The Future of Drug Development for Neglected Tropical Diseases: How the European Commission Can Continue to Make a Difference

In this article, the four coordinators of neglected tropical disease (NTD) drug development projects funded under the European Commission (EC) Framework Programme 7 argue that the EC should reassess their funding strategy to cover the steps necessary to translate a lead compound into a drug candidate for testing in clinical trials, and suggest ways in which this might be achieved

Selection of novel mediators of E2F1-induced apoptosis through retroviral expression of an antisense cDNA library

The E2F1 transcription factor is an essential mediator of p53-dependent and p53-independent apoptosis as part of an anti-tumour safeguard mechanism. In this study, a functional so-called technical knockout (TKO) approach was applied to Saos-2ERE2F1 cells that conditionally activate E2F1 by the addition of 4-hydroxytamoxifen to search for p53-independent pro-apoptotic E2F1 targets. The approach was based on random inactivation of genes after retroviral transfer of an antisense cDNA library enriched of E2F1-induced genes, followed by the selection of Saos-2ERE2F1 cells that survive in the presence of the apoptotic stimulus. We identified 13 novel E2F1 target genes encoding proteins of known cellular function, including apoptosis and RNA binding. FACS analysis revealed that E2F1-induced apoptosis was significantly attenuated in cell clones containing the antisense cDNA fragments of these genes, demonstrating their participation in E2F1 death pathways. Moreover, inactivation of the target genes resulted in a clear increase of cell viability (>80%) in response to E2F1 activation compared with controls (∼30%). Four genes showed an increase in expression intensity in the presence of cycloheximide, suggesting a direct effect of E2F1 on gene transcription, whereas one gene was identified as an indirect target. Our data provide new insight in the regulation of E2F1-induced apoptosis

Non-Abelian hydrodynamics and the flow of spin in spin-orbit coupled substances

Motivated by heavy ion collision experiments, we study the hydrodynamic properties of non-Abelian systems. These issues arise in condensed matter physics in the context of transport of spins in the presence of spin orbit coupling: the Pauli Hamiltonian governing the leading relativistic corrections in condensed matter systems can be rewritten in a language of SU(2) covariant derivatives, where the role of the non-Abelian gauge fields is taken by the physical electromagnetic fields. Taking a similar perspective as Jackiw and coworkers, we show that non-abelian hydrodynamical currents can be factored in a non-coherent 'classical' part, and a coherent part requiring macroscopic non-abelian quantum entanglement. Non-abelian flow being thus a much richer affair than familiar hydrodynamics, permits us to classify the various spin transport phenomena in in condensed matter physics in a unifying framework.In semiconductor spintronics, the absence of hydrodynamics is well known, but in our formulation it is directly associated with the fact that non-abelian currents are only covariantly conserved.We analyze the quantum mechanical single particle currents of relevance to mesoscopic transport with as highlight the Aharonov-Casher effect, where we demonstrate that the non-abelian transport structure renders it much more fragile than its abelian counterpart, the Aharonov-Bohm effect. We subsequently focus on spin flows protected by order parameters, of which the spin-spiral magnets and the spin superfluids are important examples. The surprising bonus is that the presence of an order parameter, being single-valued, restores hydrodynamics. We demonstrate a new effect: the trapping of electrical line charge, being the 'fixed frame' non-Abelian analogue of the familiar magnetic flux trapping by superconductors.Comment: 23 pages, 7 figure

Follow-up study of sensory-motor polyneuropathy in Type 1 (insulin-dependent) diabetic subjects after simultaneous pancreas and kidney transplantation and after graft rejection

The influence of successful simultaneous pancreas and kidney transplantation on peripheral polyneuropathy was investigated in 53 patients for a mean observation period of 40.3 months. Seventeen patients were followed-up for more than 3 years. Symptoms and signs were assessed every 6 months using a standard questionnaire, neurological examination and measurement of sensory and motor nerve conduction velocities. While symptoms of polyneuropathy improved (pain, paraesthesia, cramps, restless-legs) and nerve conduction velocity increased, there was no change of clinical signs (sensation, muscle-force, tendon-reflexes). Following kidney-graft-rejection there was a slight decrease of nerve conduction verlocity during the first year, which was not statistically significant. Following pancreas-graft rejection there was no change of nerve conduction velocity during the first year. Comparing the maximum nerve conduction velocity of the patients with pancreas-graft-rejection to the nerve conduction velocities of these patients at the end of the study, there was a statistically significant decrease of 6.5 m/s. In conclusion, we believe that strict normalization of glucose metabolism alters the progressive course of diabetic polyneuropathy. It may be stabilized or partly reversed after successful grafting even in long-term diabetic patients

Short photoperiod-induced decrease of histamine H3 receptors facilitates activation of hypothalamic neurons in the Siberian Hamster

Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short inter-like photoperiod, which induces physiological adaptation to winter in the Siberian hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electro physiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod

Prolactin

During an oral glucose tolerance test (OGTT) glucose and insulin levels were measured in 26 patients with prolactin-producing pituitary tumours without growth hormone excess. Basal glucose and insulin levels did not differ from the values of an age-matched control group. After glucose load the hyperprolactinaemic patients showed a decrease in glucose tolerance and a hyperinsulinaemia. Bromocriptine (CB 154), which suppressed PRL, improved glucose tolerance and decreased insulin towards normal in a second OGTT. — Human PRL or CB 154 had no significant influence on insulin release due to glucose in the perfused rat pancreas. — These findings suggest a diabetogenic effect of PRL. CB 154 might be a useful drug in improving glucose utilization in hormone-active pituitary tumours

Serum Neurofilament Light Association With Progression in Natalizumab-Treated Patients With Relapsing-Remitting Multiple Sclerosis

OBJECTIVE: The objective of this study was to investigate the potential of serum neurofilament light (NfL) to reflect or predict progression mostly independent of acute inflammatory disease activity in patients with relapsing remitting multiple sclerosis (RRMS) treated with natalizumab. METHODS: Patients were selected from a prospective observational cohort study initiated in 2006 at the VU University Medical Center Amsterdam, The Netherlands, including patients with RRMS treated with natalizumab. Selection criteria included an age of 18 years or older and a minimum follow-up of 3 years from natalizumab initiation. Clinical and MRI assessments were performedon a yearly basis, and serum NfL was measured at 5 time-points during the follow-up, including on the day of natalizumab initiation (baseline), 3 months, 1 year and 2 years after natalizumab initiation, and on last follow-up visit. Using general linear regression models, we compared the longitudinal dynamics of NfL between patients with and without confirmed EDSS progression between year 1 visit and last follow-up, and between individuals with and without EDSS+ progression, a composite endpoint including the EDSS, 9 hole peg test and timed 25 foot-walk. RESULTS: Eighty-nine natalizumab-treated patients with RRMS were included. Median follow-up time was 5.2 years (IQR 4.3-6.7, range 3.0-11.0) after natalizumab initiation, mean age at time of natalizumab initiation was 36.9 (SD: 8.5), and median disease duration was 7.4 years (IQR 3.8-12.1). Between year 1 and the last follow-up, 28/89 (31.5%) individuals showed confirmed EDSS progression. Data for the EDSS+ endpoint was available for 73 out of the 89 patients and 35/73 (47.9%) showed confirmed EDSS+ progression.We observed a significant reduction in NfL levels 3 months after natalizumab initiation, which reached its nadir of close to 50% of baseline levels 1 year after treatment initiation. We found no difference in the longitudinal dynamics of NfL in progressors versus non-progressors. NfL levels at baseline and 1 year after natalizumab initiation did not predict progression at last follow-up. DISCUSSION: In our cohort of natalizumab-treated patients with RRMS, NfL fails to capture or predict progression that occurs largely independently of clinical or radiological signs of acute focal inflammatory disease activity. Additional biomarkers may thus be needed to monitor progression in these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that serum NfL levels are not associated with disease progression in natalizumab-treated patients with RRMS