Managing future risks and building socio-ecological resilience

The Mediterranean Basin is experiencing major changes in environmental conditions, which can introduce new challenges to the resilience of its natural and human systems. This situation is combined with rapid and spatially diverse socio-economic development in the region, mainly in terms of demographic trends and settlement patterns, thus leading to higher exposure to environmental hazards. Furthermore, new risks are expected to emerge from interactions between drivers and impacts across sectors, thus increasing the vulnerability of natural systems and human populations

SAS6-like protein in Plasmodium indicates that conoid-associated apical complex proteins persist in invasive stages within the mosquito vector

The SAS6-like (SAS6L) protein, a truncated paralogue of the ubiquitous basal body/centriole protein SAS6, has been characterised recently as a flagellum protein in trypanosomatids, but associated with the conoid in apicomplexan Toxoplasma. The conoid has been suggested to derive from flagella parts, but is thought to have been lost from some apicomplexans including the malaria-causing genus Plasmodium. Presence of SAS6L in Plasmodium, therefore, suggested a possible role in flagella assembly in male gametes, the only flagellated stage. Here, we have studied the expression and role of SAS6L throughout the Plasmodium life cycle using the rodent malaria model P. berghei. Contrary to a hypothesised role in flagella, SAS6L was absent during gamete flagellum formation. Instead, SAS6L was restricted to the apical complex in ookinetes and sporozoites, the extracellular invasive stages that develop within the mosquito vector. In these stages SAS6L forms an apical ring, as we show is also the case in Toxoplasma tachyzoites. The SAS6L ring was not apparent in blood-stage invasive merozoites, indicating that the apical complex is differentiated between the different invasive forms. Overall this study indicates that a conoid-associated apical complex protein and ring structure is persistent in Plasmodium in a stage-specific manner

Valproic acid toxicokinetics: Serial hemodialysis and hemoperfusion

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission; the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 umol/L). The anion gap was 26 mmol/L (normal <12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level serial hemodialysis and hemoperfusion was performed. The first session was done with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the first hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective because of saturation of the column. In conclusion, the toxicokinetics of valproate are quite different from the pharmacokinetics at therapeutic levels. The anion gap and protein binding are important parameters in toxicokinetics

Valproic acid toxicokinetics:Serial hemodialysis and hemoperfusion

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission; the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 umol/L). The anion gap was 26 mmol/L (normal <12-14 mmol/L) and corresponded fairly well with this valproic acid level. Because of the potential toxicity of this high valproic acid level serial hemodialysis and hemoperfusion was performed. The first session was done with a charcoal column and the second session with a resin column. The patient recovered during the course of treatment. The valproic acid plasma clearances during treatment were: 80 mL/min (hemodialysis); 40 mL/min (hemoperfusion by charcoal) and 80 mL/min (hemoperfusion by resin, only in the first hour). The protein binding of valproic acid in plasma was only 32% at the start and was 54% at the end of the two sessions. In this specific case of a severe valproic acid intoxication, saturated protein binding resulted in an increased fraction of unbound valproic acid. This made hemodialysis an effective treatment, while hemoperfusion was relatively less effective because of saturation of the column. In conclusion, the toxicokinetics of valproate are quite different from the pharmacokinetics at therapeutic levels. The anion gap and protein binding are important parameters in toxicokinetics

The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations

Nigrostriatal dopaminergic function and cerebral energy metabolism were measured with PET in two brothers with early-onset parkinsonism caused by mutation of the parkin gene. Energy metabolism did not differ, but the nigrostriatal dopaminergic pattern was clearly different than that of sporadic PD. Thus parkinsonism in these two patients was shown to be pathophysiologically different than PD

Familial parkinsonism with synuclein pathology - Clinical and PET studies of A30P mutation carriers

Background: The authors identified the second known mutation in the alpha -synuclein (SNCA) gene, an alanine-to-proline exchange in amino acid position 30 (A30P), that cosegregates with the disease in one German family with autosomal dominantly inherited parkinsonism (ADP). The authors studied carriers of the A30P mutation to compare the phenotype of this mutation with idiopathic PD (:IPD) and to assess nigrostriatal dopaminergic function in symptomatic and preclinical mutation carriers. Methods: The pedigree of the A30P family spans five generations with five affected individuals. The authors performed detailed neurologic examinations followed by mutation analysis in 11 living individuals. In three mutation carriers, two individuals with definite PD and one person at risk for PD, they used L-[(18)]F-fluoro-3,4-dihydroxyphenylalanine (F-DOPA), [(11)]C-raclopride (RAC), and [(18)]F-fluorodeoxyglucose (FDG) PET to investigate presynaptic dopaminergic function, dopamine D, receptors, and cerebral energy metabolism. The authors studied the cognitive functions of carriers of the A30P mutation casing neuropsychological screening. Results: PET studies revealed striatal presynaptic dopaminergic alterations consistent with sporadic IPD in two affected family members and no evidence for nigrostriatal dopaminergic dysfunction in one presymptomatic mutation carrier. Neuropsychological testing in four mutation carriers provided evidence for cognitive impairment as a frequent and early symptom of the A30P mutation; this is also supported by regional cerebral energy metabolism alterations in the clinically presymptomatic subject. Conclusions: The phenotype of the A30P mutation in the SNCA gene is similar to that of sporadic IPD, including a high variability of the age at disease onset, ranging from 54 to 76 years. The follow-up of presymptomatic carriers of the A30P mutation may give insight into preclinical disease stages and early manifestations of PD