Duchenne muscular dystrophy (DMD) causes a progressive impairment of muscle function leading to hypercapnic respiratory failure. Most studies of respiratory function in DMD have been cross-sectional rather than longitudinal, and these data have not been related to survival. We retrospectively studied 58 patients with DMD with at least 2 yr of follow-up spirometry and known vital status. Spirometry was abnormal at entry: median FEV(1) 1.60 L (range 0.4 to 2.6 L), FVC 1.65 L (range 0.45 to 2.75 L), FVC 64% predicted (range 29 to 97%). Individual rates of change of vital capacity varied, with a median annual change of -0.18 L (range 0.04 to -0.74 L), -8.0% predicted FVC (range 2 to -39%). During the study 37 patients died; the median age of death, calculated by Kaplan-Meier analysis, was 21.5 yr (range 15 to 28.5 yr). The age when vital capacity fell below 1 L was a strong marker of subsequent mortality (5-yr survival 8%). The maximal vital capacity recorded and its rate of decline (however expressed) predicted survival time. Repeated spirometric measurement provides a simple and relatively powerful means of assessing disease progression in these patients and should be considered when planning treatment trials.

Early intervention for memory difficulties in amnestic mild cognitive impairment, using cognitive rehabilitation in compensatory strategies, can assist in minimising everyday memory failures as evaluated by performance on prospective memory tasks and knowledge of memory strategies.

Cardiac disease is a well-known complication of myotonic dystrophy, understanding of which has been increased by recent advances in both molecular techniques and cardiological investigations. Conduction disturbances and tachyarrhythmias occur commonly in myotonic dystrophy. These have been shown to have a broad correlation in severity with both neuromuscular disease and the extent of the molecular defect in some, but not all, studies. Clinical evidence of generalised cardiomyopathy is unusual. The rate of progression differs widely between individuals; sudden death may be caused by ventricular arrhythmias or complete heart block, and this can be at an early stage of disease. A familial tendency towards cardiac complications has been shown in some studies. The histopathology is of fibrosis, primarily in the conducting system and sino-atrial node, myocyte hypertrophy and fatty infiltration. Electron microscopy shows prominent I-bands and myofibrillar degeneration. Myotonin protein kinase, the primary product of the myotonic dystrophy gene, may be located at the intercalated discs and have a different isoform in cardiac tissue. The role of other genes or the normal myotonic dystrophy allele in myotonic heart disease has yet to be determined. Suggestions for clinical management include a careful cardiac history and a 12-lead ECG at least every year, with a low threshold for use of 24 h Holter monitoring. Extra care should be taken before, during and after general anaesthetics, which carry a high frequency of cardiorespiratory complications. Finally, myotonic dystrophy should be considered in previously undiagnosed patients presenting to a cardiologist or general physician with suspected arrhythmia or conduction block.

No abstract

Surface plasmon resonance (SPR) measurements provide a highly sensitive means for detecting biomolecular interactions in a label-free manner. Numerous studies of biomolecular interactions have been performed with fixed-angle SPR imaging (SPRi) on surfaces patterned with a variety of biomolecules such as DNA, RNA, proteins, and peptides. 1 Arrays increase the information obtainable in a single experiment as multiple reactions can be monitored in parallel.A current and significant limitation of SPR is that the substrate must be a metal thin film. A number of metal thin films are capable of supporting surface plasmons in the near-infrared and visible regions of the electromagnetic spectrum. 2,3 Gold surfaces have been the substrate of choice for SPR measurements for two reasons: gold is relatively stable in the aqueous environments needed for monitoring biomolecular interactions and a versatile chemistry based on the attachment of sulfur-containing ligands to the gold surface has been developed and wellcharacterized. The readily formed gold-sulfur bond enables the direct attachment of ligands to the gold surface 4 as well as attachment via an intermediate self-assembled monolayer (SAM). 5-7 This gold-thiol chemistry has made possible the routine analysis of aqueous binding processes to immobilized molecules at near-neutral pH values and moderate temperatures. The susceptibility of the gold-sulfur bond to oxidation and photodecomposition has prevented SPR sensing from finding utility in areas such as on-surface combinatorial chemistry (due to the harsh chemical conditions employed) and photolithography (due to the adverse effects of ultraviolet radiation on the gold-sulfur bond). 8Here we describe the development of a lamellar structure in which a thin layer of amorphous carbon is deposited onto a surface plasmon-active gold thin film (Figure 1a). Carbon-based surfaces are readily modified with biomolecules of interest using a well-developed and robust chemistry, based upon the attachment of alkene-containing molecules to the substrate through the UV light-mediated formation of carbon-carbon bonds. 9 Recently, a similar lamellar structure utilizing a thin silicate overlayer was used to fabricate and monitor supported bilayer membranes with SPR. 10 E-mail: smith@chem.wisc.edu. Arrays prepared on functionalized carbon-based substrates such as diamond thin films, 11,12 glassy carbon, 12 and amorphous carbon thin films 13 have superior stability to analogous arrays prepared on functionalized glass, silicon, and gold substrates. Amorphous carbon is of particular interest as it can be deposited at room temperature, allowing it to be integrated with other materials 14 such as quartz crystal microbalances, 13 electrodes, 15 and metal thin films without perturbing their structure. The utility of a multilayered substrate containing a metal thin film and an amorphous carbon overlayer is shown here by their use for in situ synthesis of oligonucleotide arrays, which are then employed in the analysis of biomolecule binding proces...

Misfolding of Amyloid β (Aβ) peptides leads to the formation of extracellular amyloid plaques. Molecular chaperones can facilitate the refolding or degradation of such misfolded proteins. Here, for the first time, we report the unique ability of Lipocalin-type Prostaglandin D synthase (L-PGDS) protein to act as a disaggregase on the pre-formed fibrils of Aβ(1–40), abbreviated as Aβ40, and Aβ(25–35) peptides, in addition to inhibiting the aggregation of Aβ monomers. Furthermore, our proteomics results indicate that L-PGDS can facilitate extraction of several other proteins from the insoluble aggregates extracted from the brain of an Alzheimer’s disease patient. In this study, we have established the mode of binding of L-PGDS with monomeric and fibrillar Aβ using Nuclear Magnetic Resonance (NMR) Spectroscopy, Small Angle X-ray Scattering (SAXS), and Transmission Electron Microscopy (TEM). Our results confirm a direct interaction between L-PGDS and monomeric Aβ40 and Aβ(25–35), thereby inhibiting their spontaneous aggregation. The monomeric unstructured Aβ40 binds to L-PGDS via its C-terminus, while the N-terminus remains free which is observed as a new domain in the L-PGDS-Aβ40 complex model.

Glass has become the standard substrate for the preparation of DNA arrays. Typically, glass is modified using silane chemistries to provide an appropriate functional group for nucleic acid synthesis or oligonucleotide immobilization. We have found substantial issues with the stability of these surfaces as manifested in the unwanted release of oligomers from the surface when incubated in aqueous buffers at moderate temperatures. To address this issue, we have explored the use of carbon-based substrates. Here, we demonstrate in situ synthesis of oligonucleotide probes on carbon-based substrates using light-directed photolithographic phosphoramidite chemistry and evaluate the stabilities of the resultant DNA arrays compared to those fabricated on silanized glass slides. DNA arrays on carbon-based substrates are substantially more stable than arrays prepared on glass. This superior stability enables the use of high-density DNA arrays for applications involving high temperatures, basic conditions, or where serial hybridization and dehybridization is desired.

REM-related oxygen desaturation occurs in advanced Duchenne muscular dystrophy (DMD) and might be an independent predictor of disease progression. We have followed 18 patients for 10 yr after an initial respiratory sleep study or until death or onset of nasal ventilation. We measured baseline spirometry, blood gas tensions, maximal respiratory pressures, and body mass index. In 11 cases, VC was recorded serially. Median survival was 50 (range, 13 to 89) mo from initial study and unrelated to age at time of study, BMI, or mouth pressures but correlated with PaCO2 (r = -0.72, p < 0.005, n = 17), minimal nocturnal SaO2 (r = 0.62, p < 0.007, n = 18) and VC (r = 0. 65, p < 0.005, n = 17). Cox regression analysis showed a VC of less than 1 L at the time of study to be the best single predictor of subsequent survival. The only measure associated with age of death was the age at which the VC fell below 1 L (r = 0.79, p < 0.004). These data suggest measurement of PaCO2 or serial assessment of VC should be studied further as valid methods of assessing prognosis in DMD.