Benfluorex and Unexplained Valvular Heart Disease: A Case-Control Study

Background

Recent case reports suggest that benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation.

Methods

We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1^st 2003 and June 30^th 2009, with mitral insufficiency diagnostic codes (ICD-10 I340 and I051). Patients with either a primary cause (degenerative, known rheumatic heart disease, infectious endocarditis, congenital, radiation-induced valvular disease, associated connective and/or vasculitis disease, trauma, tumor) or a secondary (functional) cause were considered as having an “explained” mitral regurgitation. Other patients were considered as having an “unexplained” mitral regurgitation and were included as cases. For each case, two controls were matched for gender and for the closest date of birth, among a list of patients with an “explained” mitral regurgitation. Drug exposures were assessed blindly regarding the case or control status, through contacts with patients, their family and/or their physicians.

Results

Out of the 682 eligible patients, 27 cases and 54 matched controls were identified. The use of benfluorex was reported in 22 patients: 19 of the 27 cases, versus 3 of the 54 controls, odds-ratio 17.1 (3.5 to 83), adjusted for body mass index, diabetes and dexfenfluramine use.

Conclusion

The use of benfluorex is associated with unexplained mitral regurgitation.     

SPCA1 pumps and Hailey-Hailey disease

Both the endoplasmic reticulum and the Golgi apparatus are agonist-sensitive intracellular Ca2+ stores. The Golgi apparatus has Ca2+-release channels and a Ca2+-uptake mechanism consisting of sarco(endo)plasmic-reticulum Ca2+-ATPases (SERCA) and secretory-pathway Ca2+-ATPases (SPCA). SPCA1 has been shown to transport both Ca2+ and Mn2+ in the Golgi lumen and therefore plays an important role in the cytosolic and intra-Golgi Ca2+ and Mn2+ homeostasis. Human genetic studies have provided new information on the physiological role of SPCA1. Loss of one functional copy of the SPCA1 (ATP2C1) gene causes Hailey-Hailey disease, a skin disorder arising in the adult age with recurrent vesicles and erosions in the flexural areas. Here, we review recent experimental evidence showing that the Golgi apparatus plays a much more important role in intracellular ion homeostasis than previously anticipated.     

Carboxyl nonsteroidal anti-inflammatory drugs are efficiently glucuronidated by microsomes of the human gastrointestinal tract

Limited studies have been carried out on the biotransformation of carboxyl nonsteroidal anti-inflammatory drugs (NSAIDs) in the liver. However, the role of the intestine in NSAID metabolism has not been investigated. In this report, the contribution of UDP-glucuronosyltransferases (UGTs) in the human gastrointestinal (GI) tract from five donors to the glucuronidation of the NSAIDs, RS-ketoprofen, S-naproxen, RS- and S-etodolac, was investigated. UGT activity and, for some donors, mRNA levels were evaluated. All NSAIDs were glucuronidated throughout the GI tract; however, glucuronidation was low in stomach and duodenum as compared to the remainder of the intestine. RT-PCR analysis demonstrated that the UGT1A isoforms, UGT1A3, 1A8, and 1A10, and UGT2B7 were expressed in the GI tract. Human recombinant UGT1A3, 1A9, 1A10 and 2B7 were actively involved in the glucuronidation of all NSAIDs while UGT1A7 and the intestine-specific UGT1A8 had no glucuronidating activity towards those compounds. Despite interindividual variations in both the levels of mRNA and the distribution of activity through the intestine, UGTs in the GI tract may contribute significantly to the first pass metabolism of orally administered NSAIDs.     

Concomitant recruitment of ERK1/2 and p38 MAPK signalling pathway is required for activation of cytoplasmic phospholipase A2 via ATP in articular chondrocytes

Extracellular ATP is a pro-inflammatory mediator involved in the release of prostaglandin from articular chondrocytes, but little is known about its effects on intracellular signaling. ATP triggered the rapid release of prostaglandin E(2) (PGE(2)) by acting on P2Y(2) receptors in rabbit articular chondrocytes. We have explored the signaling events involved in this synthesis. ATP significantly increased arachidonic acid production, which involved the activation of the 85-kDa cytosolic phospholipase A(2) (cPLA(2)) but not a secreted form of PLA(2), as demonstrated by various PLA(2) inhibitors and translocation experiments. We also showed that ATP induced the phosphorylation of p38 and ERK1/2 mitogen-activated-protein kinases (MAPKs). Both PD98059, an inhibitor of the ERK pathway, and SB203580, an inhibitor of p38 MAPK, completely inhibited the ATP-induced release of PGE(2). Finally, dominant-negative plasmids encoding p38 and ERK transfected alone into the cells impaired the ATP-induced release of PGE(2) to about the same extent as both plasmids transfected together. These results suggest that PGE(2) production induced by ATP requires the activation of both ERK1/2 and p38 MAPKs. Thus, ATP acts via P2Y(2)-purine receptors to recruit cPLA(2) by activating both ERK1/2 and p38 MAPKs and stimulates the release of PGE(2) from articular chondrocytes.     

Dlg,Scribble and Lgl in cell polarity,cell proliferation and cancer

Dlg (Discs large), Scrib (Scribble) and Lgl (Lethal giant larvae) are evolutionarily conserved components of a common genetic pathway that link the seemingly disparate functions of cell polarity and cell proliferation in epithelial cells. dlg, scrib and lgl have been identified as tumour suppressor genes in Drosophila, mutations of which cause similar phenotypes, involving disruption of cell polarity and neoplastic overgrowth of tissues. The molecular mechanisms by which Dlg, Scrib and Lgl proteins regulate cell proliferation are not clear, but there is some evidence that epithelial polarisation is required for this regulation. Dlg, Scrib and Lgl are highly conserved between human and Drosophila, and we discuss evidence that these proteins also play a role in cancer progression in humans.     

Mutations of genes coding for TGF-beta receptors (BMPR2 and ALK-1) in primary pulmonary arterial hypertension

Pulmonary hypertension is defined by an elevation in pulmonary artery pressure leading to progressive right heart failure and death. Primary (idiopathic) pulmonary hypertension (PPH) is a rare disease with an estimated incidence of 2 per million inhabitants per year in France. Abnormal pulmonary artery angiogenesis is a characteristic feature of this condition including endothelial and smooth muscle cell proliferation in small to medium-sized pulmonary arteries. The recent discovery of germline mutations of genes coding for receptor members of TGF-beta (BMPR-2 et ALK-1) in PPH represents a considerable progress in the understanding of this pulmonary orphan disease. This review summarizes the current genetic data obtained in this condition.     

Phosphorylation of IP3R1 and the regulation of [Ca2+]i responses at fertilization: a role for the MAP kinase pathway.

A sperm-induced intracellular Ca2+ signal ([Ca2+]i) underlies the initiation of embryo development in most species studied to date. The inositol 1,4,5 trisphosphate receptor type 1 (IP3R1) in mammals, or its homologue in other species, is thought to mediate the majority of this Ca2+ release. IP3R1-mediated Ca2+ release is regulated during oocyte maturation such that it reaches maximal effectiveness at the time of fertilization, which, in mammalian eggs, occurs at the metaphase stage of the second meiosis (MII). Consistent with this, the [Ca2+]i oscillations associated with fertilization in these species occur most prominently during the MII stage. In this study, we have examined the molecular underpinnings of IP3R1 function in eggs. Using mouse and Xenopus eggs, we show that IP3R1 is phosphorylated during both maturation and the first cell cycle at a MPM2-detectable epitope(s), which is known to be a target of kinases controlling the cell cycle. In vitro phosphorylation studies reveal that MAPK/ERK2, one of the M-phase kinases, phosphorylates IP3R1 at at least one highly conserved site, and that its mutation abrogates IP3R1 phosphorylation in this domain. Our studies also found that activation of the MAPK/ERK pathway is required for the IP3R1 MPM2 reactivity observed in mouse eggs, and that eggs deprived of the MAPK/ERK pathway during maturation fail to mount normal [Ca2+]i oscillations in response to agonists and show compromised IP3R1 function. These findings identify IP3R1 phosphorylation by M-phase kinases as a regulatory mechanism of IP3R1 function in eggs that serves to optimize [Ca2+]i release at fertilization.     

Intracellular and intramitochondrial binding of lanthanum in dark degenerating midgut cells of a collembolan (Insect)

Summary Glycogen synthetase (2.4.1.11) forms I (independent or active) and D (dependent or passive) as well as the enzymes active in the transformation of the pathways, protein kinase and phosphatase transferase, were studied in the sensory cells and glycogen rich epidermal cells of the weakly electric fish Gnathonemus petersii (Mormyridae). For light microscopy an indirect cytochemical method which differentiated between glycogen originally present and that produced during incubation in the presence of UDPG was used. This differentiation was obtained by iodine, PAS and and amylases.Glycogen synthetase is present in the sensory cells in the I and D forms. The epidermal cells only contain the D form. Protein kinase (active ID) has only been found in the sensory cells but phosphatase transferase (active DI) has been found in both the epidermal cells and the sensory cells, but only within certain organs.Electron microscopy studies of glycogen synthetase I and D and protein kinase were restricted to the sensory cells only. As with the light microscope it was possible to differentiate between native glycogen and newly formed glycogen. This was done using ultrathin sections and staining with uranyl acetate, lead citrate or by the PATAg reaction.It was possible from these observations to locate precisely the positions of these enzymes. In fact, glycogen synthetase I and D are found both in the sensory cytoplasm and in the sensory cavity with the polysaccharide filaments. Protein kinase is also abundant in the sensory cytoplasm especially in the periphery of the cell near the microvillary border.