Morell Mackenzie’s contribution to the description of spasmodic dysphonia

Objectives: Since the middle of the 20th century most discussions of Spasmodic Dysphonia reference a paper by Ludwig Traube published in1871 as the first historical citation, crediting him with priority for this clinical syndrome. However, our recent research has determined that the original observation by Traube was published in 1864 and does not in fact describe what is currently recognized as SD. It appears that many clinics throughout Europe and North America were investigating and publishing observations on a range of voice disorders.. Methods: The wider context of work on laryngeal disorders in the 1860s-1870s is considered. One of Traube’s contemporaries, Morell Mackenzie made significant contributions to the understanding of laryngeal movement disorder and its consequences for the voice. These will be examined to gain a clearer focus on the characterization of this disorder. Results: The clinical descriptions published by Morrell Mackenzie in the 1860s provide details which conform quite closely to our current day understanding of SD. Conclusions: The citation of Traube’s “hysterical” patient links to mid-20th century views of the functional nature of SD and the utility of psychiatric treatment. The description presented by Mackenzie is consistent with current views of SD as a movement disorder

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.

Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses

Coextensive space: virtual reality and the developing relationship between the body, the digital and physical space

Virtual Reality (VR) has traditionally required external sensors placed around a designated play space. In contrast, more recent wired and wireless systems, such as the Oculus Rift S (released in March 2019) and the Oculus Quest (released in May 2019) use cameras located on the outside of these devices to monitor their physical position. Users can now mark out a physical space that is then digitally tracked within their display. Once a play space has been established, users are alerted if they come close to breaching this boundary by the visual inclusion of a grid. Should this threshold be breached, the headset display shifts to an image of the surrounding concrete environment. We contend that physical space is increasingly being incorporated into the digital space of VR in a manner that meaningfully differs from older systems. We build our argument in the following way. First, the article explores how theories surrounding VR have implicated only a limited relationship with physical space. Second, the article introduces the concept of coextensive space as a way of understanding the developing relationship between the physical, digital and concrete reality enacted by current VR systems

Diagnostic value of harmonic transthoracic echocardiography in native valve infective endocarditis: comparison with transesophageal echocardiography

<p>Abstract</p> <p>Background</p> <p>Although echocardiography has been incorporated into the diagnostic algorithm of patients with suspected infective endocarditis (IE), systematic usage in clinical practice remains ill defined. To determine the diagnostic accuracy of detecting vegetations using harmonic transthoracic echocardiography (hTTE) as compared to transesophageal echocardiography (TEE) in patients with an intermediate likelihood of native valve IE.</p> <p>Methods</p> <p>Between 2004 and 2005, 36 consecutive inpatients with an intermediate likelihood of disease were prospectively evaluated by hTTE and TEE.</p> <p>Results</p> <p>Of 36 patients (21 males with a mean age of 57 ± 15 years, range 32 to 86 years), 19 patients had definite IE by TEE. The sensitivity for the detection of vegetations by hTTE was 84%, specificity of 88%, positive predictive value (PPV) of 89% and negative predictive value (NPV) of 82%. The association between hTTE and TTE interpretation for the presence and absence of vegetations were high (kappa = 0.90 and 0.85 respectively).</p> <p>Conclusion</p> <p>In patients with an intermediate likelihood of native valve IE, TTE with harmonic imaging provides diagnostic quality images in the majority of cases, has excellent concordance with TEE and should be recommended as the first line test.</p

Exploration of experiences in therapeutic groups for patients with severe mental illness: development of the Ferrara group experiences scale (FE-GES)

The study has been supported by the University of Ferrara (University Funds for Scientific Research 2008–2009

The Molecular Epidemiology and Evolution of Murray Valley Encephalitis Virus: Recent Emergence of Distinct Sub-lineages of the Dominant Genotype 1

© 2015 Williams et al. Background: Recent increased activity of the mosquito-borne Murray Valley encephalitis virus (MVEV) in Australia has renewed concerns regarding its potential to spread and cause disease. Methodology/Principal Findings: To better understand the genetic relationships between earlier and more recent circulating strains, patterns of virus movement, as well as the molecular basis of MVEV evolution, complete pre-membrane (prM) and Envelope (Env) genes were sequenced from sixty-six MVEV strains from different regions of the Australasian region, isolated over a sixty year period (1951–2011). Phylogenetic analyses indicated that, of the four recognized genotypes, only G1 and G2 are contemporary. G1 viruses were dominant over the sampling period and found across the known geographic range of MVEV. Two distinct sub-lineages of G1 were observed (1A and 1B). Although G1B strains have been isolated from across mainland Australia, Australian G1A strains have not been detected outside northwest Australia. Similarly, G2 is comprised of only Western Australian isolates from mosquitoes, suggesting G1B and G2 viruses have geographic or ecological restrictions. No evidence of recombination was found and a single amino acid substitution in the Env protein (S332G) was found to be under positive selection, while several others were found to be under directional evolution. Evolutionary analyses indicated that extant genotypes of MVEV began to diverge from a common ancestor approximately 200 years ago. G2 was the first genotype to diverge, followed by G3 and G4, and finally G1, from which subtypes G1A and G1B diverged between 1964 and 1994. Conclusions/Significance: The results of this study provides new insights into the genetic diversity and evolution of MVEV. The demonstration of co-circulation of all contemporary genetic lineages of MVEV in northwestern Australia, supports the contention that this region is the enzootic focus for this virus

Axons Amplify Somatic Incomplete Spikes into Uniform Amplitudes in Mouse Cortical Pyramidal Neurons

BACKGROUND: Action potentials are the essential unit of neuronal encoding. Somatic sequential spikes in the central nervous system appear various in amplitudes. To be effective neuronal codes, these spikes should be propagated to axonal terminals where they activate the synapses and drive postsynaptic neurons. It remains unclear whether these effective neuronal codes are based on spike timing orders and/or amplitudes. METHODOLOGY/PRINCIPAL FINDINGS: We investigated this fundamental issue by simultaneously recording the axon versus soma of identical neurons and presynaptic vs. postsynaptic neurons in the cortical slices. The axons enable somatic spikes in low amplitude be enlarged, which activate synaptic transmission in consistent patterns. This facilitation in the propagation of sequential spikes through the axons is mechanistically founded by the short refractory periods, large currents and high opening probability of axonal voltage-gated sodium channels. CONCLUSION/SIGNIFICANCE: An amplification of somatic incomplete spikes into axonal complete ones makes sequential spikes to activate consistent synaptic transmission. Therefore, neuronal encoding is likely based on spike timing order, instead of graded analogues

Altering α-dystroglycan receptor affinity of LCMV pseudotyped lentivirus yields unique cell and tissue tropism

BACKGROUND: The envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV) can efficiently pseudotype lentiviral vectors. Some strains of LCMV exploit high affinity interactions with α-dystroglycan (α-DG) to bind to cell surfaces and subsequently fuse in low pH endosomes. LCMV strains with low α-DG affinity utilize an unknown receptor and display unique tissue tropisms. We pseudotyped non-primate feline immunodeficiency virus (FIV) vectors using LCMV derived glycoproteins with high or low affinity to α-DG and evaluated their properties in vitro and in vivo. METHODS: We pseudotyped FIV with the LCMV WE54 strain envelope glycoprotein and also engineered a point mutation in the WE54 envelope glycoprotein (L260F) to diminish α-DG affinity and direct binding to alternate receptors. We hypothesized that this change would alter in vivo tissue tropism and enhance gene transfer to neonatal animals. RESULTS: In mice, hepatic α- and β-DG expression was greatest at the late gestational and neonatal time points. When displayed on the surface of the FIV lentivirus the WE54 L260F mutant glycoprotein bound weakly to immobilized α-DG. Additionally, LCMV WE54 pseudotyped FIV vector transduction was neutralized by pre-incubation with soluble α-DG, while the mutant glycoprotein pseudotyped vector was not. In vivo gene transfer in adult mice with either envelope yielded low transduction efficiencies in hepatocytes following intravenous delivery. In marked contrast, neonatal gene transfer with the LCMV envelopes, and notably with the FIV-L260F vector, conferred abundant liver and lower level cardiomyocyte transduction as detected by luciferase assays, bioluminescent imaging, and β-galactosidase staining. CONCLUSIONS: These results suggest that a developmentally regulated receptor for LCMV is expressed abundantly in neonatal mice. LCMV pseudotyped vectors may have applications for neonatal gene transfer. ABBREVIATIONS: Armstrong 53b (Arm53b); baculovirus Autographa californica GP64 (GP64); charge-coupled device (CCD); dystroglycan (DG); feline immunodeficiency virus (FIV); glycoprotein precursor (GP-C); firefly luciferase (Luc); lymphocytic choriomeningitis virus (LCMV); nuclear targeted β-galactosidase (ntLacZ); optical density (OD); PBS/0.1% (w/v) Tween-20 (PBST); relative light units (RLU); Rous sarcoma virus (RSV); transducing units per milliliter (TU/ml); vesicular stomatitis virus (VSV-G); wheat germ agglutinin (WGA); 50% reduction in binding (C50)

Altering α-dystroglycan receptor affinity of LCMV pseudotyped lentivirus yields unique cell and tissue tropism

BACKGROUND: The envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV) can efficiently pseudotype lentiviral vectors. Some strains of LCMV exploit high affinity interactions with α-dystroglycan (α-DG) to bind to cell surfaces and subsequently fuse in low pH endosomes. LCMV strains with low α-DG affinity utilize an unknown receptor and display unique tissue tropisms. We pseudotyped non-primate feline immunodeficiency virus (FIV) vectors using LCMV derived glycoproteins with high or low affinity to α-DG and evaluated their properties in vitro and in vivo. METHODS: We pseudotyped FIV with the LCMV WE54 strain envelope glycoprotein and also engineered a point mutation in the WE54 envelope glycoprotein (L260F) to diminish α-DG affinity and direct binding to alternate receptors. We hypothesized that this change would alter in vivo tissue tropism and enhance gene transfer to neonatal animals. RESULTS: In mice, hepatic α- and β-DG expression was greatest at the late gestational and neonatal time points. When displayed on the surface of the FIV lentivirus the WE54 L260F mutant glycoprotein bound weakly to immobilized α-DG. Additionally, LCMV WE54 pseudotyped FIV vector transduction was neutralized by pre-incubation with soluble α-DG, while the mutant glycoprotein pseudotyped vector was not. In vivo gene transfer in adult mice with either envelope yielded low transduction efficiencies in hepatocytes following intravenous delivery. In marked contrast, neonatal gene transfer with the LCMV envelopes, and notably with the FIV-L260F vector, conferred abundant liver and lower level cardiomyocyte transduction as detected by luciferase assays, bioluminescent imaging, and β-galactosidase staining. CONCLUSIONS: These results suggest that a developmentally regulated receptor for LCMV is expressed abundantly in neonatal mice. LCMV pseudotyped vectors may have applications for neonatal gene transfer. ABBREVIATIONS: Armstrong 53b (Arm53b); baculovirus Autographa californica GP64 (GP64); charge-coupled device (CCD); dystroglycan (DG); feline immunodeficiency virus (FIV); glycoprotein precursor (GP-C); firefly luciferase (Luc); lymphocytic choriomeningitis virus (LCMV); nuclear targeted β-galactosidase (ntLacZ); optical density (OD); PBS/0.1% (w/v) Tween-20 (PBST); relative light units (RLU); Rous sarcoma virus (RSV); transducing units per milliliter (TU/ml); vesicular stomatitis virus (VSV-G); wheat germ agglutinin (WGA); 50% reduction in binding (C50)

Geomorphic and stratigraphic evidence for an unusual tsunami or storm a few centuries ago at Anegada, British Virgin Islands

© The Author(s), 2010. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Natural Hazards 63 (2012): 51-84, doi:10.1007/s11069-010-9622-6.Waters from the Atlantic Ocean washed southward across parts of Anegada, east-northeast of Puerto Rico, during a singular event a few centuries ago. The overwash, after crossing a fringing coral reef and 1.5 km of shallow subtidal flats, cut dozens of breaches through sandy beach ridges, deposited a sheet of sand and shell capped with lime mud, and created inland fields of cobbles and boulders. Most of the breaches extend tens to hundreds of meters perpendicular to a 2-km stretch of Anegada’s windward shore. Remnants of the breached ridges stand 3 m above modern sea level, and ridges seaward of the breaches rise 2.2–3.0 m high. The overwash probably exceeded those heights when cutting the breaches by overtopping and incision of the beach ridges. Much of the sand-and-shell sheet contains pink bioclastic sand that resembles, in grain size and composition, the sand of the breached ridges. This sand extends as much as 1.5 km to the south of the breached ridges. It tapers southward from a maximum thickness of 40 cm, decreases in estimated mean grain size from medium sand to very fine sand, and contains mud laminae in the south. The sand-and-shell sheet also contains mollusks—cerithid gastropods and the bivalve Anomalocardia—and angular limestone granules and pebbles. The mollusk shells and the lime-mud cap were probably derived from a marine pond that occupied much of Anegada’s interior at the time of overwash. The boulders and cobbles, nearly all composed of limestone, form fields that extend many tens of meters generally southward from limestone outcrops as much as 0.8 km from the nearest shore. Soon after the inferred overwash, the marine pond was replaced by hypersaline ponds that produce microbial mats and evaporite crusts. This environmental change, which has yet to be reversed, required restriction of a former inlet or inlets, the location of which was probably on the island’s south (lee) side. The inferred overwash may have caused restriction directly by washing sand into former inlets, or indirectly by reducing the tidal prism or supplying sand to post-overwash currents and waves. The overwash happened after A.D. 1650 if coeval with radiocarbon-dated leaves in the mud cap, and it probably happened before human settlement in the last decades of the 1700s. A prior overwash event is implied by an inland set of breaches. Hypothetically, the overwash in 1650–1800 resulted from the Antilles tsunami of 1690, the transatlantic Lisbon tsunami of 1755, a local tsunami not previously documented, or a storm whose effects exceeded those of Hurricane Donna, which was probably at category 3 as its eye passed 15 km to Anegada’s south in 1960.The work was supported in part by the Nuclear Regulatory Commission under its project N6480, a tsunami-hazard assessment for the eastern United States