We examine the effects of arterial occlusion on the pressure, velocity and the reflected waves in the ascending aorta using wave intensity analysis. In 11 anaesthetised, open-chested dogs, snares ...were used to produce total arterial occlusion at 4 sites: the upper descending aorta at the level of the aortic valve (thoracic); the lower thoracic aorta at the level of the diaphragm (diaphragm); the abdominal aorta between the renal arteries (abdominal) and the left iliac artery, 2
cm downstream from the aorta iliac bifurcation (iliac). Pressure and flow in the ascending aorta were measured, and data were collected before and during the occlusion. During thoracic and diaphragm occlusions a significant increase in mean aortic pressure (46% and 23%) and in wave speed (25% and 10%) was observed, while mean flow rate decreased significantly (23% and 17%). Also, the reflected compression wave arrived significantly earlier (45% and 15%) and its peak intensity was significantly greater (257% and 125%), all compared with control. Aortic occlusion distal to the renal arteries, however, caused an indiscernible change in the pressure and velocity waveforms, and in the intensities and timing of the waves in the forward and backward directions. The measured pressure and velocity waveforms are the result of the interaction between the heart and the arterial system. The separated pressure, velocity and wave intensity are required to provide information about arterial hemodynamic such as the timing and magnitude of the forward and backward waves. The net wave intensity is simpler to calculate but provides information only about the predominant direction of the waves and can be misleading when forward and backward waves of comparable magnitudes are present simultaneously.
Pulmonary hypertension (PH) is a frequently under recognized complication of myelofibrosis (MF). The pathophysiology of PH in MF is unknown and no definitive therapies have been established. We ...studied 15 patients with MF-associated PH and compared their echocardiographic and PH relevant biomarkers (nitric oxide (NO), N-terminal pro-hormone of brain natriuretic peptide (NT-pro BNP), von Willebrand antigen (vWB), ristocetin-cofactor activity (RCA) and uric acid (UA)) pre- and post-ruxolitinib treatment. Ruxolitinib decreased the plasma levels of NT-pro BNP (73%; P=0.043), UA (60%), vWB (86%) and RCA (73%; P=0.036). Improvements in echocardiographic findings were also seen in 66% of patients (P=0.022). Furthermore, marked increase in NO compared with baseline (69.75 vs 40.1 picomolar (pM); P=0.001) was observed post-ruxolitinib therapy, whereas no changes were noted with conventional therapies. Treatment with ruxolitinib also resulted in the reduction of key cytokines (tumor necrosis factor alpha, interleukin-4 (IL-4), IL-6 and IL-8) and induction of interferon-gamma. Animal studies further supported the role of ruxolitinib in the induction of NO levels. In conclusion, aberrant Janus kinase (JAK)-signal transducer and activator of transcription signaling in MF may mediate PH through dysregulation of NO and cytokine levels, which can be restored by therapy with JAK inhibitors suggesting that inhibition of this pathway is a novel target for the management of patients with PH.
Abstract
The observation of electromagnetic radiation from radio to γ-ray wavelengths has provided a wealth of information about the Universe. However, at PeV (10
15
eV) energies and above, most of ...the Universe is impenetrable to photons. New messengers, namely cosmic neutrinos, are needed to explore the most extreme environments of the Universe where black holes, neutron stars, and stellar explosions transform gravitational energy into non-thermal cosmic rays. These energetic particles have millions of times higher energies than those produced in the most powerful particle accelerators on Earth. As neutrinos can escape from regions otherwise opaque to radiation, they allow an unique view deep into exploding stars and the vicinity of the event horizons of black holes. The discovery of cosmic neutrinos with IceCube has opened this new window on the Universe. IceCube has been successful in finding first evidence for cosmic particle acceleration in the jet of an active galactic nucleus. Yet, ultimately, its sensitivity is too limited to detect even the brightest neutrino sources with high significance, or to detect populations of less luminous sources. In this white paper, we present an overview of a next-generation instrument, IceCube-Gen2, which will sharpen our understanding of the processes and environments that govern the Universe at the highest energies. IceCube-Gen2 is designed to:
(a) Resolve the high-energy neutrino sky from TeV to EeV energies
(b) Investigate cosmic particle acceleration through multi-messenger observations
(c) Reveal the sources and propagation of the highest energy particles in the Universe
(d) Probe fundamental physics with high-energy neutrinos
IceCube-Gen2 will enhance the existing IceCube detector at the South Pole. It will increase the annual rate of observed cosmic neutrinos by a factor of ten compared to IceCube, and will be able to detect sources five times fainter than its predecessor. Furthermore, through the addition of a radio array, IceCube-Gen2 will extend the energy range by several orders of magnitude compared to IceCube. Construction will take 8 years and cost about $350M. The goal is to have IceCube-Gen2 fully operational by 2033.
IceCube-Gen2 will play an essential role in shaping the new era of multi-messenger astronomy, fundamentally advancing our knowledge of the high-energy Universe. This challenging mission can be fully addressed only through the combination of the information from the neutrino, electromagnetic, and gravitational wave emission of high-energy sources, in concert with the new survey instruments across the electromagnetic spectrum and gravitational wave detectors which will be available in the coming years.
Abstract Research on the relationship between insight and social cognition, in particular Theory of Mind (ToM), in schizophrenia has yielded mixed findings to date. Very few studies, however, have ...assessed both clinical insight and cognitive insight when examining their relationships with ToM in schizophrenia. The current study thus investigated the relationship between clinical insight, cognitive insight, and ToM in a sample of 56 patients with schizophrenia and 30 healthy controls. Twenty-seven patients were classified as low in clinical insight according to their scores on the ‘insight’ item (G12) of the Positive and Negative Syndrome Scale (PANSS). Moreover, cognitive insight and ToM were assessed with the Beck Cognitive Insight Scale (BCIS) and the Yoni task, respectively. The results indicated that patients with poor clinical insight performed worse on tasks of second-order cognitive and affective ToM, while the ToM performance of patients with high clinical insight was equivalent to that of healthy controls. Furthermore, while clinical insight was correlated with ToM and clinical symptoms, cognitive insight did not correlate with clinical insight, ToM, or clinical symptoms. Clinical insight thus appears to be an important factor related to ToM in schizophrenia.
Aims: To measure characteristics of the retinal blood vessels close to the optic disc in full term and preterm infants, with and without retinopathy of prematurity (ROP), using digital imaging. To ...determine whether these measures are indicative of the presence or severity of ROP in the retinal periphery. Methods: 52 digital fundus images from 42 babies were analysed with a semiautomated analysis program developed at Imperial College London. Analysis was limited to the principal temporal vessels close to the optic disc: recording venular diameter and arteriolar diameter and tortuosity. Results: Each result was categorised by the gestational age of the infant (“very premature” 24–27 weeks, “moderately premature” 28–31 weeks, and “near term” ⩾32 weeks) and by the highest stage of ROP present (“no ROP,” “mild ROP” stage 1 or 2, and “severe ROP” stage 3). Arteriolar tortuosity was found to vary significantly (Kruskal-Wallis p = 0.002) with ROP severity. Although venular and arteriolar diameters increased monotonically with ROP severity the differences were not significant. Venular diameter, arteriolar diameter, and arterial tortuosity did not vary significantly between gestational age groups. Conclusions: This study confirms it is possible to quantify the size and tortuosity of retinal blood vessels in term and preterm babies using digital image analysis software. This method detected significant increases in arteriolar tortuosity with increasing ROP severity.
Considering waves in the arteries as infinitesimal wave fronts rather than sinusoidal wavetrains, the change in pressure across the wave front, d
P, is related to the change in velocity, d
U, that it ...induces by the ‘water hammer’ equation,
dP=±ρc
dU
, where
ρ is the density of blood and
c is the local wave speed. When only unidirectional waves are present, this relationship corresponds to a straight line when
P is plotted against
U with slope
ρc. When both forward and backward waves are present, the
PU-loop is no longer linear. Measurements in latex tubes and systemic and pulmonary arteries exhibit a linear range during early systole and this provides a way of determining the local wave speed from the slope of the linear portion of the loop. Once the wave speed is known, it is also possible to separate the measured
P and
U into their forward and backward components. In cases where reflected waves are prominent, this separation of waves can help clarify the pattern of waves in the arteries throughout the cardiac cycle.
Objective: Hypertension is associated with reduced cerebral blood flow, but it is not known how this impacts on wave dynamics or potentially relates to arterial morphology. Given the location of the ...internal carotid artery (ICA) and risks associated with invasive measurements, wave dynamics in this artery have not been extensively assessed in vivo. This study explores the feasibility of studying wave dynamics in the internal carotid artery non-invasively. Approach: Normotensive, uncontrolled and controlled hypertensive participants were recruited (daytime ambulatory blood pressure <135/85 mmHg and >135/85 mmHg, respectively; n = 38). Wave intensity, reservoir pressure and statistical shape analyses were performed on the right ICA and ascending aorta high-resolution phase-contrast magnetic resonance angiography data. Main results: Wave speed in the aorta was significantly lower in normotensive compared to hypertensive participants (6.7 ± 1.8 versus 11.2 ± 6.2 m s−1 for uncontrolled and 11.8 ± 4.6 m s−1 for controlled hypertensives, p = 0.02), whilst there were no differences in wave speed in the ICA. There were no significant differences between the groups for the wave intensity or reservoir pressure. Interestingly, a significant association between the anatomy of the ICA and wave energy (FCW and size, r2 = 0.12, p = 0.04) was found. Significance: This study shows it is feasible to study wave dynamics in the ICA non-invasively. Whilst changes in aortic wave speed confirmed an expected increase in arterial stiffness, this was not observed in the ICA. This might suggest a protective mechanism in the cerebral circulation, in conjunction with the effect of vessel tortuosity. Furthermore, it was observed that ICA shape correlated with wave energy but not wave speed.
Mutation of sucker (suc) disrupts development of the lower jaw and other ventral cartilages in pharyngeal segments of the zebrafish head. Our sequencing, cosegregation and rescue results indicate ...that suc encodes an Endothelin-1 (Et-1). Like mouse and chick Et-1, suc/et-1 is expressed in a central core of arch paraxial mesoderm and in arch epithelia, both surface ectoderm and pharyngeal endoderm, but not in skeletogenic neural crest. Long before chondrogenesis, suc/et-1 mutant embryos have severe defects in ventral arch neural crest expression of dHAND, dlx2, msxE, gsc, dlx3 and EphA3 in the anterior arches. Dorsal expression patterns are unaffected. Later in development, suc/et-1 mutant embryos display defects in mesodermal and endodermal tissues of the pharynx. Ventral premyogenic condensations fail to express myoD, which correlates with a ventral muscle defect. Further, expression of shh in endoderm of the first pharyngeal pouch fails to extend as far laterally as in wild types. We use mosaic analyses to show that suc/et-1 functions nonautonomously in neural crest cells, and is thus required in the environment of postmigratory neural crest cells to specify ventral arch fates. Our mosaic analyses further show that suc/et-1 nonautonomously functions in mesendoderm for ventral arch muscle formation. Collectively our results support a model for dorsoventral patterning of the gnathostome pharyngeal arches in which Et-1 in the environment of the postmigratory cranial neural crest specifies the lower jaw and other ventral arch fates.
Aims/hypothesis
We have previously reported a high prevalence of non-alcoholic fatty liver disease (NAFLD) among women with previous gestational diabetes mellitus (pGDM). We wanted to confirm that ...intrahepatocellular lipid (IHCL) is associated with pGDM independently of adiposity and determine: (1) if VLDL metabolism is dysregulated; and (2) the extent to which NAFLD and IHCL account for the dysmetabolic phenotype in pGDM.
Methods
We analysed data from a cohort of 234 women (114 with pGDM) and identified effects of pGDM on lipid and glucoregulation that were independent of ultrasound-diagnosed NAFLD. We then measured IHCL by MR spectroscopy in a representative subgroup (
n
= 36) and conducted detailed metabolic studies (IVGTT, VLDL apolipoprotein B apoB kinetics and palmitate turnover) and measurement of regional body fat by MRI to demonstrate effects of IHCL that were independent of a history of pGDM.
Results
pGDM was associated with increased IHCL (
p
= 0.04) after adjustment for adiposity. Independently of IHCL, pGDM was associated with a lower IVGTT disposition index (
p
= 0.02) and acute insulin response to glucose (pGDM+/NAFLD−, 50% lower; pGDM+/NAFLD+, 36% lower; effect of pGDM,
p
= 0.03), increased VLDL apoB pool size (pGDM+/NAFLD−, 3.1-fold higher; pGDM+/NAFLD+, 1.2-fold higher; effect of pGDM,
p
= 0.02) and, at borderline significance (
p
= 0.05), increased rate of VLDL apoB synthesis.
Conclusions/interpretation
pGDM is associated with increased IHCL independently of adiposity. The increased liver fat contributes to the phenotype, but pGDM status is independently associated with diminished insulin secretion and (shown for the first time) augmented VLDL metabolism. IHCL with pGDM may compound a dysmetabolic phenotype.
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