Right-sided heart failure in carcinoid syndrome

We reported the case of a 63-year-old man with a history of carcinoid syndrome evaluated for an exertional dyspnoea. Two-dimensional echocardiogram showed the characteristic right-sided cardiac valves involvement associated with this uncommon enterochromaffin malignancy.     

Acute ST-segment elevation myocardial infarction complicating amoxycillin-induced anaphylaxis: a case report

A 70-year-old man experienced an amoxycillin-induced anaphylactic reaction complicated by acute inferior myocardial infarction with transient ST-segment elevation. There was a spontaneous resolution of ST-segment elevation and the patient was treated for anaphylaxis. Coronary angiography showed severe obstructive coronary atherosclerosis, but not involving the infarct-related artery. Percutaneous coronary intervention of the affected artery was then performed and the patient was discharged three days later. Acute ST-elevation myocardial infarction has been described as one of the severe, still rare cardiovascular complications of anaphylaxis. In the present case, according to the previous reports, the main pathogenetic mechanism involved appears to have been coronary vasospasm probably caused by the release of potent vasoactive mast cell derived mediators in the setting of anaphylaxis.     

Role of p38 map kinase in glycine-induced hepatocyte resistance to hypoxic injury

BACKGROUND/AIMS: Glycine hepatoprotection is well known. However, the mechanisms involved are still poorly characterized. METHODS: Glycine protection was investigated in isolated rat hepatocytes pretreated with 2 mmol/L glycine 15 min before incubation under hypoxic conditions. RESULTS: Glycine significantly reduced Na+ overload and hepatocyte death caused by hypoxia. Glycine protection required the activation of a signal pathway involving Src, Pyk2 and p38 MAP kinases. Glycine treatment also induced a 11% increase of hepatocyte volume and transient ATP release. The prevention of cell swelling by hepatocyte incubation in a hypertonic medium as well as the degradation of extracellular ATP with apyrase or the block P2 purinergic receptors with suramin reverted glycine-induced cytoprotection and inhibited Src, Pyk2 and p38 MAPK activation. Glycine down-modulated Na+/H+ exchanger (NHE) activity, without affecting the development of intracellular acidosis during hypoxia. Such an effect was reverted by inhibiting p38 MAPK that also abolished glycine protection against Na+ overload caused by hypoxia. CONCLUSIONS: Glycine-induced ATP release in response to a moderate hepatocyte swelling led to the autocrine stimulation of P2 receptors and to the activation of Src, Pyk2 and p38 MAPK that increased hepatocyte resistance to hypoxia by preventing Na+ influx through NHE.     

Primary antiphospholipid nephropathy beginning during pregnancy

We describe a 29-year-old pregnant woman at 16 weeks gestation and antiphospholipid antibodies who developed nephrotic syndrome with massive hematuria. Renal biopsy evidenced chronic glomerular lesions of ischemic nature without proliferative changes and immune deposits suggestive of lupus nephritis. Anticoagulation was initiated, along supportive measures, and the patient recovered completely. This case demonstrates that chronic renal lesions of antiphospholipid syndrome may present with marked clinical manifestation including hypertension, massive proteinuria and hematuria, resembling the course of acute thrombotic microangiopathy and/or lupus nephritis.     

Homocysteine and nitric oxide are related to blood pressure and vascular function in small-for-gestational-age children

Leptin, homocysteine (Hcy), and C-reactive protein are risk factors potentially useful in predicting future cardiac events. These plasma biomarkers may participate in the regulation of cardiovascular function through an NO-dependent mechanism. Our purpose was to investigate whether alterations in C-reactive protein, Hcy, leptin, and NO are present in small-for-gestational-age children and to determine whether the levels of these plasma biomarkers are associated with birth weight, vascular function, and blood pressure. Concentrations of leptin, Hcy, C-reactive protein, and NO were measured in 69 children (36 boys and 33 girls; ages 8 to 13 years). Leptin (means difference: 1.4 ng/mL; 95% CI: 0.4 to 2.4) and Hcy (means difference: 0.9 micromol/L; 95% CI: 0.3 to 1.5) levels were significantly elevated in children born small for gestational age compared with those with appropriate birth weight. Nevertheless, NO (means difference: 342.9 micromol; 95% CI: 124.2 to 561.6) concentration was significantly reduced in small birth weight children, and the levels of C-reactive protein remained unchanged. There was a significant association between the circulating levels of both NO and Hcy with vascular function, as well as with blood pressure levels, in our population. Because both Hcy and NO are associated with a risk of cardiovascular disease, it is possible that part of the association of low birth weight with elevated risk for vascular and metabolic disease in later life is mediated by perturbation in pathways for these biomarkers.     

Inhibitor of growth 4 (ING4) is up-regulated by a low K intake and suppresses renal outer medullary K channels (ROMK) by MAPK stimulation

Dietary K intake plays an important role in the regulation of renal K secretion: a high K intake stimulates whereas low K intake suppresses renal K secretion. Our previous studies demonstrated that the Src family protein-tyrosine kinase and mitogen-activated protein kinase (MAPK) are involved in mediating the effect of low K intake on renal K channels and K secretion. However, the molecular mechanism by which low K intake stimulates MAPK is not completely understood. Here we show that inhibitor of growth 4 (ING4), a protein with a highly conserved plant homeodomain finger motif, is involved in mediating the effect of low K intake on MAPK. K restriction stimulates the expression of ING4 in the kidney and superoxide anions, and its related products are involved in mediating the effect of low K intake on ING4 expression. We used HEK293 cells to express ING4 and observed that expression of ING4 increased the phosphorylation of p38 and ERK MAPK, whereas down-regulation of ING4 with small interfering RNA decreased the phosphorylation of p38 and ERK. Immunocytochemistry showed that ING4 was expressed in the renal outer medullary potassium (ROMK)-positive tubules. Moreover, ING4 decreased K currents in Xenopus oocytes injected with ROMK channel cRNA. This inhibitory effect was reversed by blocking p38 and ERK MAPK. These data provide evidence for the role of ING4 in mediating the effect of low K intake on ROMK channel activity by stimulation of p38 and ERK MAPK.     

Influence of base stacking on excited-state behavior of polyadenine in water, based on time-dependent density functional calculations

A thorough study of the excited-state properties of the stacked dimers and trimers of 9-methyladenine in B-DNA conformation has been performed in aqueous solution by using time-dependent density functional calculations and the solvent polarizable continuum model, and results were compared with experimental results on polyadenine oligomers. The effect of base stacking on the absorption and emission spectra is fully reproduced by our calculations. Although light absorption leads to a state (S(B)) delocalized over several nucleobases, excited-state geometry optimization indicates that S(B) subsequently evolves into a state in which the excitation is localized on a single base. Analysis of the excited-state potential energy surfaces shows that S(B) can easily decay into the lowest energy excited state, S(CT), which is a dark excimer produced by intermonomer charge transfer between two stacked bases. The subpicosecond features of the time-resolved experiments are interpreted in terms of ultrafast decay from S(B). After localization, two easy, radiationless decay channels are indeed open for S(B): (i) ground-state recovery, according to the same mechanisms proposed for isolated adenine and/or (ii) decay to S(CT). Our calculations suggest that the slowest part of the excited-state dynamics detected experimentally involves the S(CT) state.     

The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells

MicroRNAs (miRNAs) are tiny noncoding RNAs whose function as modulators of gene expression is crucial for the proper control of cell growth and differentiation. Although the profile of miRNA expression has been defined for many different cellular systems, the elucidation of the regulatory networks in which they are involved is only just emerging. In this work, we identify a crucial role for three neuronal miRNAs (9, 125a, and 125b) in controlling human neuroblastoma cell proliferation. We show that these molecules act in an additive manner by repressing a common target, the truncated isoform of the neurotrophin receptor tropomyosin-related kinase C, and we demonstrate that the down-regulation of this isoform is critical for regulating neuroblastoma cell growth. Consistently with their function, these miRNAs were found to be down-modulated in primary neuroblastoma tumors.     

Erythrocyte adenylate kinase deficiency: characterization of recombinant mutant forms and relationship with nonspherocytic hemolytic anemia

OBJECTIVE: Red cell adenylate kinase (AK) deficiency is a rare hereditary erythroenzymopathy associated with moderate to severe nonspherocytic hemolytic anemia and, in some cases, with mental retardation and psychomotor impairment. To date, diagnosis of AK deficiency depends upon demonstration of low enzyme activity in red blood cells and detection of mutations in AK1 gene. To investigate the molecular bases of the AK deficiency, we characterized five variants of AK1 isoenzyme-bearing mutations (118G>A, 190G>A, 382C>T, 418-420del, and 491A>G) found in AK-deficient patients with chronic hemolytic anemia. MATERIALS AND METHODS: The complete AK1 cDNA was obtained by standard procedures and using as template the reticulocyte RNA. The cDNA was cloned in a plasmid vector and the enzyme was expressed in Escherichia coli BL21(DE3)pLysS, and purified by standard protocols to homogeneity. DNA mutants bearing point mutations were obtained from the cloned wild-type cDNA using standard methods of site-directed mutagenesis, whereas the DNA mutant with deletion of codon 140 was obtained by a two-step method. RESULTS: Four mutant enzymes (Gly40Arg, Gly64Arg, Arg128Trp, Asp140del) were severely affected in activity, displaying a catalytic efficiency of four orders of magnitude lower than the wild-type; one (Tyr164Cys) was grossly perturbed in protein stability. CONCLUSIONS: The altered properties displayed by the mutant enzymes support the cause-effect relationship between AK1 mutations and hemolytic anemia.