Peripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase

Peripheral decarboxylase inhibitors (PDIs) prevent the conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may contribute to the required higher dosages of levodopa observed in many patients with Parkinson’s disease. We evaluated the effect of levodopa/PDI use on serum AADC enzyme activity. Serum AADC enzyme activity was evaluated in three independent cohorts of patients with Parkinson’s disease or parkinsonism (n = 301) and compared between patients on levodopa/PDI vs. patients not on this medication. AADC enzyme activity was elevated in 62% of patients on levodopa/PDI treatment, compared to 19% of patients not on levodopa/PDI (median 90 mU/L vs. 50 mU/L, p < 0.001). Patients with elevated AADC activity had longer disease duration and higher doses of levodopa/PDI. These findings may implicate that peripheral AADC induction could underlie a waning effect of levodopa, necessitating dose increases to maintain a sustained therapeutic effect

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dop

Human type 1 and type 2 conventional dendritic cells express indoleamine 2,3‐dioxygenase 1 with functional effects on T cell priming

Dendritic cells (DCs) are key regulators of the immune system that shape T cell responses. Regulation of T cell induction by DCs may occur via the intracellular enzyme indoleamine 2,3‐dioxygenase 1 (IDO), which catalyzes conversion of the essential amino acid tryptophan into kynurenine. Here, we examined the role of IDO in human peripheral blood plasmacytoid DCs (pDCs), and type 1 and type 2 conventional DCs (cDC1s and cDC2s). Our data demonstrate that under homeostatic conditions, IDO is selectively expressed by cDC1s. IFN‐γ or TLR ligation further increases IDO expression in cDC1s and induces modest expression of the enzyme in cDC2s, but not pDCs. IDO expressed by conventional DCs is functionally active as measured by kynurenine production. Furthermore, IDO activity in TLR‐stimulated cDC1s and cDC2s inhibits T cell proliferation in settings were DC‐T cell cell‐cell contact does not play a role. Selective inhibition of IDO1 with epacadostat, an inhibitor currently tested in clinical trials, rescued T cell proliferation without affecting DC maturation status or their ability to cross‐present soluble antigen. Our findings provide new insights into the functional specialization of human blood DC subsets and suggest a possible synergistic enhancement of therapeutic efficacy by combining DC‐based cancer vaccines with IDO inhibition

Policies and Sensemaking

First lines: The approach to cultural universes has a long tradition in policy science, among many other approaches. The design of policies often delves into the cultural dimension of groups of users. However, the link between policy-making and cultural universes is not direct. Sense making is by definition a nonlinear output of action. In contrast, approaching policy-making from the Re.Cri.Re. standpoint leads to a strongly cautionary attitude towards the ambition of most policies

Don’t call me a leader, but I am one: The Dutch mayor and the tradition of bridging-and-bonding leadership in consensus democracies

In some democratic contexts, there is a strong aversion to the directive, individualistic and masculine expressions of leadership that have come to dominate the study of political leadership. Such leadership is antithetical to consensus democracies in parts of continental Europe, where the antipathy to leadership has linguistic, institutional as well as cultural dimensions. Political-administrative and socio-cultural contexts in these countries provide little room for heroic expressions of leadership. Consequently, alternative forms of leadership and associated vocabularies have developed that carry profound practical relevance but that have remained underexplored. Based on an in-depth mixed-method study, this article presents the Dutch mayoralty as an insightful and exemplary case of what can be called ‘bridging-and-bonding leadership’; it provides a clear illustration of how understandings of democratic leadership can deviate from the dominant paradigm and of how leading in a consensus context brings about unique practical challenges for office holders. The analysis shows that the important leadership task of democratic guardianship that is performed by Dutch mayors is in danger of being overlooked by scholars of political leadership, as are consensus-oriented leadership roles in other parts of the world. For that reason, a recalibration of the leadership concept is needed, developing an increased theoretical sensitivity towards the non-decisive and process-oriented aspects of the leadership phenomenon. This article specifies how the future study of leadership, as a part of the change that is advocated, can benefit from adopting additional languages of leadership