Congenital Heart Disease–Causing Gata4 Mutation Displays Functional Deficits In Vivo

Defects of atrial and ventricular septation are the most frequent form of congenital heart disease, accounting for almost 50% of all cases. We previously reported that a heterozygous G296S missense mutation of GATA4 caused atrial and ventricular septal defects and pulmonary valve stenosis in humans. GATA4 encodes a cardiac transcription factor, and when deleted in mice it results in cardiac bifida and lethality by embryonic day (E)9.5. In vitro, the mutant GATA4 protein has a reduced DNA binding affinity and transcriptional activity and abolishes a physical interaction with TBX5, a transcription factor critical for normal heart formation. To characterize the mutation in vivo, we generated mice harboring the same mutation, Gata4 G295S. Mice homozygous for the Gata4 G295S mutant allele have normal ventral body patterning and heart looping, but have a thin ventricular myocardium, single ventricular chamber, and lethality by E11.5. While heterozygous Gata4 G295S mutant mice are viable, a subset of these mice have semilunar valve stenosis and small defects of the atrial septum. Gene expression studies of homozygous mutant mice suggest the G295S protein can sufficiently activate downstream targets of Gata4 in the endoderm but not in the developing heart. Cardiomyocyte proliferation deficits and decreased cardiac expression of CCND2, a member of the cyclin family and a direct target of Gata4, were found in embryos both homozygous and heterozygous for the Gata4 G295S allele. To further define functions of the Gata4 G295S mutation in vivo, compound mutant mice were generated in which specific cell lineages harbored both the Gata4 G295S mutant and Gata4 null alleles. Examination of these mice demonstrated that the Gata4 G295S protein has functional deficits in early myocardial development. In summary, the Gata4 G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans

TP53 status and taxane-platinum versus platinum-based therapy in ovarian cancer patients: A non-randomized retrospective study

<p>Abstract</p> <p>Background</p> <p>Taxane-platinum therapy (TP) has replaced platinum-based therapy (PC or PAC, DNA damaging chemotherapy) in the postoperative treatment of ovarian cancer patients; however, it is not always effective. TP53 protein plays a differential role in response to DNA-damaging agents and taxanes. We sought to define profiles of patients who benefit the most from TP and also of those who can be treated with PC.</p> <p>Methods</p> <p>We compared the effectiveness of PC/PAC (n = 253) and TP (n = 199) with respect to tumor TP53 accumulation in ovarian cancer patients with FIGO stage IIB-IV disease; this was a non-randomized retrospective study. Immunohistochemical analysis was performed on 452 archival tumors; univariate and multivariate analysis by the Cox's and logistic regression models was performed in all patients and in subgroups with [TP53(+)] and without TP53 accumulation [TP53(-)].</p> <p>Results</p> <p>The advantage of taxane-platinum therapy over platinum-based therapy was seen in the TP53(+), and not in the TP53(-) group. In the TP53(+) group taxane-platinum therapy enhanced the probability of complete remission (p = .018), platinum sensitivity (p = .014), platinum highly sensitive response (p = .038) and longer survival (OS, p = .008). Poor tumor differentiation diminished the advantage from taxane-platinum therapy in the TP53(+) group. In the TP53(-) group PC/PAC was at least equally efficient as taxane-platinum therapy and it enhanced the chance of platinum highly sensitive response (p = .010). However, in the TP53(-) group taxane-platinum therapy possibly diminished the risk of death in patients over 53 yrs (p = .077). Among factors that positively interacted with taxane-platinum therapy in some analyses were endometrioid and clear cell type, FIGO III stage, bulky residual tumor, more advanced age of patient and moderate tumor differentiation.</p> <p>Conclusion</p> <p>Our results suggest that taxane-platinum therapy is particularly justified in patients with TP53(+) tumors or older than 53 years. In the group of patients ≤53 yrs and with TP53(-) tumors platinum-based therapy is possibly equally efficient. We provide hints for planning randomized trials to verify these observations.</p

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions

Community Health Worker Interventions to Improve Glycemic Control in People with Diabetes: A Systematic Review and Meta-Analysis

OBJECTIVES: We set out to review the efficacy of Community Health Worker (CHW) interventions to improve glycemia in people with diabetes. METHODS: Data sources included the Cochrane Central Register of Controlled Trials, Medline, clinicaltrials.gov, Google Scholar, and reference lists of previous publications. We reviewed randomized controlled trials (RCTs) that assessed the efficacy of CHW interventions, as compared to usual care, to lower hemoglobin A1c (A1c). Two investigators independently reviewed the RCTs and assessed their quality. Only RCTs with a follow-up of at least 12 months were meta-analyzed. A random effects model was used to estimate, from unadjusted within-group mean reductions, the standardized mean difference (SMD) in A1c achieved by the CHW intervention, beyond usual care. RESULTS: Thirteen RCTs were included in the narrative review, and nine of them, which had at least 12 months of follow-up, were included in the meta-analysis. Publication bias could not be ruled-out due to the small number of trials. Outcome heterogeneity was moderate (I(2)= 37 %). The SMD in A1c (95 % confidence interval) was 0.21 (0.11-0.32). Meta-regression showed an association between higher baseline A1c and a larger effect size. CONCLUSIONS: CHW interventions showed a modest reduction in A1c compared to usual care. A1c reduction was larger in studies with higher mean baseline A1c. Caution is warranted, given the small number of studies

9α,11β-PGF2, a Prostaglandin D2 Metabolite, as a Marker of Mast Cell Activation in Bee Venom-Allergic Patients

Mast cell (MC) mediators, among them prostaglandin D(2) (PGD(2)) and 9α,11β-PGF(2), PGD(2)’s metabolite, play a key role in allergic reactions, including bee venom anaphylaxis (BVA). Assessment of these mediators has never been performed in BVA. The aim of the study was to assess the activation of MC during in vivo provocation with bee venom (BV) and to measure PGD(2) and 9α,11β-PGF(2) in the course of an allergen challenge. The second aim was to determine if assessment of these mediators could be useful for predicting adverse events during venom immunotherapy (VIT). In 16 BV-VIT patients and 12 healthy subjects, levels of PGD(2) and 9α,11β-PGF(2) were assessed during BV provocation by means of the skin chamber method. Chamber fluids, collected at 5 and 15 min, were analyzed for both mediators by gas chromatography mass spectrometry negative ion chemical ionization. BVA in comparison to non-allergic patients had a significantly higher ratio of 9α,11β-PGF(2) in allergen-challenged chambers to 9α,11β-PGF(2) in allergen-free chambers after 15 min of provocation (p = 0.039). Allergen challenge resulted in a significant increase of 9α,11β-PGF(2) levels between 5 and 15 min after provocation only in BVA patients (p < 0.05). Analysis of log-transformed PGD2 levels showed significant difference between changes in PGD(2) concentration between BVA and healthy subjects. No study patient developed adverse reactions during. 9α,11β-PGF(2) is actively generated during the early allergic response to BV. Skin chamber seems to be a promising, non-invasive and safe model of in vivo allergen provocation in BV-allergic patients. High or low levels of both mediators do not predict occurrence of adverse events during VIT