Sensibilité à la pollution métallique de deux grands lacs africains (Tanganyika et Malawi)

Les lacs Tanganyika et Malawi sont, de par leur volume, les deux plus grands lacs africains. Ces réservoirs semblent pour l'instant épargnés par la pollution en éléments en trace. Il est toutefois crucial, en raison de leurs caractéristiques hydrologiques, de poser la question du temps de réponse de ces systèmes à une pollution chronique potentielle véhiculée par les affluents. Cet article simule ainsi cette réponse dans la fraction dissoute suite à l'introduction pendant 50 ans de polluant par tous les affluents. Cette démarche s'appuie sur un modèle hydrologique intégrant les trois compartiments des colonnes d'eau (épi-, méta- et hypolimnion) et sur la prise en compte de la réactivité des éléments dissous dans ces compartiments par l'intermédiaire du taux de rétention élémentaire. Ainsi quatre types d'éléments sont considérés, (i) le type Cl, non réactif, (ii) le type Si, réactif-nutritif, (iii) le type Mn et (iv) le type V tous deux réactifs sensibles aux conditions d'oxydo-réduction. La réactivité de l'élément, l'efficacité du mélange vertical ainsi que la position de l'oxycline dans la colonne d'eau conditionnent l'amplitude et la cinétique de réponse des systèmes ainsi que le temps de retour à la situation initiale après l'arrêt des apports polluants. Ces caractéristiques propres à l'élément et au lac influent sur le risque potentiel encouru par l'écosystème et l'homme. Ainsi la pollution affecte principalement les eaux de surface (types Cl et V), les réseaux trophiques (type Si), les eaux profondes (types Si et Mn) et le compartiment sédimentaire (types Mn et V).Lakes Tanganyika and Malawi are the largest African lakes as measured by volume. They constitute essential water and protein resources for the surrounding populations. These aquatic systems have become stressed due to high human population density, growth and associated activities. While eutrophication was apparent locally and organic pollutants were detected in fish and water, concentrations of several dissolved trace elements of potential concern corresponded to uncontaminated systems. However, due to their hydrological features, it was important to characterise the lake response time to chronic contamination loaded by the tributaries. This paper presents two simulations of this response, in the dissolved fraction, following 50 years of pollutant input by the tributaries. The first simulation corresponded to an annual pollutant input that was the same for both lakes, resulting in mean river input concentrations of 5.0 U L-1 and 3.7 U L 1 (where U is a weight or molar unit), respectively, for lakes Tanganyika and the Malawi. The second simulation corresponded to an annual input proportional to the lake volume, with mean river input concentrations of 5.0 U L 1 and 1.5 U L 1, respectively, for lakes Tanganyika and the Malawi. The polluted input was loaded by the dissolved fraction with the exception of Mn-type elements, which were carried by the particulate fraction. This approach was based on an annual hydrological model of three water column compartments (epi-, meta- and hypolimnion) of these meromictic lakes. In addition, the reactivity of dissolved elements in the water column was taken into consideration. The reactivity was characterised by the elemental retention rate that quantifies dissolved-particulate interactions linked to biological and physico-chemical processes. The reactivity of trace elements was assessed through their concentration distribution profile in the water column. Four element types were considered: the non-reactive elements characterised by homogenous concentrations in the water column (Cl-like); the micronutrient-type elements (Si-like) characterised by a strong positive concentration gradient below the thermocline; redox-sensitive elements (Mn-like) characterised by a strong positive concentration gradient below the oxycline and other redox-sensitive elements (V-like) characterised by a strong negative concentration gradient below the oxycline. Trace elements (F, Al, Fe, Mn, V, Ba, Sr, Mo, Cr, Ni, Co, Cu and Pb) in both lakes were associated with these element types but they did not necessarily belong to the same type in both lakes. Other elemental types likely occurred (e.g., carbonate type and Fe types) but they were not clearly identified. After 50 years, surface concentrations ranged from 0 to 1.15 U L 1 in Lake Tanganyika and from 0 to 2.40 U L 1 in Lake Malawi. The difference between the lakes was linked to the greater volume of Lake Tanganyika, mainly in its hypolimnion, and to the longer vertical water exchange time in Lake Tanganyika. For Cl-type elements the concentration response decreased for both lakes from the epi- to the hypolimnion with similar kinetics for the epi- and metalimnion and a delay for the hypolimnion. For Si-type elements the response decreased in Lake Malawi from the hypo- to the epilimnion and for Lake Tanganyika the maximal concentration was calculated in the metalimnion. The concentration range was higher in Lake Malawi than in Lake Tanganyika. For the Mn-type elements, the maximum concentration was calculated in the hypolimnion with a higher response in Lake Malawi. The metalimnetic water concentration of Lake Tanganyika increased slightly and epilimnetic and metalimnetic waters of Lake Malawi did not react. For V-type elements the epilimnetic waters were more sensitive to the increase, with a higher response for Lake Malawi. In Lake Malawi concentrations also increased in the metalimnion. Concentrations in the hypolimnetic zone of both lakes and metalimnetic zone in Lake Tanganyika remained zero. Depending on the element type and on the lake, the time required to return to initial conditions, when contaminant inputs stopped, varied from 30 to 7 300 years. In the epilimnetic zone of both lakes the intensity of reaction and the pollution persistence were higher for Cl-type elements. For Si-type elements, mainly in Lake Malawi, the vertical input from deep waters was sufficient to sustain productivity even after the input of pollutants was stopped. For these elements the dissolved contamination was mainly stored in deep waters. For Mn-type elements the contamination was also stored in deep waters with a relatively slow net transfer to the sedimentary compartment. V-type pollutants were transferred from the dissolved to the particulate phase in deep waters leading to a relatively rapid net transfer to the sediment. Once the pollutant was in the system and until its evacuation to the outlet or to sediment, the risk for the ecosystem and for the population was associated with its presence in the dissolved phase of the surface water. The risk was then higher for Cl- and V-type elements as well as for the Si-type elements that were introduced into the web food. For the Si- and Mn-type elements that were mainly stored in deep waters, the associated risk was linked to a breaking of the thermo-haline stratification or to a reinforcement of vertical mixing. For the V-type elements and also for the sedimentary fraction of the Mn-type elements, the risk was also associated with possible remobilization from the sediments due to physico-chemical changes at the water-sediment interface.Element reactivity, efficiency of the vertical mixing and the depth of the oxycline control the importance and the kinetic response. They also controlled the time to attain initial conditions once contaminant inputs were stopped. These features, relative to the element and to the lake, were key parameters in the assessment of the potential risk for both the ecosystem and people that rely on these lakes. Even if the elemental typology was the same for both lakes, elements can be considered a different type from one lake to another. Contamination from the same pollutant would then have different consequences, for instance regarding the associated risk. Computed hydrochemical budgets were simple but realistic, illustrating the behaviour of elements in the water column. Computation of this budget requires the knowledge of global water column fluxes, which have to be improved mainly for Lake Tanganyika. The element's reactivity was mainly linked to liquid-solid reactions. It would be interesting in future studies to characterise particulate phases and their reactivity and to introduce such processes in hydro-geochemical models. Computations of chronic contamination response indicate that for both lakes, due to the inertia of the hydrochemical system, the lack of lake water contamination does not imply a systematic lack of pollution in the tributaries. Once pollution is detected, it will be persistent. A global watershed monitoring program should be organised in the near future. Monitored parameters should be relevant to metallic and organic pollutants, as well as eutrophication

Recovery of chronic motor neuropathy due to acute intermittent porphyria after givosiran treatment in a young boy: a case report

BACKGROUND: We describe the first case of a pediatric patient with acute intermittent porphyria and severe chronic porphyric neuropathy treated with givosiran, a small-interfering RNA that drastically decreases delta-aminolevulinic acid production and reduces porphyric attacks’ recurrence. CASE REPORT: A 12-year-old male patient with refractory acute intermittent porphyria and severe porphyric neuropathy was followed prospectively for 12 months after givosiran initiation (subcutaneous, 2.5 mg/kg monthly). Serial neurological, structural, and resting-state functional magnetic resonance imaging (MRI) evaluations were performed, including clinical scales and neurophysiological tests. Delta-aminolevulinic acid urinary levels dropped drastically during treatment. In parallel, all the administered neurological rating scales and neurophysiological assessments showed improvement in all domains. Moreover, an improvement in central motor conduction parameters and resting-state functional connectivity in the sensory- motor network was noticed. At the end of the follow-up, the patient could walk unaided after using a wheelchair for 5 years. CONCLUSIONS: A clear beneficial effect of givosiran was demonstrated in our patient with both clinical and peripheral nerve neurophysiologic outcome measures. Moreover, we first reported a potential role of givosiran in recovering central motor network impairment in acute intermittent porphyria (AIP), which was previously unknown. This study provides Class IV evidence that givosiran improves chronic porphyric neuropathy

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of \u201cself-limited focal epilepsies.\u201d In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 \ub1 11.46. Two independent general linear model models were created for each patient based on the effect of interest: \u201cindividual CTS\u201d in model 1 and \u201cCTS density\u201d in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical\u2013subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood\u2013oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of \u201cself-limited focal epilepsies.\u201d In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 \ub1 11.46. Two independent general linear model models were created for each patient based on the effect of interest: \u201cindividual CTS\u201d in model 1 and \u201cCTS density\u201d in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical\u2013subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood\u2013oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks

Multiparametric flow cytometry for MRD monitoring in hematologic malignancies: Clinical applications and new challenges

In hematologic cancers, Minimal Residual Disease (MRD) monitoring, using either molecular (PCR) or immunophenotypic (MFC) diagnostics, allows the identification of rare cancer cells, readily detectable either in the bone marrow or in the peripheral blood at very low levels, far below the limit of classic microscopy. In this paper, we outlined the state-of-the-art of MFC-based MRD detection in different hematologic settings, highlighting main recommendations and new challenges for using such a method in patients with acute leukemias or chronic hematologic neoplasms. The combination of new molecular technologies with advanced flow cytometry is progressively allowing clinicians to design a personalized therapeutic path, proportionate to the biological aggressiveness of the disease, in particular by using novel immunotherapies, in view of a modern decision-making process, based on precision medicine. Along with the evolution of immunophenotypic and molecular diagnostics, the assessment of Minimal Residual Disease (MRD) has progressively become a keystone in the clinical management of hematologic malignancies, enabling valuable post-therapy risk stratifications and guiding risk-adapted therapeutic approaches. However, specific prognostic values of MRD in different hematological settings, as well as its appropriate clinical uses (basically, when to measure it and how to deal with different MRD levels), still need further investigations, aiming to improve standardization and harmonization of MRD monitoring protocols and MRD-driven therapeutic strategies. Currently, MRD measurement in hematological neoplasms with bone marrow involvement is based on advanced highly sensitive methods, able to detect either specific genetic abnormalities (by PCRbased techniques and next-generation sequencing) or tumor-associated immunophenotypic profiles (by multiparametric flow cytometry, MFC). In this review, we focus on the growing clinical role for MFC-MRD diagnostics in hematological malignancies-from acute myeloid and lymphoblastic leukemias (AML, B-ALL and T-ALL), to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM)-providing a comparative overview on technical aspects, clinical implications, advantages and pitfalls of MFC-MRD monitoring in different clinical settings

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

A convergent rhodium-catalysed asymmetric synthesis of tetrahydroquinolines.

Rh-catalysed conjugate additions of 2-aminophenyl boronic acid derivatives were exploited in diastereoselective and asymmetric syntheses of tetrahydroquinolines. In both cases, combinatorial variation of the substitution of the tetrahydroquinoline ring system was possible

Accessing nitrosocarbonyl compounds with temporal and spatial control via the photoredox oxidation of N-substituted hydroxylamines

Photoredox catalysis is employed to generate highly reactive acylnitroso species from hydroxamic acid derivatives. The conditions are shown to be comparable to a previously developed transition metal aerobic oxidation and are amenable to a range of transformations including Diels-Alder and ene reactions. This unique application of such an approach gives access to temporal and spatial control in nitroso chemistry