Resonance as the Mechanism of Daytime Periodic Breathing in Patients with Heart Failure

Rationale: In patients with chronic heart failure, daytime oscillatory breathing at rest is associated with a high risk of mortality. Experimental evidence, including exaggerated ventilatory responses to CO2 and prolonged circulation time, implicates the ventilatory control system and suggests feedback instability (loop gain > 1) is responsible. However, daytime oscillatory patterns often appear remarkably irregular versus classic instability (Cheyne-Stokes respiration), suggesting our mechanistic understanding is limited. Objectives: We propose that daytime ventilatory oscillations generally result from a chemoreflex resonance, in which spontaneous biological variations in ventilatory drive repeatedly induce temporary and irregular ringing effects. Importantly, the ease with which spontaneous biological variations induce irregular oscillations (resonance “strength”) rises profoundly as loop gain rises toward 1. We tested this hypothesis through a comparison of mathematical predictions against actual measurements in patients with heart failure and healthy control subjects. Methods: In 25 patients with chronic heart failure and 25 control subjects, we examined spontaneous oscillations in ventilation and separately quantified loop gain using dynamic inspired CO2 stimulation. Measurements and Main Results: Resonance was detected in 24 of 25 patients with heart failure and 18 of 25 control subjects. With increased loop gain—consequent to increased chemosensitivity and delay—the strength of spontaneous oscillations increased precipitously as predicted (r = 0.88), yielding larger (r = 0.78) and more regular (interpeak interval SD, r = −0.68) oscillations (P < 0.001 for all, both groups combined). Conclusions: Our study elucidates the mechanism underlying daytime ventilatory oscillations in heart failure and provides a means to measure and interpret these oscillations to reveal the underlying chemoreflex hypersensitivity and reduced stability that foretells mortality in this population

A Rapid and Sensitive Method for Measuring NAcetylglucosaminidase Activity in Cultured Cells

A rapid and sensitive method to quantitatively assess N-acetylglucosaminidase (NAG) activity in cultured cells is highly desirable for both basic research and clinical studies. NAG activity is deficient in cells from patients with Mucopolysaccharidosis type IIIB (MPS IIIB) due to mutations in NAGLU, the gene that encodes NAG. Currently available techniques for measuring NAG activity in patient-derived cell lines include chromogenic and fluorogenic assays and provide a biochemical method for the diagnosis of MPS IIIB. However, standard protocols require large amounts of cells, cell disruption by sonication or freeze-thawing, and normalization to the cellular protein content, resulting in an error-prone procedure that is material- and time-consuming and that produces highly variable results. Here we report a new procedure for measuring NAG activity in cultured cells. This procedure is based on the use of the fluorogenic NAG substrate, 4- Methylumbelliferyl-2-acetamido-2-deoxy-alpha-D-glucopyranoside (MUG), in a one-step cell assay that does not require cell disruption or post-assay normalization and that employs a low number of cells in 96-well plate format. We show that the NAG one-step cell assay greatly discriminates between wild-type and MPS IIIB patient-derived fibroblasts, thus providing a rapid method for the detection of deficiencies in NAG activity. We also show that the assay is sensitive to changes in NAG activity due to increases in NAGLU expression achieved by either overexpressing the transcription factor EB (TFEB), a master regulator of lysosomal function, or by inducing TFEB activation chemically. Because of its small format, rapidity, sensitivity and reproducibility, the NAG one-step cell assay is suitable for multiple procedures, including the high-throughput screening of chemical libraries to identify modulators of NAG expression, folding and activity, and the investigation of candidate molecules and constructs for applications in enzyme replacement therapy, gene therapy, and combination therapies

Basin-scale transport of hydrothermal dissolved metals across the South Pacific Ocean

Hydrothermal venting along mid-ocean ridges exerts an important control on the chemical composition of sea water by serving as a major source or sink for a number of trace elements in the ocean(1-3). Of these, iron has received considerable attention because of its role as an essential and often limiting nutrient for primary production in regions of the ocean that are of critical importance for the global carbon cycle(4). It has been thought that most of the dissolved iron discharged by hydrothermal vents is lost from solution close to ridge-axis sources(2,5) and is thus of limited importance for ocean biogeochemistry(6). This long-standing view is challenged by recent studies which suggest that stabilization of hydrothermal dissolved iron may facilitate its longrange oceanic transport(7-10). Such transport has been subsequently inferred from spatially limited oceanographic observations(11-13). Here we report data from the US GEOTRACES Eastern Pacific Zonal Transect (EPZT) that demonstrate lateral transport of hydrothermal dissolved iron, manganese, and aluminium from the southern East Pacific Rise (SEPR) several thousand kilometres westward across the South Pacific Ocean. Dissolved iron exhibits nearly conservative (that is, no loss from solution during transport and mixing) behaviour in this hydrothermal plume, implying a greater longevity in the deep ocean than previously assumed(6,14). Based on our observations, we estimate a global hydrothermal dissolved iron input of three to four gigamoles per year to the ocean interior, which is more than fourfold higher than previous estimates(7,11,14). Complementary simulations with a global-scale ocean biogeochemical model suggest that the observed transport of hydrothermal dissolved iron requires some means of physicochemical stabilization and indicate that hydrothermally derived iron sustains a large fraction of Southern Ocean export productio

Marine plastics threaten giant Atlantic Marine Protected Areas.

There has been a recent shift in global perception of plastics in the environment, resulting in a call for greater action. Science and the popular media have highlighted plastic as an increasing stressor [1,2]. Efforts have been made to confer protected status to some remote locations, forming some of the world's largest Marine Protected Areas, including several UK overseas territories. We assessed plastic at these remote Atlantic Marine Protected Areas, surveying the shore, sea surface, water column and seabed, and found drastic changes from 2013-2018. Working from the RRS James Clark Ross at Ascension, St. Helena, Tristan da Cunha, Gough and the Falkland Islands (Figure 1A), we showed that marine debris on beaches has increased more than 10 fold in the past decade. Sea surface plastics have also increased, with in-water plastics occurring at densities of 0.1 items m-3; plastics on seabeds were observed at ≤ 0.01 items m-2. For the first time, beach densities of plastics at remote South Atlantic sites approached those at industrialised North Atlantic sites. This increase even occurs hundreds of meters down on seamounts. We also investigated plastic incidence in 2,243 animals (comprising 26 species) across remote South Atlantic oceanic food webs, ranging from plankton to seabirds. We found that plastics had been ingested by primary consumers (zooplankton) to top predators (seabirds) at high rates. These findings suggest that MPA status will not mitigate the threat of plastic proliferation to this rich, unique and threatened biodiversity

Climate Mitigation through Biological Conservation: Extensive and Valuable Blue Carbon Natural Capital in Tristan da Cunha’s Giant Marine Protected Zone

Carbon-rich habitats can provide powerful climate mitigation if meaningful protection is put in place. We attempted to quantify this around the Tristan da Cunha archipelago Marine Protected Area. Its shallows (&lt;1000 m depth) are varied and productive. The 5.4 km2 of kelp stores ~60 tonnes of carbon (tC) and may export ~240 tC into surrounding depths. In deep-waters we analysed seabed data collected from three research cruises, including seabed mapping, camera imagery, seabed oceanography and benthic samples from mini-Agassiz trawl. Rich biological assemblages on seamounts significantly differed to the islands and carbon storage had complex drivers. We estimate ~2.3 million tC are stored in benthic biodiversity of waters &lt;1000 m, which includes &gt;0.22 million tC that can be sequestered (the proportion of the carbon captured that is expected to become buried in sediment or locked away in skeletal tissue for at least 100 years). Much of this carbon is captured by cold-water coral reefs as a mixture of inorganic (largely calcium carbonate) and organic compounds. As part of its 2020 Marine Protection Strategy, these deep-water reef systems are now protected by a full bottom-trawling ban throughout Tristan da Cunha and representative no take areas on its seamounts. This small United Kingdom Overseas Territory’s reef systems represent approximately 0.8 Mt CO2 equivalent sequestered carbon; valued at &gt;£24 Million GBP (at the UN shadow price of carbon). Annual productivity of this protected standing stock generates an estimated £3 million worth of sequestered carbon a year, making it an unrecognized and potentially major component of the economy of small island nations like Tristan da Cunha. Conservation of near intact habitats are expected to provide strong climate and biodiversity returns, which are exemplified by this MPA.</jats:p

Endoscopic resection of giant lipoma mimicking colonic neoplasm initially presenting with massive haemorrhage: a case report

Lipomas of the colon are benign tumors that rarely occur. Their size ranges from 2 mm to several cm. They are usually asymptomatic but occasionally they present with clinical manifestations depending on tumor size, localization and complications, which often lead to diagnostic difficulty. A 40-year-old man presented with massive rectal haemorrhage. During colonoscopy a giant polyp of over 50 mm in its bigger diameter, with a thick stalk of 2 cm, located in the transverse colon, was revealed. Endoscopic resection was performed with success. Histologic examination demonstrated a giant lipoma. In this report discussion over endoscopic resection of colonic lipomas mimicking neoplasms is also performed

Option selection in whole-body rotation movements in gymnastics

Abstract When a gymnast performs a somersault, the linear and angular momentum along with a particular control of inertia during the flight phase constrain the possibilities for action. Given the complexity and dynamic nature of the human moving system, one could argue that there exist a particular amount of stable coordination states when performing somersaults. The goal of this study was to explore the manifold of movement options and coordination states along with their differentiating parameters for a single somersault in gymnastics based on a simple mathematical model reflecting gymnast’s rotation behavior during the flight phase. Biomechanical parameters determining rotation behavior during a somersault were systematically varied with regard to a particular set of biomechanical constraints defining a successful somersault performance. Batch simulations revealed that from 10229760 simulation cycles only 655346 (approximately 6.41%) led to successful somersault performance. A subsequent analysis of the movement option landscape for the optimum angular momentum revealed ten coordination states for a single somersault that could be clearly distinguished based on the simulation parameters. Taken the results together, it becomes apparent that it may be most advisable to perform a single somersault with a larger moment of inertia when achieving the tucked position, a longer duration to achieve the tucked position, a longer duration of staying tucked, and an intermediate moment of inertia during landing. This strategy comprises the largest amount of movement options associated with an upright landing and thus the highest probability of success when performing a single somersault

Cryptic Speciation in Brazilian Epiperipatus (Onychophora: Peripatidae) Reveals an Underestimated Diversity among the Peripatid Velvet Worms

Taxonomical studies of the neotropical Peripatidae (Onychophora, velvet worms) have proven difficult, due to intraspecific variation and uniformity of morphological characters across this onychophoran subgroup. We therefore used molecular approaches, in addition to morphological methods, to explore the diversity of Epiperipatus from the Minas Gerais State of Brazil.Our analyses revealed three new species. While Epiperipatus diadenoproctussp. nov. can be distinguished from E. adenocryptussp. nov. and E. paurognostussp. nov. based on morphology and specific nucleotide positions in the mitochondrial cytochrome c oxidase subunit I (COI) and small ribosomal subunit RNA gene sequences (12S rRNA), anatomical differences between the two latter species are not evident. However, our phylogenetic analyses of molecular data suggest that they are cryptic species, with high Bayesian posterior probabilities and bootstrap and Bremer support values for each species clade. The sister group relationship of E. adenocryptussp. nov. and E. paurognostussp. nov. in our analyses correlates with the remarkable morphological similarity of these two species. To assess the species status of the new species, we performed a statistical parsimony network analysis based on 582 base pairs of the COI gene in our specimens, with the connection probability set to 95%. Our findings revealed no connections between groups of haplotypes, which have been recognized as allopatric lineages in our phylogenetic analyses, thus supporting our suggestion that they are separate species.Our findings suggest high cryptic species diversity and endemism among the neotropical Peripatidae and demonstrate that the combination of morphological and molecular approaches is helpful for clarifying the taxonomy and species diversity of this apparently large and diverse onychophoran group

Construct validation of the Health Utilities Index and the Child Health Questionnaire in children undergoing cancer chemotherapy

The objective of this study was to evaluate the construct validity of two questionnaire-based measures of health-related quality of life (HRQL) in children undergoing cancer chemotherapy: the Health Utilities Index (HUI) and the Child Health Questionnaire (CHQ). Subjects were children hospitalised for chemotherapy. To examine construct validity: (1) a priori expected relations between CHQ concepts and HUI attributes were examined; (2) HUI and CHQ summary scores were compared to visual analogue scale (VAS) scores. Ease of completion was rated using a 5-point categorical scale and completion time was recorded. A total of 36 subjects were included. The maximum score was seen in 15 (47%) of HUI3 assessments. As predicted, CHQ body pain was moderately correlated with HUI3 pain (r=0.51), CHQ physical functioning was moderately correlated with HUI2 mobility (r=0.58) and CHQ mental health was moderately correlated with HUI2 emotion (r=0.53). Only the CHQ psychosocial subscale (and not HUI) was correlated with VAS (r=0.44). The CHQ and the HUI were both easy to use. The HUI questionnaires required less time to complete (mean=3.1, s.d.=1 min) compared with CHQ (mean=13.1, s.d.=3.4 min, P<0.0001). In conclusion, HUI and CHQ demonstrated construct validity in children undergoing cancer chemotherapy. The Health Utilities Index is subject to a ceiling effect whereas CHQ requires more time to complete

Comparing administrative and survey data for ascertaining cases of irritable bowel syndrome: a population-based investigation

<p>Abstract</p> <p>Background</p> <p>Administrative and survey data are two key data sources for population-based research about chronic disease. The objectives of this methodological paper are to: (1) estimate agreement between the two data sources for irritable bowel syndrome (IBS) and compare the results to those for inflammatory bowel disease (IBD); (2) compare the frequency of IBS-related diagnoses in administrative data for survey respondents with and without self-reported IBS, and (3) estimate IBS prevalence from both sources.</p> <p>Methods</p> <p>This retrospective cohort study used linked administrative and health survey data for 5,134 adults from the province of Manitoba, Canada. Diagnoses in hospital and physician administrative data were investigated for respondents with self-reported IBS, IBD, and no bowel disorder. Agreement between survey and administrative data was estimated using the κ statistic. The χ²statistic tested the association between the frequency of IBS-related diagnoses and self-reported IBS. Crude, sex-specific, and age-specific IBS prevalence estimates were calculated from both sources.</p> <p>Results</p> <p>Overall, 3.0% of the cohort had self-reported IBS, 0.8% had self-reported IBD, and 95.3% reported no bowel disorder. Agreement was poor to fair for IBS and substantially higher for IBD. The most frequent IBS-related diagnoses among the cohort were anxiety disorders (34.4%), symptoms of the abdomen and pelvis (26.9%), and diverticulitis of the intestine (10.6%). Crude IBS prevalence estimates from both sources were lower than those reported previously.</p> <p>Conclusions</p> <p>Poor agreement between administrative and survey data for IBS may account for differences in the results of health services and outcomes research using these sources. Further research is needed to identify the optimal method(s) to ascertain IBS cases in both data sources.</p