Requirements for a lead compound to become a clinical candidate

A drug candidate suitable for clinical testing is expected to bind selectively to the receptor site on the target, to elicit the desired functional response of the target molecule, and to have adequate bioavailability and biodistribution to elicit the desired responses in animals and humans; it must also pass formal toxicity evaluation in animals. The path from lead to clinical drug candidate represents the most idiosyncratic segment of drug discovery and development. Each program is unique and setbacks are common, making it difficult to predict accurately the duration or costs of this segment. Because of incidents of unpredicted human toxicity seen in recent years, the regulatory agencies and public demands for safety of new drug candidates have become very strict, and safety issues are dominant when identifying a clinical drug candidate

Slow nonequilibrium dynamics: parallels between classical and quantum glasses and gently driven systems

We review an scenario for the non-equilibrium dynamics of glassy systems that has been motivated by the exact solution of simple models. This approach allows one to set on firmer grounds well-known phenomenological theories. The old ideas of entropy crisis, fictive temperatures, free-volume... have clear definitions within these models. Aging effects in the glass phase are also captured. One of the salient features of the analytic solution, the breakdown of the fluctuation-dissipation relations, provides a definition of a bonafide {\it effective temperature} that is measurable by a thermometer, controls heat flows, partial equilibrations, and the reaction to the external injection of heat. The effective temperature is an extremely robust concept that appears in non-equilibrium systems in the limit of small entropy production as, for instance, sheared fluids, glasses at low temperatures when quantum fluctuations are relevant, tapped or vibrated granular matter, etc. The emerging scenario is one of partial equilibrations, in which glassy systems arrange their internal degrees of freedom so that the slow ones select their own effective temperatures. It has been proven to be consistent within any perturbative resummation scheme (mode coupling, etc) and it can be challenged by experimental and numerical tests, some of which it has already passed.Comment: 15 pages, 8 figure

A demonstration of 'broken' visual space

It has long been assumed that there is a distorted mapping between real and ‘perceived’ space, based on demonstrations of systematic errors in judgements of slant, curvature, direction and separation. Here, we have applied a direct test to the notion of a coherent visual space. In an immersive virtual environment, participants judged the relative distance of two squares displayed in separate intervals. On some trials, the virtual scene expanded by a factor of four between intervals although, in line with recent results, participants did not report any noticeable change in the scene. We found that there was no consistent depth ordering of objects that can explain the distance matches participants made in this environment (e.g. A > B > D yet also A < C < D) and hence no single one-to-one mapping between participants’ perceived space and any real 3D environment. Instead, factors that affect pairwise comparisons of distances dictate participants’ performance. These data contradict, more directly than previous experiments, the idea that the visual system builds and uses a coherent 3D internal representation of a scene

Adhesion and host cell modulation: critical pathogenicity determinants of Bartonella henselae

Bartonella henselae, the agent of cat scratch disease and the vasculoproliferative disorders bacillary angiomatosis and peliosis hepatis, contains to date two groups of described pathogenicity factors: adhesins and type IV secretion systems. Bartonella adhesin A (BadA), the Trw system and possibly filamentous hemagglutinin act as promiscous or specific adhesins, whereas the virulence locus (Vir)B/VirD4 type IV secretion system modulates a variety of host cell functions. BadA mediates bacterial adherence to endothelial cells and extracellular matrix proteins and triggers the induction of angiogenic gene programming. The VirB/VirD4 type IV secretion system is responsible for, e.g., inhibition of host cell apoptosis, bacterial persistence in erythrocytes, and endothelial sprouting. The Trw-conjugation system of Bartonella spp. mediates host-specific adherence to erythrocytes. Filamentous hemagglutinins represent additional potential pathogenicity factors which are not yet characterized. The exact molecular functions of these pathogenicity factors and their contribution to an orchestral interplay need to be analyzed to understand B. henselae pathogenicity in detail

Qualitative assessment of innovations in healthcare provision

<p>Abstract</p> <p>Background</p> <p>The triad of quality, innovation and economic restraint is as important in health care as it is in the business world. There are many proposals for the assessment of quality and of economic restraints in health care but only a few address assessment of innovations. We propose a strategy and new structures to standardize the description of health care innovations and to quantify them.</p> <p>Discussion</p> <p>Strategy and structure are based on the assumption that in the early phase of an innovation only data on the feasibility and possibly on the efficacy or effectiveness of an innovation can be expected. From the patient's perspective, benefit resulting from an innovation can be confirmed only in a later phase of development. Early indicators of patient's benefit will be surrogate parameters which correlate only weakly with the desired endpoints. After the innovation has been in use, there will be more evidence on correlations between surrogate parameters and the desired endpoints to provide evidence of the patient benefit. From an administrative perspective, this evidence can be considered in decisions about public financing. Different criteria are proposed for the assessment of innovations in prevention, diagnosis and therapy. For decisions on public financing a public fund for innovations may be helpful. Depending on the phase of innovation risk sharing models are proposed between manufacturers, private insurers and public funding.</p> <p>Summary</p> <p>Potential for patient benefit is always uncertain during early stages of innovations. This uncertainty decreases with increasing information on the effects of the innovation. Information about an innovation can be quantified, categorized and integrated into rational economic decisions.</p

Th17 Cells Induce Ectopic Lymphoid Follicles in Central Nervous System Tissue Inflammation

Ectopic lymphoid follicles are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sjögren's syndrome, and myasthenia gravis. However, the effector cells and mechanisms that induce their development are unknown. Here we showed that in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, Th17 cells specifically induced ectopic lymphoid follicles in the central nervous system (CNS). Development of ectopic lymphoid follicles was partly dependent on the cytokine interleukin 17 (IL-17) and on the cell surface molecule Podoplanin (Pdp), which was expressed on Th17 cells, but not on other effector T cell subsets. Pdp was also crucial for the development of secondary lymphoid structures: Pdp-deficient mice lacked peripheral lymph nodes and had a defect in forming normal lymphoid follicles and germinal centers in spleen and lymph node remnants. Thus, Th17 cells are uniquely endowed to induce tissue inflammation, characterized by ectopic lymphoid follicles within the target organ

Quark helicity distributions in the nucleon for up, down, and strange quarks from semi--inclusive deep--inelastic scattering

Polarized deep--inelastic scattering data on longitudinally polarized hydrogen and deuterium targets have been used to determine double spin asymmetries of cross sections. Inclusive and semi--inclusive asymmetries for the production of positive and negative pions from hydrogen were obtained in a re--analysis of previously published data. Inclusive and semi--inclusive asymmetries for the production of negative and positive pions and kaons were measured on a polarized deuterium target. The separate helicity densities for the up and down quarks and the anti--up, anti--down, and strange sea quarks were computed from these asymmetries in a ``leading order'' QCD analysis. The polarization of the up--quark is positive and that of the down--quark is negative. All extracted sea quark polarizations are consistent with zero, and the light quark sea helicity densities are flavor symmetric within the experimental uncertainties. First and second moments of the extracted quark helicity densities in the measured range are consistent with fits of inclusive data

Effectiveness of Teriparatide in Women Over 75 Years of Age with Severe Osteoporosis: 36-Month Results from the European Forsteo Observational Study (EFOS)

This predefined analysis of the European Forsteo Observational Study (EFOS) aimed to describe clinical fracture incidence, back pain, and health-related quality of life (HRQoL) during 18 months of teriparatide treatment and 18 months post-teriparatide in the subgroup of 589 postmenopausal women with osteoporosis aged ≥75 years. Data on clinical fractures, back pain (visual analogue scale, VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. A repeated-measures model analyzed changes from baseline in back pain VAS and EQ-VAS. During the 36-month observation period, 87 (14.8 %) women aged ≥75 years sustained a total of 111 new fractures: 37 (33.3 %) vertebral fractures and 74 (66.7 %) nonvertebral fractures. Adjusted odds of fracture was decreased by 80 % in the 30 to <36–month interval compared with the first 6-month interval (P < 0.009). Although the older subgroup had higher back pain scores and poorer HRQoL at baseline than the younger subgroup, both age groups showed significant reductions in back pain and improvements in HRQoL postbaseline. In conclusion, women aged ≥75 years with severe postmenopausal osteoporosis treated with teriparatide in normal clinical practice showed a reduced clinical fracture incidence by 30 months compared with baseline. An improvement in HRQoL and, possibly, an early and significant reduction in back pain were also observed, which lasted for at least 18 months after teriparatide discontinuation when patients were taking other osteoporosis medication. The results should be interpreted in the context of an uncontrolled observational study

Neonatal hearing screening: modelling cost and effectiveness of hospital- and community-based screening

BACKGROUND: Children with congenital hearing impairment benefit from early detection and management of their hearing loss. These and related considerations led to the recommendation of universal newborn hearing screening. In 2001 the first phase of a national Newborn Hearing Screening Programme (NHSP) was implemented in England. Objective of this study was to assess costs and effectiveness for hospital and community-based newborn hearing screening systems in England based on data from this first phase with regard to the effects of alterations to parameter values. METHODS: Design: Clinical effectiveness analysis using a Markov Model. Outcome measure: quality weighted detected child months (QCM). RESULTS: Both hospital and community programmes yielded 794 QCM at the age of 6 months with total costs of £3,690,000 per 100,000 screened children in hospital and £3,340,000 in community. Simulated costs would be lower in hospital in 48% of the trials. Any statistically significant difference between hospital and community in prevalence, test sensitivity, test specificity and costs would result in significant differences in cost-effectiveness between hospital and community. CONCLUSION: This modelling exercise informs decision makers by a quantitative projection of available data and the explicit and transparent statements about assumptions and the degree of uncertainty. Further evaluation of the cost-effectiveness should focus on the potential differences in test parameters and prevalence in these two settings