Orchestrating Role of Apoptosis Inhibitor of Macrophage in the Resolution of Acute Lung Injury [INNATE IMMUNITY AND INFLAMMATION]

Appropriate resolution of inflammation is known to be essential in tissue homeostasis. In this study, we evaluated the significance of a macrophage-derived soluble protein, apoptosis inhibitor of macrophage (AIM), in LPS-induced lung injury in mice. After oropharyngeal administration of LPS, the level of free-form serum AIM increased on days 2–4, accompanied by the resolution of inflammation, which was observed in the cellular profile of bronchoalveolar lavage fluid. In an experiment using wild-type (WT) and AIM^–/– mice, the resolution of inflammation was accelerated in AIM^–/– mice when compared with the WT mice, which was reversed when recombinant AIM protein was administered. The changes in the histopathological findings and inflammatory mediators followed similar trends, and the ratio of apoptotic cells was increased in AIM^–/– mice when compared with the WT mice. In vitro analysis showed that macrophage phagocytosis of apoptotic neutrophils was suppressed in the presence of AIM, indicating that anti-resolution property of AIM involves efferocytosis inhibition. In lipidomic analysis of lung tissues, the levels of several lipid mediators increased markedly when LPS was given to WT mice. However, in AIM^–/– mice, the concentrations of these lipid mediators were not significantly upregulated by LPS. These data reflect the significant role of AIM in lipid metabolism; it may suppress lipid metabolites at baseline, and then produce an inflammatory/pathologic pattern in the event of LPS-induced lung injury. Taken together, AIM may play an orchestrating role in the resolution process of inflammation by altering the profile of pulmonary lipid mediators in mice.

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Chemoprophylaxis for venous thromboembolism prevention in spine surgery patients

No abstract available

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Contemporary management of subclavian and axillary artery injuries—A Western Trauma Association multicenter review

BACKGROUND: Subclavian and axillary artery injuries are uncommon. In addition to many open vascular repairs, endovascular techniques are used for definitive repair or vascular control of these anatomically challenging injuries. The aim of this study was to determine the relative roles of endovascular and open techniques in the management of subclavian and axillary artery injuries comparing hospital outcomes, and long-term limb viability. METHODS: A multicenter, retrospective review of patients with subclavian or axillary artery injuries from January 1, 2004, to December 31, 2014, was completed at 11 participating Western Trauma Association institutions. Statistical analysis included χ2, t-tests, and Cochran-Armitage trend tests. A p value less than 0.05 was significant. RESULTS: Two hundred twenty-three patients were included; mean age was 36 years, 84% were men. An increase in computed tomography angiography and decrease in conventional angiography was observed over time (p = 0.018). There were 120 subclavian and 119 axillary artery injuries. Procedure type was associated with injury grade (p

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Cervical spine evaluation and clearance in the intoxicated patient: A prospective Western Trauma Association Multi-Institutional Trial and Survey

BACKGROUND: Intoxication often prevents clinical clearance of the cervical spine (Csp) after trauma leading to prolonged immobilization even with a normal computed tomography (CT) scan. We evaluated the accuracy of CT at detecting clinically significant Csp injury, and surveyed participants on related opinions and practice. METHODS: A prospective multicenter study (2013–2015) at 17 centers. All adult blunt trauma patients underwent structured clinical examination and imaging including a Csp CT, with follow-up thru discharge. alcohol- and drug-intoxicated patients (TOX+) were identified by serum and/or urine testing. Primary outcomes included the incidence and type of Csp injuries, the accuracy of CT scan, and the impact of TOX+ on the time to Csp clearance. A 36-item survey querying local protocols, practices, and opinions in the TOX+ population was administered. RESULTS: Ten thousand one hundred ninety-one patients were prospectively enrolled and underwent CT Csp during the initial trauma evaluation. The majority were men (67%), had vehicular trauma or falls (83%), with mean age of 48 years, and mean Injury Severity Score (ISS) of 11. The overall incidence of Csp injury was 10.6%. TOX+ comprised 30% of the cohort (19% EtOH only, 6% drug only, and 5% both). TOX+ were significantly younger (41 years vs. 51 years; p 12 hrs) in 25%. The survey showed marked variations in protocols, definitions, and Csp clearance practices among participating centers, although 100% indicated willingness to change practice based on these data. CONCLUSION: For intoxicated patients undergoing Csp imaging, CT scan was highly accurate and reliable for identifying clinically significant spine injuries, and had a 100% NPV for identifying unstable injuries. CT-based clearance in TOX+ patients appears safe and may avoid unnecessary prolonged immobilization. There was wide disparity in practices, definitions, and opinions among the participating centers. LEVEL OF EVIDENCE: Diagnostic tests or criteria, level II.

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Comment on clinical features of 27 shark attack cases on La Réunion Island

No abstract available

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REBOA for the IVC? Resuscitative balloon occlusion of the inferior vena cava (REBOVC) to abate massive hemorrhage in retrohepatic vena cava injuries

BACKGROUND: The use of resuscitative endovascular balloon occlusion as a maneuver for occlusion of the aorta is well described. This technique has life-saving potential in other cases of traumatic hemorrhage. Retrohepatic inferior vena cava (IVC) injuries have a high rate of mortality, in part, due to the difficulty in achieving total vascular isolation. The purpose of this study was to investigate the ability of resuscitative balloon occlusion of the IVC to control suprahepatic IVC hemorrhage in a swine model of trauma. METHODS: Thirteen swine were randomly assigned to control (seven animals) versus intervention (six animals). In both groups, an injury was created to the IVC. Hepatic inflow control was obtained via clamping of the hepatoduodenal ligament and infrahepatic IVC. In the intervention group, suprahepatic IVC control was obtained via a resuscitative balloon occlusion of the IVC placed through the femoral vein. In the control group, no suprahepatic IVC control was established. Vital signs, arterial blood gases, and lactate were monitored until death. Primary end points were blood loss and time to death. Lactate, pH, and vital signs were secondary end points. Groups were compared using the χ2 and the Student t test with significance at p

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Decompressive craniectomy versus craniotomy only for intracranial hemorrhage evacuation: A propensity matched study

BACKGROUND: Decompressive craniectomy (DC) is often performed in conjunction with evacuation of intracranial hemorrhage (ICH) to control intracranial pressure (ICP) in patients with a traumatic brain injury (TBI). The efficacy of DC in lowering ICP is well established; however, its effect on clinical outcomes remains controversial. The aim of our study is to assess outcomes in TBI patients undergoing DC versus craniotomy only (CO) for the evacuation of ICH. METHODS: We performed a 5-year retrospective analysis of TBI patients with ICH who underwent craniotomy or craniectomy for traumatic ICH. Patients were divided into two groups, those who underwent CO and those who underwent DC. Propensity scoring matched patients in a 1:2 ratio for demographics, admission Glasgow Coma Scale (GCS) score, severity of injury, type and size of ICH, and anticoagulant use. Outcome measures included mortality, adverse discharge disposition (skilled nursing facility), discharge GCS and Glasgow Outcome Scale scores, and complications. RESULTS: We reviewed 1,831 patients with TBI, of which 155 underwent craniotomy and/or craniectomy. After propensity score matching, we included 99 of those patients in our study (DC, 33; CO, 66). Matched groups were similar in age (p = 0.68), admission GCS score (p = 0.50), Injury Severity Score (p = 0.70), head Abbreviated Injury Scale score (p = 0.32), and intracranial bleeding characteristics. Overall, 26.3% (n = 26) of the patients died and 62.6% (n = 62) were discharged to Rehab/skilled nursing facility. There was no difference in the mortality rate (27.3% vs. 25.0%; p = 0.99), adverse discharge disposition (45% vs. 33%; p = 0.66), GCS score (p = 0.53), and Glasgow Outcome Scale (p = 0.80) at discharge between the DC and the CO groups. However, patients in DC group had higher complication rates and ventilator days. CONCLUSION: This study showed no significant difference in clinical outcomes for patients undergoing evacuation of ICH regardless of the procedure performed. DC did not appear to be superior to craniotomy alone for the treatment of acute ICH. LEVEL OF EVIDENCE: Therapeutic, level III.

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Attempting to validate the overtriage/undertriage matrix at a Level I trauma center

BACKGROUND: The Optimal Resources Document mandates trauma activation based on injury mechanism, physiologic and anatomic criteria and recommends using the overtriage/undertriage matrix (Matrix) to evaluate the appropriateness of trauma team activation. The purpose of this study was to assess the effectiveness of the Matrix method by comparing patients appropriately triaged with those undertriaged. We hypothesized that these two groups are different, and Matrix does not discriminate the needs or outcomes of these different groups of patients. METHODS: Trauma registry data, from January 2013 to December 2015, at a Level I trauma center, were reviewed. Overtriage and undertriage rates were calculated by Matrix. Patients with Injury Severity Score (ISS) of 16 or greater were classified by activation level (full, limited, consultation), and triage category by Matrix. Patients in the limited activation and consultation groups were compared with patients with full activation by demographics, injuries, initial vital signs, procedures, delays to procedure, intensive care unit admission, length of stay, and mortality. RESULTS: Seven thousand thirty-one patients met activation criteria. Compliance with American College of Surgeons tiered activation criteria was 99%. The Matrix overtriage rate was 45% and undertriage was 24%. Of 2,282 patients with an ISS of 16 or greater, 1,026 were appropriately triaged (full activation), and 1,256 were undertriaged. Undertriaged patients had better Glasgow Coma Scale score, blood pressure, and base deficit than patients with full activation. Intensive care unit admission, hospital stays, and mortality were lower in the undertriaged group. The undertriaged group required fewer operative interventions with fewer delays to procedure. CONCLUSION: Despite having an ISS of 16 or greater, patients with limited activations were dissimilar to patients with full activation. Level of activation and triage are not equivalent. The American College of Surgeons Committee on Trauma full and tiered activation criteria are a robust means to have the appropriate personnel present based on the available prehospital information. Evaluation of the process of care, regardless of level of activation, should be used to evaluate trauma center performance. LEVEL OF EVIDENCE: Therapeutic and care management, level III.

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Human neutrophil elastase mediates fibrinolysis shutdown through competitive degradation of plasminogen and generation of angiostatin

BACKGROUND: A subset of trauma patients undergo fibrinolysis shutdown rather than pathologic hyperfibrinolysis, contributing to organ failure. The molecular basis for fibrinolysis shutdown in trauma is incompletely understood. Elastase released from primed/activated human neutrophils (HNE) has historically been described as fibrin(ogen)olytic. However, HNE can also degrade plasminogen (PLG) to angiostatin (ANG), retaining the kringle domains but not the proteolytic function, and could thereby compete for generation of active plasmin by tissue plasminogen activator (tPA). We hypothesized that HNE can drive fibrinolysis shutdown rather than fibrinolysis. METHODS: Turbidometry was performed using light scatter (λ = 620 nm) in a purified fibrinogen + PLG system and in healthy citrate plasma clotted with Ca2+/thrombin ± tPA, ±HNE, and ±ANG to evaluate HNE effects on fibrinolysis, quantified by time to transition midpoint (Tm). ΔTm from control is reported as percent of control ±95% CI. Purified HNE coincubated with PLG or tPA was analyzed by western blot to identify cleavage products. Exogenous HNE was mixed ex vivo with healthy volunteer blood (n = 7) and used in TEG ± tPA to evaluate effects on fibrinolysis. RESULTS: HNE did not cause measurable fibrinolysis on fibrin clots, clotted plasma, or whole blood as assessed by turbidometry or TEG in the absence of tPA. Upon tPA treatment, all three methods of evaluating fibrinolysis showed delays and decreases in fibrinolysis caused by HNE relative to control: fibrin clot turbidometry ΔTm = 110.7% (CI 105.0–116.5%), clotted citrate plasma (n = 6 healthy volunteers) ΔTm = 126.1% (CI 110.4–141.8%), and whole blood native TEG (n = 7 healthy volunteers) with ΔLY30 = 28% (p = 0.043). Western blot analysis of HNE–PLG co-incubation confirmed that HNE generates angiostatin K1–3, and plasma turbidity assays treated with angiostatin K1–3 delayed fibrinolysis. CONCLUSION: HNE degrades PLG and generates angiostatin K1–3, which predominates over HNE cleavage of fibrin(ogen). These findings suggest that neutrophil release of elastase may underlie trauma-induced fibrinolytic shutdown.

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Big for small: Validating brain injury guidelines in pediatric traumatic brain injury

BACKGROUND: Brain injury guidelines (BIG) were developed to reduce overutilization of neurosurgical consultation (NC) as well as computed tomography (CT) imaging. Currently, BIG have been successfully applied to adult populations, but the value of implementing these guidelines among pediatric patients remains unassessed. Therefore, the aim of this study was to evaluate the established BIG (BIG-1 category) for managing pediatric traumatic brain injury (TBI) patients with intracranial hemorrhage (ICH) without NC (no-NC). METHODS: We prospectively implemented the BIG-1 category (normal neurologic examination, ICH ≤ 4 mm limited to one location, no skull fracture) to identify pediatric TBI patients (age, ≤ 21 years) that were to be managed no-NC. Propensity score matching was performed to match these no-NC patients to a similar cohort of patients managed with NC before the implementation of BIG in a 1:1 ratio for demographics, severity of injury, and type as well as size of ICH. Our primary outcome measure was need for neurosurgical intervention. RESULTS: A total of 405 pediatric TBI patients were enrolled, of which 160 (NC, 80; no-NC, 80) were propensity score matched. The mean age was 9.03 ± 7.47 years, 62.1% (n = 85) were male, the median Glasgow Coma Scale score was 15 (13–15), and the median head Abbreviated Injury Scale score was 2 (2–3). A subanalysis based on stratifying patients by age groups showed a decreased in the use of repeat head CT (p = 0.02) in the no-NC group, with no difference in progression (p = 0.34) and the need for neurosurgical intervention (p = 0.9) compared with the NC group. CONCLUSION: The BIG can be safely and effectively implemented in pediatric TBI patients. Reducing repeat head CT in pediatric patients has long-term sequelae. Likewise, adhering to the guidelines helps in reducing radiation exposure across all age groups. LEVEL OF EVIDENCE: Therapeutic/care management, level III.

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Peritoneal cavity lavage reduces the presence of mitochondrial damage associated molecular patterns in open abdomen patients

BACKGROUND: Mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA and N-formylated peptides, are endogenous molecules released from tissue after traumatic injury. mtDAMPs are potent activators of the innate immune system. They have similarities with bacteria, which allow mtDAMPs to interact with the same pattern recognition receptors and mediate the development of systemic inflammatory response syndrome (SIRS). Current recommendations for management of an open abdomen include returning to the operating room every 48 hours for peritoneal cavity lavage until definitive procedure. These patients are often critically ill and develop SIRS. We hypothesized that mitochondrial DAMPs are present in the peritoneal cavity fluid in this setting, and that they accumulate in the interval between washouts. METHODS: We conducted a prospective pilot study of critically ill adult patients undergoing open abdomen management in the surgical and trauma intensive care units. Peritoneal fluid was collected daily from 10 open abdomen patients. Specimens were analyzed via quantitative polymerase chain reaction (qPCR) for mitochondrial DNA (mtDNA), via enzyme immunoassay for DNAse activity and via Western blot analysis for the ND6 subunit of the NADH: ubiquinone oxidoreductase, an N-formylated peptide. RESULTS: We observed a reduction in the expression of ND6 the day after lavage of the peritoneal cavity, that was statistically different from the days with no lavage (% change in ND6 expression, postoperative from washout: −50 ± 11 vs. no washout day, 42 ± 9; p

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Valproic acid decreases brain lesion size and improves neurologic recovery in swine subjected to traumatic brain injury, hemorrhagic shock, and polytrauma

BACKGROUND: We have previously shown that treatment with valproic acid (VPA) decreases brain lesion size in swine models of traumatic brain injury (TBI) and controlled hemorrhage. To translate this treatment into clinical practice, validation of drug efficacy and evaluation of pharmacologic properties in clinically realistic models of injury are necessary. In this study, we evaluate neurologic outcomes and perform pharmacokinetic analysis of a single dose of VPA in swine subjected to TBI, hemorrhagic shock, and visceral hemorrhage. METHODS: Yorkshire swine (n = 5/cohort) were subjected to TBI, hemorrhagic shock, and polytrauma (liver and spleen injury, rib fracture, and rectus abdominis crush). Animals remained in hypovolemic shock for 2 hours before resuscitation with isotonic sodium chloride solution (ISCS; volume = 3× hemorrhage) or ISCS + VPA (150 mg/kg). Neurologic severity scores were assessed daily for 30 days, and brain lesion size was measured via magnetic resonance imaging on postinjury days (PID) 3 and 10. Serum samples were collected for pharmacokinetic analysis. RESULTS: Shock severity and response to resuscitation were similar in both groups. Valproic acid–treated animals demonstrated significantly less neurologic impairment between PID 1 to 5 and smaller brain lesions on PID 3 (mean lesion size ± SEM, mm3: ISCS = 4,956 ± 1,511 versus ISCS + VPA = 828 ± 279; p = 0.047). No significant difference in lesion size was identified between groups at PID 10 and all animals recovered to baseline neurologic function during the 30-day observation period. Animals treated with VPA had faster neurocognitive recovery (days to initiation of testing, mean ± SD: ISCS = 6.2 ± 1.6 vs ISCS + VPA = 3.6 ± 1.5; p = 0.002; days to task mastery: ISCS = 7.0 ± 1.0 vs ISCS + VPA = 4.8 ± 0.5; p = 0.03). The mean ± SD maximum VPA concentrations, area under the curve, and half-life were 145 ± 38.2 mg/L, 616 ± 150 hour·mg/L, and 1.70 ± 0.12 hours. CONCLUSIONS: In swine subjected to TBI, hemorrhagic shock, and polytrauma, VPA treatment is safe, decreases brain lesion size, and reduces neurologic injury compared to resuscitation with ISCS alone. These benefits are achieved at clinically translatable serum concentrations of VPA. LEVEL OF EVIDENCE: Therapeutic (preclinical study).

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August 2001 Volume 51 Supplement 2, Part 1: Erratum

No abstract available

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Superoxide Production by NADPH Oxidase Intensifies Macrophage Antiviral Responses during Diabetogenic Coxsackievirus Infection [AUTOIMMUNITY]

Coxsackievirus B infections are suspected environmental triggers of type 1 diabetes (T1D) and macrophage antiviral responses may provide a link to virus-induced T1D. We previously demonstrated an important role for NADPH oxidase (NOX)–derived superoxide production during T1D pathogenesis, as NOX-deficient NOD mice (NOD.Ncf1^m1J) were protected against T1D due, in part, to impaired proinflammatory TLR signaling in NOD.Ncf1^m1J macrophages. Therefore, we hypothesized that loss of NOX-derived superoxide would dampen diabetogenic antiviral macrophage responses and protect from virus-induced diabetes. Upon infection with a suspected diabetogenic virus, Coxsackievirus B3 (CB3), NOD.Ncf1^m1J mice remained resistant to virus-induced autoimmune diabetes. A concomitant decrease in circulating inflammatory chemokines, blunted antiviral gene signature within the pancreas, and reduced proinflammatory M1 macrophage responses were observed. Importantly, exogenous superoxide addition to CB3-infected NOD.Ncf1^m1J bone marrow–derived macrophages rescued the inflammatory antiviral M1 macrophage response, revealing reduction-oxidation–dependent mechanisms of signal transducer and activator of transcription 1 signaling and dsRNA viral sensors in macrophages. We report that superoxide production following CB3 infection may exacerbate pancreatic β cell destruction in T1D by influencing proinflammatory M1 macrophage responses, and mechanistically linking oxidative stress, inflammation, and diabetogenic virus infections.

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NOX2-Derived Reactive Oxygen Species Control Inflammation during Leishmania amazonensis Infection by Mediating Infection-Induced Neutrophil Apoptosis [INFECTIOUS DISEASE AND HOST RESPONSE]

Reactive oxygen species (ROS) produced by NADPH phagocyte oxidase isoform (NOX2) are critical for the elimination of intracellular pathogens in many infections. Despite their importance, the role of ROS following infection with the eukaryotic pathogen Leishmania has not been fully elucidated. We addressed the role of ROS in C57BL/6 mice following intradermal infection with Leishmania amazonensis. Despite equivalent parasite loads compared with wild-type (WT) mice, mice deficient in ROS production by NOX2 due to the absence of the gp91 subunit (gp91^phox–/–) had significantly more severe pathology in the later stages of infection. Pathology in gp91^phox–/– mice was not associated with alterations in CD4⁺ T cell–mediated immunity but was preceded by enhanced neutrophil accumulation at the dermal infection site. Ex vivo analysis of infected versus uninfected neutrophils revealed a deficiency in infection-driven apoptosis in gp91^phox–/– mice versus WT mice. gp91^phox–/– mice presented with higher percentages of healthy or necrotic neutrophils but lower percentages of apoptotic neutrophils at early and chronic time points. In vitro infection of gp91^phox–/– versus WT neutrophils also revealed reduced apoptosis and CD95 expression but increased necrosis in infected cells at 10 h postinfection. Provision of exogenous ROS in the form of H₂O₂ reversed the necrotic phenotype and restored CD95 expression on infected gp91^phox–/– neutrophils. Although ROS production is typically viewed as a proinflammatory event, our observations identify the importance of ROS in mediating appropriate neutrophil apoptosis and the importance of apoptosis in inflammation and pathology during chronic infection.

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Predictors of In-hospital Postoperative Opioid Overdose After Major Elective Operations: A Nationally Representative Cohort Study Erratum

No abstract available

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Immediate and late outcomes of endovascular therapy for lower extremity arteries in Buerger disease

Buerger disease is a rare inflammatory vasculopathy presenting with severe claudication or critical limb ischemia. In this study, we sought to evaluate the feasibility and clinical outcomes of endovascular therapy for Buerger disease involving arteries in the lower extremities.

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Endovascular treatment of the ascending aorta using a combined transapical and transfemoral approach

In high-risk patients with diseases of the ascending aorta, endovascular repair might be a therapeutic alternative to surgical repair. We developed a combined access route with transapical and transfemoral externalization of the wire and report the operative technique as well as our initial experience of six patients treated with this method. Improved wire control resulted in precise deployment of endovascular prostheses, respecting the integrity of the coronary ostia and the supra-aortic vessels.

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An open-source method to analyze optokinetic reflex responses in larval zebrafish

Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Seth D. Scheetz, Enhua Shao, Yangzhong Zhou, Clinton L. Cario, Qing Bai, Edward A. Burton
BackgroundOptokinetic reflex (OKR) responses provide a convenient means to evaluate oculomotor, integrative and afferent visual function in larval zebrafish models, which are commonly used to elucidate molecular mechanisms underlying development, disease and repair of the vertebrate nervous system.New methodWe developed an open-source MATLAB-based solution for automated quantitative analysis of OKR responses in larval zebrafish. The package includes applications to: (i) generate sinusoidally-transformed animated grating patterns suitable for projection onto a cylindrical screen to elicit the OKR; (ii) determine and record the angular orientations of the eyes in each frame of a video recording showing the OKR response; and (iii) analyze angular orientation data from the tracking program to yield a set of parameters that quantify essential elements of the OKR. The method can be employed without modification using the operating manual provided. In addition, annotated source code is included, allowing users to modify or adapt the software for other applications.ResultsWe validated the algorithms and measured OKR responses in normal larval zebrafish, showing good agreement with published quantitative data, where available.Comparison with existing method(s)We provide the first open-source method to elicit and analyze the OKR in larval zebrafish. The wide range of parameters that are automatically quantified by our algorithms significantly expands the scope of quantitative analysis previously reported.ConclusionsOur method for quantifying OKR responses will be useful for numerous applications in neuroscience using the genetically- and chemically-tractable zebrafish model.

Graphical abstract

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Clinical Reasoning: An 82-year-old man with worsening gait

An 82-year-old man with hypothyroidism presented with difficulty walking.

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Teaching NeuroImages: Myeloperoxidase-anti-neutrophil cytoplasmic antibody-positive hypertrophic pachymeningitis

A 49-year-old woman with chronic epistaxis presented with painless left monocular vision loss. Notable findings on examination of the left eye included visual acuity of 20/200 and relative afferent pupillary defect. MRI of the brain revealed enhancement of the left optic nerve sheath and diffuse dural thickening (figure). Laboratory workup yielded only lymphocytic pleocytosis (12 white blood cells) and positive serologies for perinuclear anti-neutrophil cytoplasmic antibodies (ANCA) and anti-myeloperoxidase (MPO) antibodies. Dural biopsy showed multifocal dense lymphoplasmacytic infiltration with vasculitis and reactive fibroplasia. A diagnosis of MPO-ANCA-positive hypertrophic pachymeningitis was made. This phenotypic variant of granulomatosis with polyangiitis is typically restricted to the CNS and upper airway; treatment involves immunosuppression.¹ The patient improved clinically and radiographically with prednisone and rituximab.

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Letter re: Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society

The new guideline by the American Academy of Neurology (AAN) and the American Epilepsy Society (AES) on sudden unexpected death in epilepsy (SUDEP) is a landmark.¹ The communication between medical professionals and patients about SUDEP risk remains unacceptably low. Tragically, family members often first learn about SUDEP after their loved one's death. Every patient and parent deserves to know the risks of epilepsy. For the first time, the AAN and AES recommend that neurologists inform them about SUDEP, the most common cause of epilepsy-related death.¹

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Spotlight on the November 21 issue

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Spaceflight-induced changes in white matter hyperintensity burden in astronauts

Objective:

To assess the effect of weightlessness and the respective roles of CSF and vascular fluid on changes in white matter hyperintensity (WMH) burden in astronauts.

Methods:

We analyzed prespaceflight and postspaceflight brain MRI scans from 17 astronauts, 10 who flew a long-duration mission on the International Space Station (ISS) and 7 who flew a short-duration mission on the Space Shuttle. Automated analysis methods were used to determine preflight to postflight changes in periventricular and deep WMH, CSF, and brain tissue volumes in fluid-attenuated inversion recovery and high-resolution 3-dimensional T1-weighted imaging. Differences between cohorts and associations between individual measures were assessed. The short-term reversibility of the identified preflight to postflight changes was tested in a subcohort of 5 long-duration astronauts who had a second postflight MRI scan 1 month after the first postflight scan.

Results:

Significant preflight to postflight changes were measured only in the long-duration cohort and included only the periventricular WMH and ventricular CSF volumes. Changes in deep WMH and brain tissue volumes were not significant in either cohort. The increase in periventricular WMH volume was significantly associated with an increase in ventricular CSF volume ( = 0.63, p = 0.008). A partial reversal of these increases was observed in the long-duration subcohort with a 1-month follow-up scan.

Conclusions:

Long-duration exposure to microgravity is associated with an increase in periventricular WMH in astronauts. This increase was linked to an increase in ventricular CSF volume documented in ISS astronauts. There was no associated change in or abnormal levels of WMH volumes in deep white matter as reported in U-2 high-altitude pilots.

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Ischemic lesions and superficial siderosis in CAA: Partners in crime or innocent bystanders?

Cerebral amyloid angiopathy (CAA), first described in 1927 as a congophilic angiopathy associated with amyloid plaque in brains of patients with Alzheimer dementia,¹ has an association with large and small intracranial hemorrhages (ICH). The differential diagnosis of ICH therefore includes CAA, especially in older patients or those without hypertension. The widely used Boston Criteria for diagnosis of CAA in vivo rely on the hemorrhagic characteristics of the disease.² The pathophysiology of ICH in CAA remains uncertain. Thus, its prognosis, risk stratification, and clinical management present a challenge. Additional imaging features of CAA have contributed potential new perspectives on pathophysiology. The report of ischemic lesions in CAA may represent a novel concept for most clinicians accustomed to thinking about CAA as a hemorrhagic disease. The observation that Alzheimer dementia brains with severe amyloid angiopathy had more prevalent infarcts^3–5 prompted subsequent investigations suggesting that amyloid deposition in small and medium-sized cortical vessels may play an active role in ischemia through pathologic thickening of the vessel wall, producing reduction or obliteration of the vessel lumen.^6,7 Cortical superficial siderosis (cSS), easy to detect with modern MRI, is a striking and common feature of CAA. How these additional imaging features fit into a larger model of CAA remains unclear. Are they an epiphenomenon or can they teach us about the disease? In the current issue of Neurology®, a pair of articles suggest that CAA might be a multifaceted vascular entity in its own right, and elucidation of these newer features may increase our understanding of its pathophysiology, leading to better prognosis and management.

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Quinidine-associated skin discoloration in KCNT1-associated pediatric epilepsy

A 9-month-old boy with migrating partial seizures of infancy due to a de novo KCNT1 mutation c.2278A>T (p.Ile760Phe) developed bluish discoloration of the hands, feet, and lips (figure) during a 9-month trial of quinidine (40 mg/kg/d; level 3.4 μg/mL).¹ There was no exposure to other medications that cause pigmentary changes. Given minimal improvement in seizures and development, quinidine was stopped. Discoloration persisted at 3 months but markedly improved by the 6-month follow-up. Though common with other potassium channel blockers (ezogabine and quinine), such discoloration has only rarely been reported with quinidine, all in adults.² Epileptologists should be aware of this potential complication of quinidine therapy.

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Neurofilaments in blood: (Almost) facing clinical application

Neurodegeneration is a critical pathophysiologic process of Alzheimer disease (AD) and related dementias, and correlates better with cognitive symptoms than the sole presence of pathologic proteins such as β-amyloid or α-synuclein. Thus, the identification of a biomarker that tracks with neurodegeneration is critical for following disease progression from the preclinical through the clinical phases and assessing rate of progression or therapeutic utility. The identification of a blood-based biomarker of neurodegeneration would be the Holy Grail. Compared to neuroimaging CSF collection, a blood draw is much less invasive and costly, has minimal side effects, is available in rural areas, and is feasible and acceptable by patients for serial testing to monitor disease progression and therapeutic response.

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Letter re: Dementia risk in renal dysfunction: A systematic review and meta-analysis of prospective studies

Deckers et al.¹ conducted random effects meta-analyses on the prospective association between potential markers of renal dysfunction and development of cognitive impairment or dementia. Pooled odds ratios (95% confidence intervals) of albuminuria and estimated glomerular filtration rate <60 mL/min/1.73 m² for cognitive impairment or dementia were 1.35 (1.06–1.73) and 1.28 (0.99–1.65), respectively.¹ As the number of studies was not sufficient, meta-analyses could not be done for serum creatinine, creatinine clearance, or cystatin C.¹ The authors concluded that albuminuria was a useful marker of renal dysfunction for screening the development of cognitive impairment or dementia.¹ I have 2 concerns about their study.

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GSE99854 Spatial control of gene expression by miR319-regulated TCP transcription factors during leaf development

Contributors : E Bresso ; C Schommer ; J Palatnik
Series Type : Expression profiling by high throughput sequencing
Organism : Arabidopsis thaliana

The characteristic leaf shapes we see in all plants are in good part outcome of the combined action of several transcription factor networks that translate into cell division activity during the early development of the organ. We show here that wild-type leaves have distinct transcriptomic profiles in center and marginal regions. Certain transcripts are enriched in margins, including those of CINCINATA-like TCPs, and members of the NGATHA and STYLISH gene families. We study in detail the contribution of miR319 regulated TCP (Teosinte branched, Cycloidea, PCF1/2) transcription factors to the development of the center and marginal regions of Arabidopsis leaves. We compare in molecular analyses wildtype, a tcp2 tcp4 mutant that has enlarged flat leaves and a tcp2 tcp3 tcp4 tcp10 mutant with strongly crinkled leaves. The different leaf domains of the tcp mutants show changed expression patterns for many photosynthesis related genes, indicating delayed differentiation, especially in the marginal parts of the organ. At the same time, we found an upregulation of cyclin genes and other genes that are known to participate in cell division, specifically in the marginal regions of tcp2 tcp3 tcp4 tcp10. Using GUS reporter constructs we confirmed extended mitotic activity in the tcp2 tcp3 tcp4 tcp10 leaf which persisted in small defined foci in the margins when the mitotic activity had already ceased in wild-type leaves. Our results describe the role of miR319-regulated TCP transcription factors in the coordination of activities in different leaf domains during the organs development.

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Poor Reproducibility of Gallbladder Ejection Fraction by Biliary Scintigraphy for Diagnosis of Biliary Dyskinesia

To test the reproducibility of hepatobiliary scintigraphy in the diagnosis of biliary dyskinesia, 30 consecutive patients referred with the diagnosis after an initial positive test were re-tested. On re-testing 16 of 30 patients had normal results and cholecystectomy was not recommended in them.

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Increased precipitation has stronger effects on plant production of an alpine meadow than does experimental warming in the Northern Tibetan Plateau

Publication date: 15 February 2018
Source:Agricultural and Forest Meteorology, Volume 249
Author(s): Gang Fu, Zhen-Xi Shen, Xian-Zhou Zhang
The Tibetan Plateau is overall getting warmer and wetter, whereas the relative responses of plant growth to warming and increased precipitation are not fully understood. Therefore, a field warming (control, low- and high-level) and increased precipitation (control, low- and high-level) experiment was conducted to compare the relative effects of warming and increased precipitation on the normalized difference vegetation index (NDVI), soil-adjusted vegetation index (SAVI), aboveground biomass (AGB) and gross primary production (GPP) in an alpine meadow in the Northern Tibetan Plateau since June 2014. The low- and high-level experimental warming significantly decreased soil moisture (SM) by 0.02m³m⁻³ and 0.04m³m⁻³, but significantly increased air temperature (Ta) by 1.91°C and 3.51°C, respectively, across the three growing seasons in 2014–2016. The low- and high-level warming did not significantly affect NDVI, SAVI, AGB and GPP across the three growing seasons in 2014–2016. The low- and high-level increased precipitation did not significantly affect Ta, but significantly increased SM by 0.02m³m⁻³ and 0.03m³m⁻³, respectively, across the three growing seasons in 2014–2016. The high-level increased precipitation significantly increased NDVI by 18.7%, SAVI by 18.4%, AGB by 11.4% and GPP by 25.0%, whereas the low-level increased precipitation only tended to increase NDVI by 9.8%, SAVI by 8.2%, AGB by 6.2% and GPP by 12.9%. Therefore, increased precipitation had stronger effects on NDVI, SAVI, AGB and GPP than did experimental warming in this alpine meadow site of the Northern Tibetan Plateau.



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Simple models to predict grassland ecosystem C exchange and actual evapotranspiration using NDVI and environmental variables

Publication date: 15 February 2018
Source:Agricultural and Forest Meteorology, Volume 249
Author(s): Stephen J. Del Grosso, W.J. Parton, Justin D. Derner, Maosi Chen, Compton J. Tucker
Semiarid grasslands contribute significantly to net terrestrial carbon flux as plant productivity and heterotrophic respiration in these moisture-limited systems are correlated with metrics related to water availability (e.g., precipitation, Actual EvapoTranspiration or AET). These variables are also correlated with remotely sensed metrics such as the Normalized Difference Vegetation Index (NDVI). We used measurements of growing season net ecosystem exchange of carbon (NEE), NDVI from eMODIS and AVHRR, precipitation, and volumetric soil water content (VSWC) from grazed pastures in the semiarid, shortgrass steppe to quantify the correlation of NEE with these driving variables. eMODIS NDVI explained 60 and 40% of the variability in daytime and nighttime NEE, respectively, on non-rain days; these correlations were reduced to 41 and 15%, respectively, on rain days. Daytime NEE was almost always negative (sink) on non-rain days but positive on most rain days. In contrast, nighttime NEE was always positive (source), across rain and non-rain days. A model based on eMODIS NDVI, VSWC, daytime vs. nighttime, and rain vs. non-rain days explained 48% of observed variability in NEE at a daily scale; this increased to 62% and 77%, respectively, at the weekly and monthly scales. eMODIS NDVI explained 50–52% of the variability in AET regardless of rain or non-rain days. A model based on eMODIS NDVI, VSWC, Potential EvapoTranspiration (or PET), and rain vs. non-rain days explained 70% of the observed variability in AET at a daily scale; this increased to 90 and 96%, respectively, at weekly and monthly scales. Models based on AVHRR NDVI showed similar patterns as those using eMODIS, but correlations with observations were lower. We conclude that remotely-sensed NDVI is a robust tool, when combined with VSWC and knowledge of rain events, for predicting NEE and AET across multiple temporal scales (day to season) in semiarid grasslands.



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Salient object detection using local, global and high contrast graphs

Abstract

In this paper, we propose a novel multi-graph-based method for salient object detection in natural images. Starting from image decomposition via a superpixel generation algorithm, we utilize color, spatial and background label to calculate edge weight matrix of the graphs. By considering superpixels as the nodes and region similarities as the edge weights, local, global and high contrast graphs are created. Then, an integration technique is applied to form the saliency maps using degree vectors of the graphs. Extensive experiments on three challenging datasets show that the proposed unsupervised method outperforms the several different state-of-the-art unsupervised methods.

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In vivo effects of geranylgeraniol on the development of bisphosphonate-related osteonecrosis of the jaws

Bisphosphonate-related osteonecrosis of the jaws (BRONJ) as a complication of bisphosphonate (BP) treatment is an area of increased research interest. Although several hypotheses have been proposed (Ruggiero et al., 2014), none of them fully explain the nature and mechanism of development of the disease. However, the theory that supports the inhibition of bone resorption with mediation of osteoclastic activity is the most well researched. On the other hand, studies showed that the BPs have toxic effects on soft tissue cells, as well (Landesberg et al.

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The risk of osteonecrosis on alveolar healing after tooth extraction and systemic administration of antiresorptive drugs in rodents: a systematic review

There is much concern about the increasing number of patients with medication-related osteonecrosis of the jaw (MRONJ), and many studies have been published in an attempt to understand the pathophysiology of this condition. This study aimed to systematically review the literature on MRONJ arising in rodents under antiresorptive drug therapy after tooth extraction.

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Cervical intradural disc herniation: A systematic review

Intradural disc herniation (IDH) is a rare condition for which diagnosis and treatment are challenging. In 1942, the first intradural disc rupture case, which involved the lumbar spine, was reported by Dandy. Subsequently, cases of cervical and thoracic intradural disc herniation have been described [1,2,3]. Cervical IDH (CIDH) is the least common and accounts for approximately 3% of all intradural herniations, whereas IDH in the thoracic and lumbar spine account for 5% and 92% of the cases, respectively [4,5].

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A Report from the Diabetes Professional Care Conference in London

Now in its third year, DPC2017 offered attendees in London an impressive array of presentations, debates, workshops, and networking opportunities. The two-day event at the Olympia featured contributions from over a hundred world experts covering all aspects of diabetes care, and showcased the emerging technologies underpinning tomorrow's healthcare solutions.

The vast program on offer was split into five streams over two days focusing on the prevention, diagnosis, and treatment of diabetes and other associated conditions. The line-up also included dedicated sessions on hypoglycemia and diabetic foot ulcers, with visitors even having the opportunity to experience a "hypo" event first-hand with a virtual reality hypoglycemia simulator.

Keynote speakers guided attendees through both policy and clinical practice achievements before charging the audience with the goals of better future treatment and prevention of diabetes. Further discussions focused on the unique challenges of pediatric and adolescent cases, the importance of genetic factors and obesity, as well as the demands of primary and secondary care pathways for diabetics. A number of practical sessions led by clinical staff also offered insight into tangible improvements in patient experience and treatment effectiveness, for what is so frequently a self-managed condition.

A dedicated start-up company showcase area had cutting edge and emerging technology on display for attendees to sample first-hand. These new innovations tackled improvements in insulin injection, wound repair, personal drug regimen management and diagnostic tools. Conference attendees also sampled new products from the industry's big players, while networking with speakers and thought-leaders throughout the packed two-day schedule.

Interactive workshops discussed best practices in patient management and touched on a number of very relevant areas of change in the field. Presentations covered integrating mobile health platforms and data interpretation, as well as experiences of inventing and adopting new technology in the clinical setting. In particular, the sobering fact that currently around 10% of health spending is dedicated to type II diabetes was confronted in an engaging live debate—where a full spectrum of solutions were grappled with, from early-stage prevention programs to the development of more effective pharmaceuticals.

This year's DPC meeting offered attendees a fantastic overview of the current best practices in diabetic care and introduced exciting innovations in both treatment technology and policy, equally important factors to consider as diabetes rapidly grows in both clinical significance and health system cost.

Event info page: Diabetes Professional Care…

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Surgical interns: Preparedness for opioid prescribing before and after a training intervention

Exposure to pain management curriculum in medical school is currently variable. This paper reports on formal prescribing education, self-perceived prescribing readiness, and prescribing practices among incoming surgical residents before and after a pain management training session.

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Inter-rater reliability of STOPPFrail [Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy] criteria amongst 12 physicians

Abstract

Purpose

STOPPFrail is an explicit tool, developed by Delphi consensus, to assist physicians with deprescribing medications in frail older adults with poor survival prognosis. This study aimed to determine the inter-rater reliability (IRR), amongst physicians, of STOPPFrail application.

Methods

Twenty clinical cases were collated to represent frail older patients. Eighteen cases met STOPPFrail inclusion criteria. They had a mean age of 79.5 (SD6) years and a median of 7 (IQR6–8.25) comorbidities and were prescribed a median of 9 (IQR7.75–11.25) medications. Two of the STOPPFrail originators reached complete agreement (gold standard) in determining 91 of 165 medications (55.2%) as inappropriate. Twelve physicians (6 geriatricians, 3 general practitioners and 3 palliative care physicians) independently applied STOPPFrail criteria. IRR between physicians and gold standard (GS) assessment was determined using Cohen's kappa statistic.

Results

Eighteen of the 20 cases that met STOPPFrail inclusion criteria were correctly identified by 9 of 12 physicians (75%). The average time taken per clinical case was 2.7 (SD0.94) minutes. The kappa co-efficient between physicians and GS assessment ranged from 0.71 (substantial) to 0.86 (good), with a mean kappa value of 0.758 (SD0.059). The Fleiss kappa coefficients between GS assessment and geriatricians, GPs and palliative care physicians were 0.80 (SD0.6), 0.77 (SD0.9) and 0.75 (SD0.1), respectively. No significant difference was noted, between groups or between participants within groups, as determined by one-way ANOVA, (df (2, 9) = 0.712, p = 0.516).

Conclusions

IRR of STOPPFrail criteria between physicians, practising in different specialties, is substantial, despite no prior knowledge of the criteria.

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Headache in immigrant patients: similarities and differences with Italian population

Abstract

Headache is one of the most common neurological diseases. It is well known that there are differences in the perception and in the management of pain in various populations. Immigrants represent a growing portion between neurology outpatients. We analyzed the epidemiological characteristic of headache in immigrants come to our attention, in comparison with Italians. Data collected included age at immigration, age of onset of headache, headache's type (HIS criteria), and psychiatric comorbidities. There were not substantial differences in the incidence of headache subtypes: migraine was the most frequent diagnosis in both groups, followed by tension-type headache. The incidence of depression was similar, while anxiety was significantly less frequent in immigrants. Studies on neurological diseases in immigrants are few. The data available seem to show no differences in the incidence, but rather in treatment. Our study confirms the evenness of two populations, local and foreign, afferent in a Headache Unit, according to the single similar study, except for anxiety, maybe related to language difficulties or cultural background.

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Diffuse Liver Diseases: Role of imaging

Nowadays the most common imaging techniques allow to study focal liver lesions with high diagnostic accuracy but a relatively recent emerging field of interest is represented by diffuse liver disease. They include a variegated series of storage and metabolic pathologies (i.e. iron overload disorders and steatosis) requiring a precise diagnosis not always possible at imaging due to the overlapping of findings at conventional ultrasound, CT or MR studies.In recent years several imaging tecniques and specific softwares have been developed, especially for ultrasound and MR imaging, in order to identify different parameters useful in the noninvasive recognition and follow-up of these diffusely processes diffusely involving the liver.

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A Comparative Proteome Profile of Female Mouse Gonads Suggests A Tight Link between the Electron Transport Chain and Meiosis Initiation [Research]

Generation of haploid gametes by meiosis is a unique property of germ cells and is critical for sexual reproduction. Leaving mitosis and entering meiosis is a key step in germ cell development. Several inducers or intrinsic genes are known to be important for meiotic initiation, but the regulation of meiotic initiation, especially at the protein level, is still not well understood. We constructed a comparative proteome profile of female mouse fetal gonads at specific time points (11.5, 12.5, and 13.5 days post coitum), spanning a critical window for initiation of meiosis in female germ cells. We identified 3666 proteins, of which 473 were differentially expressed. Further bioinformatics analysis showed that these differentially expressed proteins were enriched in the mitochondria, especially in the electron transport chain and, notably, 9 proteins in electron transport chain Complex I were differentially expressed. We disrupted the mitochondrial electron transport chain function by adding the complex I inhibitor, rotenone to 11.5 days post coitum female gonads cultured in vitro. This treatment resulted in a decreased proportion of meiotic germ cells, as assessed by staining for histone H2AX. Rotenone treatment also caused decreased ATP levels, increased reactive oxygen species levels and failure of the germ cells to undergo premeiotic DNA replication. These effects were partially rescued by adding Coenzyme Q10. Taken together, our results suggested that a functional electron transport chain is important for meiosis initiation. Our characterization of the quantitative proteome of female gonads provides an inventory of proteins, useful for understanding the mechanisms of meiosis initiation and female fertility.

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Luciferase Complementation Imaging Assay in Nicotiana benthamiana Leaves for Transiently Determining Protein-protein Interaction Dynamics

This manuscript describes an easy and rapid experimental procedure for determining protein-protein interactions based on the measurement of luciferase activity.

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Comparison of bioaccumulation and elimination of Escherichia coli and male-specific bacteriophages by ascidians and bivalves

Abstract

Levels of Escherichia coli and male-specific bacteriophages (MSBs) were determined in the filter feeders obtained from retail markets, commercial farms, and wild beds in Korea. The accumulation and elimination of E. coli and MSBs were compared between ascidians and bivalves (oysters and mussels) during relaying and depuration. E. coli concentrations in ascidians from retail markets ranged between < 20 and 460 most probable number/100 g while MSBs were not detected. E. coli levels in bivalves from commercial farms and wild beds were not significantly different but bacterial levels in ascidians were consistently lower. Ascidians exhibited much lower ability than bivalves to accumulate E. coli and MSBs during relaying in a polluted coastal area. This study also shows that an equilibrium was developed between levels of microbes in water and ascidians and shellfish during relaying. E. coli and MSBs in ascidians decreased quickly during depuration in a clean seawater tank. However, after 1 day, E. coli in bivalves decreased by only 1.1–1.6 logs, and the elimination of MSBs was negligible. Therefore, depuration is an effective means to reduce the health risk of contaminated ascidians.

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EMA's new headquarters: Amsterdam

The European Medicines Agency (EMA) announced on 20 November that it will relocate...

Read more on AuntMinnieEurope.com

Related Reading:

7 PRAC members opposed EMA's gadolinium decision

EMA confirms clampdown on linear gadolinium agents

EMA begins work on Brexit

EMA continues investigation of gadolinium contrast agents

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Effect of left lateral tilt-down position on cecal intubation time: a 2-center, pragmatic, randomized controlled trial

Colonoscopy insertion is technically challenging, time-consuming and painful, especially for the sigmoid. Several pilot studies indicated (left) tilt-down position could facilitate insertion procedure, but no formal trials have been published to demonstrate its efficacy. We performed the study to verify the benefits of left lateral tilt-down position (LTDP) on insertion process.

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Prognostic factors affecting outcomes in patients with malignant GI bleeding treated with a novel endoscopically delivered hemostatic powder

Endoscopic hemostatic techniques remain poorly effective for GI tumor bleeding. We assessed Tc-325 (Hemospray) for this indication and determined possible predictors of decreased recurrent bleeding and improved 6-month survival in affected patients.

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Dissection-enabled scaffold-assisted resection (DeSCAR): a novel technique for resection of residual or non-lifting GI neoplasia of the colon (with video)

Due to previous manipulation or submucosal invasion, GI lesions referred for endoscopic mucosal resection (EMR) frequently have flat areas of visible tissue that cannot be snared. Current methods for treating residual tissue may lead to incomplete eradication or not allow complete tissue sampling for histologic evaluation. Our aim is to describe dissection-enabled scaffold-assisted resection (DeSCAR), a new technique combining circumferential ESD with EMR for removal of superficial non-lifting or residual "islands" with suspected submucosal involvement/fibrosis.

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Factors Influencing Uptake of Sylvatic Plague Vaccine Baits by Prairie Dogs

Abstract

Sylvatic plague vaccine (SPV) is a virally vectored bait-delivered vaccine expressing Yersinia pestis antigens that can protect prairie dogs (Cynomys spp.) from plague and has potential utility as a management tool. In a large-scale 3-year field trial, SPV-laden baits containing the biomarker rhodamine B (used to determine bait consumption) were distributed annually at a rate of approximately 100–125 baits/hectare along transects at 58 plots encompassing the geographic ranges of four species of prairie dogs. We assessed site- and individual-level factors related to bait uptake in prairie dogs to determine which were associated with bait uptake rates. Overall bait uptake for 7820 prairie dogs sampled was 70% (95% C.I. 69.9–72.0). Factors influencing bait uptake rates by prairie dogs varied by species, however, in general, heavier animals had greater bait uptake rates. Vegetation quality and day of baiting influenced this relationship for black-tailed, Gunnison's, and Utah prairie dogs. For these species, baiting later in the season, when normalized difference vegetation indices (a measure of green vegetation density) are lower, improves bait uptake by smaller animals. Consideration of these factors can aid in the development of species-specific SPV baiting strategies that maximize bait uptake and subsequent immunization of prairie dogs against plague.

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2017 Hepatology referees (volumes 65 and 66)

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Hepatology Highlights

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Table of contents

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Notices

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Notices

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Instructions to authors and Information for readers

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Association between long sleep duration and increased risk of obesity and type 2 diabetes: A review of possible mechanisms

For the last two decades research has revealed an alarming association between short sleep duration and metabolic disorders. In tandem, the hormonal, behavioral, and genetic mechanisms underlying this relationship have been extensively investigated and reviewed. However, emerging evidence is revealing that excessive sleep duration has remarkably similar deleterious effects. Unfortunately, to date there has been little attention to what drives this connection. This narrative review therefore aims to summarize existing epidemiological findings, experimental work, and most importantly putative molecular and behavioral mechanisms connecting excessive sleep duration with both obesity and type 2 diabetes mellitus.

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Why Ancient Mapmakers Were Terrified of Blank Spaces

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Non-alcoholic Fatty Liver Disease Associates with Increased Overall Mortality and Death from Cancer, Cardiovascular Disease, and Liver Disease in Women but Not Men

It is not clear whether women vs men have increased mortality from non-alcoholic fatty liver disease (NAFLD). We investigated whether NAFLD is associated with increased overall and cause-specific deaths in a Korean population using a large health study database.

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GSE100370 Hi-C of early Drosophila melanogaster embryos

Contributors : Michael R Stadler ; Michael B Eisen
Series Type : Other
Organism : Drosophila melanogaster

We use deep-sequencing of Hi-C libraries to identify topological boundaries at high resolution and show that boundaries, insulators, and polytene interbands converge on the same short genomic elements.

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Modeling clinical efficacy of the S1P receptor modulator ponesimod in psoriasis

Psoriasis is a chronic inflammatory disorder with substantial impact on quality of life [1,2]. The most common form is plaque psoriasis. The disease is mediated by T cells [3] and manifests itself as inflammation of the skin with plaque formation and rapid growth of skin cells [4,5].

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Sweat Mechanisms and Dysfunctions in Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory dermatosis that involves a complex interplay between genetic, immunologic and environmental factors [1]. Barrier abnormalities play an important role in the pathogenesis of AD, as mutations in the gene for the structural protein filaggrin (FLG) result in increased epidermal permeability, decreased SC hydration and increased pH [2,3]. SC pH provides an acidic environment for optimal antimicrobial enzyme activity and surface microbiome diversity [4].

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A novel anti-melanogenic agent, KDZ-001, inhibits tyrosinase enzymatic activity

Skin primarily consists of three different cell types: keratinocytes, fibroblasts, and melanocytes. Melanocytes are specialized cells that synthesize pigment, which is also known as melanin. Melanin is a heterogeneous biopolymer that is produced in melanosomes, which are organelles that synthesize, store, and transport melanin through a series of enzymatic reactions known as melanogenesis. Melanogenesis involves the catalysis of tyrosine by TYR-family proteins, including TYR and TYR-related protein 1/2 (TRP-1/2) [1,2].

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Berlin Heart Explant in an Infant

MECHANICAL CIRCULATORY SUPPORT DEVICES are used with increasing frequency in both the adult and pediatric population. There are currently 3 indications for ventricular assist device (VAD) implantation: bridge to transplant, bridge to recovery, or as destination therapy. The shortage of suitable donor hearts available for transplantation and advances in VAD technology has led to the increased usage of VADs as a bridge to transplantation in the pediatric population.1 Currently, the Berlin Heart EXCOR, HeartWare, and the Heart Mate II are the devices available for long-term support in pediatric patients.

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Leading the Digital Transformation of Healthcare: The ACC Innovation Strategy

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Double Kissing Crush Versus Provisional Stenting for Left Main Distal Bifurcation Lesions: DKCRUSH-V Randomized Trial

AbstractBackground

Provisional stenting (PS) is the most common technique used to treat distal left main (LM) bifurcation lesions in patients with unprotected LM coronary artery disease undergoing percutaneous coronary intervention. The double kissing (DK) crush planned 2-stent technique has been shown to improve clinical outcomes in non-LM bifurcations compared with PS, and in LM bifurcations compared with culotte stenting, but has never been compared with PS in LM bifurcation lesions.

Objectives

The authors sought to determine whether a planned DK crush 2-stent technique is superior to PS for patients with true distal LM bifurcation lesions.

Methods

The authors randomized 482 patients from 26 centers in 5 countries with true distal LM bifurcation lesions (Medina 1,1,1 or 0,1,1) to PS (n = 242) or DK crush stenting (n = 240). The primary endpoint was the 1-year composite rate of target lesion failure (TLF): cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization. Routine 13-month angiographic follow-up was scheduled after ascertainment of the primary endpoint.

Results

TLF within 1 year occurred in 26 patients (10.7%) assigned to PS, and in 12 patients (5.0%) assigned to DK crush (hazard ratio: 0.42; 95% confidence interval: 0.21 to 0.85; p = 0.02). Compared with PS, DK crush also resulted in lower rates of target vessel myocardial infarction I (2.9% vs. 0.4%; p = 0.03) and definite or probable stent thrombosis (3.3% vs. 0.4%; p = 0.02). Clinically driven target lesion revascularization (7.9% vs. 3.8%; p = 0.06) and angiographic restenosis within the LM complex (14.6% vs. 7.1%; p = 0.10) also tended to be less frequent with DK crush compared with PS. There was no significant difference in cardiac death between the groups.

Conclusions

In the present multicenter randomized trial, percutaneous coronary intervention of true distal LM bifurcation lesions using a planned DK crush 2-stent strategy resulted in a lower rate of TLF at 1 year than a PS strategy. (Double Kissing and Double Crush Versus Provisional T Stenting Technique for the Treatment of Unprotected Distal Left Main True Bifurcation Lesions: A Randomized, International, Multi-Center Clinical Trial [DKCRUSH-V]; ChiCTR-TRC-11001213)

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Reply: Improved Outcomes With Cardiology Care in Newly Diagnosed Atrial Fibrillation: Is Tachycardia-Induced Cardiomyopathy Underestimated?

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2Ag03SZ

Correction

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2AgBci2

Renal Outcomes in Anticoagulated Patients With Atrial Fibrillation

AbstractBackground

Lifelong oral anticoagulation, either with warfarin or a non–vitamin K antagonist oral anticoagulant (NOAC), is indicated for stroke prevention in most patients with atrial fibrillation (AF). Emerging evidence suggests that NOACs may be associated with better renal outcomes than warfarin.

Objectives

This study aimed to compare 4 oral anticoagulant agents (apixaban, dabigatran, rivaroxaban, and warfarin) for their effects on 4 renal outcomes: ≥30% decline in estimated glomerular filtration rate (eGFR), doubling of the serum creatinine level, acute kidney injury (AKI), and kidney failure.

Methods

Using a large U.S. administrative database linked to laboratory results, the authors identified 9,769 patients with nonvalvular AF who started taking an oral anticoagulant agent between October 1, 2010 and April 30, 2016. Inverse probability of treatment weighting was used to balance more than 60 baseline characteristics among patients in the 4 drug cohorts. Cox proportional hazards regression was performed in the weighted population to compare oral anticoagulant agents.

Results

The cumulative risk at the end of 2 years for each outcome was 24.4%, 4.0%, 14.8%, and 1.7% for ≥30% decline in eGFR, doubling of serum creatinine, AKI, and kidney failure, respectively. When the 3 NOACs were pooled, they were associated with reduced risks of ≥30% decline in eGFR (hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.66 to 0.89; p < 0.001), doubling of serum creatinine (HR: 0.62; 95% CI: 0.40 to 0.95; p = 0.03), and AKI (HR: 0.68; 95% CI: 0.58 to 0.81; p < 0.001) compared with warfarin. When comparing each NOAC with warfarin, dabigatran was associated with lower risks of ≥30% decline in eGFR and AKI; rivaroxaban was associated with lower risks of ≥30% decline in eGFR, doubling of serum creatinine, and AKI; however, apixaban did not have a statistically significant relationship with any of the renal outcomes.

Conclusions

Renal function decline is common among patients with AF treated with oral anticoagulant agents. NOACs, particularly dabigatran and rivaroxaban, may be associated with lower risks of adverse renal outcomes than warfarin.

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Medicaid Insurance and Psychosocial Status in Patients Evaluated for Heart Transplantation

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2Ag0ahn

Another Dimension of Safety in the Prescription of Anticoagulants for Nonvalvular Atrial Fibrillation

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2z6Gqsr

Authors Have Incorrectly Calculated Need for Renal Dose Adjustments for NOACs

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Use of Fondaparinux Off-Label or Approved Anticoagulants for Management of Heparin-Induced Thrombocytopenia

AbstractBackground

Life-threatening heparin-induced thrombocytopenia (HIT) is treated with the alternative nonheparin anticoagulants argatroban, lepirudin, or danaparoid. Frequently, the pentasaccharide fondaparinux is used off-label.

Objectives

The authors sought to investigate the safety and efficacy of the different anticoagulants for treating HIT.

Methods

In a national, multicenter registry study, hospitalized patients who were diagnosed with HIT, an at least intermediate clinical HIT-risk (4Ts score ≥4 points), and received treatment with ≥1 dose of the aforementioned anticoagulants were included. Main outcome measures were the incidences of HIT-specific complications (thromboembolic venous/arterial events, amputations, recurrent/persistent thrombocytopenia, skin lesions) and bleedings.

Results

Of 195 patients, 46 (23.6%), 4 (2.1%), 61 (31.3%), and 84 (43.1%) had been treated first-line with argatroban, lepirudin, danaparoid, and fondaparinux, respectively. The composite endpoint of HIT-specific complications (thromboembolic events, amputation, skin necrosis) occurred in 11.7% of patients treated with approved alternative anticoagulation and in 0.0% of fondaparinux-treated patients. The all-cause in-hospital mortality rates were 14.4% during approved alternative anticoagulation and 0.0% during fondaparinux treatment. Bleeding complications occurred in alternatively anticoagulated patients and in fondaparinux-treated patients in 6.3% and 4.8%, respectively. Post hoc analysis of clinical and laboratory features confirmed "true" HIT in at least 74 of 195 (38.0%) patients; 35 of 74 (47.3%) were treated with fondaparinux.

Conclusions

Fondaparinux is effective and safe in suspected acute HIT; no HIT-specific complications occurred in the fondaparinux-treated patients, even among those with a high clinical HIT probability. Further data from randomized controlled trials are urgently needed because lepirudin was recalled from the market; danaparoid access has been limited and is not approved in the United States; and argatroban is contraindicated in patients with impaired liver function, and activated partial thromboplastin time confounding may interfere with monitoring. (Retrospective Registry of Patients With Acute Heparin-induced Thrombocytopenia Type II; NCT01304238)

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2B7B2GQ

Correction

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2AfZOr3

Fondaparinux for Treatment of Heparin-Induced Thrombocytopenia: Too Good to Be True?

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2B7B15K

JACC Instructions for Authors

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2B7B6q4

Effect of a Formalized Research Curriculum on Fellows-in-Training and Early Career Research Productivity

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Xenon: A Noble Member of the Cardioprotection Club

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Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients

Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zUdAPy

Effects of Intensive Blood Pressure Treatment on Acute Kidney Injury Events in the Systolic Blood Pressure Intervention Trial (SPRINT)

Treating to a lower blood pressure (BP) may increase acute kidney injury (AKI) events.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zUdx6k

The Precision of Standardized Hospitalization, Readmission, and Mortality Ratios for Dialysis Facilities

Standardized ratios are increasingly used as key indexes of quality in "value-based care" and have appeared in a number of health care arenas, such as hospitals.1 Recently, standardized ratios for hospitalization (SHR), readmission (SRR), and mortality (SMR) have been proposed or adopted to assess other smaller health care entities, among them dialysis facilities (see Item S1 for measure specifications).2 Because smaller entities treat fewer patients, calculating standardized ratios for these facilities is inherently based on fewer events, which may result in less statistical power and greater imprecision, as reflected in the variability of score estimates for individual facilities.

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Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow

Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow

Granulocyte-derived TNFα promotes vascular and hematopoietic regeneration in the bone marrow, Published online: 20 November 2017; doi:10.1038/nm.4448

In the bone marrow, granulocyte-derived TNFα acts on endothelial cells to maintain the vasculature under steady-state conditions and to promote its regeneration after injury or transplantation.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2hGxdjs

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy, Published online: 20 November 2017; doi:10.1038/nm.4441

Fry et al. report the first results from a human trial of a CD22-directed chimeric antigen receptor (CAR) T cell therapy providing evidence of efficacy in the treatment of pre–B cell acute lymphoblastic leukemia that is immunotherapy-naive or resistant to CD19-directed CAR T cells.

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Spongy clay might create huge water deposits deep inside Earth

We might finally know how ocean-sized deposits of water hundreds of kilometres below Earth's surface are getting there: a spongy sort of clay that is bringing it underground

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Your music tastes can be changed by using magnets on your brain

Around three minutes of brain stimulation is all it takes to change people's love of music, and even how much money they're willing to spend on it

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zYO9tu

Fungal Endophyte Communities in Begonia Species from the Brazilian Atlantic Rainforest

Abstract

Tropical plants represent hotspots of endophytic fungal species diversity. Based on culture-dependent methods, we evaluated the endophytic fungal communities in leaves of three plant species found in the Brazilian Atlantic Rainforest: Begonia fischeri, Begonia olsoniae, and Begonia venosa. These species are found in two distant sites: a continental region and an insular area. A total of 426 fungal endophytes in 19 genera were isolated in pure culture including Colletotrichum (51.6% of isolates) and Diaporthe (22.5%) as the most abundant, followed by Phyllosticta (3.5%), Neopestalotiopsis (1.8%), Stagonospora (1.8%), and Nigrospora (1.6%) among the genera found in minor abundance. The diversity and composition of fungal taxa differed across plant hosts. Richness and diversity of fungi were higher in B. fischeri in comparison to B. olsoniae and B. venosa. Discriminatory analysis revealed that fungal communities are structured according to hosts, which means that each plant species had its distinct endophytic communities, but dominated by common fungal taxa. This is the first study to report fungal endophytes in begonia leaves and characterize their communities.

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Estimating virus effective population size and selection without neutral markers

by Elsa Rousseau, Benoît Moury, Ludovic Mailleret, Rachid Senoussi, Alain Palloix, Vincent Simon, Sophie Valière, Frédéric Grognard, Frédéric Fabre

By combining high-throughput sequencing (HTS) with experimental evolution, we can observe the within-host dynamics of pathogen variants of biomedical or ecological interest. We studied the evolutionary dynamics of five variants of Potato virus Y (PVY) in 15 doubled-haploid lines of pepper. All plants were inoculated with the same mixture of virus variants and, variant frequencies were determined by HTS in eight plants of each pepper line, at each of six sampling dates. We developed a method for estimating the intensities of selection and genetic drift in a multi-allelic Wright-Fisher model, applicable whether these forces are strong or weak, and in the absence of neutral markers. This method requires variant frequency determination at several time points, in independent hosts. The parameters are the selection coefficients for each PVY variant and four effective population sizes N_e at different time-points of the experiment. Numerical simulations of asexual haploid Wright-Fisher populations subjected to contrasting genetic drift (N_e ∈ [10, 2000]) and selection (|s| ∈ [0, 0.15]) regimes were used to validate the method proposed. The experiment in closely related pepper host genotypes revealed that viruses experienced a considerable diversity of selection and genetic drift regimes. The resulting variant dynamics were accurately described by Wright-Fisher models. The fitness ranks of the variants were almost identical between host genotypes. By contrast, the dynamics of N_e were highly variable, although a bottleneck was often identified during the systemic movement of the virus. We demonstrated that, for a fixed initial PVY population, virus effective population size is a heritable trait in plants. These findings pave the way for the breeding of plant varieties exposing viruses to stronger genetic drift, thereby slowing virus adaptation.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zjCcl3

Subtle variation within conserved effector operon gene products contributes to T6SS-mediated killing and immunity

by Christopher J. Alteri, Stephanie D. Himpsl, Kevin Zhu, Haley L. Hershey, Ninette Musili, Jessa E. Miller, Harry L. T. Mobley

Type VI secretion systems (T6SS) function to deliver lethal payloads into target cells. Many studies have shown that protection against a single, lethal T6SS effector protein requires a cognate antidote immunity protein, both of which are often encoded together in a two-gene operon. The T6SS and an effector-immunity pair is sufficient for both killing and immunity. HereIn this paper we describe a T6SS effector operon that differs from conventional effector-immunity pairs in that eight genes are necessary for lethal effector function, yet can be countered by a single immunity protein. In this study, we investigated the role that the PefE T6SS immunity protein plays in recognition between two strains harboring nearly identical effector operons. Interestingly, despite containing seven of eight identical effector proteins, the less conserved immunity proteins only provided protection against their native effectors, suggesting that specificity and recognition could be dependent on variation within an immunity protein and one effector gene product. The variable effector gene product, PefD, is encoded upstream from pefE, and displays toxic activity that can be countered by PefE independent of T6SS-activity. Interestingly, while the entire pef operon was necessary to exert toxic activity via the T6SS in P. mirabilis, production of PefD and PefE alone was unable to exert this effector activity. Chimeric PefE proteins constructed from two P. mirabilis strains were used to localize immunity function to three amino acids. A promiscuous immunity protein was created using site-directed mutagenesis to change these residues from one variant to another. These findings support the notion that subtle differences between conserved effectors are sufficient for T6SS-mediated kin discrimination and that PefD requires additional factors to function as a T6SS-dependent effector.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zVfZJu

Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-γ gene hypermethylation

by Yushi Yao, Hui Li, Jie Ding, Yixin Xia, Lei Wang

Pregnant women and animals have increased susceptibility to a variety of intracellular pathogens including Listeria monocytogenes (LM), which has been associated with significantly increased level of sex hormones such as progesterone. CD8 T memory(Tm) cell-mediated antigen-non-specific IFN-γ responses are critically required in the host defense against LM. However, whether and how increased progesterone during pregnancy modulates CD8 Tm cell-mediated antigen-non-specific IFN-γ production and immune protection against LM remain poorly understood. Here we show in pregnant women that increased serum progesterone levels are associated with DNA hypermethylation of IFN-γ gene promoter region and decreased IFN-γ production in CD8 Tm cells upon antigen-non-specific stimulation ex vivo. Moreover, IFN-γ gene hypermethylation and significantly reduced IFN-γ production post LM infection in antigen-non-specific CD8 Tm cells are also observed in pregnant mice or progesterone treated non-pregnant female mice, which is a reversible phenotype following demethylation treatment. Importantly, antigen-non-specific CD8 Tm cells from progesterone treated mice have impaired anti-LM protection when adoptive transferred in either pregnant wild type mice or IFN-γ-deficient mice, and demethylation treatment rescues the adoptive protection of such CD8 Tm cells. These data demonstrate that increased progesterone impairs immune protective functions of antigen-non-specific CD8 Tm cells via inducing IFN-γ gene hypermethylation. Our findings thus provide insights into a new mechanism through which increased female sex hormone regulate CD8 Tm cell functions during pregnancy.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2mIjCgG

Estimating virus effective population size and selection without neutral markers

by Elsa Rousseau, Benoît Moury, Ludovic Mailleret, Rachid Senoussi, Alain Palloix, Vincent Simon, Sophie Valière, Frédéric Grognard, Frédéric Fabre

By combining high-throughput sequencing (HTS) with experimental evolution, we can observe the within-host dynamics of pathogen variants of biomedical or ecological interest. We studied the evolutionary dynamics of five variants of Potato virus Y (PVY) in 15 doubled-haploid lines of pepper. All plants were inoculated with the same mixture of virus variants and, variant frequencies were determined by HTS in eight plants of each pepper line, at each of six sampling dates. We developed a method for estimating the intensities of selection and genetic drift in a multi-allelic Wright-Fisher model, applicable whether these forces are strong or weak, and in the absence of neutral markers. This method requires variant frequency determination at several time points, in independent hosts. The parameters are the selection coefficients for each PVY variant and four effective population sizes N_e at different time-points of the experiment. Numerical simulations of asexual haploid Wright-Fisher populations subjected to contrasting genetic drift (N_e ∈ [10, 2000]) and selection (|s| ∈ [0, 0.15]) regimes were used to validate the method proposed. The experiment in closely related pepper host genotypes revealed that viruses experienced a considerable diversity of selection and genetic drift regimes. The resulting variant dynamics were accurately described by Wright-Fisher models. The fitness ranks of the variants were almost identical between host genotypes. By contrast, the dynamics of N_e were highly variable, although a bottleneck was often identified during the systemic movement of the virus. We demonstrated that, for a fixed initial PVY population, virus effective population size is a heritable trait in plants. These findings pave the way for the breeding of plant varieties exposing viruses to stronger genetic drift, thereby slowing virus adaptation.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zjCcl3

Subtle variation within conserved effector operon gene products contributes to T6SS-mediated killing and immunity

by Christopher J. Alteri, Stephanie D. Himpsl, Kevin Zhu, Haley L. Hershey, Ninette Musili, Jessa E. Miller, Harry L. T. Mobley

Type VI secretion systems (T6SS) function to deliver lethal payloads into target cells. Many studies have shown that protection against a single, lethal T6SS effector protein requires a cognate antidote immunity protein, both of which are often encoded together in a two-gene operon. The T6SS and an effector-immunity pair is sufficient for both killing and immunity. HereIn this paper we describe a T6SS effector operon that differs from conventional effector-immunity pairs in that eight genes are necessary for lethal effector function, yet can be countered by a single immunity protein. In this study, we investigated the role that the PefE T6SS immunity protein plays in recognition between two strains harboring nearly identical effector operons. Interestingly, despite containing seven of eight identical effector proteins, the less conserved immunity proteins only provided protection against their native effectors, suggesting that specificity and recognition could be dependent on variation within an immunity protein and one effector gene product. The variable effector gene product, PefD, is encoded upstream from pefE, and displays toxic activity that can be countered by PefE independent of T6SS-activity. Interestingly, while the entire pef operon was necessary to exert toxic activity via the T6SS in P. mirabilis, production of PefD and PefE alone was unable to exert this effector activity. Chimeric PefE proteins constructed from two P. mirabilis strains were used to localize immunity function to three amino acids. A promiscuous immunity protein was created using site-directed mutagenesis to change these residues from one variant to another. These findings support the notion that subtle differences between conserved effectors are sufficient for T6SS-mediated kin discrimination and that PefD requires additional factors to function as a T6SS-dependent effector.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zVfZJu

iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA

by Wei-Wei Luo, Shu Li, Chen Li, Zhou-Qin Zheng, Pan Cao, Zhen Tong, Huan Lian, Su-Yun Wang, Hong-Bing Shu, Yan-Yi Wang

VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto-ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2hFPNYT

Estimating virus effective population size and selection without neutral markers

by Elsa Rousseau, Benoît Moury, Ludovic Mailleret, Rachid Senoussi, Alain Palloix, Vincent Simon, Sophie Valière, Frédéric Grognard, Frédéric Fabre

By combining high-throughput sequencing (HTS) with experimental evolution, we can observe the within-host dynamics of pathogen variants of biomedical or ecological interest. We studied the evolutionary dynamics of five variants of Potato virus Y (PVY) in 15 doubled-haploid lines of pepper. All plants were inoculated with the same mixture of virus variants and, variant frequencies were determined by HTS in eight plants of each pepper line, at each of six sampling dates. We developed a method for estimating the intensities of selection and genetic drift in a multi-allelic Wright-Fisher model, applicable whether these forces are strong or weak, and in the absence of neutral markers. This method requires variant frequency determination at several time points, in independent hosts. The parameters are the selection coefficients for each PVY variant and four effective population sizes N_e at different time-points of the experiment. Numerical simulations of asexual haploid Wright-Fisher populations subjected to contrasting genetic drift (N_e ∈ [10, 2000]) and selection (|s| ∈ [0, 0.15]) regimes were used to validate the method proposed. The experiment in closely related pepper host genotypes revealed that viruses experienced a considerable diversity of selection and genetic drift regimes. The resulting variant dynamics were accurately described by Wright-Fisher models. The fitness ranks of the variants were almost identical between host genotypes. By contrast, the dynamics of N_e were highly variable, although a bottleneck was often identified during the systemic movement of the virus. We demonstrated that, for a fixed initial PVY population, virus effective population size is a heritable trait in plants. These findings pave the way for the breeding of plant varieties exposing viruses to stronger genetic drift, thereby slowing virus adaptation.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zjCcl3

Progesterone impairs antigen-non-specific immune protection by CD8 T memory cells via interferon-γ gene hypermethylation

by Yushi Yao, Hui Li, Jie Ding, Yixin Xia, Lei Wang

Pregnant women and animals have increased susceptibility to a variety of intracellular pathogens including Listeria monocytogenes (LM), which has been associated with significantly increased level of sex hormones such as progesterone. CD8 T memory(Tm) cell-mediated antigen-non-specific IFN-γ responses are critically required in the host defense against LM. However, whether and how increased progesterone during pregnancy modulates CD8 Tm cell-mediated antigen-non-specific IFN-γ production and immune protection against LM remain poorly understood. Here we show in pregnant women that increased serum progesterone levels are associated with DNA hypermethylation of IFN-γ gene promoter region and decreased IFN-γ production in CD8 Tm cells upon antigen-non-specific stimulation ex vivo. Moreover, IFN-γ gene hypermethylation and significantly reduced IFN-γ production post LM infection in antigen-non-specific CD8 Tm cells are also observed in pregnant mice or progesterone treated non-pregnant female mice, which is a reversible phenotype following demethylation treatment. Importantly, antigen-non-specific CD8 Tm cells from progesterone treated mice have impaired anti-LM protection when adoptive transferred in either pregnant wild type mice or IFN-γ-deficient mice, and demethylation treatment rescues the adoptive protection of such CD8 Tm cells. These data demonstrate that increased progesterone impairs immune protective functions of antigen-non-specific CD8 Tm cells via inducing IFN-γ gene hypermethylation. Our findings thus provide insights into a new mechanism through which increased female sex hormone regulate CD8 Tm cell functions during pregnancy.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2mIjCgG

Subtle variation within conserved effector operon gene products contributes to T6SS-mediated killing and immunity

by Christopher J. Alteri, Stephanie D. Himpsl, Kevin Zhu, Haley L. Hershey, Ninette Musili, Jessa E. Miller, Harry L. T. Mobley

Type VI secretion systems (T6SS) function to deliver lethal payloads into target cells. Many studies have shown that protection against a single, lethal T6SS effector protein requires a cognate antidote immunity protein, both of which are often encoded together in a two-gene operon. The T6SS and an effector-immunity pair is sufficient for both killing and immunity. HereIn this paper we describe a T6SS effector operon that differs from conventional effector-immunity pairs in that eight genes are necessary for lethal effector function, yet can be countered by a single immunity protein. In this study, we investigated the role that the PefE T6SS immunity protein plays in recognition between two strains harboring nearly identical effector operons. Interestingly, despite containing seven of eight identical effector proteins, the less conserved immunity proteins only provided protection against their native effectors, suggesting that specificity and recognition could be dependent on variation within an immunity protein and one effector gene product. The variable effector gene product, PefD, is encoded upstream from pefE, and displays toxic activity that can be countered by PefE independent of T6SS-activity. Interestingly, while the entire pef operon was necessary to exert toxic activity via the T6SS in P. mirabilis, production of PefD and PefE alone was unable to exert this effector activity. Chimeric PefE proteins constructed from two P. mirabilis strains were used to localize immunity function to three amino acids. A promiscuous immunity protein was created using site-directed mutagenesis to change these residues from one variant to another. These findings support the notion that subtle differences between conserved effectors are sufficient for T6SS-mediated kin discrimination and that PefD requires additional factors to function as a T6SS-dependent effector.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2zVfZJu