The hepatitis B virus (HBV) replicates via an error‐prone reverse transcriptase generating potential drug‐resistant quasispecies. The degree of HBV variability in liver vs peripheral blood ...mononuclear cells (PBMC) in patients on long‐term suppressive antivirals is unclear. We characterized HBV replication, drug resistance and molecular diversity in patients with plasma HBV DNA undetectable by clinical assays. Explant liver (n = 9), PBMC (n = 6) and plasma (n = 7) from nine such patients undergoing liver transplantation were evaluated for HBV genomes by sensitive PCR/nucleic acid hybridization assay. Cases with HBV DNA in liver and PBMC were tested for covalently closed circular DNA (HBV cccDNA). HBV polymerase (P) amplicons were cloned, sequenced and both P and overlapping surface (S) gene sequences were analysed. HBV DNA was detected in 43% (3/7) of plasma, 100% (9/9) of liver and 83% (5/6) of PBMC samples. HBV cccDNA was detected in all liver and one PBMC sample. Four patients had a clinical diagnosis of resistance. HBV P gene sequencing revealed 100% wild type (wt) in plasma (2/2), 83% wt in PBMC (5/6) but livers of 3/9 (33%) contained wt and 6/9 (66%) carried resistance to lamivudine and/or adefovir. The translated S gene revealed no changes affecting HBV antigenicity. Sequences from livers with antiviral resistant mutants revealed greater interpatient quasispecies diversity. Despite apparent HBV suppression, the liver continues to support HBV replication and extrahepatic HBV can be detected. PBMC may be a sanctuary for wt virus during antiviral therapy, while the liver harbours more drug‐resistant viruses. Drug resistance correlates with intrahepatic viral diversity.
SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn's disease (CD), ...suggesting a role in inflammation. We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro-generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206.sup.+ regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF, by CD14.sup.+ macrophages isolated from CD intestinal mucosa. This study identifies SP140 as a druggable epigenetic therapeutic target for CD.
Hydrogen peroxide (H
2O
2) has been observed in significant concentrations in many natural waters. Because hydrogen peroxide can act as an oxidant and reductant, it participates in an extensive suite ...of reactions in surface waters. Hydrogen peroxide is produced as a secondary photochemical product of chromophoric dissolved organic matter (CDOM) photolysis. Apparent quantum yields for the photochemical production of hydrogen peroxide were determined in laboratory irradiations of filtered surface waters from several locations in the Chesapeake Bay and in Arctic coastal waters with varying levels of CDOM. The apparent quantum yield for H
2O
2 decreases by about an order of magnitude from 280 nm to 500 nm, and the majority of H
2O
2 production occurs at wavelengths less than 340 nm. The apparent quantum yield for H
2O
2 production at 290 nm ranged from 4.2
×
10
−
4
to 2.1
×
10
−
6
mol H
2O
2 (mol photons)
−
1
from freshwater to marine waters. A linear relationship was found between the production of H
2O
2 and change in CDOM absorbance characterized as photobleaching (loss of absorbance). No significant relationship was observed between DOC concentration and peroxide production. Methylhydroperoxide (CH
3O
2H) was the only short chain peroxide produced during the irradiations, and its production is at least an order magnitude less than that of hydrogen peroxide. Peroxide production was greatest in waters containing significant amounts of terrigenous C in the form of humic substances. Surface waters whose synchronous fluorescence spectra indicated the presence of polyaromatic and/or extensive conjugated compounds exhibited the greatest peroxide production. CDOM photobleaching is not significantly linked to apparent quantum yields for peroxide production.
Summary
Background : Tegaserod reduces the symptoms associated with irritable bowel syndrome, and anti‐nociceptive effects have been demonstrated in animals. Its effect on the rectal sensitivity in ...humans has not been delineated clearly.
Aim : To evaluate the action of tegaserod on rectal sensitivity in response to distension by means of a reflexological technique based on electrophysiological recordings of the RIII nociceptive reflex.
Methods : A randomized, double‐blind, placebo‐controlled study, performed in 20 healthy women, quantified the effects of slow or rapid rectal distensions on the RIII reflex at baseline and on day 8 following treatment with either placebo or tegaserod (6 mg b.d.).
Results : At baseline, slow distensions performed up to the pain threshold induced gradual inhibitions of the RIII reflex. On day 8, these inhibitory effects were significantly reduced in the tegaserod group, but not in the placebo group (P = 0.0001). The effects of rapid distensions were not significantly modified by tegaserod or placebo. The intensity of subjective pain perception and rectal compliance were not altered by either treatment.
Conclusion : These results suggest that tegaserod reduces the sensitivity to rectal distension in healthy subjects and interacts with the processing of sensory visceral information.
Oceanic plateaus form by mantle processes distinct from those forming oceanic crust at divergent plate boundaries. Eleven drillsites into igneous basement of Kerguelen Plateau and Broken Ridge, ...including seven from the recent Ocean Drilling Program Leg 183 (1998–99) and four from Legs 119 and 120 (1987–88), show that the dominant rocks are basalts with geochemical characteristics distinct from those of mid-ocean ridge basalts. Moreover, the physical characteristics of the lava flows and the presence of wood fragments, charcoal, pollen, spores and seeds in the shallow water sediments overlying the igneous basement show that the growth rate of the plateau was sufficient to form subaerial landmasses. Most of the southern Kerguelen Plateau formed at ∼110 Ma, but the uppermost submarine lavas in the northern Kerguelen Plateau erupted during Cenozoic time. These results are consistent with derivation of the plateau by partial melting of the Kerguelen plume. Leg 183 provided two new major observations about the final growth stages of the Kerguelen Plateau. 1: At several locations, volcanism ended with explosive eruptions of volatile-rich, felsic magmas; although the total volume of felsic volcanic rocks is poorly constrained, the explosive nature of the eruptions may have resulted in globally significant effects on climate and atmospheric chemistry during the late-stage, subaerial growth of the Kerguelen Plateau. 2: At one drillsite, clasts of garnet–biotite gneiss, a continental rock, occur in a fluvial conglomerate intercalated within basaltic flows. Previously, geochemical and geophysical evidence has been used to infer continental lithospheric components within this large igneous province. A continental geochemical signature in an oceanic setting may represent deeply recycled crust incorporated into the Kerguelen plume or continental fragments dispersed during initial formation of the Indian Ocean during breakup of Gondwana. The clasts of garnet–biotite gneiss are the first unequivocal evidence of continental crust in this oceanic plateau. We propose that during initial breakup between India and Antarctica, the spreading center jumped northwards transferring slivers of the continental Indian plate to oceanic portions of the Antarctic plate.
We conducted a prospective cohort study between 1 January 2010 and 31 December 2012 at five adult and paediatric academic medical centres to identify factors associated with persistent ...methicillin-resistant Staphylococcus aureus (MRSA) colonisation. Adults and children presenting to ambulatory settings with a MRSA skin and soft tissue infection (i.e. index cases), along with household members, performed self-sampling for MRSA colonisation every 2 weeks for 6 months. Clearance of colonisation was defined as two consecutive negative sampling periods. Subjects without clearance by the end of the study were considered persistently colonised and compared with those who cleared colonisation. Of 243 index cases, 48 (19·8%) had persistent colonisation and 110 (45·3%) cleared colonisation without recurrence. Persistent colonisation was associated with white race (odds ratio (OR), 4·90; 95% confidence interval (CI), 1·38–17·40), prior MRSA infection (OR 3·59; 95% CI 1·05–12·35), colonisation of multiple sites (OR 32·7; 95% CI 6·7–159·3). Conversely, subjects with persistent colonisation were less likely to have been treated with clindamycin (OR 0·28; 95% CI 0·08–0·99). Colonisation at multiple sites is a risk factor for persistent colonisation and may require more targeted decolonisation efforts. The specific effect of clindamycin on MRSA colonisation needs to be elucidated.
Objective: To study the impact on outcomes of direct admission versus emergency room (ER) admission in patients with ST-segment elevation myocardial infarction (STEMI) Design: Nationwide ...observational registry of STEMI patients Setting: 369 intensive care units in France. Interventions: Patients were categorised on the basis of the initial management pathway (direct transfer to the coronary care unit or catheterisation laboratory versus transfer via the ER). Main outcome measures: Delays between symptom onset, admission and reperfusion therapy. Mortality at five days and one year. Results: Of 1204 patients enrolled, 66.9% were admitted direct and 33.1% via the ER. Bypassing the ER was associated with more frequent use of reperfusion (61.7% v 53.1%; p = 0.001) and shorter delays between symptom onset and admission (244 (interquartile range 158) v 292 (172) min; p < 0.001), thrombolysis (204 (150) v 258 (240) min; p < 0.01), hospital thrombolysis (228 (156) v 256 (227) min, p = 0.22), and primary percutaneous coronary intervention (294 (246) v 402 (312) min; p < 0.005). Five day mortality rates were lower in patients who bypassed the ER (4.9% v 8.6%; p = 0.01), regardless of the use and type of reperfusion therapy. After adjusting for the simplified Thrombolysis in Myocardial Infarction (TIMI) risk score, admission via the ER was an independent predictor of five day mortality (odds ratio 1.67, 95% confidence interval 1.01 to 2.75). Conclusions: In this observational analysis, bypassing the ER was associated with more frequent and earlier use of reperfusion therapy, and with an apparent survival benefit compared with admission via the ER.
Few studies have been conducted addressing the safety of thiopurine treatment in pregnant women with inflammatory bowel disease (IBD). The aim of this study was to evaluate the pregnancy outcome of ...women with IBD who have been exposed to thiopurines.
215 pregnancies in 204 women were registered and documented in the CESAME cohort between May 2004 and October 2007. Physicians documented the following information from the women: last menstrual date, delivery term, details of pregnancy outcome, prematurity, birth weight and height, congenital abnormalities, medication history during each trimester, smoking history and alcohol ingestion. Data were compared between three groups: women exposed to thiopurines (group A), women receiving a drug other than thiopurines (group B) and women not receiving any medication (group C).
Mean age at pregnancy was 28.3 years. 75.7% of the women had Crohn's disease and 21.8% had ulcerative colitis, with a mean disease duration of 6.8 years at inclusion. Of the 215 pregnancies, there were 138 births (142 newborns), and the mean birth weight was 3135 g. There were 86 pregnancies in group A, 84 in group B and 45 in group C. Interrupted pregnancies occurred in 36% of patients enrolled in group A, 33% of patients enrolled in group B, and 40% of patients enrolled in group C; congenital abnormalities arose in 3.6% of group A cases and 7.1% of group B cases. No significant differences were found between the three groups in overall pregnancy outcome.
The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.
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