Lipid phosphate phosphatase (LPP3) and vascular development

Lipid phosphate phosphatases (LPP) are integral membrane proteins with broad substrate specificity that dephosphorylate lipid substrates including phosphatidic acid, lysophosphatidic acid, ceramide 1-phosphate, sphingosine 1-phosphate, and diacylglycerol pyrophosphate. Although the three mammalian enzymes (LPP1-3) demonstrate overlapping catalytic activities and substrate preferences in vitro, the phenotypes of mice with targeted inactivation of the Ppap2 genes encoding the LPP enzymes reveal nonredundant functions. A specific role for LPP3 in vascular development has emerged from studies of mice lacking Ppap2b. A meta-analysis of multiple, large genome-wide association studies identified a single nucleotide polymorphism in PPAP2B as a novel predictor of coronary artery disease. In this review, we will discuss the evidence that links LPP3 to vascular development and disease and evaluate potential molecular mechanisms. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.     

Interaction and dose equivalence of salbutamol and salmeterol in patients with asthma.

OBJECTIVE--To examine the pharmacological interaction of salmeterol and salbutamol and to derive an estimate of dose equivalence of salmeterol for airway and systemic effects in patients with asthma. DESIGN--Randomised double blind crossover study. SUBJECTS--12 patients with mild asthma. INTERVENTION--Placebo or salmeterol 50, 100, 200 micrograms given on separate days followed two hours later by inhaled salbutamol in cumulative doses up to 3600 micrograms. MAIN OUTCOME MEASURES--Change in forced expiratory volume in one second (FEV1), heart rate, plasma potassium concentration, QTc interval, tremor amplitude, and creatine kinase myocardial isoenzyme concentration. RESULTS--Compared with placebo, the mean (95% confidence interval) changes in FEV1 and heart rate after salmeterol 200 micrograms were 0.61 (0.32 to 0.90) l and 7.0 (3.8 to 10.2) beats/min. Adding salbutamol caused a large increase in FEV1 after placebo (0.69 l) with progressively smaller changes after increasing doses of salmeterol (0.19 l after salmeterol 200 micrograms). Heart rate and QTc interval increased and plasma potassium concentration decreased roughly in parallel on the four study days with a suggestion of convergence at higher doses of salbutamol. Geometric mean dose equivalences for salmeterol 50 micrograms and 100 micrograms compared with salbutamol were 4.9 and 7.8 (mean 6.4) for FEV1 and ranged from 7.1 (2.9 to 17.0) to 12.6 (4.4 to 36.4) for heart rate, plasma potassium, and tremor (mean 9.5). CONCLUSIONS--The effect of adding salbutamol to salmeterol is largely additive. Weight for weight salmeterol may be up to 10 times more potent than salbutamol. Considering its longer duration of action salmeterol 50 micrograms twice daily could be equivalent to salbutamol in doses up to 500 micrograms four to six hourly.     

Biosynthesis of peptide neurotransmitters: studies on the formation of peptide amides

A high proportion of peptide transmitters and peptide hormones terminate their peptide chain in a C-terminal amide group which is essential for their biological activity. The specificity of an enzyme that catalyses the formation of the amide was investigated with the aid of synthetic peptide substrates. With peptides containing l-amino acids the enzyme exhibited an essential requirement for glycine in the C-terminal position; amidation did not take place with peptides that had leucine, alanine, glutamic acid, lysine or N-methylglycine at the C-terminus and a peptide extended by the attachment of lysine to the C-terminal glycine did not act as a substrate. Amidation did occur with a peptide containing C-terminal D-alanine but no reaction was detected with peptides having C-terminal, D-serine or D-leucine. In tripeptides with a neutral amino acid in the penultimate position, amidation, took place readily but the reaction was slower when this position was occupied by an acidic or a basic residue. A series of overlapping peptides with C-terminal glycine, based on partial sequences of calcitonin, underwent amidation at similar rates, indicating that the amidating enzyme recognizes only a limited sequence at the C-terminus of its substrates. The results provide evidence that the amidating enzyme has a highly compact substrate binding site.     

In vitro suppression of segmentation in Echinococcus multilocularis with morphological transformation of protoscoleces into monozoic adults.

When protoscoleces of Echinococcus multilocularis were cultured in vitro, under axenic conditions in either monophasic or diphasic media, segmentation was suppressed in most organisms, some 70-80% of which developed into unsegmented, monozoic forms with a complete set of sexually mature male and female genitalia. The most striking feature of monozoic worms was the large lateral swelling produced by the cirrus sac the effect being to produce organisms with an unusual asymmetric shape. Worms which did not become monozoic either (a) underwent some somatic growth, developed two sets of genitalia and became 'pseudo-segmented', i.e. with the inter-proglottid membranes absent or poorly defined, or (b) became vesicular or abnormal. The mechanisms which could be involved in the suppression of somatic growth and the induction of the monozoic condition, are examined in terms of cell lineage. The possible significance of these results in understanding the evolution of the cestodes is discussed.