Dyslexia and learning disabilities in Canada and the UK: the impact of its disability employment laws.

The impact of employment laws pertaining to individuals with learning disabilities in Canada and dyslexia in the UK were investigated via the extant research literature. Currently, there is very little research in this area despite Canada and the UK having laws in effect for decades. Surprisingly, their laws have been revamped despite an absence of data that measures impact and effectiveness. This finding is not unlike the Americans with Disabilities Act, reauthorized as the Americans with Disabilities Act Amendments in 2008, without substantive research to guide legal policies and practices going forward. Investigation in this area is needed to seek the positive and negative effects of legislation on those with learning disabilities in Canada and dyslexia in the UK, a high incidence population that finds most employment opportunities in competitive employment.

Validation and use of the MM-PBSA approach for drug discovery.

The MM-PBSA approach has become a popular method for calculating binding affinities of biomolecular complexes. Published application examples focus on small test sets and few proteins and, hence, are of limited relevance in assessing the general validity of this method. To further characterize MM-PBSA, we report on a more extensive study involving a large number of ligands and eight different proteins. Our results show that applying the MM-PBSA energy function to a single, relaxed complex structure is an adequate and sometimes more accurate approach than the standard free energy averaging over molecular dynamics snapshots. The use of MM-PBSA on a single structure is shown to be valuable (a) as a postdocking filter in further enriching virtual screening results, (b) as a helpful tool to prioritize de novo design solutions, and (c) for distinguishing between good and weak binders (DeltapIC(50) > or = 2-3), but rarely to reproduce smaller free energy differences.

Predicting plasma protein binding of drugs--revisited.

Plasma protein binding of drugs has been studied for almost 100 years, but despite the accumulation of large amounts of data, the accurate prediction of this ADME parameter continues to be problematic. This review outlines recent efforts on the development of prediction tools for plasma protein binding of drugs, specifically human serum albumin, in the context of its relevance and its influencing factors. The issue of why it is difficult to achieve prediction of sufficient quality for a diverse dataset will also be considered.

Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening.

Novel 2,4-diaminopyrimidines bearing N,N-disubstituted aminomethyl residues at the 5-position were designed as dihydrofolate reductase (DHFR) inhibitors. These compounds were obtained by treatment of 1-[(2,4-diamino-5-pyrimidinyl)methyl]pyridinium bromide with secondary amines in a polar solvent and in the presence of triethylamine at room temperature. The procedure was found to be very efficient and suitable for application in high-throughput synthesis. In addition, we found that high-throughput screening for enzymatic and in vitro antibacterial activity could be performed on crude reaction mixtures, thus avoiding any purification step. Over 1200 proprietary secondary amines were selected for high-throughput synthesis, based on structural and diversity-related criteria, and the resulting products were submitted to high-throughput screening. A greater number of hits, and significantly more active compounds, were obtained through structure-based library design than through diversity-based library design. Different classes of inhibitors of DHFR were identified in this way, including compounds derived from di-, tri-, and tetracyclic amines. In general, these products showed high activity against the enzymes derived from both TMP-sensitive and TMP-resistant Streptococcus pneumoniae. Some compounds possessed appreciable selectivity for the bacterial over the human enzyme, whereas other compounds were not at all selective. In most cases, active enzyme inhibitors also displayed antibacterial activity.

Predicting plasma protein binding of drugs: a new approach.

In spite of the large amount of plasma protein binding data for drugs, it is not obvious and there is no clear consensus among different disciplines how to deal with this parameter in multidimensional lead optimization strategies. In this work, we have made a comprehensive study on the importance of plasma protein binding and the influencing factors in order to get new insights for this molecular property. Our analysis of the distribution of percentage plasma protein binding among therapeutic drugs showed that no general rules for protein binding can be derived, except for the class of chemotherapeutics, where a clear trend towards lower binding could be observed. For the majority of indication areas, however, empirical rules are missing. We present here an extensive list of multiply determined primary association constants for binding to human serum albumin (HSA) for 138 compounds from the literature. Correlating these binding constants with the percentage fraction of protein bound showed that the percentage data above 90%, corresponding to a binding constant below 6 microM, are of insufficient accuracy. Furthermore, it could be demonstrated that the lipophilicity of drugs, traditionally felt to dominate binding to HSA, is not the only relevant descriptor. Here, we report a generic model for the prediction of drug association constants to HSA, which uses a pharmacophoric similarity concept and partial least square analysis (PLS) to construct a quantitative structure-activity relationship. It is able to single out the submicromolar to nanomolar binders, i.e. to differentiate between 99.0 and 99.99% plasma protein binding. Depending on the system, this can be important in medicinal chemistry programs and may together with other computed physicochemical and ADME properties assist in the prioritization of synthetic strategies.

Beyond transition: a comparison of the employment experiences of American and Canadian adults with LD.

With the passage of the Americans with Disabilities Act in the United States and the Canadian Chartre of Rights and Freedoms, there is a new work environment for individuals with learning disabilities (LD) in North America. This qualitative study sought to compare the employment experiences of 25 U.S. adults with LD and 24 Canadian adults with LD. Areas of comparison were job getting, experiences on the job, and job advancement. Remarkably, the U.S. and Canadian adults with LD had nearly the same employment experiences. In essence, each set of data mirrored the other despite marked differences in U.S. and Canadian federal disability legislation.

The impact of learning disabilities on adulthood: a review of the evidenced-based literature for research and practice in adult education.

It is now well established that learning disabilities (LD) persist into the adult years, yet despite a developing literature base in this area, there is a paucity of evidence-based research to guide research and practice. Consistent with the demands of the adult stage of development, autonomy and self-determination are crucial to quality-of-life issues to adults in general, and specifically to adults with LD. There are many areas of functioning in which adults need to adapt successfully, such as employment, family, social and emotional, daily living routines, community, and recreation and leisure. In essence, there are a myriad of challenges and outcomes as adults navigate the trials and tribulations of LD as it manifests itself into adulthood. This review of the extant evidence-based literature seeks to discover relevant knowledge that can be shared with practitioners who serve adults with LD in a variety of professional and volunteer roles, particularly in adult education settings.

Usefulness of Austroads' fitness-to-drive guidelines: lessons from the Gillett case.

Regina v Gillett deals with a man who did not disclose his epilepsy when seeking a drivers licence. Subsequently, he had a seizure while driving, causing an accident in which three people died. He was found guilty but appealed. During the trial to decide whether Gillett was guilty of dangerous driving occasioning death, the judge decided that the Austroads fitness-to-drive guidelines were extraneous to legal consideration of the acceptable risk to be attached to chronic medical conditions. Although the appeal was unsuccessful with respect to guilt and sentencing, it did reinstate the relevance of the Austroads guidelines when evaluating suitable risk with respect to potentially dangerous drivers. We suggest that even greater protection can be afforded to the community if a clearly enunciated warning, outlining a driver's responsibilities, were to appear on each drivers license.

Late-term abortion: what can be learned from Royal Women's Hospital v Medical Practitioners Board of Victoria?

In 2001, the Medical Practitioners Board of Victoria received a complaint from an Australian Government Senator regarding a late-term abortion carried out in February 2000 at the Royal Women's Hospital, Melbourne. Five years later, the complaint of professional misconduct was finally dismissed by the Board as being frivolous and vexatious. The action highlights a number of deficiencies in the way medical practitioner boards deal with complaints against medical practitioners; in particular, the Board's lack of discretion to deal with complaints lacking substance. Early mediation of the dispute between the Royal Women's Hospital and the Medical Practitioners Board could have avoided a great deal of suffering and expense. As a result of this case, it is likely that the Victorian Medical Practitioners Board will be given additional powers in the future to deal with complaints without merit.

What can we learn from the Hwang and Sudbø affairs?

The recent publication, in prestigious scientific journals, of two major studies that were subsequently shown to contain fabricated data may compel reviewers and editors to adopt a more rigorous policy in accepting articles for publication. The current manner of peer reviewing research articles provides no assurance that the proffered work is not the result of fraud. The present guidelines for contributors in large team investigations may need to be updated to avoid giving credit to co-authors who may have made little, if any, contribution to the work.

Comparison of the binding pockets of two chemically unrelated allosteric antagonists of the mGlu5 receptor and identification of crucial residues involved in the inverse agonism of MPEP.

Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], a clinically validated non-benzodiazepine anxiolytic, has been shown to be a potent and non-competitive metabotropic glutamate (mGlu)-5 receptor antagonist. In the present study, we have used the site-directed mutagenesis coupled with three-dimensional receptor-based pharmacophore modelling to elucidate the interacting mode of fenobam within the seven-transmembrane domain (7TMD) of mGlu5 receptor and its comparison with that of 2-methyl-6-(phenylethynyl)pyridine (MPEP), the prototype antagonist. The common residues involved in the recognition of MPEP and fenobam include Pro654(3.36), Tyr658(3.40), Thr780(6.44), Trp784(6.48), Phe787(6.51), Tyr791(6.55) and Ala809(7.47). The differentiating residues between both modulators' interacting modes are Arg647(3.29), Ser657(3.39) and Leu743(5.47). Our data suggest that these chemically unrelated mGlu5 antagonists act similarly, probing a functionally unique region of the 7TMD. Using [3H]inositol phosphates accumulation assay, we have also identified the critical residues involved in the inverse agonist effect of MPEP. The mutation W784(6.48)A completely blocked the inverse agonist activity of MPEP; two mutations F787(6.51)A and Y791(6.55)A, caused a drastic decrease in the MPEP inverse agonism. Furthermore, these three mutations led to an increased efficacy of quisqualate without having any effect on its potency. The fact that the residues Trp784(6.48) and Phe787(6.51) are essential equally in antagonism and inverse agonism effects emphasizes again the key role of these residues and the involvement of a common transmembrane network in receptor inactivation by MPEP.

Structural, kinetic, and thermodynamic analysis of the binding of the 40 kDa PEG-interferon-alpha2a and its individual positional isomers to the extracellular domain of the receptor IFNAR2.

Type-I Interferons exert antiviral and antiproliferative activities through the binding to a common cell surface receptor comprising two subunits, IFNAR1 and IFNAR2. Human recombinant Interferon-alpha(2a) (IFNalpha(2a)) is a potent drug (Roferon-A) used to treat various cancers and viral diseases including Hepatitis B/C infections. To significantly improve the pharmacological properties of the drug, a pegylated form of IFNalpha(2a) was developed (PEGASYS). This 40 kDa PEG-conjugated IFNalpha(2a) ((40)PEG-IFNalpha(2a)) is obtained by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side-chain of IFNalpha(2a). Here, we report the detailed structural, kinetic, and thermodynamic analysis of the binding to the extracellular domain of the receptor IFNAR2 of (40)PEG-IFNalpha(2a) and its isolated positional isomers modified at K31, K134, K131, K121, K164, and K70, respectively, in comparison with unmodified IFNalpha(2a). Our binding studies, using the surface plasmon resonance technique, show that the pegylation does not abolish the binding to the receptor, but significantly reduces the affinity mainly due to a change of the association rate. The results are supported by modeling and simulation of the binding, using Self-Avoiding-Walk calculations for the polymer conformations. A correlation between the structural parameters and the kinetic and thermodynamic parameters of the binding of the positional isomers could be established. For the Isomer-K31 and -K164, the PEG-polymer attachment point is located in proximity to the binding interface, and the isomers display affinity in the range 150-520 nM in an enthalpy-driven binding process. In contrast for the Isomer-K134, -K131, -K121, and -K70, the PEG-polymer is attached remotely from the binding interface, and the isomers exhibit a higher affinity (32-76 nM) in an entropy-driven binding process. This study constitutes an essential collection of knowledge on which the interaction of (40)PEG-IFNalpha(2a) and its positional isomers with its cellular receptors can be better understood.

An automated system for the analysis of G protein-coupled receptor transmembrane binding pockets: alignment, receptor-based pharmacophores, and their application.

G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Here, a comprehensive and automated method allowing fast analysis and comparison of these putative binding pockets across the entire GPCR family is presented. The method relies on a robust alignment algorithm based on conservation indices, focusing on pharmacophore-like relationships between amino acids. Analysis of conservation patterns across the GPCR family and alignment to the rhodopsin X-ray structure allows the extraction of the amino acids lining the TM binding pocket in a so-called ligand binding pocket vector (LPV). In a second step, LPVs are translated to simple 3D receptor pharmacophore models, where each amino acid is represented by a single spherical pharmacophore feature and all atomic detail is omitted. Applications of the method include the assessment of selectivity issues, support of mutagenesis studies, and the derivation of rules for focused screening to identify chemical starting points in early drug discovery projects. Because of the coarseness of this 3D receptor pharmacophore model, however, meaningful scoring and ranking procedures of large sets of molecules are not justified. The LPV analysis of the trace amine-associated receptor family and its experimental validation is discussed as an example. The value of the 3D receptor model is demonstrated for a class C GPCR family, the metabotropic glutamate receptors.

Failed sterilisations and the unwanted child: a new medicolegal minefield?

A recent High Court decision has held that parents are entitled, in addition to the usual costs arising from a failed sterilisation, to the reasonable costs of raising a healthy child.

Withdrawing treatment from patients in a persistent vegetative state.

Medical opinion was unanimous that English youth Anthony Bland was in a persistent vegetative state with no hope of improvement or recovery. His family agreed that withdrawal of life support was appropriate, but Anthony's case went to the House of Lords for clarification of the legal position before any action was taken by his doctors. The court applied the Bolam test--that a regimen is legally acceptable if supported by a body of competent medical opinion, a principle specifically rejected by the High Court of Australia in Rogers v. Whitaker.