Causes and consequences of decreasing atmospheric organic aerosol in the United States.

Exposure to atmospheric particulate matter (PM) exacerbates respiratory and cardiovascular conditions and is a leading source of premature mortality globally. Organic aerosol contributes a significant fraction of PM in the United States. Here, using surface observations between 1990 and 2012, we show that organic carbon has declined dramatically across the entire United States by 25-50%; accounting for more than 30% of the US-wide decline in PM. The decline is in contrast with the increasing organic aerosol due to wildfires and no clear trend in biogenic emissions. By developing a carbonaceous emissions database for the United States, we show that at least two-thirds of the decline in organic aerosol can be explained by changes in anthropogenic emissions, primarily from vehicle emissions and residential fuel burning. We estimate that the decrease in anthropogenic organic aerosol is responsible for averting 180,000 (117,000-389,000) premature deaths between 1990 and 2012. The unexpected decrease in organic aerosol, likely a consequence of the implementation of Clean Air Act Amendments, results in 84,000 (30,000-164,000) more lives saved than anticipated by the EPA between 2000 and 2010.

5-Aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) effect on glucose production, but not energy metabolism, is independent of hepatic AMPK in vivo.

Metabolic stress, as well as several antidiabetic agents, increases hepatic nucleotide monophosphate (NMP) levels, activates AMP-activated protein kinase (AMPK), and suppresses glucose production. We tested the necessity of hepatic AMPK for the in vivo effects of an acute elevation in NMP on metabolism. 5-Aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR; 8 mg·kg(-1)·min(-1))-euglycemic clamps were performed to elicit an increase in NMP in wild type (α1α2(lox/lox)) and liver-specific AMPK knock-out mice (α1α2(lox/lox) + Albcre) in the presence of fixed glucose. Glucose kinetics were equivalent in 5-h fasted α1α2(lox/lox) and α1α2(lox/lox) + Albcre mice. AMPK was not required for AICAR-mediated suppression of glucose production and increased glucose disappearance. These results demonstrate that AMPK is unnecessary for normal 5-h fasting glucose kinetics and AICAR-mediated inhibition of glucose production. Moreover, plasma fatty acids and triglycerides also decreased independently of hepatic AMPK during AICAR administration. Although the glucoregulatory effects of AICAR were shown to be independent of AMPK, these studies provide in vivo support for the AMPK energy sensor paradigm. AICAR reduced hepatic energy charge by ∼20% in α1α2(lox/lox), which was exacerbated by ∼2-fold in α1α2(lox/lox) + Albcre. This corresponded to a ∼6-fold rise in AMP/ATP in α1α2(lox/lox) + Albcre. Consistent with the effects on adenine nucleotides, maximal mitochondrial respiration was ∼30% lower in α1α2(lox/lox) + Albcre than α1α2(lox/lox) livers. Mitochondrial oxidative phosphorylation efficiency was reduced by 25%. In summary, these results demonstrate that the NMP capacity to inhibit glucose production in vivo is independent of liver AMPK. In contrast, AMPK promotes mitochondrial function and protects against a more precipitous fall in ATP during AICAR administration.

Mass spectrometry-based microassay of (2)H and (13)C plasma glucose labeling to quantify liver metabolic fluxes in vivo.

Mouse models designed to examine hepatic metabolism are critical to diabetes and obesity research. Thus, a microscale method to quantitatively assess hepatic glucose and intermediary metabolism in conscious, unrestrained mice was developed. [(13)C3]propionate, [(2)H2]water, and [6,6-(2)H2]glucose isotopes were delivered intravenously in short- (9 h) and long-term-fasted (19 h) C57BL/6J mice. GC-MS and mass isotopomer distribution (MID) analysis were performed on three 40-µl arterial plasma glucose samples obtained during the euglycemic isotopic steady state. Model-based regression of hepatic glucose and citric acid cycle (CAC)-related fluxes was performed using a comprehensive isotopomer model to track carbon and hydrogen atom transitions through the network and thereby simulate the MIDs of measured fragment ions. Glucose-6-phosphate production from glycogen diminished, and endogenous glucose production was exclusively gluconeogenic with prolonged fasting. Gluconeogenic flux from phosphoenolpyruvate (PEP) remained stable, whereas that from glycerol modestly increased from short- to long-term fasting. CAC flux [i.e., citrate synthase (VCS)] was reduced with long-term fasting. Interestingly, anaplerosis and cataplerosis increased with fast duration; accordingly, pyruvate carboxylation and the conversion of oxaloacetate to PEP were severalfold higher than VCS in long-term fasted mice. This method utilizes state-of-the-art in vivo methodology and comprehensive isotopomer modeling to quantify hepatic glucose and intermediary fluxes during physiological stress in mice. The small plasma requirements permit serial sampling without stress and the affirmation of steady-state glucose kinetics. Furthermore, the approach can accommodate a broad range of modeling assumptions, isotope tracers, and measurement inputs without the need to introduce ad hoc mathematical approximations.

Improved performance on cardiopulmonary exercise testing following DDDR pacemaker adjustment: a case report.

We report a case of improved cardiopulmonary exercise (CPX) test outcomes measured 48 h after initial CPX testing and immediately after alterations were made to the settings of a dual chamber, dual sensing pacemaker with exercise detection. The changes allowed successful abdominal surgery to be completed.

Could exercise be a new strategy to revert some patients with atrial fibrillation?

BACKGROUND: This study is the result of the anecdotal observation that a number of patients with atrial fibrillation (AF) had noted reversion to sinus rhythm (SR) with exercise.We aimed to evaluate the potential role of exercise stress test (EST) for the reversion of AF. METHODS: Patients with AF who were scheduled to undergo electrical cardioversion (DCR) underwent EST using a modified Bruce protocol. RESULTS: Eighteen patients (16 male); aged 36-74 years (mean 58 years) were studied. Five patients (27.7%) had successful reversion with exercise (group 1). Thirteen patients remained in AF (group 2). No patient who failed to revert with exercise did so spontaneously before DCR 3 h to 7 months later (median 20 days). Comparison between group 1 and group 2 did not reveal any significant difference CONCLUSION: This small preliminary study suggests that in some patients it may be possible to revert AF to SR with exercise and avoid DCR and concomitant general anaesthesia. The authors suggest that a larger multicentre randomized trial is warranted to confirm or refute these initial results and if correct identify those who might benefit.

Optimal interference of the tibial component of the cementless Oxford Unicompartmental Knee Replacement.

OBJECTIVES: The primary stability of the cementless Oxford Unicompartmental Knee Replacement (OUKR) relies on interference fit (or press fit). Insufficient interference may cause implant loosening, whilst excessive interference could cause bone damage and fracture.The aim of this study was to identify the optimal interference fit by measuring the force required to seat the tibial component of the cementless OUKR (push-in force) and the force required to remove the component (pull-out force). MATERIALS AND METHODS: Six cementless OUKR tibial components were implanted in 12 new slots prepared on blocks of solid polyurethane foam (20 pounds per cubic foot (PCF), Sawbones, Malmo, Sweden) with a range of interference of 0.1 mm to 1.9 mm using a Dartec materials testing machine HC10 (Zwick Ltd, Herefordshire, United Kingdom) . The experiment was repeated with cellular polyurethane foam (15 PCF), which is a more porous analogue for trabecular bone. RESULTS: The push-in force progressively increased with increasing interference. The pull-out force was related in a non-linear fashion to interference, decreasing with higher interference. Compared with the current nominal interference, a lower interference would reduce the push-in forces by up to 45% (p < 0.001 One way ANOVA) ensuring comparable (or improved) pull-out forces (p > 0.05 Bonferroni post hoc test). With the more porous bone analogue, although the forces were lower, the relationship between interference and push-in and pull-out force were similar. CONCLUSIONS: This study suggests that decreasing the interference fit of the tibial component of the cementless OUKR reduces the push-in force and can increase the pull-out force. An optimal interference fit may both improve primary fixation and decrease the risk of fracture.Cite this article: S. Campi, S. J. Mellon, D. Ridley, B. Foulke, C. A. F. Dodd, H. G. Pandit, D. W. Murray. Optimal interference of the tibial component of the cementless Oxford Unicompartmental Knee Replacement. Bone Joint Res 2018;7:226-231. DOI: 10.1302/2046-3758.73.BJR-2017-0193.R1.

The effect of nicotine in vitro on the integrity of tight junctions in Caco-2 cell monolayers.

Ulcerative colitis is characterised by impairment of the epithelial barrier and tight junction alterations resulting in increased intestinal permeability. UC is less common in smokers with smoking reported to decrease paracellular permeability. The aim of this study was thus to determine the effect of nicotine, the major constituent in cigarettes and its metabolites on the integrity of tight junctions in Caco-2 cell monolayers. The integrity of Caco-2 tight junctions was analysed by measuring the transepithelial electrical resistance (TER) and by tracing the flux of the fluorescent marker fluorescein, after treatment with various concentrations of nicotine or nicotine metabolites over 48 h. TER was significantly higher compared to the control for all concentrations of nicotine 0.01-10 microM at 48 h (p<0.001), and for 0.01 microM (p<0.001) and 0.1 microM and 10 microM nicotine (p < 0.01) at 12 and 24 h. The fluorescein flux results supported those of the TER assay. TER readings for all nicotine metabolites tested were also higher at 24 and 48 h only (p < or = 0.01). Western blot analysis demonstrated that nicotine up-regulated the expression of the tight junction proteins occludin and claudin-1 (p < or = 0.01). Overall, it appears that nicotine and its metabolites, at concentrations corresponding to those reported in the blood of smokers, can significantly improve tight junction integrity, and thus, decrease epithelial gut permeability. We have shown that in vitro, nicotine appears more potent than its metabolites in decreasing epithelial gut permeability. We speculate that this enhanced gut barrier may be the result of increased expression of claudin-1 and occludin proteins, which are associated with the formation of tight junctions. These findings may help explain the mechanism of action of nicotine treatment and indeed smoking in reducing epithelial gut permeability.

Correction: Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation.

[This corrects the article DOI: 10.1371/journal.pone.0170382.].

Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation.

AMPK is an energy sensor that protects cellular energy state by attenuating anabolic and promoting catabolic processes. AMPK signaling is purported to regulate hepatic gluconeogenesis and substrate oxidation; coordination of these processes is vital during nutrient deprivation or pathogenic during overnutrition. Here we directly test hepatic AMPK function in regulating metabolic fluxes that converge to produce glucose and energy in vivo. Flux analysis was applied in mice with a liver-specific deletion of AMPK (L-KO) or floxed control littermates to assess rates of hepatic glucose producing and citric acid cycle (CAC) fluxes. Fluxes were assessed in short and long term fasted mice; the latter condition is a nutrient stressor that increases liver AMP/ATP. The flux circuit connecting anaplerosis with gluconeogenesis from the CAC was unaffected by hepatic AMPK deletion in short and long term fasting. Nevertheless, depletion of hepatic ATP was exacerbated in L-KO mice, corresponding to a relative elevation in citrate synthase flux and accumulation of branched-chain amino acid-related metabolites. L-KO mice also had a physiological reduction in flux from glycogen to G6P. These results demonstrate AMPK is unnecessary for maintaining gluconeogenic flux from the CAC yet is critical for stabilizing liver energy state during nutrient deprivation.

Total hip replacement for neck of femur fracture: Comparing outcomes with matched elective cohort.

INTRODUCTION: Current literature suggests that total hip replacement (THR) is superior to hemiarthroplasty (HA) for neck of femur fracture in selected group of patients. The outcomes of THR undertaken for trauma setting remain unclear when comparing with elective THR. We compared the outcomes of THR trauma cohort with best-matched elective cohort. METHODS: We retrospectively reviewed 102 patients that underwent THR due to trauma from 2011 to 2013. We had access to 90 cases with complete records. Another 90 matched elective cases were obtained from local arthroplasty database. The elective cases were matched for gender, surgical approaches, surgeon's grade, types of implant, patient's age at operation date of ±5 years and operation date of ±60days. Subsequently, the selection criteria were relaxed to patient's age at operation date of ±10 years and operation date of ±60days. Unmatched cases were excluded. Complications and death rate were compared. RESULTS: The average age for both cohorts was 70 years. The trauma cohort had statistically significant lower BMI and longer hospital stay (p=0.001). The Functional Comorbidity Index (FCI) and Charlson Age Comorbidity Index (CACI) were the same for both cohorts, reflecting an active patient selection for THR in our centre. The trauma cohort had higher surgical complication rate (9% vs 4%), particularly higher dislocation rate (7% vs 1%); and higher medical complication rate (32% vs 6%). These were consistent with the literature. Contrary to literature, the trauma cohort had six dislocations that five of them were done via anterolateral approach. Among the eight trauma cases with surgical complications, six cases were performed by trainees. The cause of surgical complications remains unclear due to the nature of retrospective study. The trauma cohort had higher death rate than the elective cohort (14% vs 4%), with one post-operative cardiac arrest in the trauma cohort. The rest were non-orthopaedic related deaths, ranging between four months to four years. CONCLUSION: A more robust way of selecting trauma patients for THR is warranted to reduce morbidity and mortality. Follow-up for the trauma cohort is warranted, as the patients are likely to outlive the implants.

Differential effects of chronic drug treatment on alpha3* and alpha7 nicotinic receptor binding sites, in hippocampal neurones and SH-SY5Y cells.

1. The aim of this study was to compare the effects of chronic treatment (for 4 or 7 days) with nicotinic drugs and 20 mM KCl on numbers of surface alpha7 nicotinic AChR, identified by [(125)I]-alpha bungarotoxin (alpha-Bgt) binding, in primary hippocampal cultures and SH-SY5Y cells. Numbers of alpha3* nicotinic AChR were also examined in SH-SY5Y cells, using [(3)H]-epibatidine, which is predicted to label the total cellular population of predominantly alpha3beta2* nicotinic AChR under the conditions used. 2. All the nicotinic agonists examined, the antagonists d-tubocurarine and methyllycaconitine, and KCl, upregulated [(125)I]-alpha Bgt binding sites by 20 - 60% in hippocampal neurones and, where examined, SH-SY5Y cells. 3. Upregulation of [(125)I]-alpha-Bgt binding sites by KCl was prevented by co-incubation with the L-type Ca2+ channel blocker verapamil or the Ca2+-calmodulin dependent kinase II (CaM-kinase II) inhibitor KN-62. Upregulation of [(125)I]-alpha-Bgt binding sites by nicotine or 3,[(4-dimethylamino) cinnamylidene] anabaseine maleate (DMAC) was insensitive to these agents. 4. [(3)H]-Epibatidine binding sites in SH-SY5Y cells were not affected by KCl but were upregulated in a verapamil-insensitive manner by nicotine and DMAC. KN-62 itself provoked a 2 fold increase in [(3)H]-epibatidine binding. The inactive analogue KN-04 had no effect, suggesting that CaM-kinase II plays a role in regulating numbers of alpha3* nicotinic AChR. 5. These data indicate that numbers of alpha3* and alpha7 nicotinic AChR are modulated differently. Nicotinic agonists and KCl upregulate alpha7 nicotinic AChR through distinct cellular mechanisms, the latter involving L-type Ca2+ channels and CaM-kinase II. In contrast, alpha3* nicotinic AChR are not upregulated by KCl. This difference may reflect the distinct physiological roles proposed for alpha7 nicotinic AChR.

The cryopreservation of standard sera.

To determine the storage temperature needed for the preservation of standard sera for serodiagnostic tests, groups of sera were tested before and after storage at -70 degrees C and -20 degrees C for periods of up to five years. The temperature required depended on the nature of the test, but no definite advantage was found in storage at -70 degrees C. For complement fixation this temperature was inadequate and greatly inferior to liquid nitrogen. For immunofluorescence it had no apparent advantage over a temperature of -20 degrees C, and for some other tests it was no more than marginally superior.

Serum antibodies and jejunal histology in giardiasis associated with malabsorption.

An immunofluorescent test, using Giardia lamblia cysts as antigen, gave positive results in 32/36 cases of giardiasis with malabsorption, 0/2 cases of giardiasis without malabsorption, and 0/17 control patients without giardiasis or malabsorption. The test was positive in 10/34 patients with malabsorption in whom G. lamblia could not be detected by stool examination or biopsy; some of these cases were presumed to be cryptic giardiasis. There was a crude correlation between antibody titre and the severity of the histological lesion in the jejunum. The finding of a reliable source of antigen remains a problem.

Counter immunoelectrophoresis as a rapid screening test for amoebic liver abscess.

Counter immunoelectrophoresis using cellulose acetate as the supporting medium was used as a rapid screening test for amoebic abscess. All the sera from 40 cases gave positive results. No false positives were obtained, but the results in intestinal amoebiasis were less reliable. An attempt was made to account for discrepancies in previous reports.

The metabolism of norethandrolone in the horse: characterization of 16-, 20- and 21-oxygenated metabolites by gas chromatography/mass spectrometry.

After oral administration to a thoroughbred gelding, the anabolic steroid norethandrolone was converted into a complex mixture of oxygenated metabolites. These metabolites were extracted from the urine, deconjugated by methanolysis and converted to their O-methyloxime trimethylsilyl derivatives. Gas chromatographic/mass spectrometric analysis indicated the major metabolites to be 19-norpregnane-3,16,17-triols, 19-norpregnane-3,17,20-triols and 3,17-dihydroxy-19-norpregnan-21-oic acids. Some minor metabolites were also detected.

Heterologous reactions involving parasites, blood group antibodies and tissue components.

The sera of many patients with malaria and filariasis, and also anti-A and B blood group sera, were found to react by immunofluorescence with the somatic musculature of nematodes, especially Ascaris, and human and rat muscle, especially the skeletal type. These reactions were attributed to a polysaccharide related to AB substance in adult nematodes and to raised AB antibodies in malaria. Similar heterologous reactions were found to involve the integument of schistosome adult worms and the microfilariae of Loa loa, which were attributed to the incorporation of host AB blood group substances into the parasite. Other parasites and sera gave mainly negative results. These heterologous reactions constitute a potential hazard in immunofluorescence tests, against which skeletal muscle provides a control. The antibodies concerned were not operative in complement fixation tests, but there was a relationship to anti-complementary activity which suggested the transient presence of a circulating antigen.

Immunofluorescent reactions with microfilariae: 1. Diagnostic evaluation.

Microfilariae have been evaluated as antigen for the indirect immunofluorescent test in the diagnosis of filariasis. Sonicated, unlike whole, microfilariae present no problems in handling on a slide. The cytoplasmic antigen that is exposed by sonication, unlike the sheath or cuticular antigen, reacts with filariasis sera irrespective of whether or not there is a detectable microfilaraemia. The cytoplasmic antigen of microfilariae of various species was marginally superior to Dirofilaria adult worm as antigen for diagnostic immunofluorescence in respect of both sensitivity and specificity. The microfilariae extruded from the uterus of an adult D. immitis were a useful source. But the best results were obtained with the sonicated microfilariae of Brugia pahangi, with which it was possible to utilize both cytoplasmic and sheath antigens simultaneously, giving a positivity rate of 95% for filariasis infecions as a group. This test is thought to be the best available at present for the sero-diagnosis of filariasis, in spite of some lack of specificity. For individual filarial infections a homologous microfilarial antigen is probably the deal.

An evaluation of the ELISA for schistosomiasis in a hospital population.

In order to evaluate the ELISA for schistosomiasis under the conditions of clinical practice, 1576 hospital patients were tested using a crude soluble Schistosoma mansoni egg antigen. Test sensitivity in detection of S. mansoni was found to be 96.2% and in S. haematobium 92.3%. The predictive value of positive results was high, reaching 88% at antibody levels three or more times the screening level. The test was considered by clinicians to be valuable for diagnosis and patient management, though it did not distinguish active from recently treated infections. Of 37 apparently false positive schistosome ELISA results only seven could be attributed to other helminth infections. Another nine patients had hepatitis. It is suggested that the antigens and antibodies of the two diseases are mutually cross-reactive, since reports have suggested a high increase of HBsAg patients with schistosomiasis.

A histological classification of mucocutaneous leishmaniasis in Brazil and its clinical evaluation.

Biopsies of skin and mucosal lesions were made on 60 well documented Brazilian patients with untreated cutaneous or mucocutaneous leishmaniasis, whose response to treatment was subsequently evaluated in 38 cases. The biopsies were examined with a view to classification after correlation with clinical and immunological findings. Although there was no simple or unified spectrum, five histological groups were defined and found to have some clinico-prognostic significance. In two groups the cases were all cutaneous with a relatively good prognosis. In another two groups they were evolving as mucocutaneous with a poor prognosis. The fifth group showed mixed characteristics with a tendency to relapse. There was no strong correlation with serum antibodies or Montenegro skin test, which were usually positive, or with parasite load, which was always low. The tissue response was distinguished from that in oriental sore by the degree of connective tissue involvement in all groups. It was the primary response in two groups, and subsidiary to a mono-nuclear response in the others. It suggested damage due to extra-cellular parasites or immune complexes. It did not correlate with the distinction between cutaneous and mucocutaneous disease. The single, most favourable, prognostic feature in either the cellular or connective tissue component was necrosis with a reactive response.