced contact between the RNAP sigma(A) subunit and the -10 promoter sequence of trxA and B, and contact of the betabeta' subunits with core promoter DNA. No Spx-DNA contact was detected. Spx mutants, Spx(C10A) and Spx(G52R.), or RNAP alpha C-terminal domain mutants that impair productive Spx-RNAP interaction did not induce heightened sigma and betabeta' contact with the core promoter. Deletion analysis and the activity of hybrid promoter constructs having upstream trxB DNA fused at positions -31, -36 and -41 of the srf (surfactin synthetase) promoter indicated that a cis-acting site between -50 and -36 was required for Spx activity. Mutations at -43 and -44 of trxB abolished Spx-dependent transcription and Spx-induced cross-linking between the sigma subunit and the -10 region. These data are consistent with a model that Spx activation requires contact between the Spx/RNAP complex and upstream promoter DNA, which allows Spx-induced engagement of the sigma and large subunits with the core promoter.

Microbial Mn(II) oxidation has important biogeochemical consequences in marine, freshwater, and terrestrial environments, but many aspects of the physiology and biochemistry of this process remain obscure. Here, we report genomic insights into Mn(II) oxidation by the marine alphaproteobacterium Aurantimonas sp. strain SI85-9A1, isolated from the oxic/anoxic interface of a stratified fjord. The SI85-9A1 genome harbors the genetic potential for metabolic versatility, with genes for organoheterotrophy, methylotrophy, oxidation of sulfur and carbon monoxide, the ability to grow over a wide range of O(2) concentrations (including microaerobic conditions), and the complete Calvin cycle for carbon fixation. Although no growth could be detected under autotrophic conditions with Mn(II) as the sole electron donor, cultures of SI85-9A1 grown on glycerol are dramatically stimulated by addition of Mn(II), suggesting an energetic benefit from Mn(II) oxidation. A putative Mn(II) oxidase is encoded by duplicated multicopper oxidase genes that have a complex evolutionary history including multiple gene duplication, loss, and ancient horizontal transfer events. The Mn(II) oxidase was most abundant in the extracellular fraction, where it cooccurs with a putative hemolysin-type Ca(2+)-binding peroxidase. Regulatory elements governing the cellular response to Fe and Mn concentration were identified, and 39 targets of these regulators were detected. The putative Mn(II) oxidase genes were not among the predicted targets, indicating that regulation of Mn(II) oxidation is controlled by other factors yet to be identified. Overall, our results provide novel insights into the physiology and biochemistry of Mn(II) oxidation and reveal a genome specialized for life at the oxic/anoxic interface.

The antimicrobial susceptibilities of 168 Vibrio parahaemolyticus and 151 Vibrio vulnificus isolates recovered from 82 Louisiana Gulf and retail oysters in 2005 and 2006 were determined. Overall, the two vibrios remained susceptible to the majority of antimicrobials tested; reduced susceptibility was detected only in V. parahaemolyticus for ampicillin (81%; MIC > or = 16 microg/ml). Additionally, V. parahaemolyticus displayed significantly higher MICs for cefotaxime, ciprofloxacin, and tetracycline than V. vulnificus.

Spx, a transcriptional regulator of the disulfide stress response in Bacillus subtilis, is under the proteolytic control of the ATP-dependent protease ClpXP. Previous studies suggested that ClpXP activity is down-regulated in response to disulfide stress, resulting in elevated concentrations of Spx. The effect of disulfide stress on ClpXP activity was examined using the thiol-specific oxidant diamide. ClpXP-catalyzed degradation of either Spx or a green fluorescent protein derivative bearing an SsrA tag recognized by ClpXP was inhibited by diamide treatment in vitro. Spx is also a substrate for MecA/ClpCP-catalyzed proteolysis in vitro, but diamide used at the concentrations that inhibited ClpXP had little observable effect on MecA/ClpCP activity. ClpX bears a Cys4 Zn-binding domain (ZBD), which in other Zn-binding proteins is vulnerable to thiol-reactive electrophiles. Diamide treatment caused partial release of Zn from ClpX and the formation of high-molecular-weight species, as observed by electrophoresis through nonreducing gels. Reduced Spx proteolysis in vitro and elevated Spx concentration in vivo resulted when two of the Zn-coordinating Cys residues of the ClpX ZBD were changed to Ser. This was reflected in enhanced Spx activity in both transcription activation and repression in cells expressing the Cys-to-Ser mutants. ClpXP activity in vivo is reduced when cells are exposed to diamide, as shown by the enhanced stability of an SsrA-tagged protein after treatment with the oxidant. The results are consistent with the hypothesis that inhibition of ClpXP by disulfide stress is due to structural changes to the N-terminal ZBD of ClpX.

Molecular characterization (e.g., DNA-based typing methods) of Salmonella isolates is frequently employed to compare and distinguish clinical isolates recovered from animals and from patients with food-borne disease and nosocomial infections. In this study, we compared the abilities of different phenotyping and genotyping methods to distinguish isolates of Salmonella enterica serovar Typhimurium from different food animal sources. One hundred twenty-eight S. enterica serovar Typhimurium strains isolated from cattle, pigs, chickens, and turkeys or derived food products were characterized using pulsed-field gel electrophoresis (PFGE), repetitive element PCR (Rep-PCR), multilocus sequence typing (MLST), plasmid profiling, and antimicrobial susceptibility testing. Among the 128 Salmonella isolates tested, we observed 84 Rep-PCR profiles, 86 PFGE patterns, 89 MLST patterns, 36 plasmid profiles, and 38 susceptibility profiles. The molecular typing methods, i.e., PFGE, MLST, and Rep-PCR, demonstrated the best discriminatory power among Salmonella isolates. However, no apparent correlation was evident between the results of one molecular typing method and those of the others, suggesting that a combination of multiple methods is needed to differentiate S. enterica serovar Typhimurium isolates that genetically cluster according to one particular typing method.

Objectives: Although American Indians and Alaska Natives have high rates of substance abuse, few data about treatment services for this population are available. We used national data from 1997-2002 to describe recent trends in organizational and financial arrangements., Methods: Using data from the Indian Health Service (IHS), the Substance Abuse and Mental Health Services Administration, the National Institute on Alcohol Abuse and Alcoholism, the Henry J. Kaiser Family Foundation, and the Census Bureau, we estimated the number of American Indians served by substance abuse treatment programs that apparently are unaffiliated with either the IHS or tribal governments. We compared expected and observed IHS expenditures., Results: Half of the American Indians and Alaska Natives treated for substance abuse were served by programs (chiefly in urban areas) apparently unaffiliated with the IHS or tribal governments. IHS substance abuse expenditures were roughly what we expected. Medicaid participation by tribal programs was not universal., Conclusions: Many Native people with substance abuse problems are served by programs unaffiliated with the IHS. Medicaid may be key to expanding needed resources.

In the United States, multidrug-resistant phenotypes of Salmonella enterica serotype Newport (commonly referred to as MDR-AmpC) have emerged in animals and humans and have become a major public health problem. Although pulsed-field gel electrophoresis (PFGE) is the current "gold standard" typing method for Salmonella, multilocus sequence typing (MLST) may be more relevant to investigations exploring evolutionary and population biology relationships. In this study, 81 Salmonella enterica serotype Newport isolates from humans, food animals, and retail foods were examined for antimicrobial susceptibility and characterized using PFGE and MLST of seven genes, aroC, dnaN, hemD, hisD, purE, sucA, and thrA. Forty-nine percent of the isolates were resistant to nine or more of the tested antimicrobials. Salmonella isolates displayed resistance most often to sulfamethoxazole (57%), streptomycin (56%), tetracycline (56%), ampicillin (52%), and ceftiofur (49%) and, to a lesser extent, to kanamycin (19%), trimethoprim-sulfamethoxazole (17%), and gentamicin (11%). A total of 43 PFGE patterns were generated using XbaI, indicating a genetically diverse population. The largest PFGE cluster contained isolates from clinically ill swine, cattle, and humans. MLST resulted in 12 sequence types (STs), with one type encompassing 62% of the strains. Ten new sequence types and one novel allele type were identified. Furthermore, MLST typing showed that strains closely related by PFGE clustered in major STs, whereas more distantly related strains were separated into two clusters by PFGE. The results of this study demonstrated that the MLST scheme employed here clustered S. enterica serovar Newport isolates in distinct molecular populations, and strain discrimination was enhanced by combining PFGE, antimicrobial susceptibility, and MLST results.

The Spx protein of Bacillus subtilis exerts both positive and negative transcriptional control in response to oxidative stress by interacting with the C-terminal domain of the RNA polymerase (RNAP) alpha subunit (alphaCTD). Thus, transcription of the srf operon at the onset of competence development, which requires the ComA response regulator of the ComPA signal transduction system, is repressed by Spx-alphaCTD interaction. Previous genetic and structural analyses have determined that an Spx-binding surface resides in and around the alpha1 region of alphaCTD. Alanine-scanning mutagenesis of B. subtilis alphaCTD uncovered residue positions required for Spx function and ComA-dependent srf transcriptional activation. Analysis of srf-lacZ fusion expression, DNase I footprinting, and solid-phase promoter retention experiments indicate that Spx interferes with ComA-alphaCTD interaction and that residues Y263, C265, and K267 of the alpha1 region lie within overlapping ComA- and Spx-binding sites for alphaCTD interaction. Evidence is also presented that oxidized Spx, while enhancing interference of activator-RNAP interaction, is not essential for negative control.

Pregnant sows were housed in dynamic, twice-mixed, and static groups of different sizes in pens with electronic sow feeders (ESFs) to study the effect of group size and structure on sow welfare and performance. The total injury score (TIS) was significantly higher (P < 0.05) in the dynamic group than in the other groups in general and 2 wk after mixing. The salivary cortisol concentrations were similar in the 3 groups. The frequency of queuing was significantly higher (P < 0.05) in the twice-mixed group and the frequency of nonagonistic social interactions significantly lower (P < 0.05) in the dynamic group. The total number of aggressive acts was positively and significantly correlated (P < 0.05) with the frequency and duration of queuing in all the groups. Farrowing performance and longevity did not differ between the groups. The higher TIS and lower number of nonagonistic social interactions indicated that welfare was compromised in the dynamic group as compared with the other groups.

Objectives: To investigate the effects of peripheral arterial disease (PAD) on relative tolerance to upper- and lower-limb aerobic exercise., Methods: Peak cardiorespiratory responses evoked by an incremental arm-cranking test (ACT) and an incremental leg-cranking test (LCT) were compared in patients with PAD (N=101; median age 69 year, range 50-85 years). Claudication distance (CD) and total distance before intolerable claudication pain (maximum walking distance: MWD) were also assessed during walking., Results: Peak oxygen consumption (V O(2)) for the ACT was 94% of that measured for the LCT (1.01+/-0.03 versus 1.10+/-0.03lmin(-1), respectively; P<0.001), but in a significant proportion of patients (35%; P<0.001), exceeded that recorded for the LCT. The ratio of upper- to lower-limb peak V O(2) was higher (0.98+/-0.04 compared to 0.98+/-0.05lmin(-1) and 1.00+/-0.06 compared to 1.21+/-0.06lmin(-1); P<0.01), whereas walking performance (CD: 94+/-14 versus 187+/-25 m, P<0.01; MWD: 227+/-20 versus 394+/-33 m, P<0.01) was lower for patients in the lowest ankle to brachial pressure index quartile compared to patients in the highest quartile, respectively., Conclusion: Upper-limb aerobic conditioning could be a useful exercise stimulus for maintaining or improving cardiorespiratory function in patients with severe PAD as they have a greater relative upper-limb aerobic power.

Objectives: To investigate the effects of a 24-week program of upper- and lower-limb aerobic exercise training on walking performance in patients with symptomatic peripheral arterial disease (PAD) and to study the mechanisms that could influence symptomatic improvement., Methods: After approval from the North Sheffield Local Research Ethics Committee, 104 patients (median age, 69 years; range, 50 to 85 years) with stable PAD were randomized into an upper- or lower-limb aerobic exercise training group (UL-Ex or LL-Ex), or to a nonexercise training control group. Training was performed twice weekly for 24 weeks at equivalent relative exercise intensities. An incremental arm- and leg-crank test (ACT and LCT) to maximum exercise tolerance was performed before and at 6, 12, 18, and 24 weeks of the intervention to determine peak oxygen consumption (VO(2)). Walking performance, defined as the claudicating distance (CD) and maximum walking distance (MWD) achieved before intolerable claudication pain, was assessed at the same time points by using a shuttle-walk protocol. Peak blood lactate concentration, Borg ratings of perceived exertion (RPE) and pain category ratio (CR-10) were recorded during all assessments., Results: CD and MWD increased over time (P < .001) in both training groups. At 24 weeks, CD had improved by 51% and 57%, and MWD had improved by 29% and 31% (all P < .001) in the UL-Ex and LL-Ex groups, respectively. An increase in peak heart rate at MWD in the UL-Ex group (109 +/- 4 vs 115 +/- 4 beats/min; P < .01) and LL-Ex group (107 +/- 3 vs 118 +/- 3 beats/min; P = .01) was accompanied by an increase in the amount of pain experienced in both groups (P < .05), suggesting that exercising patients could tolerate a higher level of cardiovascular stress and an increased intensity of claudication pain before test termination after training. Patients assigned to exercise training also showed an increase in LCT peak VO2 at the 24-week time point in relation to baseline (P < .01) and control patients (P < .01), whereas ACT peak VO2 was only improved in the UL-Ex group (P < .05)., Conclusions: Our results suggest that a combination of physiologic adaptations and improved exercise pain tolerance account for the improvement in walking performance achieved through upper-limb aerobic exercise training in patients with PAD. Furthermore, that both arm- and leg-crank training could be useful exercise training modalities for improving cardiovascular function, walking performance, and exercise pain tolerance in patients with symptomatic PAD.

Quality control ranges were developed for broth microdilution testing of Campylobacter jejuni ATCC 33560 against 14 antimicrobials. Cation-adjusted Mueller-Hinton broth containing 2.5% laked horse blood was the preferred medium, with incubation in a microaerobic atmosphere of 10% CO(2), 5% O(2), and 85% N(2) at 36 degrees C for 48 h or 42 degrees C for 24 h.

We report population-based concentrations (stratified by age, sex, and composite race/ethnicity variables) of selective metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol; TCPY), chlorpyrifos methyl (TCPY), malathion (malathion dicarboxylic acid; MDA), diazinon (2-isopropyl-4-methyl-6-hydroxypyrimidine; IMPY), methyl parathion (para-nitrophenol; PNP), and parathion (PNP). We measured the concentrations of TCPY, MDA, IMPY, and PNP in 1997 urine samples from participants, aged 6-59 years, of the National Health and Nutrition Examination Survey, 1999-2000. We detected TCPY in more than 96% of the samples tested. Other organophosphorus pesticide metabolites were detected less frequently: MDA, 52%; IMPY, 29%; and PNP, 22%. The geometric means for TCPY were 1.77 microg/L and 1.58 microg/g creatinine. The 95th percentiles for TCPY were 9.9 microg/L and 8.42 microg/g creatinine. The 95th percentiles for MDA were 1.6 microg/L and 1.8 microg/g creatinine. The 95th percentiles for IMPY and PNP were 3.7 microg/L (3.4 microg/g creatinine) and 5.0 microg/L (4.2 microg/g creatinine), respectively. Multivariate analyses showed that children aged 6-11 years had significantly higher concentrations of TCPY than adults and adolescents. Similarly, adolescents had significantly higher TCPY concentrations than adults. Although the concentrations between sexes and among composite racial/ethnic groups varied, no significant differences were observed.

Oxidative stress in Bacillus subtilis results in the accumulation of Spx protein, which exerts both positive and negative transcriptional control over a genome-wide scale through its interaction with the RNA polymerase alpha subunit. Previous microarray transcriptome studies uncovered a unique class of genes that are controlled by Spx-RNA polymerase interaction under normal growth conditions that do not promote Spx overproduction. These genes were repressed by Spx when sulfate was present as a sole sulfur source. The genes include those of the ytmI, yxeI, and ssu operons, which encode products resembling proteins that function in the uptake and desulfurization of organic sulfur compounds. Primer extension and analysis of operon-lacZ fusion expression revealed that the operons are repressed by sulfate and cysteine; however, Spx functioned only in sulfate-dependent repression. Both the ytmI operon and the divergently transcribed ytlI, encoding a LysR-type regulator that positively controls ytmI operon transcription, are repressed by Spx in sulfate-containing media. The CXXC motif of Spx, which is necessary for redox sensitive control of Spx activity in response to oxidative stress, is not required for sulfate-dependent repression. The yxeL-lacZ and ssu-lacZ fusions were also repressed in an Spx-dependent manner in media containing sulfate as the sole sulfur source. This work uncovers a new role for Spx in the control of sulfur metabolism in a gram-positive bacterium under nonstressful growth conditions.

A 17-year-old gelding was evaluated because of dysuria, inappetence, and weight loss. Cystoscopy revealed severe mucosal ecchymoses with luminal hemorrhage and accumulations of crystalloid sludge. Analysis of a urine sample revealed isosthenuria, an alkaline pH, pyuria, hematuria, bacteriuria, and numerous calcium carbonate crystals. Histologic examination of bladder mucosa biopsy specimens revealed severe neutrophilic infiltration with mineralization. A diagnosis of encrusted cystitis exacerbated by sabulous urolithiasis was made. A Corynebacterium sp susceptible to penicillin, sulfonamide, and enrofloxacin was cultured from the urine and the bladder mucosa biopsy specimens. The horse was treated with penicillin G potassium, IV, for 5 days, followed by trimethoprim-sulfamethoxazole for 4 weeks. Bladder lavage was performed daily for the first 3 days with a balanced electrolyte solution and dimethyl sulfoxide in an attempt to aid expulsion of necrotic debris and crystalline sludge from the bladder. Molecular phylogenetic analysis based on the 16S rDNA gene sequence was used to identify the isolate and determine its phylogenetic position. Results indicated that the isolate was closely related to Corynebacterium matruchotii. To our knowledge, encrusted cystitis secondary to C matruchotii has not been previously identified in a horse.

Manganese peroxidase (MnP) is a major, extracellular component of the lignin-degrading system produced by the wood-rotting basidiomycetous fungus Phanerochaete chrysosporium. The transcription of MnP-encoding genes (mnps) in P. chrysosporium occurs as a secondary metabolic event, triggered by nutrient-nitrogen limitation. In addition, mnp expression occurs only under Mn2+ supplementation. Using a reporter system based on the enhanced green fluorescent protein gene (egfp), we have characterized the P. chrysosporium mnp1 promoter by examining the effects of deletion, replacement, and translocation mutations on mnp1 promoter-directed egfp expression. The 1,528-bp mnp1 promoter fragment drives egfp expression only under Mn2+-sufficient, nitrogen-limiting conditions, as required for endogenous MnP production. However, deletion of a 48-bp fragment, residing 521 bp upstream of the translation start codon in the mnp1 promoter, or replacement of this fragment with an unrelated sequence resulted in egfp expression under nitrogen limitation, both in the absence and presence of exogenous Mn2+. Translocation of the 48-bp fragment to a site 120 bp downstream of its original location resulted in Mn2+-dependent egfp expression under conditions similar to those observed with the wild-type mnp1 promoter. These results suggest that the 48-bp fragment contains at least one Mn2+-responsive cis element. Additional promoter-deletion experiments suggested that the Mn2+ element(s) is located within the 33-bp sequence at the 3' end of the 48-bp fragment. This is the first promoter sequence containing a Mn2+-responsive element(s) to be characterized in any eukaryotic organism., (Copyright 2004 American Society for Microbiology)

Salmonella enterica serotype Newport isolates resistant to at least nine antimicrobials (including extended-spectrum cephalosporins), known as serotype Newport MDR-AmpC isolates, have been rapidly emerging as pathogens in both animals and humans throughout the United States. Resistance to extended-spectrum cephalosporins is associated with clinical failures, including death, in patients with systemic infections. In this study, 87 Salmonella serotype Newport strains were characterized by pulsed-field gel electrophoresis (PFGE) and antimicrobial susceptibility testing and examined for the presence of class 1 integrons and bla(CMY) genes. Thirty-five PFGE patterns were observed with XbaI, and three of these patterns were indistinguishable among isolates from humans and animals. Fifty-three (60%) Salmonella serotype Newport isolates were identified as serotype Newport MDR-AmpC, including 16 (53%) of 30 human isolates, 27 (93%) of 29 cattle isolates, 7 (70%) of 10 swine isolates, and 3 (30%) of 10 chicken isolates. However, 28 (32%) Salmonella serotype Newport isolates were susceptible to all 16 antimicrobials tested. The bla(CMY) gene was present in all serotype Newport MDR-AmpC isolates. Furthermore, the plasmid-mediated bla(CMY) gene was transferable via conjugation to an Escherichia coli strain. The transconjugant showed the MDR-AmpC resistance profile. Thirty-five (40%) of the isolates possessed class 1 integrons. Sequence analyses of the integrons showed that they contained aadA, which confers resistance to streptomycin, or aadA and dhfr, which confer resistance to trimethoprim-sulfamethoxazole. One integron from a swine isolate contained the sat-1 gene, which encodes resistance to streptothricin, an antimicrobial agent that has never been approved for use in the United States. In conclusion, Salmonella serotype Newport MDR-AmpC was commonly identified among Salmonella serotype Newport isolates recovered from humans and food animals. These findings support the possibility of transmission of this organism to humans through the food chain.

Quality control (QC) ranges for disk diffusion susceptibility testing of aquatic bacterial isolates were proposed as a result of a multilaboratory study conducted according to procedures established by the National Committee for Clinical Laboratory Standards (NCCLS). Ranges were proposed for Escherichia coli ATCC 25922 and Aeromonas salmonicida subsp. salmonicida ATCC 33658 at 22 and 28 degrees C for nine different antimicrobial agents (ampicillin, enrofloxacin, erythromycin, florfenicol, gentamicin, oxolinic acid, oxytetracycline, ormetoprim-sulfadimethoxine, and trimethoprim-sulfamethoxazole). All tests were conducted on standard Mueller-Hinton agar. With >/=95% of all data points fitting within the proposed QC ranges, the results from this study comply with NCCLS guidelines and have been accepted by the NCCLS Subcommittee for Veterinary Antimicrobial Susceptibility Testing. These QC guidelines will permit greater accuracy in interpreting results and, for the first time, the ability to reliably compare susceptibility test data between aquatic animal disease diagnostic laboratories.

Thirty-five enterococcal isolates were recovered from dogs diagnosed with urinary tract infections at the Michigan State University Veterinary Teaching Hospital over a 2-year period (1996 to 1998). Isolated species included Enterococcus faecium (n = 13), Enterococcus faecalis (n = 7), Enterococcus gallinarum (n = 11), and Enterococcus casseliflavus (n = 4). Antimicrobial susceptibility testing revealed several different resistance phenotypes, with the majority of the enterococcal isolates exhibiting resistance to three or more antibiotics. One E. faecium isolate, CVM1869, displayed high-level resistance to vancomycin (MIC > 32 micro g/ml) and gentamicin (MIC > 2,048 micro g/ml). Molecular analysis of this isolate revealed the presence of Tn1546 (vanA), responsible for high-level vancomycin resistance, and Tn5281 carrying aac6'-aph2", conferring high-level aminoglycoside resistance. Pulsed-field gel electrophoresis analysis revealed that CVM1869 was a canine E. faecium clone that had acquired Tn1546, perhaps from a human vancomycin-resistant E. faecium. Transposons Tn5281 and Tn1546 were located on two different conjugative plasmids. Sequence analysis revealed that in Tn1546, ORF1 had an 889-bp deletion and an IS1216V insertion at the 5' end and an IS1251 insertion between vanS and vanH. To date, this particular form of Tn1546 has only been described in human clinical vancomycin-resistant enterococcus isolates unique to the United States. Additionally, this is the first report of a vancomycin-resistant E. faecium isolated from a companion animal in the United States.

Susceptibilities to fourteen antimicrobial agents important in clinical medicine and agriculture were determined for 752 Escherichia coli isolates of serotypes O26, O103, O111, O128, and O145. Strains of these serotypes may cause urinary tract and enteric infections in humans and have been implicated in infections with Shiga toxin-producing E. coli (STEC). Approximately 50% of the 137 isolates from humans were resistant to ampicillin, sulfamethoxazole, cephalothin, tetracycline, or streptomycin, and approximately 25% were resistant to chloramphenicol, trimethoprim-sulfamethoxazole, or amoxicillin-clavulanic acid. Approximately 50% of the 534 isolates from food animals were resistant to sulfamethoxazole, tetracycline, or streptomycin. Of 195 isolates with STEC-related virulence genes, approximately 40% were resistant to sulfamethoxazole, tetracycline, or streptomycin. Findings from this study suggest antimicrobial resistance is widespread among E. coli O26, O103, O111, O128, and O145 inhabiting humans and food animals.

Milk samples collected from dairy cattle suspected of having mastitis were submitted to the Microbiology Laboratory of the Animal Health Diagnostic Laboratory, Michigan State University, for bacteriologic culture. A total of 2778 isolates, from the years 1994 to 2000, were isolated, identified, and subjected to in vitro antimicrobial susceptibility testing using the disk diffusion method, in accordance with National Committee on Clinical Laboratory Standards (NCCLS) standards. Isolates included in this study were Streptococcus uberis, Streptococcus dysgalactiae, Streptococcus agalactiae, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Serratia marcesens, and Pseudomonas aeruginosa. The proportion of bacterial isolates determined to be susceptible did not change during the 7-yr period for the majority of bacterial-antibacterial interactions tested. However, analysis for linear trend in proportions determined that there were increases in the proportion of S. aureus isolates that were susceptible to ampicillin, penicillin, and erythromycin. For Strep. uberis, increases in the proportion of susceptible isolates occurred for oxacillin, sulfa-trimethoprim, gentamicin, and pirlimycin, and a decrease in the proportion of susceptible isolates occurred with penicillin. For Strep. dysgalactiae, increases in the proportion of susceptible isolates occurred with erythromycin, gentamicin, sulfa-trimethoprim, and tetracycline. For Strep. agalactiae, increases in the proportion of susceptible isolates occurred with sulfa-trimethoprim. Among E. coli isolates, there was an increase in the proportion that were susceptible to ampicillin and cephalothin. Among K pneumoniae isolates, there was an increase in the proportion that were susceptible to ceftiofur. Overall, there was no indication of increased resistance of mastitis isolates to antibacterials that are commonly used in dairy cattle.

Fluoroquinolones are commonly used to treat gastroenteritis caused by Campylobacter species. Domestically acquired fluoroquinolone-resistant Campylobacter infection has been documented recently in the United States. It has been proposed that the increase in resistance is due, in part, to the use of fluoroquinolones in poultry. In separate experiments, the effects of sarafloxacin and enrofloxacin treatment of Campylobacter jejuni-infected chickens on the development of ciprofloxacin resistance were measured. Fecal samples were collected before and after treatment and were cultured for C. jejuni. When enrofloxacin or sarafloxacin was used at US Food and Drug Administration-approved doses in broiler chickens, resistance developed rapidly and persisted in C. jejuni. MICs of ciprofloxacin increased from a base of 0.25 microg/mL to 32 microg/mL within the 5-day treatment time frame. These results show that the use of these drugs in chickens rapidly selects for resistant Campylobacter organisms and may result in less effective fluoroquinolone therapy for cases of human campylobacteriosis acquired from exposure to contaminated chicken.

A total of 361 Escherichia coli O157 isolates, recovered from humans, cattle, swine, and food during the years 1985 to 2000, were examined to better understand the prevalence of antimicrobial resistance among these organisms. Based on broth microdilution results, 220 (61%) of the isolates were susceptible to all 13 antimicrobials tested. Ninety-nine (27%) of the isolates, however, were resistant to tetracycline, 93 (26%) were resistant to sulfamethoxazole, 61 (17%) were resistant to cephalothin, and 48 (13%) were resistant to ampicillin. Highest frequencies of resistance occurred among swine isolates (n = 70), where 52 (74%) were resistant to sulfamethoxazole, 50 (71%) were resistant to tetracycline, 38 (54%) were resistant to cephalothin, and 17 (24%) were resistant to ampicillin. Based on the presence of Shiga toxin genes as determined by PCR, 210 (58%) of the isolates were identified as Shiga toxin-producing E. coli (STEC). Among these, resistance was generally low, yet 21 (10%) were resistant to sulfamethoxazole and 19 (9%) were resistant to tetracycline. Based on latex agglutination, 189 (52%) of the isolates were identified as E. coli O157:H7, among which 19 (10%) were resistant to sulfamethoxazole and 16 (8%) were resistant to tetracycline. The data suggest that selection pressure imposed by the use of tetracycline derivatives, sulfa drugs, cephalosporins, and penicillins, whether therapeutically in human and veterinary medicine or as prophylaxis in the animal production environment, is a key driving force in the selection of antimicrobial resistance in STEC and non-STEC O157.

Twenty-one Salmonella and 54 Escherichia coli isolates, recovered from food animals and retail ground meats, that exhibited decreased susceptibilities to ceftiofur and ceftriaxone were shown to possess a bla(CMY) gene. The bla(CMY-4) gene was identified in an E. coli isolate recovered from retail chicken and was further shown to be responsible for resistance to cephalothin, ampicillin, and amoxicillin-clavulanic acid and elevated MICs of ceftriaxone, cefoxitin, and ceftiofur.

Quality control (QC) standards for the in vitro antimicrobial susceptibility testing of two fastidious veterinary pathogens, Actinobacillus pleuropneumoniae and Haemophilus somnus, were developed in a multilaboratory study according to procedures established by the National Committee for Clinical Laboratory Standards for broth microdilution and disk diffusion testing. The medium recommended for the broth microdilution testing is cation-adjusted Mueller-Hinton broth supplemented with 2% lysed horse blood, 2% yeast extract, and 2% supplement C. This medium has been designated veterinary fastidious medium. The medium recommended for the disk diffusion testing is chocolate Mueller-Hinton agar. The recommended QC organisms are A. pleuropneumoniae ATCC 27090 and H. somnus ATCC 700025. The QC MICs of ceftiofur, enrofloxacin, florfenicol, gentamicin, penicillin, tetracycline, tilmicosin, and trimethoprim-sulfamethoxazole were determined for each isolate, as were the zone size ranges. Of the results from the participating laboratories, 94.0% of the zone diameter results and 97.0% of the MIC results fell within the suggested QC ranges for all compounds. These QC guidelines should allow greater accuracy in interpreting results when testing these antimicrobial agents against fastidious pathogens.

Between May 1996 and February 1997, 27 horses and a veterinary student at a veterinary teaching hospital developed apparent nosocomial Salmonella Typhimurium infection. The source of the multiple-drug resistant Salmonella Typhimurium was a neonatal foal admitted for treatment of septicemia. A high infection rate (approx 13% of hospitalized horses) coupled with a high case fatality rate (44%) for the initial 18 horses affected led to a decision to close the hospital for extensive cleaning and disinfection. Despite this effort and modification of hospital policies for infection control, 9 additional horses developed nosocomial Salmonella Typhimurium infection during the 6 months after the hospital reopened. Polymerase chain reaction testing of environmental samples was useful in identifying a potential reservoir of the organism in drains in the isolation facility. Coupled with clinical data, comparison of antimicrobial resistance patterns of Salmonella Typhimurium isolates provided a rapid initial means to support or refute nosocomial infection. Although minor changes in the genome of these isolates developed over the course of the outbreak, pulsed-field gel electrophoresis testing further supported that salmonellosis was nosocomial in all 27 horses.

Objective: To determine sources of Salmonella organisms in a veterinary teaching hospital, compare bacterial culture with polymerase chain reaction (PCR) testing for detection of Salmonella organisms in environmental samples, and evaluate the effects of various disinfectants on detection of Salmonella organisms on surface materials., Design: Prospective study., Sample Population: Fecal samples from 638 hospitalized horses and 783 environmental samples., Procedure: Standard bacterial culture techniques were used; the PCR test amplified a segment of the Salmonella DNA. Five disinfectants were mixed with Salmonella suspensions, and bacterial culture was performed. Swab samples were collected from 7 surface materials after inoculation of the surfaces with Salmonella Typhimurium, with or without addition of a disinfectant, and submitted for bacterial culture and PCR testing., Results: Salmonella organisms were detected in fecal samples from 35 (5.5%) horses. For environmental samples, the proportion of positive bacterial culture results (1/783) was significantly less than the proportion of positive PCR test results (110/783), probably because of detection of nonviable DNA by the PCR test. Detection of Salmonella organisms varied with the surface material tested, the method of detection (bacterial culture vs PCR testing), and the presence and type of disinfectant., Conclusions and Clinical Relevance: Results of the present study suggested that Salmonella organisms can be isolated from feces of hospitalized horses and a variety of environmental surfaces in a large animal hospital. Although recovery of Salmonella organisms was affected by surface material and disinfectant, bleach was the most effective disinfectant on the largest number of surfaces tested.

This study determined the types and magnitude of gene action, estimated heritabilities, and predicted gain from selection for resistance to Aspergillus ear rot and aflatoxin production in the cross of resistant corn inbred CI2 to susceptible inbred B73 in 1998 and 1999. The warm, dry summer of 1998 favored aflatoxin production, whereas the conditions of 1999 did not. Resistance to ear rot was mainly controlled by additive gene action. Aflatoxin values were analyzed by individual years (environments) because of the highly significant generation × environment interaction. Resistance to aflatoxin production was mainly controlled by epistasis in 1998 and by additive gene action in 1999. Heritabilities for ear rot and aflatoxin production were higher in the F 3 generation than in the BCP 1 -selfed generation. In 1998, Spearman's correlation coefficients between Aspergillus ear rot ratings and aflatoxin values for the F 3 and the BCP 1 -selfed families were not significant (P > 0.05). In 1999, both were highly significant (P < 0.01), but low at 0.41 and 0.17 for the F 3 and BCP 1 -selfed generations, respectively. We found that CI2 is not an acceptable source of resistance due to lower heritabilities and disease resistance compared to other sources of resistance.

Purpose: We have previously shown that a program of upper limb exercise training can induce significant improvements in walking distance in patients with claudication. This study assessed whether upper limb exercise avoids the systemic inflammatory responses associated with lower limb exercise and also whether the inflammatory response to acute lower limb exertion is modified by a program of supervised exercise training., Methods: Fifty-two patients with stable intermittent claudication were randomized into two groups who underwent 6 weeks of supervised upper (n = 26) or lower (n = 26) limb cardiorespiratory exercise training. A parallel control group (n = 15) was provided with lifestyle advice only. Neutrophil activation markers (CD11b and CD66b) and plasma levels of von Willebrand factor (marker of endothelial damage) in response to an acute bout of sustained upper and lower limb exercise were assessed before and after the period of training. Plasma levels of soluble E-selectin (marker of endothelial activation) were also determined before and after the training period., Results: An acute bout of sustained lower limb exercise significantly increased the intensity of CD11b and CD66b expression by peripheral blood neutrophils in all groups, whereas upper limb exercise had no effect. Resting neutrophil expression of CD11b and CD66b and circulating von Willebrand factor levels were unaffected by the training program, as were the inflammatory responses to an acute bout of sustained upper and lower limb muscular work, despite the fact that both training programs significantly increased walking distances., Conclusions: These findings indicate that upper limb exercise training programs may offer certain advantages over currently prescribed lower limb programs. Our results show that exercising nonischemic muscles in a way that promotes improved cardiorespiratory function and walking capacity can avoid the potentially deleterious systemic inflammatory responses associated with lower limb exertion in patients with stable intermittent claudication.