Phospholipase C families: Common themes and versatility in physiology and pathology

Phosphoinositide-specific phospholipase Cs (PLCs) are expressed in all mammalian cells and play critical roles in signal transduction. To obtain a comprehensive understanding of these enzymes in physiology and pathology, a detailed structural, biochemical, cell biological and genetic information is required. In this review, we cover all these aspects to summarize current knowledge of the entire superfamily. The families of PLCs have expanded from 13 enzymes to 16 with the identification of the atypical PLCs in the human genome. Recent structural insights highlight the common themes that cover not only the substrate catalysis but also the mechanisms of activation. This involves the release of autoinhibitory interactions that, in the absence of stimulation, maintain classical PLC enzymes in their inactive forms. Studies of individual PLCs provide a rich repertoire of PLC function in different physiologies. Furthermore, the genetic studies discovered numerous mutated and rare variants of PLC enzymes and their link to human disease development, greatly expanding our understanding of their roles in diverse pathologies. Notably, substantial evidence now supports involvement of different PLC isoforms in the development of specific cancer types, immune disorders and neurodegeneration. These advances will stimulate the generation of new drugs that target PLC enzymes, and will therefore open new possibilities for treatment of a number of diseases where current therapies remain ineffective

Feeding and growth in a captive-born bottlenose dolphin Tursiops truncatus

The feeding and growth of a captive-born bottlenose dolphin Tursiops trunatus calf were studied for 30 months post partum. Changes in the behaviours associated with suckling were monitored and suggested that the mammary glands need tactile stimulation before the calf can feed. The calf exhibited no teat preference and mean duration of each suckling bout (4 s) remained constant throughout the suckling period. Suckling frequency declined rapidly during the first two months and continued decreasing steadily for the remainder of the study. A reduced growth rate from seven months suggests that nutrition obtained only from milk is insufficient; however, growth rate increased from 11 months, after the calf started feeding on fish. Solid food intake increased rapidly until completion of the study, by which time the calf was eating 16 kg of fish daily. Short-term reductions in food intake after weaning resulted in corresponding reductions in weight, but appeared to have no effect on linear growth

Ligand and membrane-binding behavior of the phosphatidylinositol transfer proteins PITPα and β

Phosphatidylinositol transfer proteins (PITPs) are believed to be lipid transfer proteins due to their ability to transfer either PI or PC between membrane compartments in vitro. However, the detailed mechanism of this transfer process is not fully established. To further understand the transfer mechanism of PITPs we examined the interaction of PITPs with membranes using dual polarization interferometry (DPI) which measures protein binding affinity on a flat immobilized lipid surface. In addition, a fluorescence resonance energy transfer (FRET)-based assay was also employed to monitor how quickly PITPs transfer their ligands to lipid vesicles. DPI analysis revealed that PITPβ had a higher affinity to membranes compared to PITPα. Furthermore, the FRET-based transfer assay revealed that PITPβ has a higher ligand transfer rate compared to PITPα. However, both PITPα and PITPβ demonstrated a preference for highly curved membrane surfaces during ligand transfer. In other words, ligand transfer rate was higher when the accepting vesicles were highly curved

Association of antihypertensive monotherapy with serum sodium and potassium levels in Chinese patients

<b>Background</b> International guidelines on management of hypertension recommend any major classes of antihypertensive drugs. However, the low prescribing rate of thiazides has been attributed to concerns about electrolyte disturbances and studies between antihypertensive drug classes and hyponatremia/hypokalemia among Chinese patients were scarce. <p></p> <b>Methods</b> From clinical databases we included 2,759 patients who received their first-ever antihypertensive monotherapy from January 2004 to June 2007 in a large territory of Hong Kong. We studied the plasma sodium and potassium levels 8 weeks after prescriptions and factors associated with hyponatremia and hypokalemia by multivariable regression analyses. <p></p> <b>Results</b> Among major antihypertensive drug classes, thiazide users had the lowest sodium level (139.6 mEq/l, 95% confidence interval (CI) 139.3, 140.0, P < 0.001) and patients-prescribed calcium channel blockers (CCBs; 3.92 mEq/l, 95% CI 3.89, 3.95) or thiazide diuretics (3.99 mEq/l, 95% CI 3.93, 4.04) had the lowest potassium levels (P < 0.001). Multivariate analysis reported that advanced age (>/=70 years, odds ratio (OR) 7.49, 95% CI 2.84, 19.8, P < 0.001), male gender (OR 2.38, 95% CI 1.45, 3.91, P < 0.001), and thiazide users (OR 2.42, 95% CI 1.29, 4.56, P = 0.006) were significantly associated with hyponatremia, while renin-angiotensin system (RAS) (OR 0.31, 95% CI 0.13, 0.73, P = 0.008) and beta-blockers (BBs) (OR 0.35, 95% CI 0.23, 0.54, P < 0.001) users were less likely to present with hypokalemia. However, the proportions having normonatremic (95.1%) and normokalemic (89.4%) levels were high. <p></p> <b>Conclusions</b> In view of the low prevalence of hyponatremia and hypokalemia associated with thiazides, physicians should not be deterred from prescribing thiazide diuretics as first-line antihypertensive agents as recommended by most international guidelines

Allergen-induced airway inflammation and its therapeutic intervention

Allergen inhalation challenge has been useful for examining the mechanisms of allergen-induced airway inflammation and the associated physiological changes and for documenting the efficacy of drugs to treat asthma. Allergen inhalation by a sensitized subject results in acute bronchoconstriction, beginning within 15-30 min and lasting 1-3 hr, which can be followed by the development of a late asthmatic response. Individuals who develop both an early and late response after allergen have more marked increases in airway hyperresponsiveness, and greater increases in allergen-induced airway inflammation, particularly in airway eosinophils and basophils. All of the currently available and effective treatments for asthma modify some aspects of allergen-induced responses. These medications include short-acting and long-acting inhaled β2-agonists, inhaled corticosteroids, cromones, methylxanthines, leukotriene inhibitors, and anti-IgE monoclonal antibody. In addition, allergen inhalation challenge has become a useful method which can, in a very limited number of patients, provide key information on the therapeutic potential of new drugs being developed to treat asthma

Feeling of knowing and restudy choices

Feeling-of-knowing judgments (FOK-Js) reflect people’s confidence that they would be able to recognize a currently unrecallable item. Although much research has been devoted to the factors determining the magnitude and accuracy of FOK-Js, much less work has addressed the issue of whether FOK-Js are related to any form of metacognitive control over memory processes. In the present study, we tested the hypothesis that FOK-Js are related to participants’ choices of which unrecallable items should be restudied. In three experiments, we showed that participants tend to choose for restudy items with high FOK-Js, both when they are explicitly asked to choose for restudy items that can be mastered in the restudy session (Exps. 1a and 2) and when such specific instructions are omitted (Exp. 1b). The study further demonstrated that increasing FOK-Js via priming cues affects restudy choices, even though it does not affect recall directly. Finally, Experiment 2 showed the strategy of restudying unrecalled items with high FOK-Js to be adaptive, because the efficacy of restudy is greater for these items than for items with low FOK-Js. Altogether, the present findings underscore an important role of FOK-Js for the metacognitive control of study operations

Daily physical activity and related risk factors in COPD

Background Factors associated with reduced daily physical activity (DPA) in patients with COPD are still controversial. Physical inactivity in COPD increases risk of cardiovascular disease, frequent exacerbations, reduced health status, and increased symptoms. We hypothesised that reduced DPA in patients with COPD is independent of traditional risk factors including age and spirometry. Methods In this cross-sectional study, DPA (over 7 days) was assessed on 88 community stable patients with COPD and 40 controls free from cardiorespiratory disease. Spirometry, body composition, number of exacerbations, handgrip strength (HGS), modified Medical Research Council (mMRC), arterial stiffness, 6-min walking distance (6MWD) and BODE index were also determined. Frequent exacerbation was defined as ≥2 and non-frequent exacerbation < 2. Results Patients with COPD had reduced DPA and exercise capacity compared with controls similar in age, BMI and gender, p  0.05. The level of breathlessness was superior to lung function in predicting the level of DPA. Conclusion The level of DPA in COPD was independent of traditional risk factors. Breathlessness score is a better predictor of the DPA than lung function and handgrip strength