The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. ...However, the anatomical and pathophysiological mechanisms are not well understood. Our overarching hypothesis in this review paper is that pregnant women who are diabetic have a damaged peripheral nervous system, constituting the "first hit" hypothesis. The delivery process itself-the "second hit"-can produce neurological damage to the mother. Women with diabetes mellitus (DM) are at risk for neurological damage during both hits, but the cumulative effects of both "hits" pose a greater risk of neurological damage and pathophysiological changes during delivery. In our analysis, we introduce the different steps of our concept paper. Subsequently, we describe each of the topics. First, we outline the mechanisms by which diabetes acts as a detrimental variable in neuropathy by focusing on the most common form of diabetic neuropathy, diabetic distal symmetrical polyneuropathy, also known as distal sensorimotor neuropathy. The possible role of macrosomia in causing diabetic neuropathy and obstetric neurological injury is discussed. Second, we describe how vaginal delivery can cause various obstetrical neurological syndromes and pathophysiological changes. Third, we highlight the risk of obstetric neuropathy and discuss anatomical sites at which lesions may occur, including lesions during delivery. Fourth, we characterize the pathophysiological pathways involved in the causation of diabetic neuropathy. Finally, we highlight diabetic damage to sensory vs. motor nerves, including how hyperglycemia causes different types of damage depending on the location of nerve cell bodies.
Abstract
Background
Familial hypercholesterolaemia (FH) is considered a causal risk factor for premature coronary artery disease (CAD) with a priority placed on identifying index cases and their ...relatives for preventative interventions. However recent population sequencing studies have identified that not all FH mutation carriers develop CAD. We hypothesised that a significant burden of traditional risk factors is required in addition to genetic risk to develop CAD.
Methods
We interrogated the clinical registry of patients attending the CVD risk and Lipids clinic at St Bartholomew’s Hospital in London which serves a large multi-ethnic population. Patients were prioritized for genetic testing based on Simon Broome and Dutch Lipid criteria. A second cohort of patients from the clinic consisted of premature CAD patients without phenotypic FH. CAD was defined as > 50% stenosis in an epicardial vessel by invasive or non-invasive imaging.
Results
We identified 40 patients with genetically confirmed FH and CAD (FH+/CAD+) and 116 people with FH and without CAD (FH+/CAD-). Of 10 traditional risk factors evaluated, prevalence of each was higher in FH +/CAD+ compared to FH+/CAD- patients.
Collectively, FH+/ CAD+ patients had a median number of risk factors of 5(4,6) compared to 4(3,5) for FH+/CAD- patients, (P<0.001). In non-FH patients, risk factors burden was higher in those with CAD (FH-/CAD+), compared to those without CAD: 5(4,6) V. 4(3,5) risk factors, respectively(P<0.001). Importantly, in patients who developed CAD, the traditional risk factor burden was greater in FH- patients than that of FH+ patients whereas, the genetic risk burden was greater in FH+ patients (Figure-1).
The mean age of onset of CAD in both FH+ and FH- patients was comparable: 43± 10 V. 43± 12years. Patients with FH+/CAD+ were older (53± 11 V 49± 13 years, P=0.276) but had an earlier onset of CAD, when risk burden was greater (43± 8 years if ≥ 5 risk factors v 49± 15 years if < 5 risk factors, P=0.192).
Conclusion
In a selected population from a large specialist lipid clinic, we demonstrate that traditional risk factor burden is additive to genetic risk for the development and age of onset of CAD, supporting a disease liability threshold model in FH.Figure-1.Risk Burden in FH with CAD
The authors present a new method of recognizing different human facial gestures through their neural activities and muscle movements, which can be used in machine-interfacing applications. ...Human-machine interface (HMI) technology utilizes human neural activities as input controllers for the machine. Recently, much work has been done on the specific application of facial electromyography (EMG)-based HMI, which have used limited and fixed numbers of facial gestures. In this work, a multipurpose interface is suggested that can support 2-11 control commands that can be applied to various HMI systems. The significance of this work is finding the most accurate facial gestures for any application with a maximum of eleven control commands. Eleven facial gesture EMGs are recorded from ten volunteers. Detected EMGs are passed through a band-pass filter and root mean square features are extracted. Various combinations of gestures with a different number of gestures in each group are made from the existing facial gestures. Finally, all combinations are trained and classified by a Fuzzy c-means classifier. In conclusion, combinations with the highest recognition accuracy in each group are chosen. An average accuracy >90% of chosen combinations proved their ability to be used as command controllers.
Dicumyl peroxide (DCP) is the most commonly used peroxide crosslinking agent for polyethylene (PE) in high voltage power cables. The DCP reactions in the PE matrix lead to the formation of a range of ...byproducts, some of which remain in the final crosslinked polyethylene (XLPE) product and may have adverse effects on the cable function and its long-term properties. In this study, we utilized ReaxFF based molecular dynamics (MD) simulations and experimental techniques including Fourier transform infrared (FTIR) mapping and wide-angle X-ray scattering (WAXS) to obtain detailed atomistic scale insight into peroxide-induced crosslinking of PE. Our results indicate that a moderate curing temperature rise to 500 K leads to an increased crosslinking extent, however, temperature rise above 500 K may have adverse effects on the PE crosslinking. Additionally, our results indicate that elevating the density improves the PE crosslinking. Our study showed that a high ratio of DCP to PE can increase the amount of generated byproducts but may not necessarily lead to an increased amount of XLPE. Our MD results also indicate that the presence of an external electric field had almost no effect on crosslinking and that di-(1-decyl-1-phenylundecyl) peroxide, may not be as efficient as DCP in XLPE production. These results indicate that ReaxFF based molecular dynamics, validated by experiments, is an efficient tool for analyzing – and improving – the conditions of polymerization chemistry.
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•ReaxFF based MD simulations, FTIR mapping and WAXS techniques were utilized to obtain insight into peroxide-induced crosslinking of PE.•A moderate curing temperature leads to an increased crosslinking extent, however, temperature rise above 500 K may have adverse effects.•A high ratio of DCP to PE can increase the amount of generated byproducts but may not lead to an increased amount of XLPE.•DDPP, a functionalized version of DCP, may not be as efficient as DCP in XLPE production.
The transient current in low‐density polyethylene (LDPE) is studied, particularly in the presence of the small organic molecule acetophenone (ACP). Crosslinked LDPE is used extensively in ...high‐voltage power transmission, and acetophenone is a common byproduct of the crosslinking chemistry. Time‐dependent current measurements of LDPE with and without ACP soaked into the polymer as well as at one or both electrodes are performed by applying step voltages. The results demonstrate that the presence of ACP causes a deviation in the predicted power‐law current decay, suggesting that electron and hole injection at the anode and cathode, respectively, are affected by the presence of this small organic molecule. ACP contributes both to the ionic conduction and charge hopping mechanism. The charge mobility depends on the applied electric field and the sample thickness. The results suggests that the dispersive charge transport phenomenon influences the measured current. This study shows how such a molecule may alter charge transport in polyethylene.
Presence of acetophenone in low‐density polyethylene causes the conduction current to deviate from the conventional power‐law current decay. Charge injection increases at the electrodes due to the presence of acetophenone. Migration of the injected charges are assisted by the diffusion of acetophenone molecules and the applied electric field. The mobility of the injected charges is influenced by the sample thickness due to the dispersive nature of charge mobility and diffusion in semi‐crystalline polyethylene.
Study objective
Endothelial dysfunction and increased microvascular permeability are hallmarks of severe COVID‐19. At present, the underlying mechanisms of endothelial barrier failure in COVID‑19 ...remain elusive. Here, we show that increased thrombin activity in plasma from severe COVID‐19 patients activates endothelial protease‐activated receptor (PAR1), which mediates barrier failure by triggering TRPV4‐mediated Ca2+ influx in lung microvascular endothelial cells.
Methods
Citrate plasma was sampled as part of the Pa‐COVID‐19 cohort study (ethics approval EA2/066/20) from patients with severe COVID‐19 (high flow O2 or mechanically ventilated; WHO severity score: 5‐7) COVID‑19. Plasma samples were diluted to 10% (v/v) in cell culture medium without FCS and tested for their ability to disrupt barrier integrity of primary human pulmonary microvascular endothelial cells (HPMEC) monolayers by electrical cell‐substrate impedance sensing (ECIS), immunofluorescence for endothelial VE‐cadherin and F‐actin, western blot analyses of PAR‐1 cleavage, and real‐time Ca2+ imaging. Plasma from healthy donors served as control.
Results
COVID‐19 plasma had elevated thrombin activity while levels of antithrombin III, a key anti‐coagulant with thromboprotective function were decreased. COVID‐19 plasma caused endothelial barrier dysfunction as measured by ECIS and gap formation in HPMEC monolayers. Endothelial barrier disruption and endothelial Ca2+ influx in response to COVID‐19 plasma could be blocked by selective antagonists targeting thrombin (Argatroban), its receptor PAR1 (SCH79797), or TRPV4 (HC‐067047).
Conclusion
Here, we identify a novel signaling axis involving thrombin, its receptor PAR1, and TRPV4 as mechanism for increased microvascular permeability in COVID‑19. Targeting this signaling axis in endothelial barrier failure may provide a promising adjunctive therapy in COVID‐19.
There is a strong rationale for investigating nutritional interventions with docosahexaenoic acid (DHA) in cancer prevention and therapy; however, the effects of DHA on ovarian cancer (OC) have not ...been well studied. Here, we investigated if DHA alone and in combination with carboplatin reduces OC cell growth in vitro. In vivo, we used a high-grade serous OC patient-derived xenograft (PDX) mouse model to investigate if DHA affects OC growth and enhances the anticancer actions of carboplatin. We showed synergistic cell killing by DHA and carboplatin in DHA-resistant Kuramochi and SKOV3 OC cells, which corresponded with increased DHA incorporation into whole-cell membrane phospholipids (P < 0.05). In vivo, feeding mice a diet supplemented with 3.9% (w/w of fat) DHA resulted in a significant reduction in PDX growth with and without carboplatin (P < 0.05). This reduction in tumor growth was accompanied by an increased tumor necrotic region (P < 0.05) and improved survival. Plasma membranes in tumors and livers excised from mice fed a DHA diet had ∼ twofold increase in DHA incorporation as compared with mice fed a control diet. Our findings indicate that DHA supplementation reduces cancer cell growth and enhances the efficacy of carboplatin in preclinical models of OC through increased apoptosis and necrosis.
Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1952453
ABSTRACT
For a better understanding of multidecadal climate change, as well as for the production of solar power, there is a growing need for knowledge of the trends in incident sunlight at the ...Earth's surface, but a lack of a long‐term sunlight time series dictates that a proxy measure is needed. In this study, variations of sunshine duration and diurnal temperature range (DTR) are used as proxies for surface solar radiation. Annual and seasonal composites of both variables from 29 stations are analyzed from 1961 through 2009 across the different types of climates of Iran. The annual sunshine duration mean time series shows a decrease from the early 1960s to the late 1970s, in line with the widespread dimming of surface solar radiation observed during this period. By the early 1980s, there is an increase in sunshine through the end of the 20th century, aligning with a well‐known and well‐documented brightening period. In addition, a renewed dimming is observed during the 2000s, with a sharp drop in 2009. A linear trend estimated over the 1961–2009 period was not found to be statistically significant. However, the annual DTR time series shows a widespread and statistically significant decrease since the 1960s, although the series ends without relevant variations after the 1990s. An agreement in the interannual variability of sunshine and DTR is observed except for the summer season. On decadal time scales, only the spring DTR series shows a partial agreement with sunshine series. Nevertheless, the recent leveling off in the DTR series supports a transition in the radiative regime.
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