851 research outputs found
Early rebellion and its links to later success and conquest: Why was it that some Norman rulers profited from rebellions early in their reigns, whilst others did not?
The subject of this dissertation is the Normans. Its objective is to analyse the development of their civilisation, and to give reasons for their numerous accomplishments, both in Northern Europe and in the Mediterranean. Yet, unlike the many scholars who have studied the Normans before, the main focus here will be on rebellion, and in particular those rebellions which followed the succession of each Norman ruler (either a king or a duke/count), as it will be argued that when dealt with correctly these revolts did not hinder, but instead created the seeds of power and progress; since they gave the new ruler an opportunity to establish a lasting precedent early on, that insolence to their authority would not be tolerated; which if accomplished, then led to harmony (internal peace), development and conquest for the rest of the ruler’s reign
A Metabolic Dependency for Host Isoprenoids in the Obligate Intracellular Pathogen Rickettsia parkeri Underlies a Sensitivity to the Statin Class of Host-Targeted Therapeutics.
Gram-negative bacteria in the order Rickettsiales have an obligate intracellular growth requirement, and some species cause human diseases such as typhus and spotted fever. The bacteria have evolved a dependence on essential nutrients and metabolites from the host cell as a consequence of extensive genome reduction. However, it remains largely unknown which nutrients they acquire and whether their metabolic dependency can be exploited therapeutically. Here, we describe a genetic rewiring of bacterial isoprenoid biosynthetic pathways in the Rickettsiales that has resulted from reductive genome evolution. Furthermore, we investigated whether the spotted fever group Rickettsia species Rickettsia parkeri scavenges isoprenoid precursors directly from the host. Using targeted mass spectrometry, we found that infection caused decreases in host isoprenoid products and concomitant increases in bacterial isoprenoid metabolites. Additionally, we report that treatment of infected cells with statins, which inhibit host isoprenoid synthesis, prohibited bacterial growth. We show that growth inhibition correlates with changes in bacterial size and shape that mimic those caused by antibiotics that inhibit peptidoglycan biosynthesis, suggesting that statins lead to an inhibition of cell wall synthesis. Altogether, our results describe a potential Achilles' heel of obligate intracellular pathogens that can potentially be exploited with host-targeted therapeutics that interfere with metabolic pathways required for bacterial growth.IMPORTANCE Obligate intracellular pathogens, which include viruses as well as certain bacteria and eukaryotes, are a subset of infectious microbes that are metabolically dependent on and unable to grow outside an infected host cell because they have lost or lack essential biosynthetic pathways. In this study, we describe a metabolic dependency of the bacterial pathogen Rickettsia parkeri on host isoprenoid molecules that are used in the biosynthesis of downstream products, including cholesterol, steroid hormones, and heme. Bacteria make products from isoprenoids, such as an essential lipid carrier for making the bacterial cell wall. We show that bacterial metabolic dependency can represent a potential Achilles' heel and that inhibiting host isoprenoid biosynthesis with the FDA-approved statin class of drugs inhibits bacterial growth by interfering with the integrity of the cell wall. This work supports the potential to treat infections by obligate intracellular pathogens through inhibition of host biosynthetic pathways that are susceptible to parasitism
Occasional essay: upper motor neuron syndrome in amyotrophic lateral sclerosis
The diagnosis of amyotrophic lateral sclerosis (ALS) requires recognition of both lower (LMN) and upper motor neuron (UMN) dysfunction.1 However, classical UMN signs are frequently difficult to identify in ALS.2 LMN involvement is sensitively detected by electromyography (EMG)3 but, as yet, there are no generally accepted markers for monitoring UMN abnormalities,4 the neurobiology of ALS itself, and disease spread through the brain and spinal cord,.5 Full clinical assessment is therefore necessary to exclude other diagnoses and to monitor disease progression. In part, this difficulty regarding detection of UMN involvement in ALS derives from the definition of ‘the UMN syndrome’. Abnormalities of motor control in ALS require reformulation within an expanded concept of the UMN, together with the neuropathological, neuro-imaging and neurophysiological abnormalities in ALS. We review these issues here
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Evasion of autophagy mediated by Rickettsia surface protein OmpB is critical for virulence.
Rickettsia are obligate intracellular bacteria that evade antimicrobial autophagy in the host cell cytosol by unknown mechanisms. Other cytosolic pathogens block different steps of autophagy targeting, including the initial step of polyubiquitin-coat formation. One mechanism of evasion is to mobilize actin to the bacterial surface. Here, we show that actin mobilization is insufficient to block autophagy recognition of the pathogen Rickettsia parkeri. Instead, R. parkeri employs outer membrane protein B (OmpB) to block ubiquitylation of the bacterial surface proteins, including OmpA, and subsequent recognition by autophagy receptors. OmpB is also required for the formation of a capsule-like layer. Although OmpB is dispensable for bacterial growth in endothelial cells, it is essential for R. parkeri to block autophagy in macrophages and to colonize mice because of its ability to promote autophagy evasion in immune cells. Our results indicate that OmpB acts as a protective shield to obstruct autophagy recognition, thereby revealing a distinctive bacterial mechanism to evade antimicrobial autophagy
Preliminary Experience with Digital Subtraction Angiography in Cardiac Evaluation
iVe report our initial experience using digital subtraction angiography (DSA) techniques for cardiac evaluation. DSA of the heart may be performed with intravenous or right atrial injection of contrast medium (IVDSA) and with left ventricular or aortic root contrast injection (lADSA). The right ventricle and the atria are best demonstrated by IVDSA, while the left ventricle and coronary arteries are best demonstrated by lADSA. The advantages and disadvantages of DSA ofthe bean are discussed. Present equipment limitations restrict the routine use of cardiac DSA, but these should be overcome with advances in technology
Liposomal Encapsulation of Amoxicillin via Microfluidics with Subsequent Investigation of the Significance of PEGylated Therapeutics
With an increasing concern of global antimicrobial resistance, the efforts to improve the formulation of a narrowing library of therapeutic antibiotics must be confronted. The liposomal encapsulation of antibiotics using a novel and sustainable microfluidic method has been employed in this study to address this pressing issue, via a targeted, lower-dose medical approach. The study focusses upon microfluidic parameter optimisation, formulation stability, cytotoxicity, and future applications. Particle sizes of circa. 130 nm, with viable short-term (28-day) physical stability were obtained, using two different non-cytotoxic liposomal formulations, both of which displayed suitable antibacterial efficacy. The microfluidic method allowed for high encapsulation efficiencies (≈77 %) and the subsequent in vitro release profile suggested high limits of antibiotic dissociation from the nanovessels, achieving 90% release within 72 h. In addition to the experimental data, the growing use of poly(ethylene) glycol (PEG) within lipid-based formulations is discussed in relation to anti-PEG antibodies, highlighting the key pharmacological differences between PEGylated and non-PEGylated formulations and their respective advantages and drawbacks. It's surmised that in the case of the formulations used in this study, the addition of PEG upon the liposomal membrane would still be a beneficial feature to possess owing to beneficial features such as stability, antibiotic efficacy and the capacity to further modify the liposomal membrane.</p
Towards More Precise Survey Photometry for PanSTARRS and LSST: Measuring Directly the Optical Transmission Spectrum of the Atmosphere
Motivated by the recognition that variation in the optical transmission of
the atmosphere is probably the main limitation to the precision of ground-based
CCD measurements of celestial fluxes, we review the physical processes that
attenuate the passage of light through the Earth's atmosphere. The next
generation of astronomical surveys, such as PanSTARRS and LSST, will greatly
benefit from dedicated apparatus to obtain atmospheric transmission data that
can be associated with each survey image. We review and compare various
approaches to this measurement problem, including photometry, spectroscopy, and
LIDAR. In conjunction with careful measurements of instrumental throughput,
atmospheric transmission measurements should allow next-generation imaging
surveys to produce photometry of unprecedented precision. Our primary concerns
are the real-time determination of aerosol scattering and absorption by water
along the line of sight, both of which can vary over the course of a night's
observations.Comment: 41 pages, 14 figures. Accepted PAS
The orbits of the quadruple star system 88 Tau A from PHASES differential astrometry and radial velocity
We have used high precision differential astrometry from the Palomar
High-precision Astrometric Search for Exoplanet Systems (PHASES) project and
radial velocity measurements covering a time-span of 20 years to determine the
orbital parameters of the 88 Tau A system. 88 Tau is a complex hierarchical
multiple system comprising a total of six stars; we have studied the brightest
4, consisting of two short-period pairs orbiting each other with an 18-year
period. We present the first orbital solution for one of the short-period
pairs, and determine the masses of the components and distance to the system to
the level of a few percent. In addition, our astrometric measurements allow us
to make the first determination of the mutual inclinations of the orbits. We
find that the sub-systems are not coplanar.Comment: Corrected Author Ordering; 12 Pages, Accepted for publication in Ap
Mesenteric artery disease in the elderly
AbstractPurposeThe purpose of this study was to estimate the population-based prevalence of mesenteric artery stenosis (MAS) and occlusion among independent elderly Americans.MethodAs part of an ancillary investigation to the Cardiovascular Health Study (CHS), participants in the Forsyth County, NC cohort had visceral duplex sonography of the celiac arteries and superior mesenteric arteries (SMAs). Critical MAS was defined by celiac peak systolic velocity ≥2.0 m/s and/or SMA peak systolic velocity ≥2.7 m/s. Occlusion of either vessel was defined by lack of a Doppler-shifted signal within the imaged artery. Demographic data, blood pressures, and blood lipid levels were collected as part of the baseline CHS examination. Participants' weights were measured at baseline and before the duplex exam. Univariate tests of association were performed with two-way contingency tables, Student t tests, and Fisher exact tests. Multivariate associations were examined with logistic regression analysis.ResultsA total of 553 CHS participants had visceral duplex sonography technically adequate to define the presence or absence of MAS. The study group had a mean age of 77.2 ± 4.9 years and comprised 63% women and 37% men. Participant race was 76% white and 23% African-American. Ninety-seven participants (17.5%) had MAS. There was no significant difference in age, race, gender, body mass index, blood pressure, cholesterol, or low-density lipoproteins for participants with or without MAS. Forward stepwise variable selection found renal artery stenosis (P = .008; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.31, 6.21) and high-density lipoprotein >40 (P = .02; OR, 3.03; 95% CI, 1.17, 7.81) significantly associated with MAS in a multivariate logistic regression model. Eighty-three of the 97 participants with MAS (15.0% of the cohort) had isolated celiac stenosis. Seven participants (1.3% of the cohort) had combined celiac and SMA stenosis. Five participants (0.9% of the cohort) had isolated SMA stenosis. Two participants (0.4% of the cohort) had celiac occlusion. Considering all participants with MAS, there was no association with weight change. However, SMA stenosis and celiac occlusion demonstrated an independent association with annualized weight loss (P = .028; OR, 1.54; 95% CI, 1.05, 2.26) and with renal artery stenosis (P =.001; OR, 9.48; 95% CI, 2.62, 34.47).ConclusionThis investigation provides the first population-based estimate of the prevalence of MAS among independent elderly Americans. MAS existed in 17.5% of the study cohort. The majority had isolated celiac disease. SMA stenosis and celiac artery occlusion demonstrated a significant and independent association with weight loss and concurrent renal artery disease
Improving the early identification of COVID-19 pneumonia:a narrative review
Delayed presentation of COVID-19 pneumonia increases the risk of mortality and need for high-intensity healthcare. Conversely, early identification of COVID-19 pneumonia grants an opportunity to intervene early and thus prevent more complicated, protracted and less successful hospital admissions. To improve the earlier detection of COVID-19 pneumonia in the community we provide a narrative review of current evidence examining the clinical parameters associated with early disease progression. Through an evolving literature review, we examined: the symptoms that may suggest COVID-19 progression; the timing of deterioration; the utility of basic observations, clinical examination and chest X-ray; the value of postexertion oxygen saturations; and the use of CRP to monitor disease progression. We go on to discuss the challenges in monitoring the COVID-19 patient in the community and discuss thresholds for further assessment. Confusion, persistent fever and shortness of breath were identified as worrying symptoms suggestive of COVID-19 disease progression necessitating urgent clinical contact. Importantly, a significant proportion of COVID-19 pneumonia patients appear not to suffer dyspnoea despite severe disease. Patients with this asymptomatic hypoxia seem to have a poorer prognosis. Such patients may present with other signs of hypoxia: severe fatigue, exertional fatigue and/or altered mental status. We found duration of symptoms to be largely unhelpful in determining risk, with evidence of deterioration at any point in the disease. Basic clinical parameters (pulse, respiratory rate, blood pressure, temperature and oxygen saturations (SpO(2))) are likely of high value in detecting the deteriorating community COVID-19 patient and/or COVID-19 mimickers/complications (eg, sepsis, bacterial pneumonia and pulmonary embolism). Of these, SpO(2) carried the greatest utility in detecting COVID-19 progression. CRP is an early biochemical parameter predictive of disease progression and used appropriately is likely to contribute to the early identification of COVID-19 pneumonia. Identifying progressive COVID-19 in the community is feasible using basic clinical questions and measurements. As such, if we are to limit the mortality, morbidity and the need for complicated, protracted admissions, monitoring community COVID-19 cases for signs of deterioration to facilitate early intervention is a viable strategy
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