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BackgroundShoe inserts, orthopaedic shoes, ankle-foot orthoses (AFOs) are important devices in Charcot-Marie-Tooth disease (CMT) management, but data about use, benefits and tolerance are scanty.MethodsWe administered to Italian CMT Registry patients an online ad hoc questionnaire investigating use, complications and perceived benefit/tolerability/emotional distress of shoe inserts, orthopaedic shoes, AFOs and other orthoses/aids. Patients were also asked to fill in the Quebec User Evaluation of Satisfaction with assistive Technology questionnaire, rating satisfaction with currently used AFO and related services.ResultsWe analysed answers from 266 CMT patients. Seventy per cent of subjects were prescribed lower limb orthoses, but 19% did not used them. Overall, 39% of subjects wore shoe inserts, 18% orthopaedic shoes and 23% AFOs. Frequency of abandonment was high: 24% for shoe inserts, 28% for orthopaedic shoes and 31% for AFOs. Complications were reported by 59% of patients and were more frequently related to AFOs (69%). AFO users experienced greater emotional distress and reduced tolerability as compared with shoe inserts (p<0.001) and orthopaedic shoes (p=0.003 and p=0.045, respectively). Disease severity, degree of foot weakness, customisation and timing for customisation were determinant factors in AFOs’ tolerability. Quality of professional and follow-up services were perceived issues.ConclusionsThe majority of CMT patients is prescribed shoe inserts, orthopaedic shoes and/or AFOs. Although perceived benefits and tolerability are rather good, there is a high rate of complications, potentially inappropriate prescriptions and considerable emotional distress, which reduce the use of AFOs. A rational, patient-oriented and multidisciplinary approach to orthoses prescription must be encouraged.

We present chromosome-level genome assemblies from representative species of three independently evolved seagrass lineages: Posidonia oceanica, Cymodocea nodosa, Thalassia testudinumand Zostera marina. We also include a draft genome of Potamogeton acutifolius, belonging to a freshwater sister lineage to Zosteraceae. All seagrass species share an ancient whole-genome triplication, while additional whole-genome duplications were uncovered for C. nodosa, Z. marinaand P. acutifolius. Comparative analysis of selected gene families suggests that the transition from submerged-freshwater to submerged-marine environments mainly involved fine-tuning of multiple processes (such as osmoregulation, salinity, light capture, carbon acquisition and temperature) that all had to happen in parallel, probably explaining why adaptation to a marine lifestyle has been exceedingly rare. Major gene losses related to stomata, volatiles, defence and lignification are probably a consequence of the return to the sea rather than the cause of it. These new genomes will accelerate functional studies and solutions, as continuing losses of the ‘savannahs of the sea’ are of major concern in times of climate change and loss of biodiversity.

Natural environments are beneficial for cognitive functioning and affect. Appraisals of such benefits can lead to the development of pro-environmental attitudes and behaviors in the long run. This study aimed to investigate the effects of an indirect exposure to a natural and urban environment during a short break in a school day, using a ‘green’ video depicting a walk through a lush forest and comparing it to an urban video portraying a walk through a busy city. We involved 91 fourth and fifth graders in a within-participants design. Results show that students decreased their performance in an arithmetic calculation task after watching the urban video, while no significant differences were observed before and after the exposure to the green environment. Students also reported experiencing more negative affect in relation to the exposure to the urban than the natural environment. Moreover, the students perceived the natural environment as more restorative than the urban environment. Taken together, our findings suggest that exposure to urban environments, in contrast to natural environments, may have negative effects on cognitive and affective functioning during school breaks. Educational implications suggest that when it is not possible to stay in a natural environment around the school, or there is no access to nature due to distance, videos of natural environments can be used during short breaks. They have potential to cognitively and affectively benefit students’ who may often be exposed to environmental stressors.

In embedded computing domains, including the automotive industry, complex functionalities are split across multiple tasks that form task chains. These tasks are functionally dependent and communicate partial computations through shared memory slots based on the Logical Execution Time (LET) paradigm. This paper introduces a model that captures the behavior of a producer-consumer pair of tasks in a chain, characterizing the timing of reading and writing events. Using ring algebra, the combined behavior of the pair can be modeled as a single periodic task. The paper also presents a lightweight mechanism to eliminate jitter in an entire chain of any size, resulting in a single periodic LET task with zero jitter. All presented methods are available in a public repository.

Modern automotive applications are increasingly characterized by the need to transfer massive amounts of data in a predictable and deterministic way, possibly leveraging the Logical Execution Time (LET) paradigm. However, current proposals for LET communications are limited to core-commanded data transfers, which may result in large delays for data-intensive systems. To address this issue, we explore the use of Direct Memory Access (DMA) to handle LET communication with improved parallelism. Each DMA transfer operates on a contiguous memory area, thus calling for an optimized memory mapping to maximize performance. Modern DMA engines offer also advanced configurations, such as linked-lists of data transfers, which may provide more flexibility at the expenses of an increased (initial) programming overhead. Leveraging all such features of DMA engines, we propose a set of designs and protocols for LET communications with trade-offs between latency and space requirements. For each option we present the formulation to compute the optimal scheduling and memory allocation solution as a mixed-integer linear programming problem. Experimental results show the feasibility of the approach and a comparison of the solutions obtained using the proposed methods, showing a considerable improvement in terms of data acquisition latency when compared to LET communication without DMA.

Purpose: To report the case of a 33-year old man who disclosed the first case of bilateral ocular involvement of hand, foot, and mouth disease (HFMD) with a different stage of the disease in each eye.Methods: Retrospective case report.Results: The study included a patient who incurred in a bilateral HFMD maculopathy. During 6 months follow-up period persistent abnormalities in fundus examination and in OCT scans were reported.Conclusion: We consider that our case shows that choriocapillaris is the primary target of HFMD maculopathy, for this reason we consider that ICGA is mandatory for early diagnosis and an effective treatment.

Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.

Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by high-local recurrence rate, poorly understood molecular pathogenesis, lack of specific prognostic markers, and effective targeted therapies. To gain further insights into the disease, we analyzed a well-defined group of 133 primary MFS cases. Immunohistochemical (IHC) staining for p53, MET, RET, and RB was performed. Twenty-five cases were analyzed by targeted resequencing of known cancer driver hotspot mutations, whereas 66 and 64 MFSs were examined for the presence of genetic variants in TP53 and MET gene, respectively. All clinical, histologic, immunostaining, and genetic variables were analyzed for their impact on 5-years overall survival (OS) and 5-years event-free survival (EFS). In our series, no grade I tumors relapsed and high grade are related to a positive MET immunostaining (P = .034). Both local recurrence (P = .038) and distal metastases (P = .016) correlated to the presence of “single nucleotide variant (SNV) plus copy number variation (CNV)” in TP53. Multivariate analysis revealed that age (>60 years), metastasis at presentation, and positive IHC-p53 signal are risk factors for a poor OS (P = .003, P = .000, and P = .002), whereas age (>60 years), synchronous metastasis, and tumor size (>10 cm) predict an unfavorable 5-years EFS (P = .011, P = .000, and P = .023). Considering the smaller series (n = 66) that underwent molecular screening, the presence of “SNV+CNV” in TP53 represents a risk factor for a worse 5-years EFS (hazard ratio, 2.5; P = .017). The present series confirms that TP53 is frequently altered in MFS (86.4% of cases), appearing to play an important role in MFS tumorigenesis and being a potentially drugable target. A positive p53 immunostainings is related to a poor diagnosis, and it is the presence of a single nucleotide genetic alterations in TP53 that is essential in conferring MFS an aggressive phenotype, thus supporting the use of molecular profiling in MFS to better define the role of p53 as a prognostic factor.

Referred phantom sensations are frequently reported following a peripheral injury. However, very few cases describe such sensations of the ear, and it remains unclear how the aural nerve territory can be remapped to one specific peripheral nerve region. We report on a patient with brachial plexus avulsion who underwent sensory testing and was asked to report the location of the stimulated site and any other sensations experienced. The patient spontaneously described the sensation of his arm being separate from his body. Despite visual input, he felt that his fist was closed, with his thumb pointing inward. Importantly, he felt clear and reproducible sensations from the affected arm when the ipsilateral ear was touched. These referred sensations were noted just 15 days after sustaining the injury. The arm nerve territory was systematically remapped to a specific aural nerve territory by applying both manual and electrical stimulation. Stimulation of the external ear, which is innervated by the vagus nerve, showed high spatial specificity for the dorsal and volar skin surfaces of the limb, and clearly delineated digits. Somatosensory-evoked potentials indicated that cortical adaptation in the somatosensory stream transferred a spatially organized map of the limb to the skin of the outer ear. This referral of sensations to the ear, as distinct from the face, provides evidence of highly specific topographical reorganization of the central nervous system following peripheral injury. Rapid map changes in the phantom sensation to the ear as a function of stimulation of vagus nerve suggest that the reorganization process can occur in cortex rather than in the brainstem.

Organizational members frequently evaluate how their abilities and standing compare with those of their colleagues. Although these comparisons can have a negative impact on organizations, little attention has been paid to the role of leaders in these processes. Drawing on interviews with individuals in leadership positions in business schools, we develop a framework to explain what triggers leaders’ attention to social comparisons among faculty and how they become involved in them. Central to this framework are leaders’ self‐schemas, which encompass their preferences about the criteria members should use in making comparisons. Leaders’ self‐schemas are activated by discrepancies between their own comparative judgements and those they perceive members to be making and impel them to act in ways consistent with their preferred bases of comparison. Our framework repositions social comparisons as a multi‐perspectival, political phenomenon in which leaders see themselves as playing a role in shaping members’ evaluations and workplace interactions.

We propose that most fault slip rate variability across a range of time and spatial scales is due to intrinsic faulting processes, rather than extrinsic changes in surface loads or stress boundary conditions. This hypothesis is tested by comparing very high geologic resolution slip histories of blind thrust faults from three transects in the Northern Apennines, Italy. We investigated whether these slip histories document synchronous, or independent, behavior of the disconnected, blind thrust faults that core mountain front anticlines bordering the Po foreland. The slip history for these thrusts is reconstructed by applying forward structural modeling to deformed growth strata and fluvial terraces preserved on the limbs of the growing anticlines. We present a new age model using magnetostratigraphy and cyclostratigraphy for a section of growth strata exposed in the Panaro River and supplement this with age models for two other published transects. The blind thrust fault at each transect exhibits variable slip behavior over the past 3 Myr, but for most of that time the variability was both asynchronous and independent of boundary condition changes, such as Plio‐Pleistocene sediment accumulation variability. However, a major deceleration in slip rates at all three locations is temporally coincident with the overfilling of the Po foreland beginning in the early Pleistocene. We attribute the deceleration to a switch from shortening on shallowly detached thrusts to shortening on a crustal‐scale basement‐involved fault. This switch has implications for the time and spatial scales at which extrinsic boundary conditions may contribute to deformation variability. High‐resolution slip histories for blind thrust faults in the Northern Apennines are reconstructed using growth strataEach of the investigated faults exhibits variable slip behavior over a range of time scalesFault slip rate variability on disconnected thrusts is asynchronous and independent of external boundary conditions at intermediate time scales

Background: Recently, efforts have been made to combine complementary perspectives in the assessment of Alzheimer type dementia. Of particular interest is the definition of the fingerprints of an early stage of the disease known as Mild Cognitive Impairment or prodromal Alzheimer's Disease. Machine learning approaches have been shown to be extremely suitable for the implementation of such a combination. Methods: In the present pilot study we combined the machine learning approach with structural magnetic resonance imaging and cognitive test assessments to classify a small cohort of 11 healthy participants and 11 patients experiencing Mild Cognitive Impairment. Cognitive assessment included a battery of standardised tests and a battery of experimental visuospatial memory tests. Correct classification was achieved in 100% of the participants, suggesting that the combination of neuroimaging with more complex cognitive tests is suitable for early detection of Alzheimer Disease. Results: In particular, the results highlighted the importance of the experimental visuospatial memory test battery in the efficiency of classification, suggesting that the high-level brain computational framework underpinning the participant's performance in these ecological tests may represent a “natural filter” in the exploration of cognitive patterns of information able to identify early signs of the disease.

Engine control applications include functions that need to be executed at specific rotation angles of the crankshaft. The tasks performing these functions are activated at variable rates and are programmed to be adaptive with respect to the rotation speed of the engine to avoid overloading the CPU. Simplified control implementations are used at high speeds; for example, reducing the number of fuel injections or the complexity of the computations. Such different control implementations define execution modes with different execution times for different ranges of the rotation speed. The selection of the switching speeds for the operating modes of such tasks is an optimization problem, consisting in determining the optimal transition speeds that maximize the engine performance while guaranteeing schedulability.This article presents three methods for tackling such an optimization problem under a set of assumptions about the performance metrics: two heuristics and a branch and bound method that guarantees finding the optimal solution within a given speed granularity. In addition, a simple method to compute a performance upper bound is presented. The approach and the hypothesis are validated using a Simulink model of the engine and the computational tasks, considering the engine efficiency and the production of pollutants (NO2) as metrics of interest. Simulation experiments show that the performance of proposed heuristics is quite close to that of the upper bound and the optimum within a finite granularity.

AbstractThe short-haired Segugio Italiano and rough-haired Segugio Italiano are two breeds of Italian scenthound. The two breeds were subjected to divergent selection based on the type (long versus short) and pigmentation (fawn versus black & tan) of the hair, leading to the development of the two above-mentioned phenotypes. Microsatellites markers from 120 unrelated dogs were used to estimate the genetic variability within the two Segugio Italiano breeds and to assess if divergent selection for the two phenotypes has possibly led to the development of subpopulations distinguished by coat type and pigmentation. Finally, we also estimated the genetic distance between the two Segugio Italiano breeds and two other related breeds, Segugio Maremmano and Segugio dell'Appennino. The mean Fis, Fit and Fst values indicated a moderate level of inbreeding. In both breeds the mean observed heterozygosity was lower than the expected heterozygosity. The AMOVA, PCoA and STRUCTURE analyses showed lack of differentiation between the two breeds and the absence of substructuring in the population. Cavalli-Sforza chord distance, Nei's genetic distance and Reynolds–Weir Cockerham’s genetic distance between the two Segugio Italiano breeds were low. Low genetic distances were also found between the Segugio Italiano and the others two related breeds indicating that there is no difference in terms of genetic distance among the three breeds despite the important phenotypic differences among them. This paper provides a basis to change the breeding guidelines of the four breeds in the light of these informations.

Fluvial terraces, longitudinal river profiles, and growth strata carry comparable records of the deformation history in tectonically active mountain belts. In the northern Apennines, these markers are preserved across an actively uplifting, steep mountain front. We take advantage of this setting to model base‐level fall histories reconstructed from a linear inversion of fluvial topography on six transverse catchments spanning 110 km along the strike from Bologna to Parma. We compare these histories to records of crustal shortening preserved in growth strata. The fluvial inversion model is based on the detachment‐limited stream‐power model and considers the variable erodibility of bedrock lithology. Uplift is assumed to be spatially uniform at the catchment scale and crudely in balance with long‐term 10Be terrestrial cosmogenic nuclide (TCN) erosion rates that range from ∼0.3 to 0.7 mm yr−1. The model predicts rates of base‐level fall that are comparable with published rates of fault slip from growth strata and incision from terrace deposits. The modeling demonstrates how orogenic shortening and topographic growth are nonuniform and partitioned along the strike of the Apennine mountain front. Rivers record steady uplift in the last ∼1 Myrs, temporally coincident with overfilling of the Po Plain and reduction of shallow fault slip, supporting a proposed switch from thin‐to thick‐skinned crustal shortening. These results are a novel example of base‐level fall records assembled from both the erosional source and depositional sink and highlight the versatility and challenges of fluvial inversion modeling. We use the longitudinal profiles of river channels—plots of channel elevation against streamwise distance—to model the history of base‐level fall at river mouths. Base‐level fall is compared to published fault slip and sediment deposition rates assembled from geologic data. Each data set shows generally consistent trends through time. A synchronous increase in base‐level fall rate within the last 1 Myr is observed ubiquitously across all six catchments. We interpret this as indicative of a change in the style of mountain building ∼1 Myr ago caused by the activation of a deep thrust fault that is uplifting most of the northern Apennine northeastern flank. An assessment of all the data sets indicates how the northern Apennine mountains were built over the past ∼3 Myr and allows for discussion on the versatility and challenges of our modeling approach. These results show that river profiles can be sensitive recorders of mountain building and, when interpreted alongside other complimentary records, can be used to critically evaluate model results in the context of landscape evolution. The approach used here can be applied to understand the history of mountain building in other settings across the globe. Linear inversion of river longitudinal profiles is a versatile tool to restore base‐level fall histories from measured physical parametersWe compare base‐level fall histories from rivers to complimentary and independent records from growth strata and fluvial terracesResults add to the growing amount of data supporting out‐of‐sequence thick‐skinned deformation of the northern Apennines of Emilia Romagna Linear inversion of river longitudinal profiles is a versatile tool to restore base‐level fall histories from measured physical parameters We compare base‐level fall histories from rivers to complimentary and independent records from growth strata and fluvial terraces Results add to the growing amount of data supporting out‐of‐sequence thick‐skinned deformation of the northern Apennines of Emilia Romagna

AbstractFinding a safe place inside a building in an emergency can be a difficult task for disabled people, as they are expected to be able to find an “Area of Refuge” (AR) and wait there until rescued. Wayfinding is influenced by building features and type of instructions given. Two studies were carried out with the aim of exploring how the type of instructions affects wayfinding. In Studies 1 and 2, participants accompanied a wheelchair-bound friend inside a virtually reproduced medical clinic and once they reached a target zone, a fire alarm was sounded. Participants received either general instructions on how to behave in the event of a fire emergency, or specific instructions focusing on how to reach an AR, or no instructions (Studies 1 and 2); or alternatively they could look at a map or receive specific instructions accompanied by a map (Study 2). The results showed that participants who were given no instructions looked for more means of escape, and took more time to reach the AR than the other groups. In addition, this group also performed more actions during the pre-movement time. These findings highlight the importance of correct information in influencing wayfinding performance and suggest novel design solutions. The design of our study made it possible to examine not only the effect of different instruction types but also of different building features.

Purpose To evaluate the clinical outcome of surgical treatment for macular serous detachment associated with optic disc pit with pars plana vitrectomy (PPV) without laser photocoagulation on the temporal edge.Methods Vitrectomy was performed in 8 eyes of 8 patients (mean age 27.25 years; range 12-57 years) with unilateral macular detachment associated with optic disc pit. All patients underwent pars plana vitrectomy (cases 1, 2, 3, and 4, PPV 20 G; cases 5, 6, 7, and 8, PPV 25 G), internal limiting membrane (ILM) peeling, and SF620% gas tamponade (case 1 was treated with silicone oil tamponade). Endolaser on the temporal margin of the optic disk was not performed. Every patient was observed for a follow-up period of 59.25 months after surgery. Statistical analysis was carried out using Student t test paired data. p Value <0.05 was considered to be significant.Results Complete retinal reattachment was achieved in 7 of 8 patients. Case 8 was operated 11 months ago and he still has a small area of subretinal fluid not completely reabsorbed. Mean preoperative best-corrected visual acuity (BCVA) was 20/83 and the mean postoperative BCVA was 20/40. Mean preoperative foveal thickness was 973 μm and mean postoperative foveal thickness was 363.5 μm. Case 7 developed a macular hole after treatment.Conclusions Pars plana vitrectomy, ILM peeling, and endotamponade (SF620% gas) without endolaser on the temporal edge of optic disc is an effective treatment. This procedure achieved successful anatomical and functional results.

AimThe aim of this study is to evaluate long-term efficacy of intravitreal injections of aflibercept as primary treatment for subfoveal/juxtafoveal myopic choroidal neovascularisation (CNV).MethodsThirty-eight treatment-naive eyes of thirty-eight patients with subfoveal/juxtafoveal myopic CNV received initial intravitreal aflibercept injections and were followed for at least 18 months. Aflibercept was applied again for persistent or recurrent CNV, as required. Statistical analysis was carried out using SPSS.ResultsMean patient age was 45.8 years, and mean eye refractive error was −7.79 D. For the total patient group (n=38 eyes), mean logMAR best-corrected visual acuity (BCVA) significantly improved from 0.69 at baseline to 0.15 at 18 months (P<0.01). Over half of the treated eyes obtained resolution with one aflibercept injection. Patients were also grouped according to age, as <50 years (n=20 eyes) and ≥50 years (n=18 eyes). Mean BCVA improvement was significantly greater in eyes of the younger myopic CNV group, compared with those of ≥50 years (0.21 vs 0.35; P<0.05). The mean number of aflibercept injections was 1.8 for the <50 years myopic CNV group, and 3.6 for the ≥50 years myopic CNV group (P<0.001). Correlation between spherical equivalent refraction and final visual acuity reached statistical significance only for the <50 years myopic CNV group (P<0.001; Levene’s correlation).ConclusionsIntravitreal aflibercept provides long-term visual acuity improvement in myopic CNV. The <50 years old myopic CNV group had significantly fewer injections, with greater visual acuity improvement. Intravitreal aflibercept in myopic CNV does not require the three-injection loading phase used for aflibercept treatment of neovascular age-related macular degeneration.

Shared control is becoming widely used in many manual control tasks as a mean for improving performance and safety. Designing an effective shared control system requires extensive testing and knowledge of how operators react to the haptic sensations provided by the control device shared with the support system. Commercial general purpose haptic devices may be unfit to reproduce the operational situation typical of the control task under study, like car driving or airplane flying. Thus specific devices are needed for research on specific task; this market niche exists but is characterized by expensive products. This paper presents the development of a complete low cost haptic stick, of its initial characterization and inner loop and impedance control systems design, and finally proposes an evaluation with two test cases: pilot admittance identification with the classical tasks, and an entire haptic experiment. In particular this latter experiment tries to study what happens when a system failure happens in a pilot support system built using a classical embedded controller, compared to a system built following the haptic shared control paradigm.

ARchaeological RObot systems for the World's Seas (ARROWS) EU Project proposes to adapt and develop low-cost Autonomous Underwater Vehicle (AUV) technologies to significantly reduce the cost of archaeological operations, covering the full extent of archaeological campaign. ARROWS methodology is to identify the archaeologists requirements in all phases of the campaign and to propose related technological solutions. Starting from the necessities identified by archaeological project partners in collaboration with the Archaeology Advisory Group, a board composed of European archaeologists from outside WS, the aim is the development of a heterogeneous team of cooperating AUVs capable of comply with a complete archaeological autonomous mission. Three new different AUVs have been designed in the framework of the project according to the archaeologists’ indications: MARTA, characterized by a strong hardware modularity for ease of payload and propulsion systems configuration change; U-CAT, a turtle inspired bio-mimetic robot devoted to shipwreck penetration and A_Size AUV, a vehicle of small dimensions and weight easily deployable even by a single person. These three vehicles will cooperate within the project with AUVs already owned by ARROWS partners exploiting a distributed high-level control software based on the World Model Service (WMS), a storage system for the environment knowledge, updated in real-time through online payload data process, in the form of an ontology. The project includes also the development of a cleaning tool for well-known artifacts maintenance operations. The paper presents the current stage of the project that will lead to overall system final demonstrations, during Summer 2015, in two different scenarios, Sicily (Italy) and Baltic Sea (Estonia).

We present a geomorphological analysis of the recent extensional tectonics of a Quaternary continental basin in the Northern Apennines (Italy). The study area is focused on Upper Tiber Valley (UTV), a basin elongated for 70 km in NNW-SSE direction hosting the Tiber River. The area is characterized by a series of features that make it an excellent case study: (i) homogeneity of lithology (ii) active faults, and (iii) strong morphogenetic activity. In this study, 36 hydrographical basins, tributaries of Tiber River, have been analysed. A preliminary qualitative geomorphological setting was outlined pointing out that the drainage river network shows meaningful evidence of tectonic control, such as abrupt changes in stream directions, knickpoints and steepness anomalies alignments along meaningful length in adjacent basins. Besides, the tectonic control is well marked in base level changes and consequent tectonically induced downcutting. Signs of neotectonics are highlighted by structural landforms too. The entrenchment of alluvial fans, the triangular facets and the fault planes are mapped by field survey and aerial photo interpretation. In addition, a quantitative analysis was also performed. Linear, areal and volumetric indexes related to drainage basins and river networks are taken into account. The geometry of the escarpments delimiting the basin and the landforms detected along the adjacent piedmont are investigated. The ranges of values, according to the existing literature, confirm a condition of wide-ranging morphological disturbance. In the central part of the study area, while the western basins are almost in equilibrium, the eastern ones reveal clear signs of disequilibrium, this is particularly evident along the distal segment of the river network. These data, joined with the characteristics of the escarpment and piedmont junction, confirm that the neotectonic activity, in the centre and in the eastern side of the basin, is the main factor controlling the morphological system.

Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long‐term consequences of genotoxic exposure. Patched1heterozygous mice (Ptc1+/−) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1+/−mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and fate‐restricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long‐term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate‐restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low‐dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation‐stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors. StemCells2013;31:2506–2516

Life expectancy and quality raise have increased the request of better and customized solutions for patients. On the other side, while the health care market is continuously raising, the manufacturing industry, specially the automotive one, is facing a strongly negative trend under production and sales point of view. In this panorama, the development of biomedical devices represents a big chance for both patient's th care and manufacturing industry being an interesting opportunity for investments. In order to design a new product, it is necessary to take into account the market needs and requests, especially when it is high-tech and involves human needs. Unfortunately, it often happens that the languages and research approaches of the parts involved in the market, supply and demand, are different which makes the communication more difficult, especially when Medicine and Engineering are involved. For example, requirements such as biocompatibility, life service or biological integration have to be translated in terms of material, manufacturing process or treatment. In order to correlate performance characteristics and design choice, tools like QFD (Quality Function Deployment) are available. In particular, they use results of market investigations on existing products and market requests to identify the improvement areas, to correlate them with design specifications so outlining the features of new products able to satisfy the market requests.

Lithostratigraphic, magnetostratigraphic and rock-magnetic cyclostratigraphic data were combined to create a high-resolution age model for 342 m of Late Pliocene–Middle Pleistocene marine deposits exposed in the Stirone River, northern Italy. Magnetostratigraphic analysis of 74 oriented samples at 21 stratigraphic horizons recognized five polarity zones between c.3.0 and 1.0 Ma. Unoriented samples were collected every metre between 0 and 311 m and low-field magnetic susceptibility (χ) was measured for cyclostratigraphic analysis. The χdata series was tied to absolute time using the magnetostratigraphy and subjected to multi-taper method spectral analysis. The resultant power spectra revealed significant frequency peaks that are aligned with eccentricity, obliquity and precession Milankovitch orbital cycles. The χdata, correlated to the 41 ka obliquity and the 23 ka/19 ka precession cycles and anchored to a well-established biostratigraphic horizon, were used to create a high-resolution age model for the Stirone section between 2.99 and 1.81 Ma, where stratigraphic positions of magnetic reversals were previously poorly defined. This cyclostratigraphic age model reveals that the length of an important depositional hiatus at the base of the C2An.1n subchron is 200 ka shorter than previously determined. We link the precession-aligned variability in χto global mid-latitude, insolation-induced variability in runoff and ocean circulation.

The present study examined how people's spatial abilities and spatial preferences for representing environmental information influence the ways in which they represent information from spatial descriptions. Spatial individual differences can have a central role in sustaining the mental representation deriving from survey and route descriptions. A group of 48 undergraduates listened to survey and route spatial descriptions and performed a sentence verification task on their content. They were then administered two spatial tasks, the Mental Rotation Test (MRT) and the Minnesota Paper Form Board (MPFB), plus a self-rating scale on sense of direction and spatial representation. The results showed that spatial abilities influenced the recall of survey and route texts differently. The MPFB and the MRT positively predicted the accuracy of answers on the survey text, which was negatively predicted by a preference for a route representation. Preference for a survey representation was positively associated with the accuracy of answers on the route text. Taken together, these results support the existence of a relationship between spatial abilities, spatial styles, and the processing of spatial language that depends on whether a route or a survey perspective is adopted.

A long-held dogma in radiation biology has been that the biological effects of exposure to ionizing radiation occur as a result of damage in directly irradiated cells and that no effect would occur in neighboring unirradiated cells. This paradigm has been frequently challenged by reports of radiation effects in unirradiated or ‘bystander’ cells receiving signals from directly irradiated cells, an issue that may have substantial impact on radiation risk assessment and development of radiation-based therapies. Radiation-induced bystander effects have been shown in single-cell systems in vitro for an array of cancer relevant endpoints, and may trigger damage in more complex 3-D tissue systems. They may be mediated by soluble factors released by irradiated cells into the extracellular environment and/or by the passage of mediator molecules through gap-junction intercellular communication. To date, evidence that radiation-associated bystander or abscopal responses are effectual in vivo has been limited, but new data suggest that they may significantly affect tumor development in susceptible mouse models. Further understanding of how the signal/s is transmitted to unirradiated cells and tissues and how it provokes long-range and significant responses is crucial. By summarizing the existing evidence of radiation induced bystander-like effects in various systems with emphasis on in vivo findings, we will discuss the potential mechanisms involved in these observations and how effects in bystander cells contribute to uncertainties in assessing cancer risks associated with radiation exposure.

To compare the outcomes of two different surgical treatments for the management of isolated closed Mason Type 2 radial head fractures.

A conference proceeding is presented, introducing the round table discussion "Assetto istituzionale e organizzazione dell'Università italiana: le questioni aperte," which was part of the conference "L'Idea Di Università," which was held in the Istituto Paolo VI Auditorium Vittorio Montini in Concesio in Brescia, Italy from March 25 to 26, 2011. Topics discussed include institutional characteristics of Italian universities, reforms as of 2010, and quality and efficiency in university management.

Giant cell tumor of bone can be locally aggressive and occasionally can metastasize in the lungs. To identify new markers predictive of aggressive behavior, we analyzed five patients who developed lung metastasis and five who remained disease free for a minimum of 5 years. Using two-dimensional electrophoresis, we detected 28 differentially expressed spots. Fourteen spots were identified using mass spectrometry, including seven up-regulated and seven down-regulated in metastatic samples and classified according to functional categories. We then selected five proteins involved in cell cycle or apoptosis. Thioredoxin peroxidase, allograft inflammatory factor 1, and ubiquitin E2N had more than threefold up-regulation; glutathione peroxidase 1 had 1.9-fold up-regulation; and heat shock protein 27 showed down-regulation in metastatic samples with a very low Pvalue. After validation and analysis of protein levels, evaluation of clinical impact was assessed in a much wider cohort of primary archival specimens. Immunodetection showed a higher frequency of thioredoxin peroxidase, allograft inflammatory factor 1, ubiquitin E2N, and glutathione peroxidase 1 overexpression in primary tumors that developed into lung metastases or that locally relapsed than in the disease-free group, with variable stain intensity and distribution. Kaplan-Meier analysis showed that high expression of glutathione peroxidase 1 was strongly related to local recurrence and metastasis, suggesting that its up-regulation may identify a subset of high-risk patients with giant cell tumor prone to receive diverse clinical management.

Background: Escitalopram has never been demonstrated to be useful in the treatment of chronic low back pain (CLBP), while duloxetine has demonstrated analgesic effect in chronic pain states. The aim of this trial was to examine the efficacy of escitalopram for the treatment of CLBP compared with duloxetine. Methods: A total of 85 adult patients with non-radicular CLBP entered a 13-week randomized study comparing escitalopram 20 mg with duloxetine 60 mg once daily. The primary measure was comparison of the two drugs on reduction in weekly mean 24-h average pain. Secondary measures included Clinical Global Impressions of Severity (CGI-S) and the 36-item Short-Form Health Survey (SF-36). Results: Eighty patients (n 39 escitalopram, n 41 duloxetine) completed the study. No significant differences existed between escitalopram and duloxetine on reduction in weekly mean 24-h average pain at end point. Both escitalopram and duloxetine demonstrated significant improvement on CGI-S and SF-36. Conclusions: Escitalopram and duloxetine demonstrated efficacy and safety in the management of CLBP, with no significant differences. Results of this study should be replicated in a larger sample of patients.

Background: Hedgehog signaling is essential for the development of most metazoans. In recent years, evidence has accumulated showing that many human tumors aberrantly re-activate this developmental signaling pathway and that interfering with it may provide a new strategy for the development of novel anti-cancer therapeutics. Smoothened is a G-protein coupled receptor-like protein that is essentially involved in hedgehog signal transduction and small molecule antagonists of Smoothened have started to show antitumor activity in preclinical models and in clinical trials. Objective: We critically review the role of hedgehog signaling in normal development and in human malignancies, the available drug discovery tools and the classes of small molecule inhibitors that are in development. We further aim to address the potential impact that pathway antagonists may have on the treatment options of cancer patients. Methods: Literature, patents and clinical trial results from the past 5 years were analyzed. Conclusions: 1) A large body of evidence suggests a frequent reactivation of hedgehog signaling in human cancer. 2) Smoothened is an attractive, highly druggable target with extensive preclinical and initial clinical validation in basal cell carcinoma. Several promising novel classes of Smoothened antagonists have been discovered and are being developed as anticancer agents. 3) Our knowledge of the biology of hedgehog signaling in cancer is still very incomplete and significant efforts will be required to understand how to use the emerging novel agents in the clinic.

Abstract Polyethylene (PE) wear is a focal issue in joint replacement, so it is essential to understand how it takes place in vivo. PE wear is a multifactorial process with a complex interaction of variables related to the materials used, the mechanical conditions, operative procedures for implantation, activity of the patient and use of prosthesis. We retrieved 65 PE inserts with the respective femoral and tibial components (50 inserts of total knee prostheses and 15 monocompartmental prostheses) from first revision surgeries. The average age of the patients was 68.3 years; the average time to revision was 41.5 months. Macroscopic observation considered the grade, topography and type of wear. Degradation was also studied with scanning electron microscopy. No direct relationship was found between the level of wear and the survival of total or monocompartmental knee prostheses. The duration of 11 (22%) total prosthetic inserts with grade 2 wear was 42.6 months vs. 51.5 months of 17 (34%) total inserts with grade 1 wear. However, study of the relationship between wear grade and wear topography in total inserts suggested that there was a significant connection. In fact, the 22 (44%) prostheses with central and symmetrical wear never showed wear greater than grade 1. Instead, of the remaining 28 prostheses (56%) without central and symmetric wear, only 3 had grade 0 wear. Finally, considering the relationship between wear grade and type of wear, all 18 inserts (27.7%) with grade 2 or 3 wear had 100% delamination. In conclusion, this study suggests that the correct positioning of the prosthetic components, besides its quality, is an important cause of polyethylene wear.

The purpose of the present research is to investigate whether different components of working memory (WM) are involved in processing spatial and nonspatial texts. The interference effects of two concurrent tasks on comprehension and recall of two kinds of text were investigated in two experiments. Each participant listened to a spatial and a nonspatial text, with one of two concurrent tasks: articulatory suppression or spatial tapping. The dependent variables in Experiment 1 were accuracy of recall and verification of information inferred from the texts. In Experiment 2 response times in the verification task were also considered. Results support the hypothesis that verbal and spatial components of working memory are differentially involved in the comprehension and memory of spatial and nonspatial texts, with a selective interference effect of the spatial concurrent task on the spatial text and an interference effect of the verbal concurrent task on both the spatial and nonspatial texts. These effects emerged for recall, sentence verification, and response times. Our findings confirm previous results showing that the verbal component of working memory is involved in the process of text comprehension and memory. In addition, they show that visuospatial working memory is involved, in so far as the text conveys visuospatial information.

The two-stage skin carcinogenesis model of initiation and promotion in Carcinogenesis-susceptible (Car-S) mice has been used to investigate the pathways of promotional activity of 12- O -tetradecanoylphorbol-13-acetate (TPA), a phorbol ester tumor promoter, and benzoyl peroxide (BzPo), a free radical-generating compound. To test whether distinct populations of 9,10-dimethyl-1,2-benzanthracene (DMBA)-initiated epidermal keratinocytes are responsive to the two promoters, tandem experiments were performed. DMBA-initiated Car-S mice were promoted twice weekly with maximal promoting doses of TPA or BzPo. When the number of papillomas/mouse reached a plateau, promotion in the TPA and BzPo groups was switched to BzPo or TPA, respectively, until achievement of a new plateau. Mice promoted with BzPo developed 11.0±1.3 papillomas/mouse and subsequent TPA promotion induced 13.8 additional papillomas, for a total of 24.8±2.1 papillomas/mouse. TPA-promoted mice developed 23.3±1.1 papillomas/mouse, and subsequent BzPo promotion for 91 days did not promote additional papillomas. Our results show a less than additive tumor response after sequential promotion with BzPo and TPA, or vice versa, indicating that the pathways of promotional activity of TPA and BzPo are interacting. While the final papilloma yield was similar at the end of the two tandem promotion experiments independently of promoter sequence, the percentage of mice developing carcinomas was significantly higher in mice that were promoted with BzPo in the first stage. No significant differences in the frequency and type of c-Ha- ras mutations were observed in TPA- and BzPo-promoted tumors, suggesting that promotion of DMBA-initiated cells by BzPo requires introduction of additional molecular alterations compared to TPA.

Purpose To describe an unusual case of bilateral progressive facial hemiatrophy (Parry-Romberg syndrome (PRS)) associated with retinal vasculitis.Methods In a 37-year-old man with bilateral PRS, retinal vasculitis of the right eye was evident on fundus examination and fluorescein angiography. Right temporalis muscle biopsy and needle electromyography of the masseter muscles were performed. The patient underwent immunosuppressive therapy and retinal laser photocoagulation.Results Biopsy specimens showed large fibrosis with focal lymphohistiocytic infiltration of the muscle fibers. Electromyographic findings are consistent with a primary muscle disease. Visual acuity improved from 20/25 to 20/20 in the right eye with a follow-up of one year.Conclusions The evidence of retinal vasculitis and the histologic findings of facial changes observed in this PRS case could support the pathogenetic model of a chronic inflammatory process as a plausible explanation for progressive facial hemiatrophy.

Cardiopulmonary bypass with heparin-bonded circuits reduces systemic heparinization which is associated to a better clinical outcome in cardiac operations. In the present study, a novel biocompatible treatment, based on a phosphorylcholine coating without heparin, has been used to reduce systemic heparinization during cardiopulmonary bypass. Sixty patients underwent coronary revascularization with a fully phosphorylcholine-coated circuit. The circuit was entirely closed; suctions from the field were separated during the cardiopulmonary bypass time. A low systemic heparinization protocol based on half the loading dose of heparin (150 lU/kg) and a target activated clotting time of 320 seconds was applied. No thrombus formation inside the extracorporeal circulation circuit occurred; in-hospital mortality was absent. One patient (1.6%) had a postoperative myocardial infarction and 2 (3.3%) were surgically revised due to bleeding. Homologous blood transfusion rate was 11.6%, postoperative bleeding was 310 ± 136 ml. If compared to patients treated with heparin-coated circuits and low systemic heparinization, these patients have better platelet count preservation and lower postoperative bleeding. The low thrombogenicity of phosphorylcholine-treated surfaces, despite the absence of surface-immobilized heparin, allows a safe reduction of systemic heparinization in the setting of an ECMO-like intraoperative cardiopulmonary - bypass. This intraoperative ECMO approach offers promising results in terms of clinical outcome after coronary revascularization operations.

When an adult skeletal muscle is denervated, its end-plates degenerate and their acethylcholinesterase (AChE) activity gradually decreases. However, if the proximal segment of the nerve is sutured to the distal segment, or if the nerve is implanted in a previous denerved muscle the axons regenerate and reconstitute new end-plates over a variable period. This period depends on the time passed between the nerve cutting and the reimplantation suggesting that the degenerative processes are closely correlated to regeneration. It has been shown that cyclosporine-A (CsA) is useful in nerve regeneration but their role in nerve degeneration is not well understand. We evaluated, using AChE histochemistry, the effects of CsA, on the degeneration of the end-plates in an experimental model of gastrocnemius muscle denervation in the rat. CsA at a dose of 15 mg/kg/day did not cause any quantitative or qualitative alterations in the end-plates on normal rat muscles. Moreover, our findings showed that CsA reduced the end-plate degeneration and loss in the denerved rat muscles.

The Car-R outbred mouse line was phenotypically selected for high resistance to two-stage skin tumorigenesis. In the present study we tested the hypothesis that a subset of genetic loci responsible for resistance to skin tumorigenesis of Car-R mice might also inhibit lung tumorigenesis. Skin and lung tumorigenesis were induced in groups of Car-R, SWR/J, (SWR/JxCar-R)F1 and SWR/Jx(SWR/JxCar-R) backcross mice by i.p. urethane initiation and skin TPA promotion. Car-R mice showed a much lower susceptibility to both skin and lung tumorigenesis as compared to SWR/J mice, which are susceptible to both lung and skin tumorigenesis. The Car-R-inherited genome significantly inhibited both skin and lung cancer development in the F1 progeny of Car-R with SWR/J mice. In the backcross population, skin and lung tumor phenotypes showed a statistically significant correlation, indicating that a subset of the cancer resistance alleles, which segregated in the Car-R line during selection for resistance to skin carcinogenesis, provides resistance to both skin and lung tumorigenesis. © 2001 Wiley-Liss, Inc.

ACE-inhibitors (ACE-I) represent effective drugs more and more widely used in acute myocardial infarction (AMI) patients, in post AMI patients and mainly, today, in CHF patients.

The INK4A tumor suppressor gene plays a crucial role in the regulation of the G1 cell cycle phase. It encodes two transcripts, p16 and p14 alternate reading frame (ARF), involved in retinoblastoma protein (pRb)- and p53- cell growth control pathways, respectively. To define the role of gene status and molecule expression involved in the INK4A regulatory system, immunohistochemistry, immunoblotting, and polymerase chain reaction (PCR) analysis were performed on 35 primary high grade osteosarcomas (OS). Although p16 and p14ARF proteins were found negative or weakly detectable in 60% and 57% of the cases respectively, INK4A gene analysis of exons 1α, 1β and 2 did not reveal any deletion or mutation. However, methylation status of the 5'CpG promoter region, assessed by methylation-specific PCR, was found in 12 out of 21 OSs with negative or weak p16 expression. A statistical analysis based on pRb/p16 and p53/p14ARF staining status showed that pRb and p16 co-expression was inversely correlated to tumor relapse and was a marker for a more favorable prognosis. A statistically significant inverse correlation was found between wt-p53 and p14ARF expression. In the group of wt-p53 tumors, the loss of p14ARF was associated with a decreased expression of p21 protein, suggesting a down-regulation of the transcriptional activity of p53. The current results suggest that, in OS, the altered expression of INK4A products plays a primary role in the deregulation of both pRb and p53 cell growth control pathways, contributing to tumor pathogenesis and development. Cancer 2001;92:3062–7. © 2001 American Cancer Society.

Abstract: Numerous systems of osteosynthesis of olecranon fractures are avaible. The numero-ulnar articulation badly bears the smallest incongruence and easily faces rigidity. Therefore the aim of therapy is the anatomical and permanent reconstruction of the articular surface of the olecranon, in order to mobilize the elbow as soon as possible. We analyzed 85 olecranon fractures, classified according to Merle d'Aubign� and treated with two different surgical techniques (intramedullart screw and AO tension band wiring technique). The results were compared at an average follow-up of 88 months. Excellent clinical results were obtained in 74,12%, good in 29.00%, sufficient 3,53%, insufficient in 2,35% of patients, with a mean of recovery in 2 months and only 2 cases of pseudoarthrosis (with dynamic procedure). Objective results were similar for two techniques adopted, whereas the subjective results in patients with screw. The screw is more suitable in medio-olecranic and basis-olecranic fractures, while the dynamic procedure gives better results in fractures of the apex of olecranon and comminute fracture. Tolerance of the intramedullary screw has generally proved to be better (65% of cases), while the dynamic assembling has been removed in most cases after fracture consolidation. Periarticular calcifications correlated with the type of fracture (e. g. comminuted, associated) rather than with the means of synthesis employed.

This study investigated differences between individuals with survey and landmark-centred spatial representations in different visuo-spatial tasks and in two way-finding tasks. The Mental Rotation Test (MRT; Vanderberg & Kuse, 1978), and the Minnesota Paper Form Board Test (MPFB; Likert & Quasha, 1941) were administered to two groups of high-survey and landmark-centred undergraduate students. The groups also performed two way-finding tasks where they were required to study the route they were going to take, in one case with a map and in the other with a verbal description. Differences between the two groups emerged; high-survey individuals performed the MRT better than the landmark-centred ones. In the way-finding task an interaction, instruction by group, was found, supporting the idea that the two groups are influenced differently by the format (map or verbal description) of instructions. The landmark-centred group made fewer errors than the high-survey group with the verbal descriptions.

The exponential growth of resources on the web, and the wide deployment of devices for multimodal access to the Internet, lead to new problems in information management. In this context, and as part of the European project Vision, we have built an interactive telematic handbook of the culture and the territory of Sardinia. A team of cultural experts browsed the web to get a large collection of Internet resources.The system built for the management of this data uses emerging Internet technologies such as the XML language suite and its applications. The result obtained is a multimodal service, called Eiha?!?, available through PCs and mobile phones.

We report on bidirectional selective breeding, initiated from a genetically defined foundation population and carried out to selection limit, for producing lines of mice endowed with maximal resistance (Car-R) or maximal susceptibility (Car-S) to 2-stage skin tumorigenesis. The initial population resulted from a balanced intercrossing of 8 inbred strains of mice. The tumors, induced by a single application of DMBA (initiation) and twice weekly applications of TPA (promotion), were benign papillomas; their number at the end of the promotion period was the phenotype chosen for assortative mating. Afterward, the majority of them regressed while others progressed to malignant carcinomas. The Car-R line was selected through a strong challenge, while the Car-S line selection was based on responses to decreasing concentrations of DMBA and TPA. The selection limit was reached after 14 or 15 generations showing progressive interline divergence, which strongly suggests the interaction of several quantitative trait loci (QTL). The phenotypic difference was extremely large: the tumor response was 73 times higher in Car-S than in Car-R mice, though the applied concentrations of DMBA and TPA were 100 and 40 times lower, respectively. The mean heritability realized during the selective breeding was 0.20 in Car-R and 0.49 in Car-S. Our results are compatible with a minimal QTL estimate of 8 in the Car-R line and of 9 or 10 in the Car-S line. The Car-S line is also much more susceptible to carcinoma induction. An association of coat color with tumorigenesis was observed in interline F2 segregants. The Car-R and Car-S lines, obtained through a long-lasting breeding program, are a unique model for identifying the QTL involved in chemical tumorigenesis and will be provided to interested investigators. Int. J. Cancer 88:424–431, 2000. © 2000 Wiley-Liss, Inc.