Early Versus Late Effort in Dynamic Agencies with Unverifiable Information

In this paper we analyze a dynamic agency problem where contracting parties do not know the agent's future productivity at the beginning of the relationship. We consider a two-period model where both the agent and the principal observe the agent's second-period productivity at the end of the first period. This observation is assumed to be non-verifiable information. We compare long-term contracts with short-term contracts with respect to their suitability to motivate effort in both periods. On the one hand, short-term contracts allow for a better fine-tuning of second-period incentives as they can be aligned with the agent's second-period productivity. On the other hand, in short-term contracts first-period effort incentives might be distorted as contracts have to be sequentially optimal. Hence, the difference between long-term and short-term contracts is characterized by a trade-off between inducing effort in the first and in the second period. We analyze the determinants of this trade-off and demonstrate its implications for performance measurement and information system design.

Cardiac phenotype of Duchenne Muscular Dystrophy: Insights from cellular studies

Dilated cardiomyopathy is a serious and almost inevitable complication of Duchenne Muscular Dystrophy, a devastating and fatal disease of skeletal muscle resulting from the lack of functional dystrophin, a protein linking the cytoskeleton to the extracellular matrix. Ultimately, it leads to congestive heart failure and arrhythmias resulting from both cardiac muscle fibrosis and impaired function of the remaining cardiomyocytes. Here we summarize findings obtained in several laboratories, focusing on cellular mechanisms that result in degradation of cardiac functions in dystrophy. This article is part of a Special Issue entitled "Calcium Signaling in Heart".

IMILAST: A community effort to intercompare extratropical cyclone detection and tracking algorithms: assessing method-related uncertainties

The variability of results from different automated methods of detection and tracking of extratropical cyclones is assessed in order to identify uncertainties related to the choice of method. Fifteen international teams applied their own algorithms to the same dataset - the period 1989-2009 of interim European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERAInterim) data. This experiment is part of the community project Intercomparison of Mid Latitude Storm Diagnostics (IMILAST; see www.proclim.ch/imilast/index.html). The spread of results for cyclone frequency, intensity, life cycle, and track location is presented to illustrate the impact of using different methods. Globally, methods agree well for geographical distribution in large oceanic regions, interannual variability of cyclone numbers, geographical patterns of strong trends, and distribution shape for many life cycle characteristics. In contrast, the largest disparities exist for the total numbers of cyclones, the detection of weak cyclones, and distribution in some densely populated regions. Consistency between methods is better for strong cyclones than for shallow ones. Two case studies of relatively large, intense cyclones reveal that the identification of the most intense part of the life cycle of these events is robust between methods, but considerable differences exist during the development and the dissolution phases.

Counting scars on tree stems to assess rockfall hazards: A low effort approach, but how reliable?

Rockfall is a widespread and hazardous process in mountain environments, but data on past events are only rarely available. Growth-ring series from trees impacted by rockfall were successfully used in the past to overcome the lack of archival records. Dendrogeomorphic techniques have been demonstrated to allow very accurate dating and reconstruction of spatial and temporal rockfall activity, but the approach has been cited to be labor intensive and time consuming. In this study, we present a simplified method to quantify rockfall processes on forested slopes requiring less time and efforts. The approach is based on a counting of visible scars on the stem surface of Common beech (Fagus sylvatica L.). Data are presented from a site in the Inn valley (Austria), where rocks are frequently detached from an ~ 200-m-high, south-facing limestone cliff. We compare results obtained from (i) the “classical” analysis of growth disturbances in the tree-ring series of 33 Norway spruces (Picea abies (L.) Karst.) and (ii) data obtained with a scar count on the stem surface of 50 F. sylvatica trees. A total of 277 rockfall events since A.D. 1819 could be reconstructed from tree-ring records of P. abies, whereas 1140 scars were observed on the stem surface of F. sylvatica. Absolute numbers of rockfalls (and hence return intervals) vary significantly between the approaches, and the mean number of rockfalls observed on the stem surface of F. sylvatica exceeds that of P. abies by a factor of 2.7. On the other hand, both methods yield comparable data on the spatial distribution of relative rockfall activity. Differences may be explained by a great portion of masked scars in P. abies and the conservation of signs of impacts on the stem of F. sylvatica. Besides, data indicate that several scars on the bark of F. sylvatica may stem from the same impact and thus lead to an overestimation of rockfall activity.

The craniosacral progression of muscle development influences the emergence of neuromuscular junction alterations in a severe murine model for spinal muscular atrophy.

AIMS As 4-day-old mice of the severe spinal muscular atrophy (SMA) model (dying at 5-8 days) display pronounced neuromuscular changes in the diaphragm but not the soleus muscle, we wanted to gain more insight into the relationship between muscle development and the emergence of pathological changes and additionally to analyse intercostal muscles which are affected in human SMA. METHODS Structures of muscle fibres and neuromuscular junctions (NMJs) of the diaphragm, intercostal and calf muscles of prenatal (E21) and postnatal (P0 and P4) healthy and SMA mice were analysed by light and transmission electron microscopy. NMJ innervation was studied by whole mount immunofluorescence in diaphragms of P4 mice. RESULTS During this period, the investigated muscles still show a significant neck-to-tail developmental gradient. The diaphragm and calf muscles are most and least advanced, respectively, with respect to muscle fibre fusion and differentiation. The number and depth of subsynaptic folds increases, and perisynaptic Schwann cells (PSCs) acquire a basal lamina on their outer surface. Subsynaptic folds are connected to an extensive network of tubules and beaded caveolae, reminiscent of the T system in adult muscle. Interestingly, intercostal muscles from P4 SMA mice show weaker pathological involvement (that is, vacuolization of PSCs and perineurial cells) than those previously described by us for the diaphragm, whereas calf muscles show no pathological changes. CONCLUSION SMA-related alterations appear to occur only when the muscles have reached a certain developmental maturity. Moreover, glial cells, in particular PSCs, play an important role in SMA pathogenesis.

Acute muscular sarcocystosis: an international investigation among ill travelers returning from tioman island, malaysia, 2011-2012.

BACKGROUND Through 2 international traveler-focused surveillance networks (GeoSentinel and TropNet), we identified and investigated a large outbreak of acute muscular sarcocystosis (AMS), a rarely reported zoonosis caused by a protozoan parasite of the genus Sarcocystis, associated with travel to Tioman Island, Malaysia, during 2011-2012. METHODS Clinicians reporting patients with suspected AMS to GeoSentinel submitted demographic, clinical, itinerary, and exposure data. We defined a probable case as travel to Tioman Island after 1 March 2011, eosinophilia (>5%), clinical or laboratory-supported myositis, and negative trichinellosis serology. Case confirmation required histologic observation of sarcocysts or isolation of Sarcocystis species DNA from muscle biopsy. RESULTS Sixty-eight patients met the case definition (62 probable and 6 confirmed). All but 2 resided in Europe; all were tourists and traveled mostly during the summer months. The most frequent symptoms reported were myalgia (100%), fatigue (91%), fever (82%), headache (59%), and arthralgia (29%); onset clustered during 2 distinct periods: "early" during the second and "late" during the sixth week after departure from the island. Blood eosinophilia and elevated serum creatinine phosphokinase (CPK) levels were observed beginning during the fifth week after departure. Sarcocystis nesbitti DNA was recovered from 1 muscle biopsy. CONCLUSIONS Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS, noting the apparent biphasic aspect of the disease, the later onset of elevated CPK and eosinophilia, and the possibility for relapses. The exact source of infection among travelers to Tioman Island remains unclear but needs to be determined to prevent future illnesses.

IMAGING DIAGNOSIS-MUSCULAR HYPERTROPHY OF THE SMALL INTESTINE AND PSEUDODIVERTICULA IN A HORSE.

A 14-year-old Thoroughbred gelding was presented for chronic colic and weight loss. Transcutaneous and transrectal abdominal ultrasonography revealed distended, thickened small intestine with primary thickening of the muscularis and a focally more thickened loop with an echoic structure crossing the wall from the mucosa to the serosa. Visualization of diffuse thickening of the muscularis (muscular hypertrophy of the small intestine) and a focal lesion (pseudodiverticulum) helped clinicians make informed decisions. This case illustrates the importance of transabdominal and transrectal ultrasonography in horses with chronic colic and the relevance of considering the abnormalities in layering pattern of the intestinal wall.

Electrodiagnostic evaluation in feline hypertrophic muscular dystrophy

Standard needle electromyography (EMG) of 56 muscles and nerve conduction velocities (NCV) of the ulnar and common peroneal nerves were investigated in each of six cats affected with hypertrophic feline muscular dystrophy, 10 related heterozygote carriers and 10 normal cats. The EMG findings were considered normal in carrier and control cats, and consisted of 33% normal readings, 22% myotonic discharges, 18% fibrillation potentials, 11% prolonged insertional potentials, 10% complex repetitive discharges and 6% positive sharp waves in affected cats. Muscles of the proximal limbs were most frequently affected. No differences in NCV were found between the three cat groups. It was concluded that dystrophin-deficient dystrophic cats have widespread and frequent EMG changes, predominantly myotonic discharges and fibrillation potentials, which are most pronounced in the proximal appendicular muscles.

Saving the Australian War Effort in 1916? The Significance and Impact of Global Climatic Conditions and Pests on William Morris Hughes’ Negotiations with the British Government

Taking up the thesis of Dipesh Chakrabarty (2009) that human history (including cultural history) on the one hand and natural history on the other must be brought into conversation more than has been done so in the past, this presentation will focus more closely on the significance and the impact of global climatic conditions and pests on the negotiations that Australian Prime Minister William Morris Hughes carried on with the British government between March and November 1916. Whereas Australia had been able to sell most of its produce in 1914 and 1915 the situation looked more serious in 1916, not least due to the growing shortage in shipping. It was therefore imperative for the Australian government to find a way to solve this problem, not least because it wanted to keep up its own war effort at the pace it had been going so far. In this context intentions to make or press ahead with a contribution to a war perceived to be more total those of the past interacted with natural phenomena such as the declining harvest in many parts of the world in 1916 as a consequence of climatic conditions as well as pests in many parts of the world.

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers

Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders1, 2. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin3, 4 and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure5 and neurocognitive impairment6. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment.

Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.