Bariatric surgery partially reverses subclinical proarrhythmic structural, electrophysiological, and autonomic changes in obesity.

BACKGROUND: Obesity confers higher risks of cardiac arrhythmias. The extent to which weight loss reverses subclinical proarrhythmic adaptations in arrhythmia-free obese individuals is unknown. OBJECTIVE: The purpose of this study was to study structural, electrophysiological, and autonomic remodeling in arrhythmia-free obese patients and their reversibility with bariatric surgery using electrocardiographic imaging (ECGi). METHODS: Sixteen arrhythmia-free obese patients (mean age 43 ± 12 years; 13 females; BMI 46.7 ± 5.5 kg/m2) had ECGi pre-bariatric surgery, of whom 12 had ECGi postsurgery (BMI 36.8 ± 6.5 kg/m2). Sixteen age- and sex-matched lean healthy individuals (mean age 42 ± 11 years; BMI 22.8 ± 2.6 kg/m2) acted as controls and had ECGi only once. RESULTS: Obesity was associated with structural (increased epicardial fat volumes and left ventricular mass), autonomic (blunted heart rate variability), and electrophysiological (slower atrial conduction and steeper ventricular repolarization gradients) remodeling. After bariatric surgery, there was partial structural reverse remodeling, with a reduction in epicardial fat volumes (68.7 cm3 vs 64.5 cm3; P = .0010) and left ventricular mass (33 g/m2.7 vs 25 g/m2.7; P < .0005). There was also partial electrophysiological reverse remodeling with a reduction in mean spatial ventricular repolarization gradients (26 mm/ms vs 19 mm/ms; P = .0009), although atrial activation remained prolonged. Heart rate variability, quantified by standard deviation of successive differences in R-R intervals, was also partially improved after bariatric surgery (18.7 ms vs 25.9 ms; P = .017). Computational modeling showed that presurgery obese hearts had a larger window of vulnerability to unidirectional block and had an earlier spiral-wave breakup with more complex reentry patterns than did postsurgery counterparts. CONCLUSION: Obesity is associated with adverse electrophysiological, structural, and autonomic remodeling that is partially reversed after bariatric surgery. These data have important implications for bariatric surgery weight thresholds and weight loss strategies.

Comparative analysis of the anthelmintic efficacy of European heather extracts on Teladorsagia circumcincta and Trichostrongylus colubriformis egg hatching and larval motility.

BACKGROUND: Gastrointestinal nematode (GIN) control is traditionally achieved with the use of anthelmintic drugs, however due to regulations in organic farming and the rise in anthelmintic resistance, alternatives are sought after. A promising alternative is the use of bioactive plant feeding due to the presence of plant secondary metabolites (PSMs) such as proanthocyanidins (PAs). This study focussed on the perennial shrub heather (Ericaceae family), a plant rich in PAs, highly abundant across Europe and with previously demonstrated anthelmintic potential. METHODS: In vitro assays were used to investigate heather's anthelmintic efficacy against egg hatching and larval motility. Heather samples were collected from five European countries across two seasons, and extracts were tested against two GIN species: Teladorsagia circumcincta and Trichostrongylus colubriformis. Polyphenol group-specific ultraperformance liquid chromatography-tandem mass spectrometry analysis was performed to identify relevant polyphenol subgroups present, including the PA concentration and size and ratio of the subunits. Partial least squares analysis was performed to associate efficacy with variation in PSM composition. RESULTS: Heather extracts reduced egg hatching of both GIN species in a dose-dependent manner by up to 100%, while three extracts at the highest concentration (10 mg/ml) reduced larval motility to levels that were not significantly different from dead larvae controls. PAs, particularly the procyanidin type, and flavonol derivatives were associated with anthelmintic activity, and the particular subgroup of polyphenols associated with the efficacy was dependent on the GIN species and life stage. CONCLUSIONS: Our results provide in vitro evidence that heather, a widely available plant often managed as a weed in grazing systems, has anthelmintic properties attributed to various groups of PSMs and could contribute to sustainable GIN control in ruminant production systems across Europe.

Carvacrol Suppresses Inflammatory Biomarkers Production by Lipoteichoic Acid- and Peptidoglycan-Stimulated Human Tonsil Epithelial Cells.

Pharyngitis is an inflammation of the pharynx caused by viral, bacterial, or non-infectious factors. In the present study, the anti-inflammatory efficacy of carvacrol was assessed using an in vitro model of streptococcal pharyngitis using human tonsil epithelial cells (HTonEpiCs) induced with Streptococcus pyogenes cell wall antigens. HTonEpiCs were stimulated by a mixture of lipoteichoic acid (LTA) and peptidoglycan (PGN) for 4 h followed by exposure to carvacrol for 20 h. Following exposure, interleukin (IL)-6, IL-8, human beta defensin-2 (HBD-2), epithelial-derived neutrophil-activating protein-78 (ENA-78), granulocyte chemotactic protein-2 (GCP-2), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and prostaglandin (PGE2) were measured by enzyme-linked immunosorbent assays (ELISA). The levels of pro-inflammatory cytokines, IL-6, IL-8, ENA-78, and GCP-2 were decreased in a carvacrol dose-dependent manner. The production of HBD-2 was significantly suppressed over 24 h carvacrol treatments. PGE2 and COX-2 levels in the cell suspensions were affected by carvacrol treatment. TNF-α was not detected. The cell viability of all the tested carvacrol concentrations was greater than 80%, with no morphological changes. The results suggest that carvacrol has anti-inflammatory properties, and carvacrol needs to be further assessed for potential clinical or healthcare applications to manage the pain associated with streptococcal pharyngitis.

Chronic obstructive pulmonary disease mortality, a competing risk analysis.

BACKGROUND: Current risk factors for Chronic Obstructive Pulmonary Disease mortality focus only on overall and respiratory death. We investigated whether risk factors for each specific cause of mortality are different depending on the outcome under consideration. METHODS: This retrospective cohort study included patients with a clinical diagnosis of COPD, older than 40, greater than 20 pack-years smoking history, and obstructive pattern on spirometry. Collected data included baseline spirometry, comorbidities, medication use, tobacco exposure, severe exacerbations, and cause-specific mortality. RESULTS: This 512 patient cohort of heavy smokers included 277 (54.1%) males, was on average 66.4 ± 9.4 years of age and primarily non-Hispanic white, 395 (83.2%). The average FEV1% was 52.1% (SD = 16.9%) and the median COTE score was 2 (IQR: 0-6). A total of 67 deaths were of respiratory causes in 26 patients (38.8%), malignancies in 21 (31.1%), cardiovascular causes in 6 (9%), and from other etiologies in 14 patients (20.1%). COTE index,low predicted FEV1%, and lower body mass index were significant predictors of overall mortality. Predictors of respiratory deaths were significantly impacted by lower FEV1%, history of COPD exacerbations, lower BMI, and higher number of pack-years smoked. Risk factors for all other cause-specific mortality combined included history of malignancy or cardiovascular disease and smoking status. CONCLUSION: Cause-specific mortality risk factors differ in patients with COPD.

Novel Iron-Chelator DIBI Inhibits Staphylococcus aureus Growth, Suppresses Experimental MRSA Infection in Mice and Enhances the Activities of Diverse Antibiotics in vitro.

DIBI, a purpose-designed hydroxypyridinone-containing iron-chelating antimicrobial polymer was studied for its anti-staphylococcal activities in vitro in comparison to deferiprone, the chemically related, small molecule hydroxypyridinone chelator. The sensitivities of 18 clinical isolates of Staphylococcus aureus from human, canine and bovine infections were determined. DIBI was strongly inhibitory to all isolates, displaying approximately 100-fold more inhibitory activity than deferiprone when compared on their molar iron-binding capacities. Sensitivity to DIBI was similar for both antibiotic-resistant and -sensitive isolates, including hospital- and community-acquired (United States 300) MRSA. DIBI inhibition was primarily bacteriostatic in nature at low concentration and was reversible by addition of Fe. DIBI also exhibited in vivo anti-infective activity in two distinct MRSA ATCC43300 infection and colonization models in mice. In a superficial skin wound infection model, topical application of DIBI provided a dose-dependent suppression of infection along with reduced wound inflammation. Intranasal DIBI reduced staphylococcal burden by >2 log in a MRSA nares carriage model. DIBI was also examined for its influence on antibiotic activities with a reference isolate ATCC6538, typically utilized to assess new antimicrobials. Sub-bacteriostatic concentrations of DIBI resulted in Fe-restricted growth and this physiological condition displayed increased sensitivity to GEN, CIP, and VAN. DIBI did not impair antibiotic activity but rather it enhanced overall killing. Importantly, recovery growth of survivors that typically followed an initial sub-MIC antibiotic killing phase was substantially suppressed by DIBI for each of the antibiotics examined. DIBI has promise for restricting staphylococcal infection on its own, regardless of the isolate's animal source or antibiotic resistance profile. DIBI also has potential for use in combination with various classes of currently available antibiotics to improve their responses.

Iron Restriction to Clinical Isolates of Candida albicans by the Novel Chelator DIBI Inhibits Growth and Increases Sensitivity to Azoles In Vitro and In Vivo in a Murine Model of Experimental Vaginitis.

Candida albicans is an important opportunistic pathogen causing various human infections that are often treated with azole antifungals. The U.S. CDC now regards developing candidal antifungal resistance as a threat, creating a need for new and more effective antifungal treatments. Iron is an essential nutrient for all living cells, and there is growing evidence that interference with iron homeostasis of C. albicans can improve its response to antifungals. This study was aimed at establishing whether withholding iron by currently used medical iron chelators and the novel chelator DIBI could restrict growth and also enhance the activity of azoles against clinical isolates of C. albicans DIBI, but not deferoxamine or deferiprone, inhibited the growth of C. albicans at relatively low concentrations in vitro, and this inhibition was reversed by iron addition. DIBI in combination with various azoles demonstrated stronger growth inhibition than the azoles alone and greatly prolonged the inhibition of cell multiplication. In addition, the administration of DIBI along with fluconazole (FLC) to mice inoculated with an FLC-sensitive isolate in a model of experimental C. albicans vaginitis showed a markedly improved clearance of infection. These results suggest that iron chelation by DIBI has the potential to enhance azole efficacy for the treatment of candidiasis.

Toward an iron(II) spin-crossover grafted phosphazene polymer.

Two new cyclotriphosphazene ligands with pendant 2,2':6',2″-terpyridine (Terpy) moieties, namely, (pentaphenoxy){4-[2,6-bis(2-pyridyl)]pyridoxy}cyclotriphosphazene (L(1)), (pentaphenoxy){4-[2,6-terpyridin-4-yl]phenoxy}cyclotriphosphazene (L(2)), and their respective polymeric analogues, L(1P) and L(2P), were synthesized. These ligands were used to form iron(II) complexes with an Fe(II)Terpy(2) core. Variable-temperature resonance Raman, UV-visible, and Mössbauer spectroscopies with magnetic measurements aided by density functional theory calculations were used to understand the physical characteristics of the complexes. By a comparison of measurements, the polymers were shown to behave in the same way as the cyclotriphosphazene analogues. The results showed that spin crossover (SCO) can be induced to start at high temperatures by extending the spacer length of the ligand to that in L(2) and L(2P); this combination provides a route to forming a malleable SCO material.

Detection of mumps virus RNA by real-time one-step reverse transcriptase PCR using the LightCycler platform.

A real-time reverse transcriptase PCR (RT-PCR) assay that targeted both the mumps virus F gene and human RNase P in clinical samples was adapted for use with the LightCycler platform. LightCycler RT-PCR is as sensitive as conventional nested RT-PCR and significantly less expensive and labor-intensive, making it ideal for mumps diagnosis during outbreaks.

Morphology and localization of interstitial cells in the guinea pig bladder: structural relationships with smooth muscle and neurons.

PURPOSE: In the current study we examined the location of interstitial cell of Cajal (ICC)-like cells in the guinea pig bladder wall and studied their structural interactions with nerves and smooth muscle cells. MATERIALS AND METHODS: Whole mount samples and cryosections of bladder tissue were labeled with primary and fluorescent secondary antibodies, and imaged using confocal and multiphoton microscopy. RESULTS: Kit positive ICC-like cells were located below the urothelium, in the lamina propria region and throughout the detrusor. In the suburothelium they had a stellate morphology and appeared to network. They made connections with nerves, as shown by double labeling experiments with anti-kit and anti-protein gene product 9.5. A network of vimentin positive cells was also found, of which many but not all were kit positive. In the detrusor kit positive cells were most often seen at the edge of smooth muscle bundles. They were elongated with lateral branches, running in parallel with the bundles and closely associated with intramural nerves. Another population of kit positive cells was seen in the detrusor between muscle bundles. These cells had a more stellate-like morphology and made connections with each other. Kit positive cells were seen tracking nerve bundles and close to intramural ganglia. Vimentin positive cells were present in the detrusor, of which some were also kit positive. CONCLUSIONS: There are several populations of ICC-like cells throughout the guinea pig bladder wall. They differ in morphology and orientation but all make connections with intramural nerves and in the detrusor they are closely associated with smooth muscle cells.