Milestone Article Research Articles

Current understanding of dystrophin-related muscular dystrophy and therapeutic challenges ahead

To review the recent research progress in dystrophin-related muscular dystrophy includes X-linked hereditary Duchenne and Becker muscular dystrophies (DMD and BMD). Information included in this article was identified by searches of PUBMED and other online resources using the key terms DMD, dystrophin, mutations, animal models, pathophysiology, gene expression, stem cells, gene therapy, cell therapy, and pharmacological. Study selection Mainly original milestone articles and timely reviews written by major pioneer investigators of the field were selected. The key issues related to the genetic basis and pathophysiological factors of the diseases were critically addressed. The availabilities and advantages of various animal models for the diseases were described. Major molecular and cellular therapeutic approaches were also discussed, many of which have indeed exhibited some success in pre-clinical studies but at the same time encountered a number of technical hurdles, including the efficient and systemic delivery of a functional gene and myogenic precursor/stem cells to repair genetic defects. Further understanding of pathophysiological mechanisms at molecular levels and regenerative properties of myogenic precursor/stem cells will promote the development of multiple therapeutic strategies. The combined use of multiple strategies may represent the major challenge as well as the greatest hope for the therapy of these diseases in coming years.

Unacceptable Performance and the Lack of Reproducibility Results in the Report of Colorimetric Methods for Early Detection of Vancomycin and Oxacillin Resistance in Staphylococcus aureus

In a recent paper by Coban and colleagues (6), two colorimetric methods for early detection of vancomycin and oxacillin resistance in Staphylococcus aureus were reported. The authors state that the results were compared by calculating essential agreement, absolute agreement, and minor, major, and very major errors, as recommended by the FDA (10). However, in the cited version of the FDA document, these terms were replaced by categorical agreement and minor, major, and very major discrepancy (10). The authors noted that all tests were performed in the duplicate (6, 10, 14). However, the authors did not report the results of duplicate testing that is necessary for the reproducibility evaluation. In fact, the cited FDA document describes a separate reproducibility (i.e., ≥95%) evaluation step with a triplicate testing (10). The aim of the FDA document is premarket evaluation of new methods which may not guarantee the validity of performance, and even the literature that assays the validity of performance should be read critically (13). In parallel to this view, the Journal of Clinical Microbiology's editorial policy advocates Standards for Reporting of Diagnostic Accuracy (STARD) guidance in the description of diagnostic microbiology assays and comparison of assay performance (1a, 4, 15). However, to our knowledge, a study design in compliance with STARD criteria in the field of microbiology does not exist in the literature to date, possibly because this evidence-based initiative is both new and not easy to comply with. Additionally, the authors report lower-than-90% essential agreement for both methods, except in the nitrate reductase assay for oxacillin testing, and state that results were in concordance with the standard method (6). Contrarily, this is an unacceptable performance according to the criteria described in the cited FDA document (10). In conclusion, the report lacks the reproducibility evaluation, and whether this affects the final performance metrics cannot be known. In addition, the report does not show an acceptable performance of essential agreement, except in the nitrate reductase assay for oxacillin testing. Therefore, this research note should be considered a report of colorimetric methods with preliminary results that need reproducibility testing before acceptable validation through a study design as recommended by the FDA scheme or STARD initiative. It should also be noted that there are founding and preceding milestone articles that either contributed to the development of or directly used the oxidation-reduction color indicators and nitrate reductase assays in susceptibility testing of microorganisms, none of which are cited by the authors (1, 2, 3, 5, 7, 12, 16-18). It should be underlined that the use of the rapid colorimetric method for MIC testing is not new and is already available as FDA-approved and patented technology in certain nonautomated and automated commercial susceptibility systems (9, 16). The authors stated that such an automated system is expensive, which may refer to only the original capital investment for the initial technology acquisition purchase, but the reagent rental option usually also exists (8). In fact, it has been shown that the use of approved and standardized automated systems in routine rapid susceptibility testing can be cost-effective, not to mention the added values of computerized expert systems for data analysis and interpretation (9).

Debilissimae Entitates?

Over the past decades a number of scholars have identified Johann Heinrich Bisterfeld as one of the most decisive early influences on Leibniz. In particular, the impressive similarity between their conceptions of universal harmony has been stressed. Since the issue of relations is at the heart of both Bisterfeld and Leibniz's doctrines of universal harmony, the extent of the similarity between their doctrines will depend, however, on Bisterfeld and Leibniz's respective theories of relations, and especially on their ontolo­ gies of relations. This paper attempts to determine in more detail whether Bisterfeld's ontology of relations contains at least the germ of the defining features of the ontology of relations later developed by Leibniz. It comes to the conclusion that, although Bisterfeld's theory of relations is not as fully developed and explicit as that of Leibniz, it does contain all the key ingredients of it. T here is agreement amongst Leibniz's scholars on the fact that there are strikingly similarities between Leibniz's thought and that of the German philosopher and theologian Johann Heinrich Bisterfeld (c. 1605-1655).2 After the groundbreaking studies of Willy Kabitz, Paolo Rossi, and Leroy E. Loemker, and the milestone article by Massimo Mugnai published in Studia Leibnitiana in 1973,3 many scholars have pointed out Bisterfeld as one of the most decisive early int1uences on Leibniz,4 Between 1663 and 1666 the young Leibniz read with great enthusiasm and annotated with care three posthumously published works by Bisterfeld. 5 On the basis of the analysis of these and other works by Bisterfeld,6 the impressive similarity between two fundamental features of both Bisterfeld and Leibniz's philosophy has been emphasised: their conception of universal harmony and the thesis ~ central to Leibniz's monadology - that all beings are endowed with perception and appetite. 7 These two doctrines are, so to speak, two sides of the same coin. As Donald Rutherford insightfully summarises, both Bisterfeld and Leibniz see universal harmony as involving three main claims: 1) Within the world, there is a primitive connection between the states of any one substance and those of every other substance. 2) This connection is grounded in a substance's capacity to perceive everything that happens within the world. 3) It is a necessary condition for the maintenance of the world's harmony that every substance be endowed with an intrinsic activity.~ According to Leibniz's own interpretation in his Dissertatio de Arte Combinatoria (1666), the central tenet of Bisterfeld's philosophy is the thesis of the universal

Recollections of acoustics at Brown University in the early fifties.

When I arrived at Brown in 1950, Bob Beyer, a young assistant professor, was already becoming well known as an acoustician. Within a year he was promoted to associate professor and took over the ‘‘References’’ section of JASA at the death of Arthur Tabor Jones. Having previously translated works in German, soon he had taught himself Russian and become known as the editor of JETP, the Russian translation journal. I took an ultrasonics course from him, about the time the milestone article on acoustic absorption by Markham, Beyer, and Lindsay came out in Reviews of Modern Physics. In those days Brown Physics was a powerhouse of expertise in acoustics, with three out of every four faculty members specializing in that field. In 1952 distinguished acousticians from around the world gathered at Brown for an ONR ultrasonics symposium. As the field of nonlinear acoustics began to evolve, Beyer, along with Lindsay, Nyborg, Westervelt, and their students, was busy exploring high amplitude effects such as anomalous absorption, acoustic streaming, and, later, scattering of sound by sound. All this took place in an ancient relic of a building called Wilson Hall, with an attic full of dusty apparatus left from a departed 19th century department chairman, and a basement full of great, mosquito‐infested ultrasonic water tanks.

Where to Now, Henry? A Commentary on The Battered Child Syndrome

On March 30, 1984, I was given the privilege of delivering the introductory speech at the first American Medical Association (AMA) meeting exclusively for child abuse and neglect. Although one might wonder why 22 years lapsed between the Journal of the American Medical Association (JAMA) publication of the milestone article by Henry Kempe1 and the first meeting, the fact remains that the AMA is now paying attention to the needs of abused children and their families. My talk at this conference came just 3 weeks after the death of Henry Kempe, some 20 years almost to the date when he asked if I would like to be involved with his study of the battered child syndrome.