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

The role of parental achievement goals in predicting autonomy-supportive and controlling parenting

Although autonomy-supportive and controlling parenting are linked to numerous positive and negative child outcomes respectively, fewer studies have focused on their determinants. Drawing on achievement goal theory and self-determination theory, we propose that parental achievement goals (i.e., achievement goals that parents have for their children) can be mastery, performance-approach or performance-avoidance oriented and that types of goals predict mothers' tendency to adopt autonomy-supportive and controlling behaviors. A total of 67 mothers (aged 30-53 years) reported their goals for their adolescent (aged 13-16 years; 19.4 % girls), while their adolescent evaluated their mothers' behaviors. Hierarchical regression analyses showed that parental performance-approach goals predict more controlling parenting and prevent acknowledgement of feelings, one autonomy-supportive behavior. In addition, mothers who have mastery goals and who endorse performance-avoidance goals are less likely to use guilt-inducing criticisms. These findings were observed while controlling for the effect of maternal anxiety

Momentum asymmetries as CP violating observables

Three body decays can exhibit CP violation that arises from interfering diagrams with different orderings of the final state particles. We construct several momentum asymmetry observables that are accessible in a hadron collider environment where some of the final state particles are not reconstructed and not all the kinematic information can be extracted. We discuss the complications that arise from the different possible production mechanisms of the decaying particle. Examples involving heavy neutralino decays in supersymmetric theories and heavy Majorana neutrino decays in Type-I seesaw models are examined.Comment: 20 pages, 9 figures. Clarifying comments and one reference added, matches published versio

The Economic Impact of Early Life Environmental Tobacco Smoke Exposure: Early Intervention for Developmental Delay

BACKGROUND AND OBJECTIVES: Early-life exposure to environmental tobacco smoke (ETS) can result in developmental delay as well as childhood asthma and increased risk of cancer. The high cost of childhood asthma related to ETS exposure has been widely recognized; however, the economic impact of ETS-related developmental delay has been less well understood. METHODS AND RESULTS:The Columbia Center for Children\u27s Environmental Health (CCCEH) has reported adverse effects of prenatal ETS exposure on child development in a cohort of minority women and children in New York City (odds ratio of developmental delay = 2.36; 95% confidence interval 1.22-4.58). Using the environmentally attributable fraction (EAF) approach, we estimated the annual cost of one aspect of ETS-related developmental delay: Early Intervention Services. The estimated cost of these services per year due to ETS exposure is \u3e Dollars 50 million per year for New York City Medicaid births and Dollars 99 million per year for all New York City births. CONCLUSION:The high annual cost of just one aspect of developmental delay due to prenatal exposure to ETS provides further impetus for increased prevention efforts such as educational programs to promote smoke-free homes, additional cigarette taxes, and subsidizing of smoking cessation programs

Mindfulness based interventions in multiple sclerosis: a systematic review

<b>Background</b> Multiple sclerosis (MS) is a stressful condition; depression, anxiety, pain and fatigue are all common problems. Mindfulness based interventions (MBIs) mitigate stress and prevent relapse in depression and are increasingly being used in healthcare. However, there are currently no systematic reviews of MBIs in people with MS. This review aims to evaluate the effectiveness of MBIs in people with MS.<p></p> <b>Methods</b> Systematic searches were carried out in seven major databases, using both subject headings and key words. Papers were screened, data extracted, quality appraised, and analysed by two reviewers independently, using predefined criteria. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Perceived stress was the primary outcome. Secondary outcomes include mental health, physical health, quality of life, and health service utilisation. Statistical meta-analysis was not possible. Disagreements were adjudicated by a third party reviewer.<p></p> <b>Results</b> Three studies (n = 183 participants) were included in the final analysis. The studies were undertaken in Wales (n = 16, randomised controlled trial - (RCT)), Switzerland (n = 150, RCT), and the United States (n = 17, controlled trial). 146 (80%) participants were female; mean age (SD) was 48.6 (9.4) years. Relapsing remitting MS was the main diagnostic category (n = 123, 67%); 43 (26%) had secondary progressive disease; and the remainder were unspecified. MBIs lasted 6–8 weeks; attrition rates were variable (5-43%); all employed pre- post- measures; two had longer follow up; one at 3, and one at 6 months. Socio-economic status of participants was not made explicit; health service utilisation and costs were not reported. No study reported on perceived stress. All studies reported quality of life (QOL), mental health (anxiety and depression), physical (fatigue, standing balance, pain), and psychosocial measures. Statistically significant beneficial effects relating to QOL, mental health, and selected physical health measures were sustained at 3- and 6- month follow up.<p></p> <b>Conclusion</b> From the limited data available, MBIs may benefit some MS patients in terms of QOL, mental health, and some physical health measures. Further studies are needed to clarify how MBIs might best serve the MS population.<p></p&gt

State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

The clinical features of the piriformis syndrome: a systematic review

Piriformis syndrome, sciatica caused by compression of the sciatic nerve by the piriformis muscle, has been described for over 70 years; yet, it remains controversial. The literature consists mainly of case series and narrative reviews. The objectives of the study were: first, to make the best use of existing evidence to estimate the frequencies of clinical features in patients reported to have PS; second, to identify future research questions. A systematic review was conducted of any study type that reported extractable data relevant to diagnosis. The search included all studies up to 1 March 2008 in four databases: AMED, CINAHL, Embase and Medline. Screening, data extraction and analysis were all performed independently by two reviewers. A total of 55 studies were included: 51 individual and 3 aggregated data studies, and 1 combined study. The most common features found were: buttock pain, external tenderness over the greater sciatic notch, aggravation of the pain through sitting and augmentation of the pain with manoeuvres that increase piriformis muscle tension. Future research could start with comparing the frequencies of these features in sciatica patients with and without disc herniation or spinal stenosis

Apolipoprotein epsilon 3 alleles are associated with indicators of neuronal resilience

<p>Abstract</p> <p>Background</p> <p>Epilepsy is associated with precocious development of Alzheimer-type neuropathological changes, including appearance of senile plaques, neuronal loss and glial activation. As inheritance of <it>APOE ε4 </it>allele(s) is reported to favor this outcome, we sought to investigate neuronal and glial responses that differ according to <it>APOE </it>genotype. With an eye toward defining ways in which <it>APOE ε3 </it>alleles may foster neuronal well-being in epilepsy and/or <it>APOE ε4 </it>alleles exacerbate neuronal decline, neuronal and glial characteristics were studied in temporal lobectomy specimens from epilepsy patients of either <it>APOE ε4,4 </it>or <it>APOE ε3,3 </it>genotype.</p> <p>Methods</p> <p>Tissue and/or cellular expressions of interleukin-1 alpha (IL-1α), apolipoprotein E (ApoE), amyloid β (Aβ) precursor protein (βAPP), synaptophysin, phosphorylated tau, and Aβ were determined in frozen and paraffin-embedded tissues from 52 <it>APOE ε3,3 </it>and 7 <it>APOE ε4,4 </it>(0.25 to 71 years) epilepsy patients, and 5 neurologically normal patients using Western blot, RT-PCR, and fluorescence immunohistochemistry.</p> <p>Results</p> <p>Tissue levels of IL-1α were elevated in patients of both <it>APOE ε3,3 </it>and <it>APOE ε4,4 </it>genotypes, and this elevation was apparent as an increase in the number of activated microglia per neuron (<it>APOE </it>ε<it>3,3 </it>vs <it>APOE ε4,4 </it>= 3.7 ± 1.2 vs 1.5 ± 0.4; <it>P </it>< 0.05). This, together with increases in βAPP and ApoE, was associated with apparent neuronal sparing in that <it>APOE ε4,4 </it>genotype was associated with smaller neuron size (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 173 ± 27 vs 356 ± 45; <it>P </it>≤ 0.01) and greater DNA damage (<it>APOE ε4,4 </it>vs <it>APOE ε3,3 </it>= 67 ± 10 vs 39 ± 2; <it>P </it>= 0.01). 3) Aβ plaques were noted at early ages in our epilepsy patients, regardless of <it>APOE </it>genotype (<it>APOE ε4,4 </it>age 10; <it>APOE ε3,3 </it>age 17).</p> <p>Conclusions</p> <p>Our findings of neuronal and glial events, which correlate with lesser neuronal DNA damage and larger, more robust neurons in epilepsy patients of <it>APOE ε3,3 </it>genotype compared to <it>APOE ε4,4 </it>genotype carriers, are consistent with the idea that the <it>APOE </it>ε<it>3,3 </it>genotype better protects neurons subjected to the hyperexcitability of epilepsy and thus confers less risk of AD (Alzheimer's disease).</p> <p>Please see related article: <url>http://www.biomedcentral.com/1741-7015/10/36</url></p