Adjunctive albuterol enhances the response to enzyme replacement therapy in late-onset Pompe disease.

Effective dosages for enzyme replacement therapy (ERT) in Pompe disease are much higher than for other lysosomal storage disorders, which has been attributed to low cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle. We have previously demonstrated the benefit of increased CI-MPR-mediated uptake of recombinant human acid-α-glucosidase during ERT in mice with Pompe disease following addition of albuterol therapy. Currently we have completed a pilot study of albuterol in patients with late-onset Pompe disease already on ERT for >2 yr, who were not improving further. The 6-min walk test (6MWT) distance increased in all 7 subjects at wk 6 (30±13 m; P=0.002), wk 12 (34±14 m; P=0.004), and wk 24 (42±37 m; P=0.02), in comparison with baseline. Grip strength was improved significantly for both hands at wk 12. Furthermore, individual subjects reported benefits; e.g., a female patient could stand up from sitting on the floor much more easily (time for supine to standing position decreased from 30 to 11 s), and a male patient could readily swing his legs out of his van seat (hip abduction increased from 1 to 2+ on manual muscle testing). Finally, analysis of the quadriceps biopsies suggested increased CI-MPR at wk 12 (P=0.08), compared with baseline. With the exception of 1 patient who succumbed to respiratory complications of Pompe disease in the first week, only mild adverse events have been reported, including tremor, transient difficulty falling asleep, and mild urinary retention (requiring early morning voiding). Therefore, this pilot study revealed initial safety and efficacy in an open label study of adjunctive albuterol therapy in patients with late-onset Pompe disease who had been stable on ERT with no improvements noted over the previous several years.

Neuroimaging assessment of early and late neurobiological sequelae of traumatic brain injury: implications for CTE.

Traumatic brain injury (TBI) has been increasingly accepted as a major external risk factor for neurodegenerative morbidity and mortality. Recent evidence indicates that the resultant chronic neurobiological sequelae following head trauma may, at least in part, contribute to a pathologically distinct disease known as Chronic Traumatic Encephalopathy (CTE). The clinical manifestation of CTE is variable, but the symptoms of this progressive disease include impaired memory and cognition, affective disorders (i.e., impulsivity, aggression, depression, suicidality, etc.), and diminished motor control. Notably, mounting evidence suggests that the pathology contributing to CTE may be caused by repetitive exposure to subconcussive hits to the head, even in those with no history of a clinically evident head injury. Given the millions of athletes and military personnel with potential exposure to repetitive subconcussive insults and TBI, CTE represents an important public health issue. However, the incidence rates and pathological mechanisms are still largely unknown, primarily due to the fact that there is no in vivo diagnostic tool. The primary objective of this manuscript is to address this limitation and discuss potential neuroimaging modalities that may be capable of diagnosing CTE in vivo through the detection of tau and other known pathological features. Additionally, we will discuss the challenges of TBI research, outline the known pathology of CTE (with an emphasis on Tau), review current neuroimaging modalities to assess the potential routes for in vivo diagnosis, and discuss the future directions of CTE research.

Response to Comment on "Whole-genome analyses resolve early branches in the tree of life of modern birds".

Mitchell et al. argue that divergence-time estimates for our avian phylogeny were too young because of an "inappropriate" maximum age constraint for the most recent common ancestor of modern birds and that, as a result, most modern bird orders diverged before the Cretaceous-Paleogene mass extinction event 66 million years ago instead of after. However, their interpretations of the fossil record and timetrees are incorrect.

THE COMPLETE PRELUDES OF ALEXANDER SCRIABIN: THE EVOLUTION OF HIS REVOLUTIONARY COMPOSITIONAL STYLE

During the second half of the nineteenth century, a series of remarkable advances in musical composition emerged in the works of such innovative spirits as Franz Liszt, Hector Berlioz and Richard Wagner. Their pioneering works exerted an extraordinary impact on the music of the subsequent generation of composers--of disparate nationalities-who were active at the dawn of the 20th century: Including most notably Claude-Achille Debussy, Gustav Mahler, Richard Strauss, and Alexander Nikolayevich Scriabin. These important musical figures, each one leaving an indelible and formative imprint on late-nineteenth century Romantic style, together launched the modern era in music. Scriabin stands alone as a transcendental visionary: His music, initiated in the fashion of Chopin and Liszt, wanders through the realms of Debussy and Wagner, and, ultimately abandoning late Romantic tradition, unlocks the heretofore unforeseen power of atonality, bitonality, polyrhythms and key-signature free compositions. Arguably, Scriabin's compositions count among the most innovative, idiosyncratic and bewitching of all time. The development of Scriabin's groundbreaking compositional style is best understood by means of his piano works, which comprise the majority of his oeuvre. Beyond the larger works-his twelve sonatas, a concerto and a fantasy-Scriabin's piano explorations are also represented by miniature gems: The mazurkas, impromptus, waltzes, poems, a polonaise, etudes, nocturnes, morceaux and, in particular, the preludes. Scriabin's 90 preludes for piano, arranged in several opus numbers, richly exemplify the striking evolution of his ingenious music, his idiosyncratic philosophy and his provocative personality.

Two Cases of Late Shone Syndrome With Pulmonary Hypertension: Heart-Lung Transplant or Valve Surgery?

Two cases of Shone syndrome with severe mitral and aortic valve problems and pulmonary hypertension were referred for heart-lung transplantation. Severely elevated pulmonary vascular resistance (PVR) was confirmed as was severe periprosthetic mitral and aortic regurgitation. Based on the severity of the valve lesions in both patients, surgery was decided upon and undertaken. Both experienced early pulmonary hypertensive crises, one more than the other, that gradually subsided, followed by excellent recovery and reversal of pulmonary hypertension and PVR. These cases illustrate Braunwald's concept that pulmonary hypertension secondary to left-sided valve disease is reversible.

The Voyage of Impressionism in Three Violin Recitals: To See the World in Different Colors

Impressionism serves as the transition between romantic and modern music. This dissertation examines the varying characteristics and colors of Impressionism in the works of late-romantic French composers, French Impressionistic composers, and composers with Impressionistic influence from countries other than France. Violin Sonata in g minor, L. 140 (1917) is the last work composed by Claude Debussy. The impressionistic characters in this work includes the ambiguous yet innovative and variant sonority and form. As a work also written in 1917, Ottorino Respighi's Violin Sonata in b minor is deeply rooted in Italian Romanticism. Some of the Impressionistic characters can be found in the second movement where the harmonies are in parallel motion. César Franck, a forerunner of impressionism, heavily influenced Debussy with the use of cyclic form. The Violin Sonata in A major (1886) is rich in harmonic language. Ernest Chausson's works mark the transition between Franck and Debussy. The Poème portrays a love story, Song of Love Triumphant by Turgenev. The work is a symphonic poem for violin and orchestra. The Mythes, Op. 30 (1915) by Karol Szymanowski is based on Greek mythology. Ravel's Sonata for Violin and Cello (1922), dedicated to Debussy, points to the future with a sophisticated harmonic language extending into atonality, spare texture, and expanded palate of impressionistic colors and techniques. Ernest Bloch's Violin Sonata No. 1 (1920) portrays the feeling of torment. Beneath the soaring cries of the violin, the harmonic sonority of Impressionism are present. Gabriel Fauré's Violin Sonata No. 1 in A major, op. 13 (1876) is the earliest work of this project. The scherzo movement became a prototype for future scherzo movements for Ravel and Debussy. Ravel's Tzigane (1924), at once a paragon of French impressionism, a delightful gypsy-style dance-fantasy, and a breathtaking virtuoso piece, is the perfect conclusion to my dissertation project. The pieces discussed above were presented in three recitals. Compact disc recordings of these recitals are available in the Michelle Smith Performing Arts Library of the Clarice Smith Performing Arts Center at the University of Maryland.

[Book Review] Vardah Shiloh, Millon 'Ivri-'Arami-'Aššuri bs-Lahag Yihude Zaxo (A New Neo-Aramaic Dictionary: Jewish Dialect of Zakho). Volume I: 'alef—nun\ Volume II: samex-tav. V. Shilo (16 Ben-Gamla Street), Jerusalem 1995. Pp. xiv + 488 (Vol. I); 489-963 (Vol. II). (Modern Hebrew, Zakho Jewish Neo-Aramaic).

Review of: Vardah Shiloh, Millon 'Ivri-'Arami-'Aššuri bs-Lahag Yihude Zaxo (A New Neo-Aramaic Dictionary: Jewish Dialect of Zakho). Volume I: 'alef—nun\ Volume II: samex-tav. V. Shilo (16 Ben-Gamla Street), Jerusalem 1995. Pp. xiv + 488 (Vol. I); 489-963 (Vol. II). (Modern Hebrew, Zakho Jewish Neo-Aramaic). Hbk.

[BSHM meetings] Topics in the history of financial mathematics: early commerce to chaos in modern stock markets

This account provides an overview of the study day, entitled 'Topics in the History of Financial Mathematics: Early commerce to chaos in modern stock markets,' held by the British Society for the History of Mathematics jointly with Gresham College, at Gresham College, London on 25th April 2008. The series of talks explored the development of mathematics and mathematical techniques in a commercial and financial context.

Spaces of observation and obscurity: cinematic prisons of light and dark

In The Eye of Power, Foucault delineated the key concerns surrounding hospital architecture in the latter half of the eighteenth century as being the ‘visibility of bodies, individuals and things'. As such, the ‘new form of hospital' that came to be developed ‘was at once the effect and support of a new type of gaze'. This was a gaze that was not simply concerned with ways of minimising overcrowding or cross-contamination. Rather, this was a surveillance intended to produce knowledge about the pathological bodies contained within the hospital walls. This would then allow for their appropriate classification. Foucault went on to describe how these principles came to be applied to the architecture of prisons. This was exemplified for him in the distinct shape of Bentham's panopticon. This circular design, which has subsequently become an often misused synonym for a contemporary culture of surveillance, was premised on a binary of the seen and the not-seen. An individual observer could stand at the central point of the circle and observe the cells (and their occupants) on the perimeter whilst themselves remaining unseen. The panopticon in its purest form was never constructed, yet it conveys the significance of the production of knowledge through observation that became central to institutional design at this time and modern thought more broadly. What is curious though is that whilst the aim of those late eighteenth century buildings was to produce wellventilated spaces suffused with light, this provoked an interest in its opposite. The gothic movement in literature that was developing in parallel conversely took a ‘fantasy world of stone walls, darkness, hideouts and dungeons…' as its landscape (Vidler, 1992: 162). Curiously, despite these modern developments in prison design, the façade took on these characteristics. The gothic imagination came to describe that unseen world that lay behind the outer wall. This is what Evans refers to as an architectural ‘hoax'. The façade was taken to represent the world within the prison walls and it was the façade that came to inform the popular imagination about what occurred behind it. The rational, modern principles ordering the prison became conflated with the meanings projected by and onto the façade. This confusion of meanings have then been repeated and reenforced in the subsequent representations of the prison. This is of paramount importance since it is the cinematic and televisual representation of the prison, as I argue here and elsewhere, that maintain this erroneous set of meanings, this ‘hoax'.

Reality-experiential history documentaries: the Trench (BBC, 2002) and Britain's modern memory of the First World War

Culloden (BBC, 1964) The Great War (BBC, 1964) 1914-18 (BBC/KCET, 1996) Haig: the Unknown Soldier (BBC, 1996) Veterans: the Last Survivors of the Great War (BBC, 1998) 1900s House (Channel 4, 1999) The Western Front (BBC, 1999) History of Britain (BBC, 2000) 1940s House (Channel 4, 2001) The Ship (BBC, 2002) Surviving the Iron Age (BBC, 2001) The Trench (BBC, 2002) Frontier House (Channel 4, 2002) Lad's Army (BBC, 2002) Edwardian Country House (Channel 4, 2002) Spitfire Ace (Channel 4, 2003) World War One in Colour (Channel 5, 2003) 1914: the War Revolution (BBC, 2003) The First World War (Channel 4, 2003) Dunkirk (BBC, 2004) Dunkirk: The Soldier's Story (BBC, 2004) D-Day to Berlin (BBC, 2004) Bad Lad's Army (ITV, 2004) Destination D-Day: Raw Recruits (BBC, 2004) Bomber Crew (Channel 4, 2004) Battlefield Britain (BBC, 2004) The Last Battle (ARTE/ZDF, 2005) Who Do You Think You Are? (BBC, 2004, 2006) The Somme (Channel 4, 2005) [From the Publisher]

When deterrence works - and when it doesn't: a comparison of Sweden's prostitution law and UK's Dangerous Dogs Act

Many pieces of legislation have been implemented with the anticipation - or justification - that they will have a deterrent effect. Deterrence was clearly argued in the debate preceding the Swedish prostitution law prohibiting the purchase of sexual services, but less so regarding the Dangerous Dogs Act, which was a very rapid response to a particular moral panic. As it turned out, the Swedish law has had a deterrent effect on street prostitution in that 'respectable' buyers were deterred. It will be argued that it is this very 'respectability' that makes deterrence work in this case. Regarding the Dangerous Dogs Act, the owners of Pit Bulls and other banned breeds are not considered 'respectable' and the banning might have had the reversed effect - increasing the attraction of these dogs, rather than deterring the ownership. Apart from deterrence and its consequences, the rendering invisible of key actors - buyers and owners respectively - and the use of symbolic legislation to promote moral messages will also be considered. [From the Author]

The use of fluorescence microscopy to define polymer localisation to the late endocytic compartments in cells that are targets for drug delivery

Macromolecular therapeutics and nano-sized drug delivery systems often require localisation to specific intracellular compartments. In particular, efficient endosomal escape, retrograde trafficking, or late endocytic/lysosomal activation are often prerequisites for pharmacological activity. The aim of this study was to define a fluorescence microscopy technique able to confirm the localisation of water-soluble polymeric carriers to late endocytic intracellular compartments. Three polymeric carriers of different molecular weight and character were studied: dextrin (Mw~50,000 g/mol), a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer (Mw approximately 35,000 g/mol) and polyethylene glycol (PEG) (Mw 5000 g/mol). They were labelled with Oregon Green (OG) (0.3-3 wt.%; <3% free OG in respect of total). A panel of relevant target cells were used: THP-1, ARPE-19, and MCF-7 cells, and primary bovine chondrocytes (currently being used to evaluate novel polymer therapeutics) as well as NRK and Vero cells as reference controls. Specific intracellular compartments were marked using either endocytosed physiological standards, Marine Blue (MB) or Texas-red (TxR)-Wheat germ agglutinin (WGA), TxR-Bovine Serum Albumin (BSA), TxR-dextran, ricin holotoxin, C6-7-nitro-2,1,3-benzoxadiazol-4-yl (NBD)-labelled ceramide and TxR-shiga toxin B chain, or post-fixation immuno-staining for early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins (LAMP-1, Lgp-120 or CD63) or the Golgi marker GM130. Co-localisation with polymer-OG conjugates confirmed transfer to discreet, late endocytic (including lysosomal) compartments in all cells types. The technique described here is a particularly powerful tool as it circumvents fixation artefacts ensuring the retention of water-soluble polymers within the vesicles they occupy.