COVID-19 has seen the propagation of alternative remedies to treat respiratory disease, such as nebulization of hydrogen peroxide (H
O
). As H
O
has known cytotoxicity, it was hypothesised that H
O
...inhalation would negatively impact respiratory cilia function. To test this hypothesis, mouse tracheal samples were incubated with different H
O
concentrations (0.1-1%) then cilia motility, cilia generated flow, and cell death was assessed 0-120 min following H
O
treatment. 0.1-0.2% H
O
caused immediate depression of cilia motility and complete cessation of cilia generated flow. Higher H
O
concentrations (≥0.5%) caused immediate complete cessation of cilia motility and cilia generated flow. Cilia motility and flow was restored 30 min after 0.1% H
O
treatment. Cilia motility and flow remained depressed 120 min after 0.2-0.5% H
O
treatment. No recovery was seen 120 min after treatment with ≥1% H
O
. Live/dead staining revealed that H
O
treatment caused preferential cell death of ciliated respiratory epithelia over non-ciliated epithelia, with 1% H
O
causing 35.3 ± 7.0% of the ciliated epithelia cells to die 120 min following initial treatment. This study shows that H
O
treatment significantly impacts respiratory cilia motility and cilia generated flow, characterised by a significant impairment in cilia motility even at low concentrations, the complete cessation of cilia motility at higher doses, and a significant cytotoxic effect on ciliated respiratory epithelial cells by promoting cell death. While this data needs further study using
models, it suggests that extreme care should be taken when considering treating respiratory diseases with nebulised H
O
.
There are numerous reference equations available for the single-breath transfer factor of the lung for carbon monoxide (
); however, it is not always clear which reference set should be used in ...clinical practice. The aim of the study was to develop the Global Lung Function Initiative (GLI) all-age reference values for
Data from 19 centres in 14 countries were collected to define
reference values. Similar to the GLI spirometry project, reference values were derived using the LMS (lambda, mu, sigma) method and the GAMLSS (generalised additive models for location, scale and shape) programme in R.12 660
measurements from asymptomatic, lifetime nonsmokers were submitted; 85% of the submitted data were from Caucasians. All data were uncorrected for haemoglobin concentration. Following adjustments for elevation above sea level, gas concentration and assumptions used for calculating the anatomic dead space volume, there was a high degree of overlap between the datasets. Reference values for Caucasians aged 5-85 years were derived for
, transfer coefficient of the lung for carbon monoxide and alveolar volume.This is the largest collection of normative
data, and the first global reference values available for
.
The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, ...red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, in particular, short- and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, or mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading and metabolic rewiring toward the hexose monophosphate shunt, RBCs from COVID-19 patients may be less capable of responding to environmental variations in hemoglobin oxygen saturation/oxidant stress when traveling from the lungs to peripheral capillaries and vice versa.
Ciliopathies are associated with wide spectrum of structural birth defects (SBDs), indicating important roles for cilia in development. Here, we provide novel insights into the temporospatial ...requirement for cilia in SBDs arising from deficiency in Ift140, an intraflagellar transport (IFT) protein regulating ciliogenesis. Ift140-deficient mice exhibit cilia defects accompanied by wide spectrum of SBDs including macrostomia (craniofacial defects), exencephaly, body wall defects, tracheoesophageal fistula (TEF), randomized heart looping, congenital heart defects (CHDs), lung hypoplasia, renal anomalies, and polydactyly. Tamoxifen inducible CAGGCre-ER deletion of a floxed Ift140 allele between E5.5 to 9.5 revealed early requirement for Ift140 in left-right heart looping regulation, mid to late requirement for cardiac outflow septation and alignment, and late requirement for craniofacial development and body wall closure. Surprisingly, CHD were not observed with 4 Cre drivers targeting different lineages essential for heart development, but craniofacial defects and omphalocele were observed with Wnt1-Cre targeting neural crest and Tbx18-Cre targeting epicardial lineage and rostral sclerotome through which trunk neural crest cells migrate. These findings revealed cell autonomous role of cilia in cranial/trunk neural crest-mediated craniofacial and body wall closure defects, while non-cell autonomous multi-lineage interactions underlie CHD pathogenesis, revealing unexpected developmental complexity for CHD associated with ciliopathies.
Planar cell polarity (PCP) regulates cell alignment required for collective cell movement during embryonic development. This requires PCP/PCP effector proteins, some of which also play essential ...roles in ciliogenesis, highlighting the long-standing question of the role of the cilium in PCP. Wdpcp, a PCP effector, was recently shown to regulate both ciliogenesis and collective cell movement, but the underlying mechanism is unknown. Here we show Wdpcp can regulate PCP by direct modulation of the actin cytoskeleton. These studies were made possible by recovery of a Wdpcp mutant mouse model. Wdpcp-deficient mice exhibit phenotypes reminiscent of Bardet-Biedl/Meckel-Gruber ciliopathy syndromes, including cardiac outflow tract and cochlea defects associated with PCP perturbation. We observed Wdpcp is localized to the transition zone, and in Wdpcp-deficient cells, Sept2, Nphp1, and Mks1 were lost from the transition zone, indicating Wdpcp is required for recruitment of proteins essential for ciliogenesis. Wdpcp is also found in the cytoplasm, where it is localized in the actin cytoskeleton and in focal adhesions. Wdpcp interacts with Sept2 and is colocalized with Sept2 in actin filaments, but in Wdpcp-deficient cells, Sept2 was lost from the actin cytoskeleton, suggesting Wdpcp is required for Sept2 recruitment to actin filaments. Significantly, organization of the actin filaments and focal contacts were markedly changed in Wdpcp-deficient cells. This was associated with decreased membrane ruffling, failure to establish cell polarity, and loss of directional cell migration. These results suggest the PCP defects in Wdpcp mutants are not caused by loss of cilia, but by direct disruption of the actin cytoskeleton. Consistent with this, Wdpcp mutant cochlea has normal kinocilia and yet exhibits PCP defects. Together, these findings provide the first evidence, to our knowledge, that a PCP component required for ciliogenesis can directly modulate the actin cytoskeleton to regulate cell polarity and directional cell migration.
The waist-hip ratio, namely waist circumference (WC) divided by hip circumference (HC), has been referred to in thousands of articles, generally as a correlate and predictor either of health ...conditions such as cardiovascular disease and diabetes, or of amounts of visceral and subcutaneous abdominal fat. It has been argued that combining WC and HC as a ratio is inappropriate, and yet their individual roles can only be fully elucidated if considered jointly. Whereas WC is positively associated with cardiovascular disease, diabetes and premature mortality, the opposite is true of HC. With health-related measures taken as dependent variables, the present novel approach establishes that WC and HC are far better treated as separate independent variables in multiple regression equations than as their ratio. This necessarily produces closer fits to data. One should then allow for variations in height, or some other such measure of general body size, by including this in the regression equations. The widespread concern with the ratio seems to have distracted attention from HC, for this is discussed notably less often than WC. Given that other body parts, such as the thighs, may share relevant properties with the hips, measurements of these could perhaps replace HC.
Gravity models are powerful tools for mapping tectonic structures, especially in the deep ocean basins where the topography remains unmapped by ships or is buried by thick sediment. We combined new ...radar altimeter measurements from satellites CryoSat-2 and Jason-1 with existing data to construct a global marine gravity model that is two times more accurate than previous models. We found an extinct spreading ridge in the Gulf of Mexico, a major propagating rift in the South Atlantic Ocean, abyssal hill fabric on slow-spreading ridges, and thousands of previously uncharted seamounts. These discoveries allow us to understand regional tectonic processes and highlight the importance of satellite-derived gravity models as one of the primary tools for the investigation of remote ocean basins.
BACKGROUNDReprogramming of host metabolism supports viral pathogenesis by fueling viral proliferation, by providing, for example, free amino acids and fatty acids as building blocks.METHODSTo ...investigate metabolic effects of SARS-CoV-2 infection, we evaluated serum metabolites of patients with COVID-19 (n = 33; diagnosed by nucleic acid testing), as compared with COVID-19-negative controls (n = 16).RESULTSTargeted and untargeted metabolomics analyses identified altered tryptophan metabolism into the kynurenine pathway, which regulates inflammation and immunity. Indeed, these changes in tryptophan metabolism correlated with interleukin-6 (IL-6) levels. Widespread dysregulation of nitrogen metabolism was also seen in infected patients, with altered levels of most amino acids, along with increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and renal dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis. Interestingly, metabolite levels in these pathways correlated with clinical laboratory markers of inflammation (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen).CONCLUSIONIn conclusion, this initial observational study identified amino acid and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.FUNDINGBoettcher Foundation Webb-Waring Biomedical Research Award; National Institute of General and Medical Sciences, NIH; and National Heart, Lung, and Blood Institute, NIH.
Aims
Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy in humans, can cause acute haemolysis resulting from exposure to certain medications, chemicals, infections and ...fava beans. Rasburicase, used to manage elevated uric acid levels in the oncologic emergency of tumour lysis syndrome, is one such drug. The US Food and Drug Administration (FDA) recommends testing of G6PD status prior to rasburicase administration for patients at higher risk for G6PD deficiency.
Methods
We performed a retrospective chart review of all oncology patients for whom a semi‐quantitative biochemical test for detecting G6PD deficiency was performed prior to rasburicase administration over a 2.5‐year period, in a large academic metropolitan hospital.
Results
We identified 16 out of 260 tested individuals as G6PD‐deficient (6.1%), including six females. On average, test results were electronically available to health care providers within 4 hours of sample collection, with most results available within 2–3 hours. Four G6PD‐deficient patients developed elevated uric acid levels. Two of the G6PD‐deficient patients were treated with rasburicase, and subsequently developed haemolysis, which was appropriately managed.
Conclusion
In summary, by providing information about G6PD status with a rapid turnaround time, we have taken a significant step towards personalized medicine in our institution. In spite of the test implementation, two out of four G6PD‐deficient patients, who were no longer candidates for rasburicase use, still received the drug, highlighting the need for improved provider education.
Synchronicity Jung, C. G; Jung, C. G
2011., 20120112, 2012, 2010, 2011-01-01, Letnik:
30
eBook
Jung was intrigued from early in his career with coincidences, especially those surprising juxtapositions that scientific rationality could not adequately explain. He discussed these ideas with ...Albert Einstein before World War I, but first used the term "synchronicity" in a 1930 lecture, in reference to the unusual psychological insights generated from consulting the I Ching. A long correspondence and friendship with the Nobel Prize-winning physicist Wolfgang Pauli stimulated a final, mature statement of Jung's thinking on synchronicity, originally published in 1952 and reproduced here. Together with a wealth of historical and contemporary material, this essay describes an astrological experiment Jung conducted to test his theory. Synchronicity reveals the full extent of Jung's research into a wide range of psychic phenomena.
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