Magnesium for alcohol withdrawal.

BACKGROUND: Patients have been given magnesium to treat or prevent alcohol withdrawal syndrome (AWS). Evidence to support this practice is limited, and is often based on the controversial link between hypomagnesaemia and AWS. OBJECTIVES: To assess the effects of magnesium for the prevention or treatment of AWS in hospitalised adults. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Register of Controlled Trials (August 2012), PubMed (from 1966 to August 2012 ), EMBASE (from 1988 to August 2012), CINAHL (from 1982 to March 2010), Web of Science (1965 to August 2012). We also carried out Internet searches. SELECTION CRITERIA: Randomised or quasi-randomised trials of magnesium for hospitalised adults with, or at risk for, acute alcohol withdrawal. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data with a standardised data extraction form, contacting the correspondence investigator if the necessary information was not available in the reports. Dichotomous outcomes were analysed by calculating the risk ratio (RR) for each trial, with the uncertainty in each result expressed with a 95% confidence interval (CI). Continuous outcomes were to be analysed by calculating the standardised mean difference (SMD) with 95% CI. For outcomes assessed by scales we compared and pooled the mean score differences from the end of treatment to baseline (post minus pre) in the experimental and control groups. MAIN RESULTS: Four trials involving 317 people met the inclusion criteria. Three trials studied oral magnesium, with doses ranging from 12.5 mmol/day to 20 mmol/day. One trial studied parenteral magnesium (16.24 mEq q6h for 24 hours). Each trial demonstrated a high risk of bias in at least one domain. There was significant clinical and methodological variation between trials.We found no study that measured all of the identified primary outcomes and met the objectives of this review. Only one trial measured clinical symptoms of seizure, delirium tremens or components of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score. A single outcome (handgrip strength) in three trials (113 people), was amenable to meta-analysis. There was no significant increase in handgrip strength in the magnesium group (SMD 0.04; 95% CI -0.22 to 0.30). No clinically important changes in adverse events were reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether magnesium is beneficial or harmful for the treatment or prevention of alcohol withdrawal syndrome.

The structure of the CS1 pilus of enterotoxigenic Escherichia coli reveals structural polymorphism.

Enterotoxigenic Escherichia coli (ETEC) is a bacterial pathogen that causes diarrhea in children and travelers in developing countries. ETEC adheres to host epithelial cells in the small intestine via a variety of different pili. The CS1 pilus is a prototype for a family of related pili, including the CFA/I pili, present on ETEC and other Gram-negative bacterial pathogens. These pili are assembled by an outer membrane usher protein that catalyzes subunit polymerization via donor strand complementation, in which the N terminus of each incoming pilin subunit fits into a hydrophobic groove in the terminal subunit, completing a ß-sheet in the Ig fold. Here we determined a crystal structure of the CS1 major pilin subunit, CooA, to a 1.6-Å resolution. CooA is a globular protein with an Ig fold and is similar in structure to the CFA/I major pilin CfaB. We determined three distinct negative-stain electron microscopic reconstructions of the CS1 pilus and generated pseudoatomic-resolution pilus structures using the CooA crystal structure. CS1 pili adopt multiple structural states with differences in subunit orientations and packing. We propose that the structural perturbations are accommodated by flexibility in the N-terminal donor strand of CooA and by plasticity in interactions between exposed flexible loops on adjacent subunits. Our results suggest that CS1 and other pili of this class are extensible filaments that can be stretched in response to mechanical stress encountered during colonization.

Structure of the Vibrio cholerae Type IVb Pilus and stability comparison with the Neisseria gonorrhoeae type IVa pilus.

Type IV pili are multifunctional filaments displayed on many bacterial pathogens. Members of the Type IVa pilus subclass are found on a diverse group of human pathogens, whereas Type IVb pili are found almost exclusively on enteric bacteria. The Type IVa and IVb subclasses are distinguished by differences in the pilin subunits, including the fold of the globular domain. To understand the implications of the distinct pilin folds, we compared the stabilities of pilin subunits and pilus filaments for the Type IVa GC pilus from Neisseria gonorrhoeae and the Type IVb toxin-coregulated pilus (TCP) from Vibrio cholerae. We show that while recombinant TCP pilin is more stable than GC pilin, the GC pili are more resistant to proteolysis, heat and chemical denaturation than TCP, remaining intact in 8 M urea. To understand these differences, we determined the TCP structure by electron microscopy and three-dimensional image reconstruction. TCP have an architecture similar to that of GC pili, with subunits arranged in a right-handed 1-start helix and related by an 8.4-Å axial rise and a 96.8° azimuthal rotation. However, the TCP subunits are not as tightly packed as GC pilins, and the distinct Type IVb pilin fold exposes a segment of the α-helical core of TCP. Hydrophobic interactions dominate for both pilus subtypes, but base stacking by aromatic residues conserved among the Type IVa pilins may contribute to GC pilus stability. The extraordinary stability of GC pili may represent an adaptation of the Type IVa pili to harsh environments and the need to retract against external forces.

Type IV pili: paradoxes in form and function.

Type IV pili are filaments on the surfaces of many Gram-negative bacteria that mediate an extraordinary array of functions, including adhesion, motility, microcolony formation and secretion of proteases and colonization factors. Their prominent display on the surfaces of many bacterial pathogens, their vital role in virulence, and their ability to elicit an immune response make Type IV pilus structures particularly relevant for study as targets for component vaccines and therapies. Structural studies of the pili and components of the pilus assembly apparatus have proven extremely challenging, but new approaches and methods have produced important breakthroughs that are advancing our understanding of pilus functions and their complex assembly mechanism. These structures provide insights into the biology of Type IV pili as well as that of the related bacterial secretion and archaeal flagellar systems. This review will summarize the most recent structural advances on Type IV pili and their assembly components and highlight their significance.

Vibrio cholerae toxin-coregulated pilus structure analyzed by hydrogen/deuterium exchange mass spectrometry.

The bacterial pathogen Vibrio cholerae uses toxin-coregulated pili (TCP) to colonize the human intestine, causing the severe diarrheal disease cholera. TCP are long, thin, flexible homopolymers of the TcpA subunit that self-associate to hold cells together in microcolonies and serve as the receptor for the cholera toxin phage. To better understand TCP's roles in pathogenesis, we characterized its structure using hydrogen/deuterium exchange mass spectrometry and computational modeling. We show that the pilin subunits are held together by tight packing of the N-terminal alpha helices, but loose packing of the C-terminal globular domains leaves substantial gaps on the filament surface. These gaps expose a glycine-rich, amphipathic segment of the N-terminal alpha-helix, contradicting the consensus view that this region is buried in the filament core. Our results explain extreme filament flexibility, suggest a molecular basis for pilus-pilus interactions, and reveal a previously unrecognized therapeutic target for V. cholerae and other enteric pathogens.

Isolation of pulmonary veins using a transvenous curvilinear cryoablation catheter: feasibility, initial experience, and analysis of recurrences.

INTRODUCTION: Pulmonary vein isolation (PVI) using focal cryothermal catheters is safe and moderately effective, but associated with long procedure times. We hypothesized that a linear freezing segment could shorten fluoroscopic and procedure times. We report our initial experience with a novel circular cryothermal catheter. METHODS AND RESULTS: Complete PV isolation (PVI) was achieved in 41 of 45 PVs by cryoablation (91%) in 18 patients who underwent Lasso-guided cryothermal using a novel 7 F circular catheter (2.5 +/- 0.7 veins per patient). A mean of 27.2 +/- 11 applications per patient (9.2 +/- 4.7 per vein) with a mean temperature -79.8 +/- 4 degrees C were delivered. Recorded temperatures did not predict complete or incomplete isolation. Focal cryothermal ablation using a 7 F 4-mm tip was required in the remainder for isolation. During 14.8 +/- 6.2 month follow-up, 4 (22%) had no recurrence of AF, and 7/18 (39%) had >90% reduction in symptoms without antiarrhythmic agents (AAA). Computed tomography scans at 3 months showed no stenosis (14.1 +/- 2.5 mm, 13.9 +/- 2.4 mm; P = 0.2). Eight patients underwent repeat ablation. Mapping demonstrated 13 of 14 (93%) previously isolated veins had recovery of over 64 +/- 24% of the ostium. All were successfully isolated with RF and 7 of 8 were arrhythmia free 6.0 +/- 2.9 months after ablation. Overall, 14 of 18 (78%) patients had their arrhythmia clinically controlled without drugs after one or two procedures. CONCLUSIONS: Our initial experience demonstrates safety and feasibility of circular cryothermal ablation with less fluoroscopic and procedure times as compared to focal cryothermy. As with RF, complete and permanent isolation of the PVs is not easily achieved. Reducing heat load due to PV flow may improve results.

Dietary accumulation and metabolism of polybrominated diphenyl ethers by juvenile carp (Cyprinus carpio).

Polybrominated diphenyl ethers (PBDEs) are hydrophobic organic contaminants with properties and nomenclature similar to polychlorinated biphenyls (PCBs). While much information is available on the bioaccumulation and pharamcokinetics of PCBs, little information is available on PBDEs. In this study, juvenile carp were exposed to a diet spiked with a cocktail of four BDE congeners (2,4,4'-tribromoDE [BDE 28], 2,2',4,4'-tetrabromoDE [BDE 47], 2,2',4,4',5-pentabromoDE [BDE 99], and 2,2',4,4',5,5'hexabromoDE [BDE 153]) for 60 d followed by a 40-d depuration period. As a positive control, three PCB congeners with similar log K(ow), values (2,2',5,5'-tetrachlorobiphenyl [PCB 52], 2,2',4,4', 5,5'-hexachlorobiphenyl [PCB 153], and 2,2',3,4,4',5,5'-heptachlorobiphenyl [PCB 180]) were included in the cocktail to compare their assimilation and fate with the model BDE congeners. Concentrations of BDEs and PCBs were monitored in whole-fish tissues and liver tissues over the duration of the experiment. In addition, blood serum samples were taken and pooled among replicates to determine if any phenolic metabolites of BDE and PCBs were formed. Rapid assimilation of BDE 47 was observed relative to all other BDE and PCB congeners, whereas apparently no accumulation of BDE 99 occurred over the course of the experiment. Assimilation efficiencies for BDE 47 suggest that approximately 100% of the BDE 47 exposure was absorbed by carp tissues after 60 d. However, based on the time course of BDE 47 assimilation, it is improbable that all BDE 47 was assimilated; more likely, production of BDE 47 in carp tissues occurred as a result of debromination of higher-brominated compounds, possibly BDE 99. The net assimilation efficiencies of BDE 28 and BDE 153 were also apparently low (20 and 4%, respectively) relative to the three PCBs (40% assimilated) examined in this study. The low assimilation efficiency and high depuration rates for BDEs suggest a higher potential for biotransformation. While all three PCB compounds displayed very similar assimilation and depuration rates, three of the four BDE compounds displayed significantly different assimilation rates among BDE congeners and relative to the PCBs. This study suggests that BDEs have significantly different fate dynamics relative to PCBs in wild carp and likely other species of fish.