Renal tubular damage and worsening renal function in chronic heart failure: Clinical determinants and relation to prognosis (Bio-SHiFT study)

Background: It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes. Hypothesis: Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants. Methods: During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-β-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation. Results: Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m2 eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m2 eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]). Conclusion: Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive

Allergische bronchopulmonale aspergillose bij astma en cystische fibrose

Three children developed allergic bronchopulmonary aspergillosis (ABPA) as a complication of either asthma or cystic fibrosis (CF). The first patient was a 14-year-old boy with CF who presented with an episode of haemoptysis and a decrease in lung function. He was initially treated with intravenous antibiotics but there was no improvement of his lung function. After starting prednisone-itraconazole his condition improved substantially. The second patient was a 16-year-old girl with CF complicated by ABPA. She was treated for 2 years with prednisone-itraconazole. Although the symptoms worsened when the prednisone dosage was gradually reduced, her growth retardation and increased weight decided us to stop prednisone treatment. Two years later, her CF was once again complicated by ABPA. The third patientwas a 16-year-old boy with asthma who had initially been treated for an asthma exacerbation. In retrospect, the cause of his pulmonary exacerbation was probably an ABPA episode. These cases illustrate how important but also how difficult the early diagnosis of ABPA is, and the dilemmas faced in treatment to prevent the fibrotic end stage

Fattori di controllo della respirazione del suolo di origine radicale e microbica in ecosistemi prativi

Soil historically has been a major source of atmospheric enrichment of CO2 and in the same time is one of the biggest storing reservoirs of carbon on the global scale. In fact, soils hold three times as much carbon as the terrestrial biosphere and about twice as much as the atmosphere and exert a large influence on the cycling of carbon between different pools. Soil respiration, which is the flux of CO2 from soils to the atmosphere, is thus an important component of the ecosystem C budgets and is a major source of CO2 released by terrestrial ecosystems. Soil respiration is the result of the production of CO2 from the biological activity of roots and associated microorganisms and the activity of heterotrophic bacteria and fungi living on litter and in the root-free soil. Different sources of soil CO2 efflux are known to experience high spatial and temporal variation with different controlling factors involved on different time-scales. However, up to now not so many studies have deal with the interannual variability of soil respiration and its components and only few of them were performed in grassland ecosystems despite the fact that it is one of the world’s most widespread vegetation types which comprises 32% of the earth’s area of natural vegetation. This study aimed to advance the understanding of the processes and factors controlling the behaviour of different soil respiration sources in grassland ecosystems. It provides the analysis of the response of soil CO2 efflux and its components: root- and microbial-derived respiration to different biotic and abiotic factors as well as to widely diffused management activities over a period of three years in a mediterranean grassland site and integrates also different laboratory and in situ methodological approaches for deeper studying of the contribution of various respiration sources to total CO2 efflux from soil and the speed of C cycling within the plant community. Soil respiration was partitioned in the field using micro (1mm) and macro (1 cm) pore meshes. Soil respiration obtained from the cores with different pore-sized meshes and from the control undisturbed soil were used to calculate values of root-derived and microbial-derived respiration sources. These fluxes were then related to canopy photosynthetic activity, soil temperature, soil moisture and some soil biochemical parameters. Methodological approach based on pulse labeling of plants in artificial 13CO2 or 14CO2 atmosphere was used to found out the speed of the cycling of C in grassland ecosystem (in situ) as well as to study the effect of different plant species, plant growing stages, and different nutrient supply on the magnitude of root respiration and on the speed of translocation and respiration of recently assimilated C through roots (on a single species, in laboratory). The obtained results showed an importance of C assimilate supply in the determination of the variability of root component of soil respiration. It was closely related to gross primary production with a time lag of circa 20h for time scales from daily to annual. Soil temperature which often masks the direct relationship between root respiration and photosynthetic C supply failed to explain diurnal and seasonal changes in root-derived respiration. Laboratory experiments with a single plant species have shown however that the observed time lag is not stable during the plant ontogenesis, and vary depending on the plant growing stage. The same photosynthetic activity could also result in different magnitude of root respiration, depending on the type of nutrient supply (ex: N in form of NH+ 4 or NO-3). All these finings suggest that root respiration is a complex process, tightly coupled to plant canopy activity and could not be explained simply by changes in soil temperature and moisture. Further studies are needed to verify the bonds between aboveground and belowground processes for different species and vegetation types, as well as for various plant growing stages. Soil temperature and soil water content exerted a significant effect on microbial component of soil respiration. Being a larger part of total CO2 efflux from soil at Amplero (» 70%), these factors influenced also total soil respiration dynamic on different time scales. Introduction of a management regime have modified however the activity of microbial community by an increase of the quantity of easily available C substrates from the rhizodeposition process, resulting in a general suppression of microbial enzymatic activity and further decrease C mineralization rates. Combination of laboratory studies and in situ measurements is necessary for understanding of the effect of changing substrate quality, nutrient and moisture conditions on microbial activity and its C use efficiency.Il suolo è stato storicamente la fonte principale di emissioni di CO2 nell’atmosfera e al contempo la maggiore riserva di carbonio a scala globale. Infatti i suoli stoccano tre volte la quantità di carbonio presente nella biosfera terrestre e circa il doppio dell’atmosfera esercitando un’importante influenza sul ciclo del carbonio globale. La respirazione del suolo che rappresenta il flusso di CO2 dal suolo verso l’atmosfera è dunque una componente rilevante del bilancio del carbonio a scala eco sistemica ed è la principale fonte di anidride carbonica emessa dagli ecosistemi terrestri. La respirazione del suolo è il risultato della produzione di CO2 dall’attività biologica delle radici e dei microrganismi ad esse associati da una parte e dall’attività eterotrofa di batteri e funghi presenti nella lettiera e nel suolo dall’altra. Le differenti fonti di CO2 dal suolo sono caratterizzate da un’ampia variabilità temporale e spaziale e sono controllate da diversi fattori che intervengono in relazione alle diverse scale temporali considerate. Tuttavia ad oggi non molti studi si sono occupati della variabilità interannuale della respirazione del suolo e delle sue componenti, inoltre solo alcuni di questi si sono occupati di ecosistemi di prateria nonostante questi comprendano il 32% della superficie coperta da vegetazione sulla Terra. L’obiettivo del presente studio è il miglioramento della comprensione dei processi e dei fattori di controllo delle diverse origini della respirazione del suolo in ecosistemi prativi. Si analizza la risposta del flusso di CO2 dal suolo e delle sue componenti: della respirazione microbica e radicale rispetto ai principali fattori biotici ed abiotici così come all’effetto della gestione estensiva del pascolo osservati durante un periodi di 3 anni in una prateria mediterranea. L’approccio metodologico include l’integrazione di misure in situ con analisi in laboratorio per un’analisi approfondita del contributo delle diverse fonti della flusso totale di CO2 dal suolo e dei tempi di turn-over del carboni all’interno della comunità vegetale. La respirazione del suolo è stata ripartita nelle distinte componenti utilizzando speciali reti con pori fini dal diametro di 1mm e 1 cm definiti rispettivamente “micro” e macro” che permettono di escludere selettivamente il contributo radicale alla respirazione del suolo misurata in appositi plot. I flussi delle componenti radicali e microbiche della respirazione del suolo vengono quindi ricavati per differenza con le misure effettuate nei plot manipolati ed in quelli di controllo. I flussi così ricavati vengono messi in relazione all’attività foto sintetica delle piante, alla temperatura ed umidità del suolo e a diversi parametri biochimici del suolo. La tecnica del “pulse labeling” delle piante in atmosfera arricchita con 13CO2 or 14CO2 è stata impiegata per investigare la velocità di turn-over del carbonio assimilato dalla vegetazione (in situ) e per studiare l’effetto della diversità specifica, della fenologia, della nutrizione minerale sull’intensità del flusso respiratorio radicale e sulla velocità di translocazione e respirazione attraverso le radici del carbonio assimilato ( studio di laboratorio, su di una specie). I risultati ottenuti mostrano l’importanza dell’assimilazione del carbonio come rispetto alla variabilità della componente di respirazione radicale che è risultata correlata alla produzione lorda eco sistemica da base giornaliera fino ad annuale e che ha presentato un time lag di circa 20 ore. La respirazione del suolo che spesso maschera la relazione diretta tra respirazione radicale e d assimilazione fotosintetica del carbonio non è in grado di spiegare le variazioni giornaliere e stagionali della respirazione radicale. La sperimentazione in laboratorio su di una sola specie ha comunque che il time lag non è costante durante l’ontogenesi della pianta, ma varia in funzione dello stadio fenologico. La stessa attività fotosintetica è stata osservata anche in associazione a livelli di respirazione radicale diversi, a seconda del del tipo di nutrizione minerale (es.: N in forma di NH+ 4 o NO- 3). Questi risultati suggeriscono che la respirazione radicale è un processo complesso, strettamente legato all’attività fotosintetica delle piante e che non può essere spiegato esclusivamente da cambiamenti della temperatura e dell’umidità del suolo. Ulteriori studi sono necessari per verificare le relazioni tra processi epigei ed ipogei per diversi tipi di vegetazione, di specie vegetali per diversi stadi di sviluppo. La temperatura ed il contenuto idrico del suolo esercitano una significativa influenza sulla componente microbica della respirazione del suolo, che per il sito di Amplero rappresenta circa il 70% essendo quindi prevalente. Conseguentemente temperatura ed umidità del suolo influenzano le dinamiche di respirazione del suolo per differenti scale temporali. L’introduzione delle attività del pascolo ha modificato l’attività microbica aumentando la quantità di carbonio facilmente disponibile derivante dalle rizodeposizioni, con il risultato di una ridotta attività enzimatica della comunità microbica ed un conseguente decremento dell’attività di mineralizzazione del carbonio. La combinazione di studi di laboratorio e di misure in situ è necessaria per la comprensione dell’effetto del cambiamento della qualità del substrato, dei nutrienti e delle condizioni di umidità sull’attività microbica e la sua efficienza nell’uso del carbonio.Dottorato di ricerca in Ecologia forestal

Restricted dynamic programming: a flexible framework for solving realistic VRPs

Most solution methods for solving large vehicle routing and schedu- ling problems are based on local search. A drawback of these ap- proaches is that they are designed and optimized for specific types of vehicle routing problems (VRPs). As a consequence, it is hard to adapt these solution methods to handle new restrictions, without los- ing solution quality. We present a new framework for solving VRPs that can handle a wide range of different types of VRPs. Within this framework, restricted dynamic programming is applied to the VRP through the giant-tour representation. This algorithm is a con- struction heuristic which finds provably optimal solutions when unre- stricted. We demonstrate the flexibility of the framework for a wide variety of different types of VRPs. The quality of solutions found by the framework is demonstrated by solving a set of benchmark instances for the capacitated VRP. The computational experiments show that restricted dynamic programming, which is a construction heuristic, develops routes of high quality. Therefore, this new framework for solving VRPs is highly valuable in practice

Exponentially better than brute force: solving the jobshop scheduling problem optimally by dynamic programming

Scheduling problems received substantial attention during the last decennia. The job-shop problem is a very important scheduling problem, which is NP-hard in the strong sense and with well-known benchmark instances of relatively small size which attest the practical difficulty in solving it. The literature on job-shop scheduling problem includes several approximation and optimal algorithms. So far, no algorithm is known which solves the job-shop scheduling problem optimally with a lower complexity than the exhaustive enumeration of all feasible solutions. We propose such an algorithm, based on the well-known Bellman equation designed by Held and Karp to find optimal sequences and which offers the best complexity to solve the Traveling Salesman Problem known to this date. For the TSP this means O(n22n) which is exponentially better than O(n!) required to evaluate all feasible solutions. We reach similar results by first recovering the principle of optimality, which is not obtained for free in the case of the job-shop scheduling problem, and by performing a complexity analysis of the resulting algorithm. Our analysis is conservative but nevertheless exponentially better than brute force. We also show very promising results obtained from our implementation of this algorithm, which seem to indicate two things: firstly that there is room for improvement in the complexity analysis (we observe the generation of a number of solutions per state for the benchmark instances considered which is orders of magnitude lower than the bound we could devise) and secondly that the potential practical implications of this approach are at least as exciting as the theoretical ones, since we manage to solve some celebrated benchmark instances in processing times ranging from seconds to minutes.Job-shop scheduling; dynamic programming; complexity analysis