Today’s and tomorrow’s imaging and circulating biomarkers for pulmonary arterial hypertension

The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients' long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed.     

Newton’s De gravitatione: a review and reassessment

The widely accepted supposition that Newton’s De gravitatione was written in 1684/5 just before composing the Principia is examined. The basis for this determination has serious difficulties starting with the failure to examine the numerical estimates for the resistance of aether. The estimated range is not nearly nil as claimed but comparable with air at or near the earth’s surface. Moreover, the evidence provided most likely stems from experiments by Boyle, Hooke, and others in the 1660s and does not use evidence available in the late 1684. The document supports Newton’s contention that the aether medium incorporates very large voids thereby proving that body and space differ but does by no means completely reject its corporeal nature or eliminate its resistance. Newton’s use of the term inertia provides no conclusive evidence for a late date as often claimed and his definition of gravitas is difficult to reconcile with a late one.     

Common features between diabetes mellitus and Alzheimer’s disease

Epidemiological studies establish a link between Type 2 diabetes (T2DM) and Alzheimer’s disease (AD), both leading causes of morbidity and mortality in the elderly. These diseases also share clinical and biochemical features suggesting common pathogenic mechanisms. Specifically, both are amyloidoses as they are characterized by fibrillar protein aggregates – amylin in T2DM pancreatic islets, and β-amyloid (Aβ) and neurofibrillary tangles (NFTs) in AD brain. Amylin aggregation is associated with pancreatic β-cell loss, and Aβ and NFT formation with neuronal cell loss. We discuss the possibility that amylin and Aβ exert their toxicity by similar mechanisms, with components of the pathocascades shared, and that therapies based on amyloidogenic properties are beneficial for both T2DM and AD. Received 27 January 2009; received after revision 17 February 2009; accepted 23 February 2009     

Monocytes and their pathophysiological role in Crohn’s disease

Our immune system shows a stringent dichotomy, on the one hand displaying tolerance towards commensal bacteria, but on the other hand vigorously combating pathogens. Under normal conditions the balance between flora tolerance and active immunity is maintained via a plethora of dynamic feedback mechanisms. If, however, the balancing act goes faulty, an inappropriate immune reaction towards an otherwise harmless intestinal flora causes disease, Crohn’s disease for example. Recent developments in the immunology and genetics of mucosal diseases suggest that monocytes and their derivative cells play an important role in the pathophysiology of Crohn’s disease. In our review, we summarize the recent studies to discuss the dual function of monocytes - on the one hand the impaired monocyte function initiating Crohn’s disease, and on the other hand the overactivation of monocytes and adaptive immunity maintaining the disease. With a view to developing new therapies, both aspects of monocyte functions need to be taken into account. Received 1 June 2008; received after revision 24 July 2008; accepted 13 August 2008     

Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review, we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt, Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD. Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006     

Boyle’s teleological mechanism and the myth of immanent teleology

According to recent commentators, medieval natural philosophers endorsed immanent teleology, the view that natural agents possess immanent active powers to achieve certain ends. Moreover, some scholars have argued that Robert Boyle, despite his intentions, failed to eliminate immanent teleology from his natural philosophy. I argue in this paper that it is not at all clear that immanent teleology was widely endorsed in the medieval period. Moreover, I argue that a proper understanding of immanent teleology, and why it was rejected by mainstream medieval natural philosophers, reveals that Boyle did not fail to eliminate immanent teleology from his natural philosophy. I conclude that any attempt to describe the break between medieval and early modern natural philosophy in terms of a break with immanent teleology is likely not on target.     

Kuhn’s Structure of Scientific Revolutions between sociology and epistemology

The aim of the paper is to clarify Kuhn’s theory of scientific revolutions. We propose to discriminate between a scientific revolution, which is a sociological event of a change of attitude of the scientific community with respect to a particular theory, and an epistemic rupture, which is a linguistic fact consisting of a discontinuity in the linguistic framework in which this theory is formulated. We propose a classification of epistemic ruptures into four types. In the paper, each of these types of epistemic ruptures is illustrated by examples from physics. The classification of epistemic ruptures can be used as a basis for a classification of scientific revolutions and thus for a refinement of our view of the progress of science.     

Neurobiology and neuroimmunology of Tourette’s syndrome: an update

Tourettes syndrome is a childhood-onset neuropsychiatric disorder characterized by the presence of both multiple motor and vocal tics. While the pathogenesis at a molecular and cellular level remains unknown, structural and functional neuroimaging studies point to the involvement of the basal ganglia and related cortico-striato-thalamo-cortical circuits as the neuroanatomical site for Tourettes syndrome. Moreover, Tourettes syndrome has a strong genetic component, and considerable progress has been made in understanding the mode of transmission and in identifying potential genomic loci. Summaries of recent findings in these areas will be reviewed, followed by a critical overview of findings both supporting and challenging the proposed autoimmune hypothesis of Tourettes syndrome. We conclude that Tourettes syndrome is a heterogeneous disorder, and that immune factors may indeed be involved in some patients.Received 12 August 2003; received after revision 8 October 2003; accepted 31 October 2003     

Two problems in Aristarchus’s treatise on the sizes and distances of the sun and moon

The book of Aristarchus of Samos, On the distances and sizes of the sun and moon, is one of the few pre-Ptolemaic astronomical works that have come down to us in complete or nearly complete form. The simplicity and cleverness of the basic ideas behind the calculations are often obscured in the reading of the treatise by the complexity of the calculations and reasoning. Part of the complexity could be explained by the lack of trigonometry and part by the fact that Aristarchus appears unwilling to make some simplifications that could be simply taken for granted. But an important part of the complexities is due to some unnecessary inconsistencies, as recently discovered by Berggren and Sidoli (Arch Hist Exact Sci 61:213–254, 2007). In the first part of this paper, I will try to show that some of these inconsistencies are just apparent. But the complexity of the calculations and reasoning is not the only reason that could disturb a reader of the treatise. The great inaccuracy—even for the measurement methods and instruments available at those times—of one of the three input values of the treatise is really astonishing. In the sixth and last hypothesis, Aristarchus states that the moon’s apparent size is equal to 2 $^{\circ }$ , while the correct value is one-fourth of that. Some attempts have been made in order to explain such a big value, but all of them have problems. In the second part of this paper, I will propose a new speculative but plausible explanation of the origin of this value.     

Anti-amyloidogenic therapies: strategies for prevention and treatment of Alzheimer’s disease

Deposition of amyloid β-protein (Aβ) in the brain is an early and invariant neuropathological feature of Alzheimer’s disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Aβ in the brain. Here, we review four anti-amyloidogenic strategies: (i) reduction of Aβ production, which has mainly been approached with secretase inhibition, (ii) promotion of the Aβ degrading catabolic pathway, including an Aβ degrading enzyme, neprilysin, (iii) immunotherapy for Aβ and (iv) inhibition of Aβ aggregation. We have reported that AD patients have a favorable molecular environment for Aβ aggregation and that various compounds, such as polyphenols, interfere with Aβ aggregation and destabilize preformed Aβ fibrils. Received 21 December 2005; received after revision 14 February 2006; accepted 29 March 2006     

Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies

Huntington’s disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary movements (chorea), personality changes and dementia, leading to death within 10–20 years. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin. Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to new therapeutic approaches. Received 24 May 2006; received after revision 5 July 2006; accepted 23 August 2006     

Connections between simulations and observation in climate computer modeling. Scientist’s practices and “bottom-up epistemology” lessons

Climate modeling is closely tied, through its institutions and practices, to observations from satellites and to the field sciences. The validity, quality and scientific credibility of models are based on interaction between models and observation data. In the case of numerical modeling of climate and climate change, validation is not solely a scientific interest: the legitimacy of computer modeling, as a tool of knowledge, has been called into question in order to deny the reality of any anthropogenic climate change; model validations thereby bring political issues into play as well. There is no systematic protocol of validation: one never validates a model in general, but the capacity of a model to account for a defined climatic phenomenon or characteristic. From practices observed in the two research centers developing and using a climate model in France, this paper reviews different ways in which the researchers establish links between models and empirical data (which are not reduced to the latter validating the former) and convince themselves that their models are valid. The analysis of validation practices—relating to parametrization, modes of variability, climatic phenomena, etc.—allows us to highlight some elements of the epistemology of modeling.     

Lagrange’s theory of analytical functions and his ideal of purity of method

We reconstruct essential features of Lagrange’s theory of analytical functions by exhibiting its structure and basic assumptions, as well as its main shortcomings. We explain Lagrange’s notions of function and algebraic quantity, and we concentrate on power-series expansions, on the algorithm for derivative functions, and the remainder theorem—especially on the role this theorem has in solving geometric and mechanical problems. We thus aim to provide a better understanding of Enlightenment mathematics and to show that the foundations of mathematics did not, for Lagrange, concern the solidity of its ultimate bases, but rather purity of method—the generality and internal organization of the discipline.     

Synphilin-1 isoforms in Parkinson’s disease: regulation by phosphorylation and ubiquitylation

Parkinson’s disease (PD) is characterized by the death of dopaminergic neurons and the presence of Lewy bodies in the substantia nigra pars compacta. The mechanisms involved in the death of neurons as well as the role of Lewy bodies in the pathogenesis of the disease are still unclear. Lewy bodies are made of aggregated proteins, in which α-synuclein represents their major component. α-Synuclein interacts with synphilin-1, a protein that is also present in Lewy bodies. When expressed in cells, synphilin-1 forms inclusions together with α-synuclein that resemble Lewy bodies. Synphilin-1 is ubiquitylated by various E3 ubiquitin-ligases, such as SIAH, parkin and dorfin. Ubiquitylation of synphilin-1 by SIAH is essential for its aggregation into inclusions. We recently identified a new synphilin-1 isoform, synphilin-1A, that is toxic to neurons, aggregation-prone and accumulates in detergent-insoluble fractions of brains from α-synucleinopathy patients. Synphilin-1A inclusions recruit both α-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells. We now discuss several aspects of the neurobiology and pathology of synphilin-1 isoforms, focusing on possible implications for PD. Received 26 July 2007; received after revision 19 September 2007; accepted 15 October 2007     

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

In the present study we demonstrated that neurotoxin MPP⁺-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP⁺-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson’s disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G₀/G₁ cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP⁺ leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP⁺ and cell-cycle re-entry through retinoblastoma protein phosphorylation.