Rendu–Osler–Weber syndrome presenting with pulmonary arteriovenous fistula

A pulmonary arteriovenous fistula is an abnormal connection between pulmonary arteries and veins. Patients with Rendu–Osler–Weber syndrome may present with this vascular malformation, which is a typical finding of the disease. Approximately 5–15% of Rendu–Osler–Weber syndrome patients have pulmonary arteriovenous malformations (AVM) and there is usually a family history of AVM in these patients. The malformations are usually located in the lower lobes. In this paper, I describe a 49‐year‐old male patient with dyspnoea, cough, haemoptysis and epistaxis. Physical examination showed nasal telangiectasias, cyanosis of the lips and nails, and a systolic bruit over the left lung. Chest X‐ray revealed a 5‐cm mass in the left lower lobe and after magnetic resonance examination, together with 3‐D magnetic resonance angiography, it was demonstrated to be a pulmonary arteriovenous fistula. The history of a niece with a similiar history of suspected pulmonary arteriovenous fistula led me to consider the possibility of Rendu–Osler–Weber syndrome presenting with a pulmonary arteriovenous fistula.     

Animal soundscapes reveal key markers of Amazon forest degradation from fire and logging

Safeguarding tropical forest biodiversity requires solutions for monitoring ecosystem structure over time. In the Amazon, logging and fire reduce forest carbon stocks and alter habitat, but the long-term consequences for wildlife remain unclear, especially for lesser-known taxa. Here, we combined multiday acoustic surveys, airborne lidar, and satellite time series covering logged and burned forests (n = 39) in the southern Brazilian Amazon to identify acoustic markers of forest degradation. Our findings contradict expectations from the Acoustic Niche Hypothesis that animal communities in more degraded habitats occupy fewer “acoustic niches” defined by time and frequency. Instead, we found that aboveground biomass was not a consistent proxy for acoustic biodiversity due to the divergent patterns of “acoustic space occupancy” between logged and burned forests. Ecosystem soundscapes highlighted a stark, and sustained reorganization in acoustic community assembly after multiple fires; animal communication networks were quieter, more homogenous, and less acoustically integrated in forests burned multiple times than in logged or once-burned forests. These findings demonstrate strong biodiversity cobenefits from protecting burned Amazon forests from recurrent fire. By contrast, soundscape changes after logging were subtle and more consistent with acoustic community recovery than reassembly. In both logged and burned forests, insects were the dominant acoustic markers of degradation, particularly during midday and nighttime hours, which are not typically sampled by traditional biodiversity field surveys. The acoustic fingerprints of degradation history were conserved across replicate recording locations, indicating that soundscapes may offer a robust, taxonomically inclusive solution for digitally tracking changes in acoustic community composition over time.

Biological diversity is disappearing rapidly in response to human activity, especially in tropical forests, which are home to well over half of Earth’s terrestrial species (1). Global concern over greenhouse gas emissions from tropical forests (2) has led to international efforts to Reduce Emissions from Deforestation and Forest Degradation (REDD+) (3). Retention of diverse ecosystems supports climate change mitigation and adaptation (4); yet, carbon-focused conservation may not result in a commensurate win for tropical forest biodiversity (5). Longstanding data gaps on species distributions and uncertainty regarding the direct and indirect impacts of human activity on biodiversity complicate efforts to quantify the interplay between carbon and biodiversity (6, 7).Across the tropics, the Brazilian Amazon has the highest rates of deforestation (8), and forest degradation from fire and logging may double biodiversity loss from deforestation alone (9). However, the long-term impacts of human activity on Amazon biodiversity remain highly uncertain due, in part, to the spatial heterogeneity among degraded forests from differences in the timing, frequency, extent, and severity of disturbances (10). Time-varying heterogeneity in the biodiversity of degraded forests may also explain some of the apparent contradictions in previous studies of degradation impacts on birds, the most well-studied Amazonian taxa. Many nectarivorous birds, for example, increase in abundance immediately after logging but ultimately decline. Yet, many insectivorous birds show immediate sensitivity to changes in habitat from logging but continue to decline in abundance over time (11). Time dependence also complicates efforts to measure the effects of degradation on insects, a problem confounded by limited research (12).Addressing the tropical biodiversity extinction crisis, therefore, requires an efficient, distributed, long-term monitoring system to assess ecosystem structure (13). Traditional, ground-based biodiversity inventories are logistically prohibitive to conduct at scale, and limited taxonomic expertise perpetuates large data discrepancies for lesser-known taxa, such as insects, which constitute the bulk of tropical biodiversity (7). Advances in the emerging discipline of acoustic remote sensing, or ecoacoustics, may permit large-scale biodiversity monitoring for multiple taxa, including unidentifiable species, based on the aggregate sound signature of the animal community, or soundscape (14–16). Since multiple sites can be recorded simultaneously over time, sound surveys reduce the effort and cost associated with routine monitoring and facilitate standardized assessments of community variation and ecosystem recovery. Most previous efforts to utilize acoustic data for biodiversity monitoring have focused on detecting known vocalizations associated with individual species (17, 18), but there is increasing interest in evaluating the entire collection of signals in a given soundscape to derive measures of ecosystem intactness that include all sound-generating taxa without definitive species identification (15, 16, 19, 20).The Acoustic Niche Hypothesis (ANH) (21) is a core premise of ecoacoustics and the prevailing organizing principle for assessing diversity (16), community similarity (22), and human impacts (23, 24) using soundscape data. The ANH posits that more intact habitats support more biodiverse communities that occupy more “acoustic niches.” Greater niche partitioning of available acoustic space, defined by frequency and time of day, is posited to minimize communication interference among coexisting species. The ANH implies a positive linear relationship between habitat intactness (i.e., biomass) and acoustic niche infilling or acoustic space occupancy (ASO) by the “animal orchestra.” The corollary is that more degraded habitats support less acoustic infilling due to vacant acoustic niches from local species extirpations (25). Ecoacoustic approaches have great potential to extend monitoring capabilities in the hyperdiverse tropics, where competition for acoustic space is strongest (16, 26). Still, large uncertainties remain as to whether soundscape infilling can be used as a robust proxy for ecosystem intactness to monitor landscapes altered by human activity (27).Here, we test the ANH across logged and burned Amazon forests to identify acoustic markers of forest degradation (Fig. 1). We collected coincident high-density airborne lidar data and multiday acoustic recordings (214 24-h surveys) during September and October 2016 in 39 forests with different times since logging (4 to 23 y) and histories of fire activity (1 to 5 fires), stratified based on a 33-y time series of annual Landsat imagery (10). We used space-for-time substitution and two complementary analytic approaches to characterize threshold effects and time dependence for changes in the structure of animal soundscapes along gradients of degradation history (see Materials and Methods). First, we calculated ASO for each site at hourly and 1-min time steps to test the ANH and to quantify the magnitude, persistence, and variability in the infilling of acoustic space following forest degradation. Second, we developed a network-based approach to capture additional complexity from the soundscape data to track the composition and co-occurrences of “acoustic pseudotaxa” (defined as the community components that occupy the same acoustic niche) along degradation and recovery pathways. Our findings demonstrate that soundscapes encode digital markers of the history of degradation from human activity, revealing distinct patterns of community change following logging and fire. This study paves the way for more widespread use of ecoacoustics to benchmark and monitor changes in acoustic community composition in human-altered tropical forest landscapes, especially in remote regions with many unknown species.Open in a separate windowFig. 1.Acoustic recording sites in logged and burned forests (n = 39) were distributed across 9,400 km² in northern Mato Grosso, Brazil (Upper Left). Colored boxes identify subsets of the study domain to illustrate how the triplicate sampling scheme was designed to capture the heterogeneity in habitat structure and acoustic community composition in logged (yellow) and burned (black) forests. False-color composites of Landsat imagery (2014, 543-RGB) in each panel show deforested areas in magenta and gradients of forest cover in shades of green.     

The Value of Bedside Rounds: A Multicenter Qualitative Study

Background: Bedside rounds have decreased on teaching services, raising concern about trainees’ clinical skills and patient–physician relationships. Purpose: We sought to identify recognized bedside teachers’ perceived value of bedside rounds to assist in the promotion of bedside rounds on teaching services. Methods: Authors used a grounded theory, qualitative study design of telephone semistructured interviews with bedside teachers (n = 34) from 10 U.S. institutions (2010–2011). Main outcomes were characteristics of participants, themes pertaining to the perceived value of bedside rounds, and quotations highlighting each respective theme. Results: The mean years in academic medicine was 13.7, and 51% were associate or full professors. Six main themes emerged: (a) skill development for learners (e.g., physical examination, communication, and clinical decision-making skills); (b) observation and feedback; (c) role-modeling; (d) team building among trainees, attending, and patient; (e) improved patient care delivery through combined clinical decision-making and team consensus; and (f) the culture of medicine as patient-centered care, which was embodied in all themes. Conclusions: Bedside teachers identify potential benefits of bedside rounds, many of which align with national calls to change our approach to medical education. The practice of bedside rounds enables activities essential to high-quality patient care and education.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

The Akt inhibitor,triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis

Background and Purpose

Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt-mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear.

Experimental Approach

We investigated the role of the Akt-mTOR pathway and its downstream molecular mechanisms in chronic hypoxia- and TGFβ-induced pulmonary vascular pruning and fibrosis in mice. We also determined the therapeutic benefits of the Akt inhibitor triciribine and the mTOR inhibitor rapamycin for the treatment of pulmonary fibrosis in mice.

Key Results

Akt1^−/− mice were protected from chronic hypoxia-induced peripheral vascular pruning. In contrast, hyperactivation of Akt1 induced focal fibrosis similar to TGFβ-induced fibrosis. Pharmacological inhibition of Akt, but not the Akt substrate mTOR, inhibited hypoxia- and TGFβ-induced pulmonary vascular rarefaction and fibrosis. Mechanistically, we found that Akt1 modulates pulmonary remodelling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1^−/− mice lungs expressed less TSP1. Moreover, TSP1^−/− mice were resistant to adMyrAkt1-induced pulmonary fibrosis.

Conclusions and Implications

Our study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides preclinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease.     

Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients

Fifty consecutive patients admitted with acute liver failure, minimal grade II encephalopathy, were studied prospectively to determine the incidence, timing and cause of bacterial infection, the relationship to clinical criteria for infection; and the influence of early microbiological diagnosis on clinical outcome. There were 53 proven bacterial infections in 40 patients, whereas in 5 of the remaining 10 patients infection was suspected on clinical grounds in the absence of significant cultures. Seven patients (14%) had more than one bacterial infection, and four patients had simultaneous infections caused by different organisms at each site. Fourteen infections (26.4%) were associated with bacteremia, and in six of these no source was found. Twenty-five infections (47.1%) arose from the respiratory tract, 12 (22.6%) from the urinary tract and 2 (3.7%) from central venous cannulas. Thirty-seven (69.8%) of the 53 infections were due to gram-positive bacteria; Staphylococcus aureus accounted for 19 (35.8%) of all the infections. Thirty patients died (60%), 28 of whom had bacterial infection at some time; in 24 of these the infection was diagnosed less than 24 hr before death. All nine deaths that occurred more than 7 days after admission were directly attributable to microbial infection. Clinical features such as elevated temperature and elevated peripheral white blood cell count were poor indicators of bacterial infection because these were absent in 30.2% of cases. These data show that there is a high incidence of bacterial infection early in the course of acute liver failure and suggest that prophylactic antimicrobial therapy, although unproven, might be justified.     

Cytoprotective effects of calcium channel blockers. Mechanisms and potential applications in hepatocellular injury

Deregulation of calcium homeostasis is strongly implicated in the development of cellular injury, including in hepatocytes, and is thought to be the limiting step in transition to an irreversible stage. Calcium channel blockers appear to exert their cytoprotective effects through several mechanisms. These may involve blockade of L-(long-lasting)-type calcium channels, reduction of oxidative stress, antagonism at inflammatory mediator receptor sites and interaction at other intracellular sites. Studies relating to the liver are few but suggest that calcium channel blockers may have a role to play in limiting hepatocellular damage, especially those arising from exposure to a variety of toxic agents.