PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-ß generation by reducing ß-secretase in an Alzheimer's disease model.

Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aß pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of ß-APP cleaving enzyme (BACE1), the main enzyme involved in Aß generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aß deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aß pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

Pain severity as a mediator of the association between depressive symptoms and physical performance in knee osteoarthritis.

OBJECTIVE: Depressive symptoms in knee osteoarthritis (OA) are associated with increased pain severity and declines in physical performance. This study examined whether pain severity mediates the association between depressive symptoms and physical performance in persons with radiographic knee OA. METHOD: Three years of annual data from participants (n = 1,463) with radiographic knee OA in the Osteoarthritis Initiative (OAI) were analyzed. Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES-D) scale. Pain severity was evaluated with the Western Ontario and McMaster Universities Arthritis Index. Physical performance was assessed via standardized gait speed. Marginal structural models were used to assess the direct (unmediated) effects of depressive symptoms on physical performance and indirect (mediated) effects through pain severity. RESULTS: Direct and indirect effects for a difference in CES-D score of 0-1 were -0.0051 (95% confidence intervals (CI): -0.0053, -0.0049) and -0.0016 (95% CI: -0.0024, -0.0007) standard deviations in gait speed, respectively. Higher depressive symptom severity exhibited diminishing, incremental, direct and indirect effects and for a difference in CES-D score of 15-16 were -0.0045 (95% CI: -0.0047, -0.0042) and -0.0009 (95% CI: -0.0014, -0.0004) standard deviations in gait speed, respectively. Therefore, the magnitude of the mediated, indirect effect, was never larger than 24%. CONCLUSION: Pain severity mediated approximately one-fifth of the association between depressive symptoms and physical performance in persons with radiographic knee OA, and the diminishing incremental effects may explain why unimodal treatment strategies with a single disease target are often ineffective in depressed OA patients.

Mapping transmembrane residues of proteinase activated receptor 2 (PAR2) that influence ligand-modulated calcium signaling.

Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor involved in metabolism, inflammation, and cancers. It is activated by proteolysis, which exposes a nascent N-terminal sequence that becomes a tethered agonist. Short synthetic peptides corresponding to this sequence also activate PAR2, while small organic molecules show promising PAR2 antagonism. Developing PAR2 ligands into pharmaceuticals is hindered by a lack of knowledge of how synthetic ligands interact with and differentially modulate PAR2. Guided by PAR2 homology modeling and ligand docking based on bovine rhodopsin, followed by cross-checking with newer PAR2 models based on ORL-1 and PAR1, site-directed mutagenesis of PAR2 was used to investigate the pharmacology of three agonists (two synthetic agonists and trypsin-exposed tethered ligand) and one antagonist for modulation of PAR2 signaling. Effects of 28 PAR2 mutations were examined for PAR2-mediated calcium mobilization and key mutants were selected for measuring ligand binding. Nineteen of twenty-eight PAR2 mutations reduced the potency of at least one ligand by >10-fold. Key residues mapped predominantly to a cluster in the transmembrane (TM) domains of PAR2, differentially influence intracellular Ca2+ induced by synthetic agonists versus a native agonist, and highlight subtly different TM residues involved in receptor activation. This is the first evidence highlighting the importance of the PAR2 TM regions for receptor activation by synthetic PAR2 agonists and antagonists. The trypsin-cleaved N-terminus that activates PAR2 was unaffected by residues that affected synthetic peptides, challenging the widespread practice of substituting peptides for proteases to characterize PAR2 physiology.

Update to the Hong Kong Epilepsy Guideline: evidence-based recommendations for clinical management of women with epilepsy throughout the reproductive cycle.

Since the publication of the Hong Kong Epilepsy Guideline in 2009, there has been significant progress in antiepileptic drug development. New AEDs have emerged, and data about their uses have been published. Women require special attention in epilepsy care. Drug teratogenicity, pregnancy, breastfeeding, contraception, reproduction technology, menopause, and catamenial epilepsy are major topics. Antiepileptic drugs should be chosen individually for patients who are pregnant or may become pregnant with consideration of their teratogenicity and seizure control properties. Folate is commonly prescribed for women of childbearing age who are taking antiepileptic drugs. Spontaneous vaginal delivery and breastfeeding are not contra-indicated in most cases but need to be considered individually based on the patient's medical condition and wishes. Serum drug level monitoring of certain antiepileptic drugs during pregnancy and puerperium can guide dosage adjustment. For catamenial epilepsy, intermittent benzodiazepines such as clobazam during the susceptible phase of the menstrual cycle could be a treatment option.

Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria.

Dihydropyrimidinase deficiency is an autosomal recessive inborn error of metabolism characterised by the presence of dihydropyrimidinuria. Its clinical presentation is variable and has also been reported in asymptomatic subjects. We report the first case of dihydropyrimidinase deficiency in Hong Kong, which is also the first reported in a Chinese subject. The patient was a 32-month-old boy who presented with language development delay. Biochemical analysis confirmed markedly increased urinary excretion of dihydrouracil and dihydrothymine, whilst DNA testing confirmed that the patient was compound heterozygous for two missense mutations, one known (p.R302Q) and the other was novel (p.N16K).

When patients teach students empathy: a systematic review of interventions for promoting medical student empathy.

Background: Despite growing emphasis on empathic care, numerous studies demonstrate diminishing empathy in medical students. Involving patient educators in medical curricula may be a solution. Therefore, we conducted a systematic review to evaluate patient-involved interventions that promote empathy among medical students. Method: A literature search of MEDLINE, Embase, PsycINFO, and ERIC databases was performed using the keywords "empathy," "medical student," and their synonyms. Results were independently screened in duplicate. Conflicts were resolved by group consensus. All English studies describing interventions that promote empathy in medical students engaging patient educators were included. Relevant data was extracted and summarized. Results: 1467 studies were screened. 14 studies were included, of which 10 were pilot studies. Studies included patient involved interventions such as storytelling (5/14), shadowing patients (3/14), recorded videos (3/14), or combinations of methods (3/14). Qualitative measurements of empathy included written feedback and group discussions. Quantitative measurements included validated scales measuring empathy. All studies demonstrated increase in empathy among medical students. Participants reported satisfaction with training and patients reported being proud of giving back by training future physicians. Conclusion: Interventions engaging patient educators were shown to have a positive impact on medical student empathy. Furthermore, patient-led education was shown to increase medical student understanding of subject and knowledge retention while empowering patients. Further implementation of patient-involved education is an important step forward in patient-partnered care and may identify additional advantages of patient engagement in medical education.

Contexte: Malgré l'importance grandissante accordée à l'empathie dans les soins de santé, de nombreuses études démontrent une diminution de l'empathie chez les étudiants en médecine. La participation de patients éducateurs dans les programmes d'études médicales pourrait être une solution. Nous avons donc réalisé une revue systématique pour évaluer les interventions qui visent à promouvoir l'empathie chez les étudiants et qui font participer des patients. Méthode: Nous avons effectué une recherche dans les bases de données MEDLINE, Embase, PsycINFO et ERIC en utilisant les mots-clés «empathie¼, «étudiant en médecine¼ et leurs synonymes. Les résultats ont été examinés de manière indépendante et en double. Les conflits ont été résolus par consensus de groupe. Toutes les études en anglais décrivant des interventions visant à promouvoir l'empathie chez les étudiants en médecine avec la participation de patients éducateurs ont été incluses. Les données pertinentes ont été extraites et résumées. Résultats: Des 1467 études examinées, 14 ont été incluses, dont 10 études pilotes. Les interventions avec des patients mentionnées dans les études comprenaient des récits (5/14), l'observation des patients (3/14), des vidéos enregistrées (3/14) ou des combinaisons de méthodes (3/14). Les mesures qualitatives de l'empathie comprenaient des commentaires écrits et des discussions de groupe. Les mesures quantitatives étaient des échelles validées mesurant l'empathie. Toutes les études indiquent une augmentation de l'empathie chez les étudiants en médecine. Les participants se disent satisfaits de la formation et les patients déclarent être fiers de redonner aux soignants en contribuant à former les futurs médecins. Conclusion: Les interventions faisant appel à des patients éducateurs ont eu un effet positif sur le développement de l'empathie des étudiants en médecine. En outre, il a été démontré que la participation de patients dans la formation augmentait la compréhension du sujet et la rétention des connaissances par les étudiants en médecine tout en responsabilisant les patients. La généralisation de l'intervention des patients dans l'éducation constitue une avancée importante dans les soins en partenariat avec le patient et pourrait révéler d'autres avantages de la participation des patients dans l'éducation médicale.