Bubble accumulation and its role in the evolution of magma reservoirs in the upper crust.

Volcanic eruptions transfer huge amounts of gas to the atmosphere. In particular, the sulfur released during large silicic explosive eruptions can induce global cooling. A fundamental goal in volcanology, therefore, is to assess the potential for eruption of the large volumes of crystal-poor, silicic magma that are stored at shallow depths in the crust, and to obtain theoretical bounds for the amount of volatiles that can be released during these eruptions. It is puzzling that highly evolved, crystal-poor silicic magmas are more likely to generate volcanic rocks than plutonic rocks. This observation suggests that such magmas are more prone to erupting than are their crystal-rich counterparts. Moreover, well studied examples of largely crystal-poor eruptions (for example, Katmai, Taupo and Minoan) often exhibit a release of sulfur that is 10 to 20 times higher than the amount of sulfur estimated to be stored in the melt. Here we argue that these two observations rest on how the magmatic volatile phase (MVP) behaves as it rises buoyantly in zoned magma reservoirs. By investigating the fluid dynamics that controls the transport of the MVP in crystal-rich and crystal-poor magmas, we show how the interplay between capillary stresses and the viscosity contrast between the MVP and the host melt results in a counterintuitive dynamics, whereby the MVP tends to migrate efficiently in crystal-rich parts of a magma reservoir and accumulate in crystal-poor regions. The accumulation of low-density bubbles of MVP in crystal-poor magmas has implications for the eruptive potential of such magmas, and is the likely source of the excess sulfur released during explosive eruptions.

[Individualized treatment strategies for Clostridium difficile infections]. / Individuelle Therapiestrategien bei Clostridium-difficile-Infektionen.

Upon hospitalization, up to 15.5% of patients are already colonized with a toxigenic Clostridium difficile strain (TCD). The rate of asymptomatic colonization is 0-3% in healthy adults and up to 20-40% in hospitalized patients. The incidence and mortality of C. difficile infection (CDI) has significantly increased during recent years. Mortality lies between 3 and 14%. CDI is generally caused by intestinal dysbiosis, which can be triggered by various factors, including antibiotics or immune suppressants. If CDI occurs, ongoing antibiotic therapy should be discontinued. The choice of treatment is guided by the clinical situation: Mild courses of CDI should be treated with metronidazole. Oral vancomycin is suitable as a first-line therapy of mild CDI occurring during pregnancy and lactation, as well as in cases of intolerance or allergy to metronidazole. Severe courses should be treated with vancomycin. Recurrence should be treated with vancomycin or fidaxomicin. Multiple recurrences should be treated with vancomycin or fidaxomicin; if necessary, a vancomycin taper regimen may also be used. An alternative is fecal microbiota transplant (FMT), with healing rates of more than 80%. Bezlotoxumab is the first available monoclonal antibody which neutralizes the C. difficile toxin B, and in combination with an antibiotic significantly reduces the rate of a new C. difficile infection compared to placebo. A better definition of clinical and microbiota-associated risk factors and the ongoing implementation of molecular diagnostics are likely to lead to optimized identification of patients at risk, and an increasing individualization of prophylactic and therapeutic approaches.

[New biologics for treatment of chronic inflammatory bowel diseases]. / Neue Biologika für die Behandlung chronisch-entzündlicher Darmerkrankungen.

BACKGROUND: The therapeutic options for chronic inflammatory bowel diseases have seen an enormous development over the last decades. However, there are several unmet needs which warrant the development of additional biologics for a better and complete control of the inflammatory process. STATE OF DEVELOPMENT: Novel biological therapies that will be approved in the near future include blockade of the adhesion molecule integrin alpha4beta7 and the cytokine interleukin 23. Large phase III trials have established the clinical efficacy in ulcerative colitis and Crohn's disease, respectively. The development of biologic therapies in earlier stages includes additional antibodies that block adhesion molecules as well as biologics that intercept the interleukin 6 pathway. CONCLUSION: The therapeutic landscape in inflammatory bowel disease will be enriched by additional biologic therapies. Clinical studies should investigate the interaction with existing therapies, e.g. anti-tumor necrosis factor (TNF) therapies and the development of new endpoints for a better disease control and for improved long-term outcome.

[Neurological complications of inflammatory bowel diseases]. / Neurologische Komplikationen entzündlicher Darmerkrankungen.

Inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, autoantibody driven celiac disease and infectious Whipple's disease can all be associated with neurological symptoms. The neurological manifestation may occur even before the gastrointestinal symptoms or the enteropathic symptoms can even be absent as in celiac disease. These diseases can be caused by malresorption and lack of vitamins due to enteral inflammation as well as (auto-)immunological mechanisms and drug-associated side effects. Thus, inflammatory bowel diseases have to be considered in the differential diagnosis. In this review the most common neurological manifestations of these diseases will be described as well as the diagnostic approach.

A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin.

AIMS: To test the hypothesis that glycaemic control achieved when switching sitagliptin to exenatide twice daily plus metformin is non-inferior to adding exenatide twice daily to sitagliptin and metformin. METHODS: Patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin were randomly assigned to 20 weeks of treatment with twice-daily exenatide plus placebo and metformin (SWITCH, n = 127) or twice-daily exenatide plus sitagliptin and metformin (ADD, n = 128). RESULTS: Non-inferiority (0.4% margin) of SWITCH to ADD treatment, measured by change in HbA(1c) from baseline to week 20, was not shown {between-treatment difference in least-squares mean [95% CI 3 mmol/mol (0.30%)] [0.8-5.8 (0.07-0.53)]}. A greater reduction (P = 0.012) in HbA(1c) [least-squares mean (se)] was experienced by patients in the ADD group {-7 mmol/mol [-0.68%] [0.9 (0.08)]}, compared with those in the SWITCH group {-4 mmol/mol [-0.38%] [1.0 (0.09)]} and a greater proportion (P = 0.027) of patients in the ADD group (41.7%) reached < 7.0% (< 53 mmol/mol) HbA(1c) target, compared with those in the SWITCH group (26.6%) by week 20. Patients in the ADD group experienced greater fasting serum glucose (P = 0.038) and daily mean postprandial self-monitored blood glucose (P = 0.048) reductions, compared with patients in the SWITCH group, by week 20. Patients in both groups experienced a lower incidence of nausea and vomiting compared with previous exenatide studies. CONCLUSIONS: Non-inferiority of SWITCH to ADD treatment was not supported by the results of this study. In patients with Type 2 diabetes inadequately controlled with sitagliptin plus metformin, adding exenatide provided better glycaemic control than switching to exenatide. These results are consistent with the clinical approach that adding is better than switching to another oral anti-hyperglycaemic medication.

Zircon U-Pb geochronology and trace element dataset from the Southern Rocky Mountain Volcanic Field, Colorado, USA.

This contribution provides in-situ LA-ICP-MS U-Pb ages and trace element determinations of zircons from dacitic to rhyolitic lavas, ignimbrites and intrusions in the Southern Rocky Mountain Volcanic Field (SRMVF) in Colorado, USA. The data record a period of intense magmatic activity in the Oligocene-early Miocene (∼37-22 Ma) which gave rise to some of the largest explosive ignimbrites in the geological record (e.g. the Fish Canyon Tuff). Age data are drift corrected, but not corrected for radiation dosage or Th disequilibrium, in order to allow users to apply their own algorithms. Xenocrysts (much older crystals up to 2 Ga from the Proterozoic basement) are included in this record.

[Pulmonary manifestations of inflammatory bowel disease]. / Pulmonale Manifestation chronisch entzündlicher Darmerkrankungen.

Pulmonary disease is a rare complication of inflammatory bowel disease. Airway inflammation, interstitial lung disease and several other manifestations have been described, and typical symptoms are productive cough, chest pain, and progressive dyspnea. Due to the frequency of preceding pulmonary disease and the common temporal dissociation regarding intestinal disease, pulmonary manifestations of inflammatory bowel disease are at high risk of being overlooked. If suspected, early work-up including CT scan and bronchoscopy should be initiated, since the natural course often involves rapidly progressive lung damage. The best therapeutic results have been obtained with topic and systemic steroids, while classic immunosuppressants are commonly not efficacious. Several case reports describe a beneficial effect of infliximab.

Post-eruptive mobility of lithium in volcanic rocks.

To reflect magmatic conditions, volcanic rocks must retain their compositions through eruption and post-eruptive cooling. Mostly, this is the case. However, welded ignimbrites from the Yellowstone-Snake River Plain magmatic province reveal systematic modification of the lithium (Li) inventory by post-eruptive processes. Here we show that phenocrysts from slowly cooled microcrystalline ignimbrite interiors consistently have significantly more Li than their rapidly quenched, glassy, counterparts. The strong association with host lithology and the invariance of other trace elements indicate that Li remains mobile long after eruption and readily passes into phenocrysts via diffusion as groundmass crystallisation increases the Li contents of the last remaining melts. Li isotopic measurements reveal that this diffusion during cooling combined with efficient degassing on the surface may significantly affect the Li inventory and isotopic compositions of volcanic rocks. Utilisation of Li for petrogenetic studies is therefore crucially dependent on the ability to 'see through' such post-eruptive processes.

Oak tree-rings record spatial-temporal pollution trends from different sources in Terni (Central Italy).

Monitoring atmospheric pollution in industrial areas near urban center is essential to infer past levels of contamination and to evaluate the impact for environmental health and safety. The main aim of this study was to understand if the chemical composition of tree-ring wood can be used for monitoring spatial-temporal variability of pollutants in Terni, Central Italy, one of the most polluted towns in Italy. Tree cores were taken from 32 downy oaks (Quercus pubescens) located at different distances from several pollutant sources, including a large steel factory. Trace element (Cr, Co, Cu, Pb, Hg, Mo, Ni, Tl, W, U, V, and Zn) index in tree-ring wood was determined using high-resolution laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). We hypothesized that the presence of contaminants detected in tree-rings reflected industrial activities over time. The accumulation of contaminants in tree-rings was affected by anthropogenic activities in the period 1958-2009, though signals varied in intensity with the distance of trees from the industrial plant. A stronger limitation of tree growth was observed in the proximity of the industrial plant in comparison with other pollutant sources. Levels of Cr, Ni, Mo, V, U and W increased in tree-ring profiles of trees close to the steel factory, especially during the 80's and 90's, in correspondence to a peak of pollution in this period, as recorded by air quality monitoring stations. Uranium contents in our tree-rings were difficult to explain, while the higher contents of Cu, Hg, Pb, and Tl could be related to the contaminants released from an incinerator located close to the industrial plant. The accumulation of contaminants in tree-rings reflected the historical variation of environmental pollution in the considered urban context.

Patient Education in a 14-month Randomised Trial Fails to Improve Adherence in Ulcerative Colitis: Influence of Demographic and Clinical Parameters on Non-adherence.

BACKGROUND AND AIM: Recent observational studies document that non-adherence to mesalamine therapy during remission is frequent. We aimed to investigate patient impact of patient education using objective assessments of adherence. METHODS: A 14-month randomised, prospective clinical trial of adherence to mesalamine was conducted in 248 patients with ulcerative colitis [UC], Colitis Activity Index [CAI] ≤ 9, receiving standard care [n = 122] versus a standardised patient education programme [n = 126]. Primary endpoint was adherence at all visits (5-aminosalicylic acid [5-ASA] urine levels). Secondary endpoints included quality of life (inflammatory bowel disease questionnaise [IBDQ]), disease activity, partial adherence, and self-assessment of adherence. RESULTS: Patient allocation was well balanced. Baseline non-adherence was high in quiescent/mildly active UC [52.4%] without difference between the groups (52.4% of patients in the education group versus 52.5% in the standard care group [p = 0.99]). No difference between the intervention group and standard care was seen in IBDQ, partial adherence, self-assessment of adherence, or therapy satisfaction at all visits. We suggest a model in which individual risks for non-adherence are driven by patients with young age, short disease duration, and low education levels. CONCLUSIONS: Non-adherence is frequent in a population with quiescent/mildly active UC. Although more than 25% of the population was not in remission at the various time points, no relationship between disease activity and adherence was seen over the 14-month observation period. Physicians should maximise their efforts to motivate high-risk patients for adherence. Future trials should use objective exposure assessments to examine the impact of continuous education and consultations on the background of individual risks to develop non-adherence.

Effects of intravenous and dietary lipid challenge on intramyocellular lipid content and the relation with insulin sensitivity in humans.

An increased intramyocellular lipid (IMCL) content, as quantified by (1)H-magnetic resonance spectroscopy ((1)H-MRS), is associated with reduced insulin sensitivity. At present, it is unclear which factors determine IMCL formation and how rapidly IMCL accumulation can be induced. We therefore studied the impact of hyperinsulinemia and elevated circulating nonesterified fatty acid (NEFA) levels on IMCL formation and insulin sensitivity. We further evaluated the influence of a high-fat diet on IMCL storage. In the infusion protocol, 12 healthy male subjects underwent a 6-h hyperinsulinemic-euglycemic glucose clamp with concomitant infusion of Intralipid plus heparin. IMCL was quantified by (1)H-MRS in soleus (SOL) and tibialis anterior (TA) muscle at baseline and then every hour. IMCL levels started to increase significantly after 2 h, reaching a maximum of 120.8 +/- 3.4% (SOL) and 164.2 +/- 13.8% (TA) of baseline after 6 h (both P < 0.05). In parallel, the glucose infusion rate (GIR) decreased progressively, reaching a minimum of 60.4 +/- 5.4% of baseline after 6 h. Over time, the GIR was strongly correlated with IMCL in TA (r = -0.98, P < or = 0.003) and SOL muscle (r = -0.97, P < or = 0.005). In the diet protocol, 12 male subjects ingested both a high-fat and low-fat diet for 3 days each. Before and after completion of each diet, IMCL levels and insulin sensitivity were assessed. After the high-fat diet, IMCL levels increased significantly in TA muscle (to 148.0 +/- 16.9% of baseline; P = 0.005), but not in SOL muscle (to 114.4 +/- 8.2% of baseline; NS). Insulin sensitivity decreased to 83.3 +/- 5.6% of baseline (P = 0.033). There were no significant changes in insulin sensitivity or IMCL levels after the low-fat diet. The effects of the high-fat diet showed greater interindividual variation than those of the infusion protocol. The data from the lipid infusion protocol suggest a functional relationship between IMCL levels and insulin sensitivity. Similar effects could be induced by a high-fat diet, thereby underlining the physiological relevance of these observations.

Expression and function of Na+HCO3- cotransporters in the gastrointestinal tract.

The stomach, duodenum, colon, and pancreas secrete HCO3- ions into the lumen. Although the importance of HCO3- secretion for the maintenance of mucosal integrity, a normal digestion, and the reabsorption of Cl- has been well established, the molecular nature of the apical and basolateral HCO3- transporting proteins has remained largely unknown. Functional studies have suggested that a Na+HCO3- cotransport system, similar but not identical to the well-characterized Na+HCO3- cotransporter in the basolateral membrane of the kidney proximal tubule, is present in duodenal and colonic enterocytes, pancreatic ducts cells, and gastric cells and involved in HCO3- uptake from the interstitium. This report describes our work towards understanding the molecular nature, cellular origin, and functional relevance of the Na+HCO3- cotransporter(s) in the stomach and intestine and reviews work by others on the function and localization of Na+HCO3- cotransport processes in the gastrointestinal tract.

Na+/HCO3- cotransport in normal and cystic fibrosis intestine.

In a search for the HCO(3)(-) supply mechanisms to the enterocyte we cloned and sequenced an intestinal subtype of the Na(+)HCO(3)(-) cotransporter isoform I (dNBC1), which turned out to be identical to the pancreatic NBC1 subtype (pNBC1). Within the intestine, we found particularly high NBC1 expression levels in the duodenum and proximal colon. Experiments with stripped rabbit duodenum in Ussing-chambers revealed that Na(+)HCO(3)(-) cotransport (NBC) and CO(2) hydration/Na(+)/H(+) exchange were equally important duodenal HCO(3)(-) supply pathways and were both upregulated during cAMP-mediated secretion. In the proximal colon, however, HCO(3)(-) secretion was low but NBC1 expression even higher than in the duodenum. Ussing-chamber experiments with an NBC-specific inhibitor revealed that NBC, coupled to basolateral Cl(-)/HCO(3)(-) exchange, was an important alternative Cl(-) supply pathway to Na(+)K(+)2Cl(-) cotransport (NKCC) during cAMP-stimulated colonic Cl(-) secretion. To investigate the functional integrity of anion uptake pathways in the absence of cystic fibrosis transmembrane conductance regulator (CFTR), we fluorometrically assessed NBC and NKCC transport rates and cell volume before and during forskolin-stimulation in isolated colonic crypts from normal and CFTR (-/-) mice. Although forskolin stimulation decreased cell volume only in normal, not in CFTR (-/-) crypts, it activated NBC and NKCC to a similar degree in both normal and CFTR (-/-) crypts. We conclude that, depending on the intestinal segment, NBC1 plays an important role in basolateral HCO(3)(-) or Cl(-) uptake. Expression and activation by cAMP is preserved in CFTR (-/-) intestine.

Recent advances in the molecular and functional characterization of acid/base and electrolyte transporters in the basolateral membranes of gastric and duodenal epithelial cells.

All segments of the gastrointestinal tract are comprised of an elaborately folded epithelium that expresses a variety of cell types and performs multiple secretory and absorptive functions. While the apical membrane expresses the electrolyte transporters that secrete or absorb electrolytes and water, basolateral transporters regulate the secretory or absorptive rates. During gastric acid formation, Cl⁻/HCO3⁻ and Na(+) /H(+) exchange and other transporters secure Cl⁻ re-supply as well as pH and volume regulation. Gastric surface cells utilize ion transporters to secrete HCO3⁻, maintain pH(i) during a luminal acid load and repair damaged surface areas during the process of epithelial restitution. Na(+)/H(+) exchange and Na(+)/HCO3⁻ cotransport serve basolateral acid/base import for gastroduodenal HCO3⁻ secretion. The gastric and duodenal epithelium also absorbs salt and water. Recent molecular information on novel ion transporters expressed in the gastric and duodenal epithelium has exploded; however, a function has not been found yet for all transporters. The purpose of this review is to summarize current knowledge on the molecular identity and cellular function of basolateral ion transporters in the gastric and duodenal epithelium.

Basolateral ion transporters involved in colonic epithelial electrolyte absorption, anion secretion and cellular homeostasis.

Electrolyte transporters located in the basolateral membrane of the colonic epithelium are increasingly appreciated as elaborately regulated components of specific transport functions and cellular homeostasis: During electrolyte absorption, Na(+) /K(+) ATPase, Cl⁻ conductance, Cl⁻/HCO3⁻ exchange, K(+) /Cl⁻ cotransport and K(+) channels are candidates for basolateral Na(+) , Cl⁻ and K(+) extrusion. The process of colonic anion secretion involves basolateral Na(+) /K(+) /2Cl⁻ , and probably also Na(+) /HCO3⁻ cotransport, as well as Na(+) /K(+) ATPase and K(+) channels to supply substrate, stabilize the membrane potential and generate driving force respectively. Together with a multitude of additional transport systems, Na(+) /H(+) exchange and Na(+) /HCO3⁻ cotransport have been implicated in colonocyte pH(i) and volume homeostasis. The purpose of this article is to summarize recently gathered information on the molecular identity, function and regulation of the involved basolateral transport systems in native tissue. Furthermore, we discuss how these findings can help to integrate these systems into the transport function and the cellular homoeostasis of colonic epithelial cells. Finally, disturbances of basolateral electrolyte transport during disease states such as mucosal inflammation will be reviewed.

Carbachol increases Na+-HCO3- cotransport activity in murine colonic crypts in a M3-, Ca2+/calmodulin-, and PKC-dependent manner.

The Na(+)-HCO(3)(-) cotransporter (NBC) mediates HCO(3)(-) import into the colonocyte via its pNBC1 isoform. Whereas renal kNBC1 is inhibited by increased cAMP levels, pNBC1 is stimulated. Cholinergic stimulation activates renal NBC, but the effect on intestinal NBC is unknown. Therefore, crypts were isolated from the murine proximal colon by Ca(2+) chelation and loaded with the pH-sensitive dye 2',7'-bis-carboxyethyl-5,6-carboxyfluorescein. Na(+)-HCO(3)(-) cotransport activity was calculated from the dimethylamiloride-insensitive (500 microM) intracellular pH recovery from an acid load in the presence of CO(2)-HCO(3)(-) and the intracellular buffering capacity. Carbachol strongly increased Na(+)-HCO(3)(-) cotransport activity compared with control rates. Ca(2+) chelation with BAPTA-AM, blockade of the M(3) subtype of muscarinergic receptors with 4-diphenylacetoxy-N-methylpiperidine methiodide, and inhibition of Ca(2+)/calmodulin kinase II with KN-62 all caused significant inhibition of the carbachol-induced NBC activity increase. Furthermore, PKC inhibition with Gö-6976 and Gö-6850 significantly reduced the carbachol effect, which may be related to the unique NH(2)-terminal consensus site for PKC-dependent phosphorylation of pNBC1. We conclude that NBC in the murine colon is thus activated by carbachol, consistent with its presumed function as an anion uptake pathway during intestinal anion secretion, but that the signal transductions pathways are distinct from those involved in the cholinergic activation of renal NBC1.

[Incarcerated Spieghel-Hernie mimicking an acute exacerbation of Crohn's disease]. / "Akute Exazerbation des Morbus Crohn" erweist sich sonographisch als inkarzerierte Spieghel-Hernie.

We report on a 25-year-old woman with long-standing Crohn's disease. Upon admittance to the emergency department, the patient complained of abdominal pain with increasing intensity over the last few days. Clinical examination revealed an abdominal mass in the right lower quadrant, and blood tests showed elevated markers of inflammation. Surprisingly, abdominal ultrasound did not show the suspected complication of Crohn's disease, but rather an incarcerated abdominal wall hernia, which turned out to be a spigelian hernia upon surgical repair. This case stresses the importance of abdominal ultrasound to rule out other diagnoses in patients with chronic inflammatory bowel disease in the emergency setting before starting a potentially dangerous treatment with high-dose steroids.