We present an analytic evaluation of the runtime behavior of the C4.5 algorithm which highlights some efficiency improvements. Based on the analytic evaluation, we have implemented a more efficient ...version of the algorithm, called EC4.5. It improves on C4.5 by adopting the best among three strategies for computing the information gain of continuous attributes. All the strategies adopt a binary search of the threshold in the whole training set starting from the local threshold computed at a node. The first strategy computes the local threshold using the algorithm of C4.5, which, in particular, sorts cases by means of the quicksort method. The second strategy also uses the algorithm of C4.5, but adopts a counting sort method. The third strategy calculates the local threshold using a main-memory version of the RainForest algorithm, which does not need sorting. Our implementation computes the same decision trees as C4.5 with a performance gain of up to five times.
Abstract Objective Assessing the frequency of Wearing-Off (WO) in Parkinson's disease (PD) patients, and its impact on Quality of Life (QoL). Methods Consecutive ambulatory patients, who were on ...dopaminergic treatment for ≥1 year, were included in this multicentre, observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as using the validated Italian version of a patient self-rated 19-question Wearing-Off Questionnaire (WOQ-19); WO was defined for scores ≥ 2. QoL was evaluated by the 8-item Parkinson's Disease Questionnaire (PDQ-8). Results 617 subjects were included, with a mean anti-Parkinson treatment duration of 6.6 ± 4.6 years, 87.2% were on levodopa treatment. Neurologists identified presence of WO in 351 subjects (56.9%), whereas 415 subjects (67.3%) were identified by the self-administered WOQ-19. In patients with a <2.5 years disease duration, WO was diagnosed in 12 subjects (21.8%) by neurologists and in 23 subjects (41.8%) by the WOQ-19. The most frequent WO symptoms, as identified by WOQ-19, were “slowness of movements” (55.8%) and “reduced dexterity” (48.8%). Younger age, female gender, Unified Parkinson's Disease Rating Scale (UPDRS) part II score and duration of anti-Parkinson treatment were found significantly associated with WO. The number of motor ( p < 0.0001) and non-motor ( p < 0.0001) WO symptoms correlated with PDQ-8 total score. Conclusions WO is common already at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of WO symptoms, both motor and non motor, increases along with disease duration and has a negative impact on patients QoL.
Abstract Freezing of Gait (FOG) is a common and disabling symptom in patients with Parkinson disease (PD). The relationship between FOG and dopaminergic medication is complex. The aim of the present ...study was to estimate the prevalence of self-reported FOG, its associated clinical features, and its relationship with wearing-off in a wide PD population. This is an observational multicenter study of 634 consecutive non-demented PD patients. Patients were identified either as freezers or non-freezers based on item-3 of the Freezing of Gait-Questionnaire. FOG was then classified as on, off and onoff freezing based on its relationship with wearing-off. Patients were assessed with Unified Parkinson's Disease Rating Scale, Hoehn and Yahr scale, 8-item Parkinson's disease Questionnaire, Mini-Mental State Examination. Data from 593 patients were analyzed, 325 (54.3%) were freezers of whom 200 (61.6%) experienced FOG only during off state (off-freezers), 6 (1.8%) only during on state and 119 (36.6%) either in on and off states or independently of dopaminergic response-related symptoms (onoff-freezers). Overall, freezers vs non-freezers had longer disease duration, more advanced disease and greater disability. Moreover, freezers more frequently reported wearing-off and experienced worse quality of life. Onoff-freezers vs off-freezers were older, more severely disabled, less likely to experience wearing-off, treated with lower levodopa equivalent daily dose and with poorer cognitive performance. Self-reported FOG is mainly recognizable in advanced PD and is associated with more disability and worse quality of life. Onoff-FOG may represent the result of under-treatment or rather interpretable as a distinct clinical entity.
Background:
Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease.
Objectives:
The Magnetic Imaging in MS ...(MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS.
Methods:
Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups).
Results:
In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability.
Conclusions:
Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.
Bortezomib (bort) has improved overall survival in patients with multiple myeloma (MM), but the majority of them develop drug resistance. In this study, we demonstrate that bone marrow (BM) ...fibroblasts (cancer-associated fibroblasts; CAFs) from bort-resistant patients are insensitive to bort and protect the RPMI8226 and patients' plasma cells against bort-induced apoptosis. Bort triggers CAFs to produce high levels of interleukin (IL)-6, IL-8, insulin-like growth factor (IGF)-1 and transforming growth factor (TGF) β. Proteomic studies on CAFs demonstrate that bort resistance parallels activation of oxidative stress and pro-survival autophagy. Indeed, bort induces reactive oxygen species in bort-resistant CAFs and activates autophagy by increasing light chain 3 protein (LC3)-II and inhibiting p62 and phospho-mammalian target of rapamycin. The small-interfering RNA knockdown of Atg7, and treatment with 3-methyladenine, restores bort sensitivity in bort-resistant CAFs and produces cytotoxicity in plasma cells co-cultured with CAFs. In the syngeneic 5T33 MM model, bort-treatment induces the expansion of LC3-II(+) CAFs. TGFβ mediates bort-induced autophagy, and its blockade by LY2109761, a selective TβRI/II inhibitor, reduces the expression of p-Smad2/3 and LC3-II and induces apoptosis in bort-resistant CAFs. A combination of bort and LY2109761 synergistically induces apoptosis of RPMI8226 co-cultured with bort-resistant CAFs. These data define a key role for CAFs in bort resistance of plasma cells and provide the basis for a novel targeted therapeutic approach.
The role of cancer-associated fibroblasts (CAFs) has not been previously studied in multiple myeloma (MM). Here, cytofluorimetric analysis revealed higher proportions of bone marrow (BM) CAFs in ...patients with active MM (both at diagnosis and relapse) compared with patients in remission or those with monoclonal gammopathy of undetermined significance or deficiency anemia (controls). CAFs from MM patients produced increased levels of transforming growth factor-β, interleukin-6, stromal cell-derived factor-1α, insulin-like growth factor-1, vascular endothelial growth factor and fibroblast growth factor-2 and displayed an activated and heterogeneous phenotype, which supported their origin from resident fibroblasts, endothelial cells and hematopoietic stem and progenitor cells via the endothelial-mesenchymal transition as well as mesenchymal stem cells via the mesenchymal transition, as both of these processes are induced by MM cells and CAFs. Active MM CAFs fostered chemotaxis, adhesion, proliferation and apoptosis resistance in MM cells through cytokine signals and cell-to-cell contact, which were inhibited by blocking CXCR4, several integrins and fibronectin. MM cells also induced the CAFs proliferation. In syngeneic 5T33MM and xenograft mouse models, MM cells induced the expansion of CAFs, which, in turn, promoted MM initiation and progression as well as angiogenesis. In BM biopsies from patients and mice, nests of CAFs were found in close contact with MM cells, suggesting a supportive niche. Therefore, the targeting of CAFs in MM patients may be envisaged as a novel therapeutic strategy.
Enzymology of NAD+ homeostasis in man Magni, G; Amici, A; Emanuelli, M ...
Cellular and molecular life sciences : CMLS
61, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This review describes the enzymes involved in human pyridine nucleotide metabolism starting with a detailed consideration of their major kinetic, molecular and structural properties. The presentation ...encompasses all the reactions starting from the de novo pyridine ring formation and leading to nicotinamide adenine dinucleotide (NAD(+)) synthesis and utilization. The regulation of NAD(+) homeostasis with respect to the physiological role played by the enzymes both utilizing NAD(+) through the nonredox NAD(+)-dependent reactions and catalyzing the recycling of the common product, nicotinamide, is discussed. The salient features of other enzymes such as NAD(+) pyrophosphatase, nicotinamide mononucleotide 5'-nucleotidase, nicotinamide riboside kinase and nicotinamide riboside phosphorylase, described under 'miscellaneous', are likewise presented.
Parkinson’s disease (PD) is a neurodegenerative disorder which leads to severe movement impairment; however, Parkinsonian patients frequently suffer from gastrointestinal (GI) problems which at ...present are poorly understood, scarcely investigated, and lack an effective cure. Traditionally, PD is attributed to the loss of mesencephalic dopamine‐containing neurons; nonetheless, additional nuclei, such as the dorsal motor nucleus of the vagus nerve and specific central noradrenergic nuclei, are now identified as targets of PD. While the effects of PD on the somatic motor systems are well characterized, the influence on the digestive system still needs to be clarified. Recent findings demonstrate the occurrence of pathological alterations within peripheral neuronal networks in the GI tract of Parkinsonian patients. However, it remains unclear whether a real cell loss occurs, and whether this happens specifically for a subclass of autonomic neurons or if it reflects the sole loss of autonomic nerves. This review summarizes the neurochemical and morphological changes which might be responsible for impaired GI motility. Moreover, we focus on the experimental models to reproduce the altered digestive system of Parkinsonian patients since an experimental model able to mimic such features of PD is required. In the last part of the manuscript, we suggest potential therapeutic targets.
Spatial heterogeneity in soil properties has an impact on crop response. There is a growing demand for rapid and non-invasive acquisition of fine-scale information on soil and plant variation for ...site-specific management. Proximal sensing (Electromagnetic Induction (EMI), Ground Penetrating Radar (GPR), hyperspectral spectroscopy (HS)) and remote sensing (RS) can complement direct sampling. However, sensor data fusion techniques, jointly analysing data from different sources, are still being developed.
The objective of this work was to define a multivariate and multi-sensor approach by combining EMI, GPR, RS and HS data, without any previous weighing, in order to differentiate an 1.5-ha arable field into homogenous zones.
The multi-sensor data were split into four groups: 1) bulk electrical conductivity (EC) from EMI data, 2) amplitude of GPR signal data, 3) the first principal components relating to five bands (green, yellow, red, rededge, near-infrared (NIR) PCs) of hyperspectral reflectance data and 4) the vegetation indices (NDVI, NDRE and NIR/Green) calculated from the remote sensing image. The data of each group were separately analysed and interpolated at the nodes of a same grid by using cokriging or kriging. To obtain spatially contiguous clusters, a combined approach was used, based on multivariate geostatistics and a non‐parametric density function algorithm of clustering, applied to the overall multi-sensor data set of the estimates.
The full approach allowed to identify three homogenous areas. In particular cluster 1, in the NW part of the field, with the lowest values of bulk electrical conductivity and GPR amplitude, and the highest red PC values. The other two clusters were delineated in the SE part of the field, with the highest values of green, yellow, red edge and NIR PCs for cluster 2, and the highest values of bulk electrical conductivity and vegetation indices for cluster 3. The delineation might be related to the intrinsic spatial variability of soil and the health status of plants and be used to produce a prescription map for site-specific management.
► Proximal and remote sensors integrated to delineate homogeneous areas. ► Multi-sensor data integrated using multivariate geostatistics and clustering. ► Clusters reflect intrinsic variability of soil and the health status of plants. ► Homogeneous areas necessary for site-specific management.
New oral drugs for multiple sclerosis Gasperini, Claudio; Ruggieri, S.
Neurological sciences,
10/2009, Letnik:
30, Številka:
Suppl 2
Journal Article
Recenzirano
Disease-modifying treatments are now available in relapsing–remitting and secondary progressive multiple sclerosis (MS), and their beneficial effects have been shown in several clinical studies. ...However, as these treatments are only partially effective in halting the MS disease process and are frequently associated with side effects and suboptimal patient adherence, new oral therapeutic approaches are warranted. This review focuses on advances in current and novel oral treatment approaches for MS. Several pivotal reports have provided promising results for new oral therapies evaluating the safety and efficacy of new agents including fingolimod, fumaric acid, cladribine, teriflunomide and laquinimod.
PDF
