Lipoprotein lipase: A bioinformatics criterion for assessment of mutations as a risk factor for cardiovascular disease

Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism. Decrease of the LPL enzymatic activity leads to elevated triglycerides (TG) and reduced high-density lipoprotein (HDL-C levels), both risk factors for cardiovascular disease (CVD). Therefore, mutations, which decrease the LPL activity, may confer susceptibility to CVD. Here, the informational spectrum method (ISM), a virtual spectroscopy method for structure/function analysis of nucleotide and protein sequences, is applied for identification of evolutionary highly conserved information encoded by the primary structure of LPL. It was demonstrated that mutations, which alter the LPL enzymatic activity also alter this information. On the basis of this finding, an efficient and simple bioinformatics criterion for assessment of the pathogenic effect of LPL nonsynonymous single nucleotide substitution as a risk factor of CVD has been proposed.     

Cytotoxin‐Associated Gene‐A – Positive Helicobacter pylori Strains Infection Increases the Risk of Recurrent Atherosclerotic Stroke

Background: CagA‐positive Helicobacter pylori infection has been found to be associated with a first‐ever atherosclerotic stroke. The aim of this study was to investigate whether these strains represent an independent risk factor for recurrent atherosclerotic stroke. Materials and Methods: We performed a longitudinal study of patients with a first‐ever large vessels stroke and resulted positive at H. pylori serology. Patients had clinical examination 1 month after the acute event, and were subsequently visited or contacted by telephone up to 3 years at 6‐month intervals. Sera obtained at the time of enrollment were frozen and analyzed for the presence of anti‐CagA antibodies at the end of the study. The primary outcome event was any fatal or nonfatal stroke after the index stroke. Results: One hundred seventy H. pylori‐positive patients were included (n = 68 CagA positive and n = 102 CagA negative). No significant difference regarding age and other stroke risk factors was detected. According to Kaplan‐Meier survival analysis, CagA‐positive patients showed a significantly higher risk for stroke recurrence than CagA‐negative ones (45.6% vs 17.6%; p < .001). Difference in the rate of recurrent stroke between the two groups persisted after Cox regression analysis taking into account possible confounding factors (hazard ratio = 3.5; 95% CI = 1.9–6.4; p < .001). Conclusions: Infection with H. pylori CagA‐positive strains increases the risk of recurrent atherosclerotic stroke. Seropositivity determination should be performed in order to identify high‐risk patients requiring a strict clinical surveillance, and the possible beneficial effect of eradication therapy should be evaluated.     

Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM

We identified a key oncogenic pathway underlying neuroblastoma progression: specifically, MYCN, expressed at elevated level, transactivates the miRNA 17-5p-92 cluster, which inhibits p21 and BIM translation by interaction with their mRNA 3' UTRs. Overexpression of miRNA 17-5p-92 cluster in MYCN-not-amplified neuroblastoma cells strongly augments their in vitro and in vivo tumorigenesis. In vitro or in vivo treatment with antagomir-17-5p abolishes the growth of MYCN-amplified and therapy-resistant neuroblastoma through p21 and BIM upmodulation, leading to cell cycling blockade and activation of apoptosis, respectively. In primary neuroblastoma, the majority of cases show a rise of miR-17-5p level leading to p21 downmodulation, which is particularly severe in patients with MYCN amplification and poor prognosis. Altogether, our studies demonstrate for the first time that antagomir treatment can abolish tumor growth in vivo, specifically in therapy-resistant neuroblastoma.     

Special aspects of the curve of the oral glucose tolerance test]

The insulin response of 10 lean and 23 obese subjects with lag-type and borderline O.G.T.T. has been studied. The O.G.T.T. was interpreted according to the criteria of Fajans and Conn. The maximum increase and the area of increase were examined both for blood glucose and plasma I.R.I., and the corresponding I.R.I./glucose ratios calculated. The shape of the insulin response curve is similar to that of glucose curve. The I.R.I./glucose ratios are decreased in the lag-type curves as compared to borderline in the lean subjects while we observed opposite results in obese ones. A possible physiopathological interpretation of this curves is proposed.     

AmphiD1/β, a dopamine D1/β-adrenergic receptor from the amphioxus <Emphasis Type="Italic">Branchiostoma floridae</Emphasis>: evolutionary aspects of the catecholaminergic system during development

Catecholamine receptors mediate wide-ranging functions in vertebrates and invertebrates but are largely unknown in invertebrate chordates such as amphioxus. Catecholaminergic cells have been described in amphioxus adults, but few data are known about the transmembrane signal transduction pathways and the expression pattern of related receptors during development. In Branchiostoma floridae, we cloned a full-length cDNA (AmphiD1/β) that corresponds to the dopamine D1/β receptor previously cloned from a related species of amphioxus, Branchiostoma lanceolatum, but no expression studies have been performed for such receptor in amphioxus. In B. floridae, AmphiD1/β encodes a polypeptide with typical G-protein-coupled receptor features, characterized by highest sequence similarity with D1 dopamine and β-adrenergic receptors. The expression of AmphiD1/β mRNA in different regions of the cerebral vesicle corresponds to that of D1-like receptors in vertebrate homologous structures. Furthermore, in situ experiments show that during development, the expression in the nervous system is restricted to cells located anteriorly. A further expression was found in larvae at the level of the endostyle, but it has no counterpart in the predominant expression domains of vertebrate dopamine and/or adrenergic receptor genes. At the same time, we compared the dopaminergic system, consisting of AmphiTH-expressing cells, with the AmphiD1/β expression. In conclusion, the identification of the AmphiD1/β receptor provides further basis for understanding the evolutionary history of the dopaminergic system at the transition from invertebrates and vertebrates.     

HNE-dependent molecular damage in diabetic nephropathy and its possible prevention by N-acetyl-cysteine and oxerutin

Accumulation of Advanced Lipoxidation End-products (ALE), such as MDA- and HNE-protein adducts, and Advanced Glycation End-products, such as carboxymethyl-lysine (CML), are probably involved in the development of diabetic nephropathy. In this study the effect of some antioxidant treatments (oxerutin, N-acetylcysteine, taurine and N-acetylcysteine+taurine) on kidney lipoxidative damage has been evaluated by immunohistochemistry in streptozotocined rats. Diabetic rats showed marked glomerular positivity for ALE, while the samples from Control rats were negative. All treatments except taurine were able to protect the glomeruli from ALE accumulation; the failure of taurine may be due to residual oxidative properties of its derivatives. These data are consistent with those of our previous study, which showed that all the antioxidants used except taurine protected the glomeruli from diabetes-induced enlargement, increased apoptotic rate, decreased cell density and CML accumulation. These data attest to a role of glycoxidative and lipoxidative damage in diabetes-dependent damage of the kidney, and indicate that specific antioxidants can prevent or attenuate diabetic nephropathy.     

Multiple Actions of the Human Immunodeficiency Virus Type-1 Tat Protein on Microglial Cell Functions

The human immunodeficiency virus type-1 (HIV-1) regulatory protein Tat is produced in the early phase of infection and is essential for virus replication. Together with other viral products, Tat has been implicated in the pathogenesis of HIV-1-associated dementia (HAD). As HIV-1 infection in the brain is very limited and macrophage/microglial cells are the only cellular type productively infected by the virus, it has been proposed that many of the viral neurotoxic effects are mediated by microglial products. We and others have shown that Tat affects the functional state of microglial cells, supporting the hypothesis that activated microglia play a role in the neuropathology associated with HIV-1 infection. This review describes the experimental evidence indicating that Tat stimulates microglia to synthesize potentially neurotoxic molecules, including proinflammatory cytokines and free radicals, and interferes with molecular mechanisms controlling cAMP levels, intracellular [Ca2+], and ion channel expression.     

Constitutive heterochromatin and transposable elements in Drosophila melanogaster

Several families of transposable elements (TEs), most of them belonging to the retrotransposon catagory, are particularly enriched in Drosophila melanogaster constitutive heterochromatin. The enrichment of TE-homologous sequences into heterochromatin is not a peculiar feature of the Drosophila genome, but appears to be widespread among higher eukaryotes. The constitutive heterochromatin of D. melanogaster contains several genetically active domains; this raises the possibility that TE-homologous sequences inserted into functional heterochromatin compartments may be expressed. In this review, I present available data on the genetic and molecular organization of D. melanogaster constitutive heterochromatin and its relationship with transposable elements. The implications of these findings on the possible impact of heterochromatic TEs on the function and evolution of the host genome are also discussed. This revised version was published online in August 2006 with corrections to the Cover Date.     

Intragenomic Distribution and Stability of Transposable Elements in Euchromatin and Heterochromatin of Drosophila melanogaster: Elements with Inverted Repeats Bari 1, hobo, and pogo

The elements of the Bari 1, hobo, and pogo transposon families that are located in euchromatin, heterochromatin, and on the Y chromosome have been identified, and their stability has been assessed by Southern blot analysis. The fraction of heterochromatic elements appears to be distinctive of all transposon families tested, except for Bari 1. Evidence for instability of heterochromatic elements is described. The analysis of unstable elements in different Drosophila stocks suggests that the host genome contributes to the stability/instability of transposon families. Received: 21 August 1996 / Accepted: 24 March 1997