Anthropogenic, biogenic, and photochemical influences on surface formaldehyde and its significant decadal (2006-2017) decrease in the Lewiston-Clarkston valley of the northwestern United States.

Formaldehyde (HCHO) is a key carcinogen and plays an important role in atmospheric chemistry. Both field measurements and Positive Matrix Factorization (PMF) modeling have been employed to investigate the concentrations and sources of HCHO in the Lewiston-Clarkston (LC) valley of the mountainous northwestern U.S. Different instruments were deployed to measure surface formaldehyde and other related compounds in July of 2016 and 2017. The measurements reveal that the average HCHO concentrations have significantly decreased to 2-5 ppb in the LC valley in comparison to its levels (10-20 ppb) observed in July 2006. This discovery with surface measurements deserves attention given that satellite retrievals showed an increasing long-term trend from 2005 to 2014 in total vertical column density of HCHO in the region, suggesting that satellite instruments may not adequately resolve small valleys in the mountainous region. Our PMF modeling identified four major sources of HCHO in the valley: (1) emissions from a local paper mill, (2) secondary formation and background, (3) biogenic sources, and (4) traffic. This study reveals that the emissions from the paper mill cause high HCHO spikes (6-19 ppb) in the early morning. It is found that biogenic volatile organic compounds (VOCs) in the area are influenced by national forests surrounding the region (e.g., Nez Perce-Clearwater, Umatilla, Wallowa-Whitman, and Idaho Panhandle National Forests). The results provide useful information for developing strategies to control HCHO levels and have implications for future HCHO studies in atmospheric chemistry, which affects secondary aerosols and ozone formation.

Fire safety and emergency evacuation guidelines for intensive care units and operating theatres: for use in the event of fire, flood, power cut, oxygen supply failure, noxious gas, structural collapse or other critical incidents: Guidelines from the Association of Anaesthetists and the Intensive Care Society.

The need to evacuate an ICU or operating theatre complex during a fire or other emergency is a rare event but one potentially fraught with difficulty: Not only is there a risk that patients may come to harm but also that staff may be injured and unable to work. Designing newly-built or refurbished ICUs and operating theatre suites is an opportunity to incorporate mandatory fire safety features and improve the management and outcomes of such emergencies: These include well-marked manual fire call points and oxygen shut off valves (area valve service units); the ability to isolate individual zones; multiple clear exit routes; small bays or side rooms; preference for ground floor ICU location and interconnecting routes with operating theatres; separate clinical and non-clinical areas. ICUs and operating theatre suites should have a bespoke emergency evacuation plan and route map that is readily available. Staff should receive practical fire and evacuation training in their clinical area of work on induction and annually as part of mandatory training, including 'walk-through practice' or simulation training and location of manual fire call points and fire extinguishers, evacuation routes and location and operation of area valve service units. The staff member in charge of each shift should be able to select and operate fire extinguishers and lead an evacuation. Following an emergency evacuation, a network-wide response should be activated, including retrieval and transport of patients to other ICUs if needed. A full investigation should take place and ongoing support and follow-up of staff provided.

Novel DNA methylation signatures of tobacco smoking with trans-ethnic effects.

BACKGROUND: Smoking remains one of the leading preventable causes of death. Smoking leaves a strong signature on the blood methylome as shown in multiple studies using the Infinium HumanMethylation450 BeadChip. Here, we explore novel blood methylation smoking signals on the Illumina MethylationEPIC BeadChip (EPIC) array, which also targets novel CpG-sites in enhancers. METHOD: A smoking-methylation meta-analysis was carried out using EPIC DNA methylation profiles in 1407 blood samples from four UK population-based cohorts, including the MRC National Survey for Health and Development (NSHD) or 1946 British birth cohort, the National Child Development Study (NCDS) or 1958 birth cohort, the 1970 British Cohort Study (BCS70), and the TwinsUK cohort (TwinsUK). The overall discovery sample included 269 current, 497 former, and 643 never smokers. Replication was pursued in 3425 trans-ethnic samples, including 2325 American Indian individuals participating in the Strong Heart Study (SHS) in 1989-1991 and 1100 African-American participants in the Genetic Epidemiology Network of Arteriopathy Study (GENOA). RESULTS: Altogether 952 CpG-sites in 500 genes were differentially methylated between smokers and never smokers after Bonferroni correction. There were 526 novel smoking-associated CpG-sites only profiled by the EPIC array, of which 486 (92%) replicated in a meta-analysis of the American Indian and African-American samples. Novel CpG sites mapped both to genes containing previously identified smoking-methylation signals and to 80 novel genes not previously linked to smoking, with the strongest novel signal in SLAMF7. Comparison of former versus never smokers identified that 37 of these sites were persistently differentially methylated after cessation, where 16 represented novel signals only profiled by the EPIC array. We observed a depletion of smoking-associated signals in CpG islands and an enrichment in enhancer regions, consistent with previous results. CONCLUSION: This study identified novel smoking-associated signals as possible biomarkers of exposure to smoking and may help improve our understanding of smoking-related disease risk.

Therapeutic glucocorticoids prevent bone loss but drive muscle wasting when administered in chronic polyarthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) experience extra-articular manifestations including osteoporosis and muscle wasting, which closely associate with severity of disease. Whilst therapeutic glucocorticoids (GCs) reduce inflammation in RA, their actions on muscle and bone metabolism in the context of chronic inflammation remain unclear. We utilised the TNF-tg model of chronic polyarthritis to ascertain the impact of therapeutic GCs on bone and muscle homeostasis in the context of systemic inflammation. METHODS: TNF-tg and wild-type (WT) animals received either vehicle or the GC corticosterone (100 µg/ml) in drinking water at onset of arthritis. Arthritis severity and clinical parameters were measured, serum collected for ELISA and muscle and bone biopsies collected for µCT, histology and mRNA analysis. In vivo findings were examined in primary cultures of osteoblasts, osteoclasts and myotubes. RESULTS: TNF-tg mice receiving GCs showed protection from inflammatory bone loss, characterised by a reduction in serum markers of bone resorption, osteoclast numbers and osteoclast activity. In contrast, muscle wasting was markedly increased in WT and TNF-tg animals receiving GCs, independently of inflammation. This was characterised by a reduction in muscle weight and fibre size, and an induction in anti-anabolic and catabolic signalling. CONCLUSIONS: This study demonstrates that when given in early onset chronic polyarthritis, oral GCs partially protect against inflammatory bone loss, but induce marked muscle wasting. These results suggest that in patients with inflammatory arthritis receiving GCs, the development of interventions to manage deleterious side effects in muscle should be prioritised.

11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.

OBJECTIVE: In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11ß-HSD1 to the pathology of persistent chronic inflammatory disease. METHODS: To determine the contribution of 11ß-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11ß-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. RESULTS: Global deletion of 11ß-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11ß-HSD1 failed to recapitulate this phenotype suggesting that 11ß-HSD1 within leukocytes mediate its protective actions in vivo. CONCLUSIONS: We demonstrate a fundamental role for 11ß-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11ß-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.

Operationalising resilience in longitudinal studies: a systematic review of methodological approaches.

Over the life course, we are invariably faced with some form of adversity. The process of positively adapting to adverse events is known as 'resilience'. Despite the acknowledgement of 2 common components of resilience, that is, adversity and positive adaptation, no consensus operational definition has been agreed. Resilience operationalisations have been reviewed in a cross-sectional context; however, a review of longitudinal methods of operationalising resilience has not been conducted. The present study conducts a systematic review across Scopus and Web of Science capturing studies of ageing that posited operational definitions of resilience in longitudinal studies of ageing. Thirty-six studies met inclusion criteria. Non-acute events, for example, cancer, were the most common form of adversity identified and psychological components, for example, the absence of depression, the most common forms of positive adaptation. Of the included studies, 4 used psychometrically driven methods, that is, repeated administration of established resilience metrics, 9 used definition-driven methods, that is, a priori establishment of resilience components and criteria, and 23 used data-driven methods, that is, techniques that identify resilient individuals using latent variable models. Acknowledging the strengths and limitations of each operationalisation is integral to the appropriate application of these methods to life course and longitudinal resilience research.

Loss of a chromosomal region with synteny to human 13q14 occurs in mouse chronic lymphocytic leukemia that originates from early-generated B-1 B cells.

A common feature of B-cell chronic lymphocytic leukemia (CLL) is chromosomal loss of 13q14, containing the miR15a/16-1 locus controlling B-cell proliferation. However, CLL etiology remains unclear. CLL is an adult leukemia with an incidence that increases with advancing age. A unique feature of CLL is biased B-cell antigen receptor (BCR) usage, autoreactivity with polyreactivity and CD5 expression, all suggest a role for the BCR in driving CLL pathogenesis. Among human CLLs, BCRs autoreactive with non-muscle myosin IIA (AMyIIA) are recurrent. Here we identify an unmutated AMyIIA BCR in mouse, with distinctive CDR3 segments capable of promoting leukemogenesis. B cells with this AMyIIA BCR are generated by BCR-dependent signaling during B-1 fetal/neonatal development with CD5 induction, but not in adults. These early-generated AMyIIA B-1 B cells self-renew, increase during aging and can progress to become monoclonal B-cell lymphocytosis, followed by aggressive CLL in aged mice, often with the loss of a chromosomal region containing the miR15a/16-1 locus of varying length, as in human CLL. Thus, the ability to generate this defined autoreactive BCR by B-1 B cells is a key predisposing step in mice, promoting progression to chronic leukemia.

Environmental and health impacts of February 14, 2014 radiation release from the nation's only deep geologic nuclear waste repository.

The environmental impact of the February 14, 2014 radiation release from the nation's only deep geologic nuclear waste repository, the Waste Isolation Pilot Plant (WIPP) was assessed using monitoring data from an independent monitoring program conducted by the Carlsbad Environmental Monitoring & Research Center (CEMRC). After almost 15 years of safe and efficient operations, the WIPP had one of its waste drums rupture underground resulting in the release of moderate levels of radioactivity into the underground air. A small amount of radioactivity also escaped to the surface through the ventilation system and was detected above ground. It was the first unambiguous release from the WIPP repository. The dominant radionuclides released were americium and plutonium, in a ratio that matches the content of the breached drum. The accelerated air monitoring campaign, which began following the accident, indicates that releases were low and localized, and no radiation-related health effects among local workers or the public would be expected. The highest activity detected was 115.2 µBq/m(3) for (241)Am and 10.2 µBq/m(3) for (239+240)Pu at a sampling station located 91 m away from the underground air exhaust point and 81.4 µBq/m(3) of (241)Am and 5.8 µBq/m(3) of (239+240)Pu at a monitoring station located approximately one kilometer northwest of the WIPP facility. CEMRC's recent monitoring data show that the concentration levels of these radionuclides have returned to normal background levels and in many instances, are not even detectable, demonstrating no long-term environmental impacts of the recent radiation release event at the WIPP. This article presents an evaluation of almost one year of environmental monitoring data that informed the public that the levels of radiation that got out to the environment were very low and did not, and will not harm anyone or have any long-term environmental consequence. In terms of radiological risk at or in the vicinity of the WIPP site, the increased risk from the WIPP releases is exceedingly small, approaching zero.

Overweight across the life course and adipokines, inflammatory and endothelial markers at age 60-64 years: evidence from the 1946 birth cohort.

BACKGROUND/OBJECTIVES: There is growing evidence that early development of obesity increases cardiovascular risk later in life, but less is known about whether there are effects of long-term excess body weight on the biological drivers associated with the atherosclerotic pathway, particularly adipokines, inflammatory and endothelial markers. This paper therefore investigates the influence of overweight across the life course on levels of these markers at retirement age. SUBJECTS/METHODS: Data from the Medical Research Council National Survey of Health and Development (n=1784) were used to examine the associations between overweight status at 2, 4, 6, 7, 11, 15, 20, 26, 36, 43, 53 and 60-64 years (body mass index (BMI)⩾25 kg m(-2) for adult ages and gender-specific cut-points for childhood ages equivalent to BMI⩾25 kg m(-2)) and measurements of adipokines (leptin and adiponectin), inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6)) and endothelial markers (E-selectin, tissue plasminogen activator (t-PA) and von Willebrand factor) at 60-64 years. In addition, the fit of different life course models (sensitive periods/accumulation) were compared using partial F-tests. RESULTS: In age- and sex-adjusted models, overweight at 11 years and onwards was associated with higher leptin, CRP and IL-6 and lower adiponectin; overweight at 15 years and onwards was associated with higher E-selectin and t-PA. Associations between overweight at all ages earlier than 60-64 with leptin, adiponectin, CRP and IL-6 were reduced but remained apparent after adjustment for overweight at 60-64 years; whereas those with E-selectin and t-PA were entirely explained. An accumulation model best described the associations between overweight across the life course with adipokines and inflammatory markers, whereas for the endothelial markers, the sensitive period model for 60-64 years provided a slightly better fit than the accumulation model. CONCLUSIONS: Overweight across the life course has a cumulative influence on adipokines, inflammatory and possibly endothelial markers. Avoidance of overweight from adolescence onwards is likely important for cardiovascular disease prevention.

Radiation release at the nation's only operating deep geological repository--an independent monitoring perspective.

Recent incidents at the nation's only operating deep geologic nuclear waste repository, the Waste Isolation Pilot Plant (WIPP), resulted in the release of americium and plutonium from one or more defense-related transuranic (TRU) waste containers into the environment. WIPP is a U.S. Department of Energy mined geologic repository that has been in operation since March, 1999. Over 85,000 m3 of waste in various vented payload containers have been emplaced in the repository. The primary radionuclides within the disposed waste are 239+240Pu and 241Am, which account for more than 99% of the total TRU radioactivity disposed and scheduled for disposal in the repository. For the first time in its 15 years of operation, there was an airborne radiation release from the WIPP at approximately 11:30 PM Mountain Standard Time (MST) on Friday, February 14, 2014. The radiation release was likely caused by a chemical reaction inside a TRU waste drum that contained nitrate salts and organic sorbent materials. In a recent news release, DOE announced that photos taken of the waste underground showed evidence of heat and gas pressure resulting in a deformed lid, in material expelled through that deformation, and in melted plastic and rubber and polyethylene in the vicinity of that drum. Recent entries into underground Panel 7 have confirmed that at least one waste drum containing a nitrate salt bearing waste stream from Los Alamos National Laboratory was breached underground and was the most likely source of the release. Further investigation is underway to determine if other containers contributed to the release. Air monitoring across the WIPP site intensified following the first reports of radiation detection underground to ascertain whether or not there were releases to the ground surface. Independent analytical results of air filters from sampling stations on and near the WIPP facility have been released by us at the Carlsbad Environmental Monitoring & Research Center and confirmed trace amounts of 241Am and 239+240Pu, at ratios reflecting the suspect waste stream. The highest activity detected offsite was 115.2 µBq/m3 for 241Am and 10.2 µBq/m3 for 239+240 Pu. These concentrations in air were very small, localized, and below any level of public health or environmental concern.

Modification of genetic influences on adiposity between 36 and 63 years of age by physical activity and smoking in the 1946 British Birth Cohort Study.

BACKGROUND: Previous studies reporting on the interaction between physical activity and genetic susceptibility on obesity have been cross-sectional and have not considered the potential influences of other lifestyle behaviours. The aim of this study was to examine modification of genetic influences on changes across age in adiposity during mid-adulthood by physical activity and smoking. METHODS: The sample comprised 2444 participants who were genotyped for 11 obesity variants and had body mass index (BMI), waist circumference-to-height ratio (WHtR), physical activity and smoking measures at 36, 43, 53 and 60-64 years of age. A genetic risk score (GRS) comprising the sum of risk alleles was computed. Structural equation models investigated modification of the longitudinal GRS associations by physical activity (active versus inactive) and smoking (non-smoker versus smoker), using a latent linear spline to summarise BMI or WHtR (multiplied by 100) at the age of 36 years and their subsequent rates of change over age. RESULTS: Physical activity at the age of 36 years attenuated the GRS associations with BMI and WHtR at the same age (P-interaction 0.009 and 0.004, respectively). Further, physical activity at the age of 53 years attenuated the GRS association with rate of change in BMI between 53 and 63 years of age (by 0.012 kg m(-2) per year (95% confidence interval (CI): 0.001, 0.024), P-interaction 0.004). Conversely, smoking at the age of 43 years showed a trend towards augmenting the GRS association with rate of change in WHtR between 43 and 63 years of age (by 0.012 (95% CI: 0.001, 0.026), P-interaction 0.07). Estimated GRS effect sizes were lowest at all ages in the healthiest group (e.g., active non-smokers). CONCLUSIONS: Healthy lifestyle behaviours appeared to attenuate the genetic influence on changes across age in BMI and central adiposity during mid-adulthood. An active lifestyle and not smoking may have additive effects on reducing the genetic susceptibility to obesity in adults.

Irregular consumption of energy intake in meals is associated with a higher cardiometabolic risk in adults of a British birth cohort.

BACKGROUND/OBJECTIVES: A potential risk factor for cardiometabolic diseases is irregular or inconsistent eating, however, research on this topic is scarce. We aimed to study associations between irregular consumption of energy intake in meals and cardiometabolic risk factors. SUBJECT AND METHODS: Dietary intake data were derived from 5-day estimated diet diaries of 1768 participants of the National Survey of Health and Development. Energy intakes during predefined meals (breakfast, lunch, dinner, between meals) and daily totals were analyzed using a score for irregularity based on the deviation from the 5-day mean energy intake. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for having the metabolic syndrome or one of its components. Models were adjusted for sex, physical activity, socioeconomic status, marital status and smoking. RESULTS: Irregularity scores of energy intake ranged from 0-160 and were highest for between meals. An increased risk of the metabolic syndrome was associated with more irregular energy intake during breakfast (OR=1.34 (0.99, 1.81); P trend=0.04) and between meals (OR=1.36 (1.01, 1.85); P trend=0.04). Moreover, increased waist circumference was associated with irregular energy intake during breakfast (OR=1.90 (1.47, 2.45); P trend <0.01), evening meal (OR=1.36 (1.06, 1.75); P trend=0.02) and daily total (OR=1.34 (1.04, 1.72); P trend=0.01). No significant associations were found for the other components of the metabolic syndrome. CONCLUSIONS: Individuals with a more irregular intake of energy, especially during breakfast and between meals, appeared to have an increased cardiometabolic risk.

Using a birth cohort to study ageing: representativeness and response rates in the National Survey of Health and Development.

Britain's oldest birth cohort study, the MRC National Survey of Health and Development (NSHD) provides data to explore life time influences on ageing. The latest data collection was undertaken between 2006 and 2011 when study members were aged 60-64 and consisted of postal and pre-assessment questionnaires to eligible study members, followed by invitation to attend one of six clinical research facilities (CRFs) across the UK for clinical assessments, and dietary diaries and activity monitors in the days following the CRF visit. The option of a home visit for clinical assessments was provided if the study member refused or was unable to attend the CRF. We examined response and attrition, here describing rates overall and for postal and clinical assessment modes of data collection, identifying socioeconomic and health-related predictors of response, and assessing the continued representativeness of the sample. In total, 2,661 (84 % of the target sample) responded. Lower educational attainment, lower childhood cognition and lifelong smoking independently predicted lower likelihood of both overall response and CRF cooperation. At 53 years, not owning one's home and not being married predicted lower likelihood of overall response whereas manual social class and obesity predicted lower likelihood of CRF cooperation. Providing for collection of biomedical data in the home and use of assessment instruments and modes to retain study members with lower education attainment, lower cognition and poorer health behaviours should be priorities for helping reduce attrition amongst vulnerable ageing study members.

Time-of-day and nutrient composition of eating occasions: prospective association with the metabolic syndrome in the 1946 British birth cohort.

BACKGROUND: Diet is a key modifiable factor in the prevention and treatment of the metabolic syndrome. However, few studies have examined the prospective association between time-of-day of nutrient intake and the metabolic syndrome. OBJECTIVE: To examine the association between time-of-day and nutrient composition of eating occasions and the long-term development of metabolic syndrome in the Medical Research Council (MRC) National Survey of Health and Development (NSHD; 1946 British birth cohort). METHODS: The analysis comprised 1488 survey members who completed at least 3 days of estimated diet records at age 43 years (1989) and for whom data on metabolic syndrome at age 53 years (1999) were available. Dietary records were divided into seven meal slots: breakfast, mid-morning, lunch, mid-afternoon, dinner, late evening and extras. Metabolic syndrome was defined by the criteria of the adult treatment panel (ATPIII8), and was modified to include glycosylated haemoglobin instead of fasting glucose. Associations between time-of-day of nutrient intake at age 43 years and prevalence of metabolic syndrome at age 53 years were assessed using multivariate nutrient density logistic models after adjustment for sex, social class, smoking status, region, alcohol intake and recreational physical activity. RESULTS: There were 390 cases of metabolic syndrome at age 53 years. Substituting 5% of energy from carbohydrate for a similar amount of energy from fat at breakfast (odds ratio=0.93; 95% confidence interval=0.89-0.98; P=0.002) and mid-morning at age 43 years (odds ratio=0.96; 95% confidence interval=0.93-0.99; P=0.011) was associated with lower odds of the metabolic syndrome at age 53 years. Carbohydrate intake at breakfast or mid-morning was particularly protective against abdominal obesity (P0.001). Increasing carbohydrate intake at breakfast while simultaneously decreasing fat intake was also negatively related to triacylglycerols (P0.001). CONCLUSIONS: Increasing carbohydrate intake in the morning while simultaneously reducing fat intake could be protective against long-term development of the metabolic syndrome and its components.

A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications.

BACKGROUND: Pyridoxine is frequently used to treat capecitabine-induced hand-foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes. METHODS: A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily. RESULTS: Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival. CONCLUSION: Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

Double-masked, placebo-controlled study of intravenous levetiracetam for the treatment of status epilepticus and acute repetitive seizures in dogs.

BACKGROUND: Status epilepticus (SE) and acute repetitive seizures (ARS) are common canine neurologic emergencies. No evidence-based studies are available to guide treatment in veterinary patients. Parenteral levetiracetam (LEV) has many favorable properties for the emergency treatment of seizures, but its safety and efficacy in dogs for SE and ARS are unknown. HYPOTHESIS: Intravenous LEV is superior to placebo in controlling seizures in dogs with SE or ARS after treatment with IV diazepam. ANIMALS: Nineteen client-owned dogs admitted for SE or ARS. METHODS: Randomized, placebo-controlled, double-masked study. Dogs with SE or ARS were randomized to receive IV LEV (30 or 60 mg/kg using an adaptive dose-escalation approach) or placebo, in addition to standard of care treatment. They were monitored for at least 24 hours after admission for additional seizures. RESULTS: The responder rate (defined as dogs with no additional seizures after administration of the study medication) after LEV was 56% compared with 10% for placebo (P = .06). Dogs in the placebo group required significantly more boluses of diazepam compared with the LEV group (P < .03). Seizure etiologies identified were idiopathic epilepsy (n = 10), inflammatory central nervous system disease (n = 4), intracranial neoplasia (n = 2), hepatic encephalopathy (n = 1), and 2 dogs had no cause determined. No serious adverse effects were attributable to LEV administration. CONCLUSIONS AND CLINICAL IMPORTANCE: LEV was safe and potentially effective for the treatment of SE and ARS in these client-owned dogs. Larger, controlled clinical trials are needed to confirm this preliminary observation.

Synthesis and distribution of CARDS toxin during Mycoplasma pneumoniae infection in a murine model.

Mice were infected with Mycoplasma pneumoniae and monitored for the synthesis and distribution of the unique adenosine diphosphate-ribosylating and vacuolating Community Acquired Respiratory Distress Syndrome (CARDS) toxin in bronchiolar lavage fluid (BALF) and lung. We noted direct relationships between the concentration of CARDS toxin and numbers of mycoplasma genomes in BALF and the degree of histologic pulmonary inflammation. Immunostaining of lungs revealed extensive colonization by mycoplasmas, including the detection of CARDS toxin in the corresponding inflamed airways. Lung lesion scores were higher during the early stages of infection, decreased gradually by day 14 postinfection, and reached substantially lower values at day 35. Infected mouse immunoglobulin (Ig) M and IgG titers were positive for CARDS toxin as well as for the major adhesin P1 of M. pneumoniae. These data reinforce the proposed pathogenic role of CARDS toxin in M. pneumoniae-mediated pathologies.