Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease

Although it has been known since the 1960s that trypsin and chymotrypsin can mimic hormone action in tissues, it took until the 1990s to discover that serine proteinases can regulate cells by cleaving and activating a unique four-member family of GPCRs known as proteinase-activated receptors (PARs). PAR activation involves the proteolytic exposure of its N-terminal receptor sequence that folds back to function as a ‘tethered’ receptor-activating ligand (TL). A key N-terminal arginine in each of PARs 1 to 4 has been singled out as a target for cleavage by thrombin (PARs 1, 3 and 4), trypsin (PARs 2 and 4) or other proteases to unmask the TL that activates signalling via G_q, G_i or G_12/13. Similarly, synthetic receptor-activating peptides, corresponding to the exposed ‘TL sequences’ (e.g. SFLLRN—, for PAR1 or SLIGRL— for PAR2) can, like proteinase activation, also drive signalling via G_q, G_i and G_12/13, without requiring receptor cleavage. Recent data show, however, that distinct proteinase-revealed ‘non-canonical’ PAR tethered-ligand sequences and PAR-activating agonist and antagonist peptide analogues can induce ‘biased’ PAR signalling, for example, via G_12/13-MAPKinase instead of G_q-calcium. This overview summarizes implications of this ‘biased’ signalling by PAR agonists and antagonists for the recognized roles the PARs play in inflammatory settings.Linked ArticlesThis article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-5     

Assessing the impact of the local environment on birth outcomes: a case for HLM

Hierarchical linear Models (HLM) is a useful way to analyze the relationships between community level environmental data, individual risk factors, and birth outcomes. With HLM we can determine the effects of potentially remediable environmental conditions (e.g., air pollution) after controlling for individual characteristics such as health factors and socioeconomic factors. Methodological limitations of ecological studies of birth outcomes and a detailed analysis of the varying models that predict birth weight will be discussed. Ambient concentrations of criterion air pollutants (e.g., lead and sulfur dioxide) demonstrated a sizeable negative effect on birth weight; while the economic characteristics of the mother's residential census tract (ex. poverty level) also negatively influenced birth weight.     

Empirical Bayes estimation of the prevalence of uninsured individuals by county in the state of Tennessee and analyses of predictive factors

Lawmakers at the state level require good estimates of those without health insurance in the areas they serve to inform policy decisions. These estimates are often built on inadequate data from smaller geographic areas, such as counties. The Small Area Estimates Branch of the U.S. Census Bureau developed a method to generate stable estimates at the county level using data from the Annual Social and Economic Supplement to the Current Population Survey and several other sources. Using data collected in the state of Tennessee, this article presents a less complicated and arguably less expensive alternative to that method, while providing comparable results. Limitations of both methods and suggestions for future research are discussed.     

VEGF mitigates histone‐induced pyroptosis in the remote liver injury associated with renal allograft ischemia–reperfusion injury in rats

Clinical evidence has indicated a possible link between renal injury and remote liver injury. We investigated whether extracellular histone mediates remote hepatic damage after renal graft ischemia–reperfusion injury, while vascular endothelial growth factor (VEGF) is protective against remote hepatic injury. In vitro, hepatocyte HepG2 cultures were treated with histone. In vivo, the Brown‐Norway renal graft was stored in 4°C preservation solution for 24 hours and then transplanted into a Lewis rat recipient; blood samples and livers from recipients were harvested 24 hours after surgery. Prolonged cold ischemia in renal grafts enhanced liver injury 24 hours after engraftment. Caspase‐1, ASC, NLRP3, and AIM2 expressions in hepatocyte, CD68⁺‐infiltrating macrophages, tissue, and serum interleukin‐1β and ‐18 were greatly elevated, indicating that pyroptosis occurred in the liver and resulted in acute liver functional impairment. Blocking the caspase‐1 pathway decreased the number of necrotic hepatocytes. VEGF treatment suppressed the hepatocyte pyroptosis and liver function was partially restored. Our data suggested that renal allograft ischemia–reperfusion injury is likely associated with acute liver damage due to hepatocyte pyroptosis induced by histone and such injury may be protected by VEGF administration. VEGF, therefore, may serve as a new strategy against other remote organ injuries related to renal transplantation.     

Predictors of Treatment-Resistant and Clozapine-Resistant Schizophrenia: A 12-Year Follow-up Study of First-Episode Schizophrenia-Spectrum Disorders

Studies on the long-term development and early predictors of treatment-resistant schizophrenia (TRS) and clozapine-resistant TRS (CR-TRS) in patients with first-episode schizophrenia-spectrum disorders (FES) are limited and have not considered the impact of early intervention services (EIS). This study aimed to explore the development of TRS and CR-TRS among patients with FES over 12 years of follow-up. Of the 1234 patients with FES, 15% developed TRS. A total of 450 patients with schizophrenia or schizoaffective disorder were included in a nested case-control study (157 TRS and 293 non-TRS). Younger age of onset, poorer premorbid social adjustment during adulthood, longer duration of first episode, a greater number of relapses, and a higher antipsychotic dose in the first 24 months were associated with earlier TRS. CR-TRS patients, constituting 25% of TRS patients, had a poorer premorbid social adjustment in late adolescence and longer delay before clozapine initiation compared with non-CR-TRS. CR-TRS had poorer clinical and functional outcomes at 12-year follow-up. However, TRS patients on clozapine had a lower mortality rate compared with non-TRS patients. EIS did not have a significant impact on the development of TRS, but patients in the EIS group had a shorter delay of clozapine initiation. Results suggested that neurodevelopmental factors, early clinical characteristics, and requirement for higher antipsychotic dose may be associated with TRS development, highlighting multiple pathways leading to this form of illness. Specific interventions including relapse prevention and early initiation of clozapine during the early course of illness may reduce the rate of TRS and improve patient outcomes.     

Prefrontal resting-state connectivity and antidepressant response: no associations in the ELECT-TDCS trial

European Archives of Psychiatry and Clinical Neuroscience - Functional and structural MRI of prefrontal cortex (PFC) may provide putative biomarkers for predicting the treatment response to...     

Survey of parents of children with cancer who look for alternative therapies

Alternative therapies are regimens that run counter to the mainstream of Western medicine. The main purpose of this study was to investigate and evaluate the alternative medicine with which parents of children with cancer seek to have their children treated. The research took as its subjects the parents of children with cancer who were outpatients or inpatients in six medical centers from September to December, 1999. Data were collected by questionnaire and 110 copies were effective. The results showed that 69.1% of the parents had been seeking alternative therapies. The most popular form of alternative therapy identified by this research was folk and religious therapy (68.4%), followed by Chinese medical treatment (57.9%), followed by special diets (50.0%). Other forms were used, such as herbal and arcanum therapy (13.2%), human electricity (3.9%), meditation (1.3%), and aromatherapy (1.3%). The results also showed that 61.8% of the parents had not discussed the use of the alternative therapies with the children's doctors. Hospital workers, therefore, should try to understand the situations of pediatric patients using alternative therapies, and provide appropriate suggestions to parents of pediatric patients as well as more humane, thoughtful medical care.