Drilling constraints on lithospheric accretion and evolution at Atlantis Massif, Mid-Atlantic Ridge 30°N

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 116 (2011): B07103, doi:10.1029/2010JB007931.Expeditions 304 and 305 of the Integrated Ocean Drilling Program cored and logged a 1.4 km section of the domal core of Atlantis Massif. Postdrilling research results summarized here constrain the structure and lithology of the Central Dome of this oceanic core complex. The dominantly gabbroic sequence recovered contrasts with predrilling predictions; application of the ground truth in subsequent geophysical processing has produced self-consistent models for the Central Dome. The presence of many thin interfingered petrologic units indicates that the intrusions forming the domal core were emplaced over a minimum of 100–220 kyr, and not as a single magma pulse. Isotopic and mineralogical alteration is intense in the upper 100 m but decreases in intensity with depth. Below 800 m, alteration is restricted to narrow zones surrounding faults, veins, igneous contacts, and to an interval of locally intense serpentinization in olivine-rich troctolite. Hydration of the lithosphere occurred over the complete range of temperature conditions from granulite to zeolite facies, but was predominantly in the amphibolite and greenschist range. Deformation of the sequence was remarkably localized, despite paleomagnetic indications that the dome has undergone at least 45° rotation, presumably during unroofing via detachment faulting. Both the deformation pattern and the lithology contrast with what is known from seafloor studies on the adjacent Southern Ridge of the massif. There, the detachment capping the domal core deformed a 100 m thick zone and serpentinized peridotite comprises ∼70% of recovered samples. We develop a working model of the evolution of Atlantis Massif over the past 2 Myr, outlining several stages that could explain the observed similarities and differences between the Central Dome and the Southern Ridge

Critical appraisal of nonrandomized studies-a review of recommended and commonly used tools

Rationale, aims, and objectives: When randomized controlled trial data are limited or unavailable, or to supplement randomized controlled trial evidence, health technology assessment (HTA) agencies may rely on systematic reviews of nonrandomized studies (NRSs) for evidence of the effectiveness of health care interventions. NRS designs may introduce considerable bias into systematic reviews, and several methodologies by which to evaluate this risk of bias are available. This study aimed to identify tools commonly used to assess bias in NRS and determine those recommended by HTA bodies. Methods: Appraisal tools used in NRS were identified through a targeted search of systematic reviews (January 2013‐March 2017; MEDLINE and EMBASE [OVID SP]). Recommendations for the critical appraisal of NRS by expert review groups and HTA bodies were reviewed. Results: From the 686 studies included in the narrative synthesis, 48 critical appraisal tools were identified. Commonly used tools included the Newcastle‐Ottawa Scale, the methodological index for NRS, and bespoke appraisal tools. Neither the Cochrane Handbook nor the Centre for Reviews and Dissemination recommends a particular instrument for the assessment of risk of bias in NRS, although Cochrane has recently developed their own NRS critical appraisal tool. Among HTA bodies, only the Canadian Agency for Drugs and Technologies in Health recommends use of a specific critical appraisal tool—SIGN 50 (for cohort or case‐control studies). Several criteria including reporting, external validity, confounding, and power were examined. Conclusion: There is no consensus between HTA groups on the preferred appraisal tool. Reviewers should select from a suite of tools on the basis of the design of studies included in their review

Mycobacterium marinum Causes a Latent Infection that Can Be Reactivated by Gamma Irradiation in Adult Zebrafish

The mechanisms leading to latency and reactivation of human tuberculosis are still unclear, mainly due to the lack of standardized animal models for latent mycobacterial infection. In this longitudinal study of the progression of a mycobacterial disease in adult zebrafish, we show that an experimental intraperitoneal infection with a low dose (~35 bacteria) of Mycobacterium marinum, results in the development of a latent disease in most individuals. The infection is characterized by limited mortality (25%), stable bacterial loads 4 weeks following infection and constant numbers of highly organized granulomas in few target organs. The majority of bacteria are dormant during a latent mycobacterial infection in zebrafish, and can be activated by resuscitation promoting factor ex vivo. In 5–10% of tuberculosis cases in humans, the disease is reactivated usually as a consequence of immune suppression. In our model, we are able to show that reactivation can be efficiently induced in infected zebrafish by γ-irradiation that transiently depletes granulo/monocyte and lymphocyte pools, as determined by flow cytometry. This immunosuppression causes reactivation of the dormant mycobacterial population and a rapid outgrowth of bacteria, leading to 88% mortality in four weeks. In this study, the adult zebrafish presents itself as a unique non-mammalian vertebrate model for studying the development of latency, regulation of mycobacterial dormancy, as well as reactivation of latent or subclinical tuberculosis. The possibilities for screening for host and pathogen factors affecting the disease progression, and identifying novel therapeutic agents and vaccine targets make this established model especially attractive.Public Library of Science open acces

Zebrafish mortality, the development of bacterial load and the number of lesions have dose-dependent patterns.

<p>Adult zebrafish were i.p. infected with either a low (34±15 cfu) (n = 180) or a high dose (2029±709 cfu) (n = 104) of <i>M. marinum</i>. (A) Survival was followed for 32 weeks. * P<0.05 (B) The figure shows the average loads for 5 fish (except 32 wk high dose, n = 2). Low-dose statistics: * sig. diff. from 1 wk, ** sig. diff. from 1 and 2 wk. High-dose statistics: *** sig. diff. from 1, 2, 8, 11 and 20 wk. Low-dose vs. high-dose statistics: loads at time-points marked with † are sig. diff. (C) By default, 4 individuals per dose were analyzed by Ziehl-Neelsen staining (except 20 wk high dose, n = 3) per time-point The gonads, pancreas, liver, muscle, mesentery, spleen, gut and kidney were assessed and the number of organs with visible bacteria was determined. *P<0.05. (D) The total number of granulomas in a sample set for each individual was counted. * P<0.05.</p

<i>M. marinum</i> induces the formation of granulomas that mature into well-defined structures during an infection.

<p>In fish infected with a low dose (34±15 cfu) of <i>M. marinum</i>, Ziehl-Neelsen staining at 2 wpi commonly reveals areas with free bacteria (C). Some slightly better formed and restricted areas containing bacteria, here referred to as early granulomas, are also seen (A), but as shown in (B) trichrome staining of the adjacent slide, encapsulation around the mycobacterial lesions is absent at the early stage of infection. At 20 weeks, fish that have survived have mature granulomas (D–F) many of which are multicentric surrounded by a fibrous capsule (D&E). (E) Trichrome staining shows the fibrous capsule in blue (F). The amount of bacteria inside granulomas has increased from the earliest time-points.</p

A major part of the mycobacteria are in a dormant state in latent infection.

<p>(A) Parallel dilutions of fresh logarithmic or old plateau phase <i>M. marinum</i> cultures were plated +/− Rpf to show the resuscitating effect of <i>Micrococcus luteus</i> Rpf on dormant <i>M. marinum</i>. (B) Parallel homogenate sample dilutions from low-dose (34±15 cfu) infected fish (wt or rag1 (−/−)) were plated at different time points +/− Rpf to detect dormant mycobacteria. (C) <i>GltA1</i> expression was measured from low-dose infected rag1 (−/−) and wt fish and high-dose infected wt fish and normalized to the total <i>M. marinum</i> load in each fish measured by qPCR. *P<0.05.</p

Bacterial dose and the presence of functional adaptive immunity define the outcome of mycobacterial infection.

<p>(A) The early cytokine response at 1 d post infection was measured from wt fish infected with a high (2029±709 cfu) or a low (34±15 cfu) dose or injected with sterile PBS buffer (n in each group 10–20). *P<0.05 (B) Wt fish were infected with a high or a low dose or sterile PBS buffer (for early time-points), and rag1 (−/−) fish were infected with a low dose Nos2b expression was measured with q-RT-PCR (n in each group was 9–20/time point). *P<0.05 (C) Fish were infected as in (B) and <i>IFNγ1–2</i> was measured with q-RT-PCR. *P<0.05. (D) Adult wt and rag1 (−/−) zebrafish were infected with a low dose (n = 30) and followed for survival. *P<0.05 (E) Adult wt and rag1 (−/−) fish were infected with a low dose. Average mycobacterial load was measured by qPCR at 2, 4, and 7 wpi (n = 10 per time point). *P<0.05.</p

Gamma irradiation induces reactivation resulting in increased mortality due to uncontrolled growth of mycobacteria.

<p>(A–C) Zebrafish (n = 17) with a latent <i>M. marinum</i> infection were irradiated twice with 25 Gy with one month between the irradiations. Twice irradiated, non-infected zebrafish (n = 23) as well as zebrafish with a latent infection (n = 14) were included as controls. (A) Survival was followed for 30 days after the second dose. *P<0.05. (B) During this period, moribund or recently dead fish were collected 15–22 days after the second radiation dose. Bacterial loads were compared with those of similarly infected, non-irradiated control fish that were collected at the end-point of the experiment. *P<0.05 (C&D) A representative Ziehl-Neelsen stained sample from a reactivated fish showing large numbers of free mycobacteria (purple areas) in the zebrafish body cavity (C). The sides of the body cavity are marked with arrowheads O = ovary, P = pancreas, L = liver, G = gut, K = kidney. (D) A picture taken with a higher magnification showing individual rods (few examples pointed out with arrows). (E) Four groups of 4 adult zebrafish (1 rag2-gfp, 1 lck-gfp and 2 wild-type groups) were γ-irradiated with 25 Gy. Similar control groups were left untreated. Kidneys were collected 8 d post irradiation, pooled and analyzed by FCM. FSC-SSC -plots were gated based on cell size and granularity as described in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002944#ppat.1002944-Traver2" target="_blank">[56]</a> (gates shown in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002944#ppat.1002944.s003" target="_blank">Figure S3</a>) to assess the effect of irradiation on leukocyte populations. *P<0.05. For further verification of the effect of radiation on lymphocytes, a GFP gate was used for the rag2 and lck groups expressing GFP in B and T cells, or T cells, respectively. (F) Adult non-infected wt zebrafish were irradiated with 25 Gy once (grey bars) (n = 3) or twice (n = 7) (black bars) with one month between the doses. Leukocyte recovery and re-depletion were assessed by FCM. Non-irradiated fish (n = 4) were used as controls. *P<0.05 (G) Fish with a latent infection (n = 7) were irradiated twice with 25 Gy with one month between the doses and plated +/− Rpf for 18 d after the second radiation dose. (H) Fish (n = 6) with a latent infection were plated +/− Rpf.</p

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10−4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10−8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals

Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort.

BACKGROUND Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883