Chemical Biology, Molecular Mechanism and Clinical Perspective of ��-Secretase Modulators in Alzheimer��s Disease

Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer''s disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.     

Psychological and behavioural impacts of the 2008 China earthquake on blood donors

Background and Objectives On May 12, 2008, a severe earthquake hit Sichuan province in China. A post‐earthquake survey was conducted to study the earthquake’s effect on blood donor behaviour and stress at three blood centres at varying distances from the epicentre. Materials and Methods A questionnaire was developed to assess donor post‐traumatic stress disorders (PTSD) and attitudes toward giving blood. Responses were compared by centre and donor characteristics using multivariate logistic regression techniques. Results Of all 17 456 donors, the overall prevalence of PTSD was 13·2%. Donors who knew someone killed or injured by the earthquake were 2·1 times more likely to have PTSD than others (95% CI: 1·8–2·4). 85·2% of donors cited the earthquake as their reason for donating. 16·1% of donors felt it acceptable to be less honest about one’s health history in an emergency. After adjusting for PTSD, geographic and demographic characteristics, the donors knowing someone killed or injured by the earthquake were 1·4 times (95% CI: 1·2–1·7) more likely to cite the earthquake as reason for donating, and 1·8 times (95% CI: 1·5–2·1) more likely to accept being less honest about one’s health history in case of national emergency. Conclusions The psychological and behavioural impacts of the earthquake on blood donors extended far from the epicentre. After a disaster, it is important to emphasize that donors must be truthful on the donor questionnaire as some donors appear willing to be less than honest when they perceive an increased need for blood products.     

Interobserver variability in the assessment of clinical criteria for suspected urinary tract infection in nursing home residents.

We determined the interobserver variability in the assessment of clinical criteria for urinary tract infection (UTI) in nursing home residents. Pairs of nursing home staff caring for 30 residents were interviewed at the time UTI was suspected. At least one measure from each of 7 clinical criteria categories was reliably assessed by nursing home staff members.     

Cost-utility of one-time colonoscopic screening for colorectal cancer at various ages

OBJECTIVE: One-time colonoscopy has been recommended as a possible colorectal cancer (CRC) screening strategy. Because the incidence of colorectal neoplasia increases with age, the effectiveness and cost of this strategy depend on the age at which screening occurs. The purpose of this study was to investigate the age-dependent cost-utility of one-time colonoscopic screening. METHODS: We constructed a computer simulation model of the natural history of colorectal neoplasia. This model was used to compare the cost-utility of no screening and age-based strategies employing one-time colonoscopic screening (age ranges evaluated: 45-49, 50-54, 55-59, and 60-64 yr). RESULTS: We determined that one-time colonoscopic screening in men age <60 yr and in women age <65 yr dominates never screening and screening at older ages. For both sexes, one-time colonoscopic screening between 50 and 54 yr of age is associated with a marginal cost-utility of less than $10,000 per additional quality-adjusted life-year compared to screening between 55 and 60 yr of age. One-time colonoscopic screening between 45 and 49 yr of age is either dominated (women) or associated with a marginal cost-utility of $69,000/per quality-adjusted life-year (men) compared to screening between 50 and 54 yr of age. The marginal cost-utility of one-time colonoscopic screening is relatively insensitive to plausible changes in the cost of colonoscopy, the cost of CRC treatment, the sensitivity of colonoscopy for colorectal neoplasia, the utility values representing the morbidity associated with the CRC-related health states, and the discount rate. CONCLUSIONS: One-time colonoscopic screening between 50 and 54 yr of age is cost-effective compared to no screening and screening at older ages in both men and women. Screening in men between 45 and 49 yr of age may be cost-effective compared to screening between 50 and 54 yr of age depending on societal willingness to pay.     

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.