Protein expression profiles in patients carrying NFU1 mutations. Contribution to the pathophysiology of the disease

Cofactor disorders of mitochondrial energy metabolism are a heterogeneous group of diseases with a wide variety of clinical symptoms, particular metabolic profiles and variable enzymatic defects. Mutations in NFU1 were recently identified in patients with fatal encephalopathy displaying a biochemical phenotype consistent with defects in lipoic acid-dependent enzymatic activities and respiratory chain complexes. This discovery highlighted the molecular function of NFU1 as an iron-sulfur(Fe-S) cluster protein necessary for lipoic acid biosynthesis and respiratory chain complexes activities. To understand the pathophysiological mechanisms underlying this disease we have characterized the protein expression profiles of patients carrying NFU1 mutations. Fibroblasts from patients with the p.Gly208Cys mutation showed complete absence of protein-bound lipoic acid and decreased SDHA and SDHB subunits of complex II. In contrast, subunits of other respiratory chain complexes were normal. Protein lipoylation was also decreased in muscle and liver but not in other tissues available (brain, kidney, lung) from NFU1 patients. Although levels of the respiratory chain subunits were unaltered in tissues, BN-PAGE showed an assembly defect for complex II in muscle, consistent with the low enzymatic activity of this complex. This study provides new insights into the molecular bases of NFU1 disease as well as into the regulation of NFU1 protein in human tissues. We demonstrate a ubiquitous expression of NFU1 protein and further suggest that defects in lipoic acid biosynthesis and complex II are the main molecular signature of this disease, particularly in patients carrying the p.Gly208Cys mutation.     

RNA Structural Elements of Hepatitis C Virus Controlling Viral RNA Translation and the Implications for Viral Pathogenesis

Hepatitis C virus (HCV) genome multiplication requires the concerted action of the viral RNA, host factors and viral proteins. Recent studies have provided information about the requirement of specific viral RNA motifs that play an active role in the viral life cycle. RNA regulatory motifs controlling translation and replication of the viral RNA are mostly found at the 5'' and 3'' untranslated regions (UTRs). In particular, viral protein synthesis is under the control of the internal ribosome entry site (IRES) element, a complex RNA structure located at the 5''UTR that recruits the ribosomal subunits to the initiator codon. Accordingly, interfering with this RNA structural motif causes the abrogation of the viral cycle. In addition, RNA translation initiation is modulated by cellular factors, including miRNAs and RNA-binding proteins. Interestingly, a RNA structural motif located at the 3''end controls viral replication and establishes long-range RNA-RNA interactions with the 5''UTR, generating functional bridges between both ends on the viral genome. In this article, we review recent advances on virus-host interaction and translation control modulating viral gene expression in infected cells.     

Assessment of proadrenomedullin as diagnostic or prognostic biomarker of acute appendicitis in children with acute abdominal pain

BackgroundAcute appendicitis (AA) is one of the most frequent surgical pathologies in pediatrics.ObjectivesTo investigate the utility of proadrenomedullin (pro-ADM) for the diagnosis of AA.MethodsProspective, analytical, observational, and multicenter study conducted in 6 pediatric emergency departments. Children up to 18 years of age with suspected AA were included. Clinical, epidemiological, and analytical data were collected.ResultsWe studied 285 children with an average age of 9.5 years (95% confidence interval [CI], 9.1–9.9). AA was diagnosed in 103 children (36.1%), with complications in 10 of them (9.7%). The mean concentration of pro-ADM (nmol/L) was higher in children with AA (0.51 nmol/L, SD 0.16) than in children with acute abdominal pain (AAP) of another etiology (0.44 nmol/L, SD 0.14; p < 0.001). This difference was greater in complicated cases compared with uncomplicated AA (0.64 nmol/L, SD 0.17 and 0.50 nmol/L, SD 0.15, respectively; p = 0.005). The areas under the receiver-operating characteristic curves were 0.66 (95% CI, 0.59–0.72) for pro-ADM, 0.70 (95% CI, 0.63–0.76) for C-reactive protein (CRP), 0.84 (95% CI, 0.79–0.89) for neutrophils, and 0.84 (95% CI, 0.79–0.89) for total leukocytes. The most reliable combination to rule out AA was CRP ≤1.25 mg/dL and pro-ADM ≤0.35 nmol/L with a sensitivity of 96% and a negative predictive value of 93%.ConclusionChildren with AA presented higher pro-ADM values than children with AAP of other etiologies, especially in cases of complicated AA. The combination of low values of pro-ADM and CRP can help to select children with low risk of AA.     

Granulocyte‐Monocyte Apheresis as an Adjuvant Therapy to Anti‐Tumor Necrosis Factor Drugs for Ulcerative Colitis

Biologic anti‐tumor necrosis factor (TNF) drugs have demonstrated their efficacy for the treatment of ulcerative colitis. Nevertheless, some patients will not respond to this therapy or will develop loss of response. Leukapheresis is the main non‐pharmacological therapy for some immune‐mediated diseases. The aim of our study was to describe our experience with this therapy in ulcerative colitis patients after loss of response to anti‐TNF treatment. Leukapheresis was indicated in four patients with left‐sided or extensive colitis because of partial response to biological therapy or secondary loss of response to it. All patients received 8 to 10 sessions in an intensive regimen. Globally, a decrease in the Mayo score was observed. The overall response rate was 50% with one patient who displayed sustained response. No patients have required colectomy during follow‐up. Adjuvant treatment with leukapheresis in patients with inadequate response to anti‐TNF treatment showed some beneficial effect, although of limited duration, in patients with ulcerative colitis.     

Strengths in older adults: differential effect of savoring,gratitude and optimism on well-being

Objetive: The present study aimed to compare the efficacy of three separate strengths training-based interventions – Gratitude, Savoring, and Optimism – in older adults.

Method: The sample comprised 124 older adults, namely, 74 women and 50 men, non-institutionalized individuals who regularly attend day centers in the provinces of Jaén and Córdoba, southern Spain. Their ages ranged between 60 and 89 years. The measures used were Anxiety, Depression, Life Satisfaction, Positive and Negative Affect, Subjective Happiness, and Resilience.

Results: Training in Gratitude and Savoring increased scores in Life Satisfaction, Positive Affect, Subjective Happiness and Resilience, and reduced Negative Affect, whereas training in Optimism failed to produce a significant change in these variables. The Savoring and Optimism interventions decreased scores in Depression but, contrary to hypothesis, this was not the case for Gratitude.

Conclusion: These results represent an important step in understanding what type of strengths work best when it comes to enhancing well-being in older adults and consequently helping them tackle the challenges of everyday life and recover as quickly as possible from the adverse situations and events that may arise.