Diagnostic value of MRI for the detection of suspected placental invasion: Does it depend on observers' experience?

Purpose: To evaluate the diagnostic value of specific MR features for detection of suspected placental invasion according to observers' experience.Methods and Materials: Our study population included 25 pregnant women (mean age 35.16) investigated by prenatal MRI. In twelve out of them placental invasion was histopathologically proven, the 13 other women (52%) without placental invasion served as control group. Multiplanar T1- and T2-weighted sequences had been performed mostly without IV contrast injection (1.5 T). MR examinations of the two groups were rendered anonymous, mixed, then independently and retrospectively reviewed by two senior and two junior radiologists in view of 8 MR features indicating placentar invasion including the degree. Results were compared with surgical diagnosis (placenta normal/increta/accreta/percreta). Interobserver agrement between senior and junior readers were calculated. Stepwise logistic regression and receiver operating (ROC) curvers were performed.Results: Demographics between the two groups were not statistically different. Overall sensitivity and specificity for detecting placentar invasion was 90.9% and 75.0% for senior readers, and 81.8% and 61.8% for junior readers respectively. The most significant MR features indicating placentar invasion were T2 hypointense placental bands, followed by placenta praevia, focally interrupted myometrial border, posterior placental insertion, and heterogeneous placental signal. For each of the evaluated MR features the interobserver agreement kappa between the two senior readers was superior than that between the junior readers, ranging from bad (<0.4) to good (0.4-0.75).Conclusions: MRI can be a reliable and reproducible tool for detection of suspected placentar invasion, however very variable according to the observers' experience.

Differential reactivity of TCR Vbeta10 alleles to a mouse mammary tumor virus superantigen.

Mouse mammary tumor virus (MMTV) expresses a superantigen (SAg) which plays a critical role in the viral life cycle. We have recently described the new infectious MMTV (SIM) encoding a Vbeta4-specific SAg in mice with a TCR-Vbeta(b) haplotype. We have now compared the SAg activity of this virus in BALB/c mice harboring the TCR-Vbeta(a), TCR-Vbeta(b) or TCR-Vbeta(c) haplotypes which differ by a central deletion in the TCR-Vbeta(a) and TCR-Vbeta(c) locus and by mutations in some of the remaining Vbeta elements. Injection of MMTV (SIM) led to a strong stimulation of Vbeta4+ CD4+ T cells in TCR-Vbeta(b) mice, but only to a weak stimulation of these cells in TCR-Vbeta(a) or TCR-Vbeta(c) mice. A large increase in the percentage of Vbeta10+ cells was observed among CD4+ T cells in mice with the Vbeta(a) or Vbeta(c), but not the Vbeta(b) TCR-Vbeta haplotype. Vbeta10+ cells dominated the response when Vbeta10(a/c) and Vbeta4 subsets were present together. This is the first report of a viral SAg interacting with murine Vbeta10+ cells. Six amino acid differences between Vbeta10(a/c) and Vbeta10(b) could account for the gain of reactivity of Vbeta10(a/c) to the MMTV(SIM) SAg. No mutations were found in the hypervariable region 4 (HV4) of the TCR. Mutations at positions 22 and 28 introduce into Vbeta10(a/c) the same amino acids which are found at these positions in the MMTV(SIM)-reactive Vbeta4. Tridimensional models indicated that these amino acids lie close to HV4 and are likely to be important for the interaction of the SAg with the TCR.

Differential effectiveness of microbially induced resistance against herbivorous insects in Arabidopsis.

Rhizobacteria-induced systemic resistance (ISR) and pathogen-induced systemic acquired resistance (SAR) have a broad, yet partly distinct, range of effectiveness against pathogenic microorganisms. Here, we investigated the effectiveness of ISR and SAR in Arabidopsis against the tissue-chewing insects Pieris rapae and Spodoptera exigua. Resistance against insects consists of direct defense, such as the production of toxins and feeding deterrents and indirect defense such as the production of plant volatiles that attract carnivorous enemies of the herbivores. Wind-tunnel experiments revealed that ISR and SAR did not affect herbivore-induced attraction of the parasitic wasp Cotesia rubecula (indirect defense). By contrast, ISR and SAR significantly reduced growth and development of the generalist herbivore S. exigua, although not that of the specialist P. rapae. This enhanced direct defense against S. exigua was associated with potentiated expression of the defense-related genes PDF1.2 and HEL. Expression profiling using a dedicated cDNA microarray revealed four additional, differentially primed genes in microbially induced S. exigua-challenged plants, three of which encode a lipid-transfer protein. Together, these results indicate that microbially induced plants are differentially primed for enhanced insect-responsive gene expression that is associated with increased direct defense against the generalist S. exigua but not against the specialist P. rapae.

Differential expression of peroxisome proliferator-activated receptor-alpha, -beta, and -gamma during rat embryonic development.

The expression patterns of the three different peroxisome proliferator-activated receptor (PPAR) isotypes have been determined during rat embryonic development by in situ hybridization. The expression of PPARalpha starts late in development, with increasing levels in organs such as liver, kidney, intestine, and pancreas, in which it will also be present later in adulthood to regulate its specific target genes. PPARalpha is also transiently expressed in the embryonic epidermis and central nervous system. PPARgamma presents a very restricted pattern of expression, being strongly expressed in brown adipose tissue, in which differentiation it has been shown to participate. Like PPARalpha, it is also expressed transiently in the central nervous system. Interestingly, PPARalpha, -beta and -gamma are coexpressed at high levels in brown adipose tissue. Finally, the high and ubiquitous expression of PPARbeta suggests some fundamental role(s) that this receptor might play throughout development.

Prognostic value of fractional flow reserve: linking physiologic severity to clinical outcomes.

BACKGROUND: Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES: The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS: Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS: A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS: FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056.

Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). We detected no response in 18 patients with partial promoter methylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.

Differential responses of newborn pulmonary arteries and veins to atrial and C-type natriuretic peptides.

Atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) are important dilators of the pulmonary circulation during the perinatal period. We compared the responses of pulmonary arteries (PA) and veins (PV) of newborn lambs to these peptides. ANP caused a greater relaxation of PA than of PV, and CNP caused a greater relaxation of PV than of PA. RIA showed that ANP induced a greater increase in cGMP content of PA than CNP. In PV, ANP and CNP caused a similar moderate increase in cGMP content. Receptor binding study showed more specific binding sites for ANP than for CNP in PA and more for CNP than for ANP in PV. Relative quantitative RT-PCR for natriuretic peptide receptor A (NPR-A) and B (NPR-B) mRNAs show that, in PA, NPR-A mRNA is more prevalent than NPR-B mRNA, whereas, in PV, NPR-B mRNA is more prevalent than NPR-A mRNA. In conclusion, in the pulmonary circulation, arteries are the major site of action for ANP, and veins are the major site for CNP. Furthermore, the differences in receptor abundance and the involvement of a cGMP-independent mechanism may contribute to the heterogeneous effects of the natriuretic peptides in PA and PV of newborn lambs.

Leishmania major: differential regulation of the surface metalloprotease in amastigote and promastigote stages.

During its life cycle, the protozoan parasite Leishmania major alternates from an intracellular amastigote form in the mammalian host to a flagellated promastigote form in the insect vector. The expression of the surface metalloprotease (PSP) during differentiation in vitro was investigated by Western and Northern blots, by immunoprecipitation of cells metabolically labeled with [35S]methionine or labeled at the surface with radioactive iodine, and by quantification of the proteolytic activity in substrate-containing polyacrylamide gels. We report that the surface metalloprotease is down-regulated at both the mRNA and the protein level in amastigotes, where it represents less than 1% of the equivalent proteolytic activity detected in promastigotes. A significant amount of mRNA is detected 4 hr after the onset of differentiation. The expression of the protease begins at that time and reaches steady state 8 hr later. The synthesis of PSP precedes the complete morphological differentiation to the promastigote stage and the appearance of the lipophosphoglycan, another major promastigote surface component. In contrast to PSP, a family of mercaptoethanol-activated proteases present in the amastigote exists only at a reduced level in the promastigote. The confinement of the surface metalloprotease to the insect stage of the parasite suggests that it has no physiological function in the parasitism maintenance of mammalian host macrophages.

Clinical value of immunoscintigraphy in colorectal carcinoma patients: a prospective study.

Fifty-seven patients with suspected CEA-producing tumors were studied prospectively by radioimmunoscintigraphy (RIS) using a 123I-labeled anti-CEA monoclonal antibody (MAb) (essentially the F(ab')2 or Fab fragments) and emission computed tomography (ECT). Results of RIS were compared to those of a comprehensive diagnostic study. Final diagnosis was based on surgery, biopsy and autopsy (n = 39) or follow-up findings (n = 18). Three groups of patients were defined: Group A with suspected primary tumors (n = 11), Group B with probable (n = 19) and Group C with questionable (n = 27) tumor relapse. Eighty-eight per cent, 93% and 71% of the anatomic regions studied were correctly identified as being involved, and 97%, 97%, and 87% as being free from tumor in Groups A, B, and C, respectively. In the 27 patients from Group C with no definite diagnosis of relapse, and in whom diagnosis was most difficult, 38 tumor sites were involved. Of these, 21 were detected by both prospective RIS and repeated comprehensive study, six by RIS only and seven by conventional methods only. Four sites remained undetected by both approaches. Ten of the 21 lesions were detected by RIS more than 1 mo earlier than by any other method. Among the seven tumor sites detected by other diagnostic modalities only, three were identified at the time of RIS and four became positive more than 6 mo later. Overall diagnosis was entirely correct in 30, partially correct in 16 and incorrect in six patients studied. RIS with ECT and 123I-labeled anti-CEA MAb allows early detection of recurrence or metastasis of colorectal cancer. It thus contributes to reduced delay between diagnosis and treatment.

Differential distribution of MAP1A isoforms in the adult mouse barrel cortex and comparison with the serotonin 5-HT2A receptor.

Microtubule-associated protein 1A (MAP1A) is essential during the late differentiation phase of neuronal development. Here, we demonstrated the presence of two MAP1A isoforms with a differential spatial distribution in the adult mouse barrel cortex. Antibody A stained MAP1A in pyramidal and stellate cells, including dendrites that crossed layer IV in the septa between barrels. The other antibody, BW6 recognized a MAP1A isoform that was mainly confined to the barrel hollow and identified smaller caliber dendrites. Previously, an interaction of MAP1A and the serotonin 5-hydroxytryptamine 2A (5-HT(2A)) receptor was shown in the rat cortex. Here, we identified, by double-immunofluorescent labeling, MAP1A isoform and serotonin 5-HT(2A) receptor distribution. MAP1A co-localized mainly with 5-HT(2A) receptor in larger apical dendrites situated in septa. This differential staining of MAP1A and a serotonin receptor in defined barrel compartments may be due to changes in the expression or processing of MAP1A during dendritic transport as a consequence of functional differences in processing of whisker-related sensory input.

Scientific value of systematic reviews: survey of editors of core clinical journals.

BACKGROUND: Synthesizing research evidence using systematic and rigorous methods has become a key feature of evidence-based medicine and knowledge translation. Systematic reviews (SRs) may or may not include a meta-analysis depending on the suitability of available data. They are often being criticised as 'secondary research' and denied the status of original research. Scientific journals play an important role in the publication process. How they appraise a given type of research influences the status of that research in the scientific community. We investigated the attitudes of editors of core clinical journals towards SRs and their value for publication.¦METHODS: We identified the 118 journals labelled as "core clinical journals" by the National Library of Medicine, USA in April 2009. The journals' editors were surveyed by email in 2009 and asked whether they considered SRs as original research projects; whether they published SRs; and for which section of the journal they would consider a SR manuscript.¦RESULTS: The editors of 65 journals (55%) responded. Most respondents considered SRs to be original research (71%) and almost all journals (93%) published SRs. Several editors regarded the use of Cochrane methodology or a meta-analysis as quality criteria; for some respondents these criteria were premises for the consideration of SRs as original research. Journals placed SRs in various sections such as "Review" or "Feature article". Characterization of non-responding journals showed that about two thirds do publish systematic reviews.¦DISCUSSION: Currently, the editors of most core clinical journals consider SRs original research. Our findings are limited by a non-responder rate of 45%. Individual comments suggest that this is a grey area and attitudes differ widely. A debate about the definition of 'original research' in the context of SRs is warranted.

Expression analyses of three members of the AtPHO1 family reveal differential interactions between signaling pathways involved in phosphate deficiency and the responses to auxin, cytokinin, and abscisic acid.

The PHO1 protein is involved in loading inorganic phosphate (Pi) to the root xylem. Ten genes homologous to AtPHO1 are present in the Arabidopsis thaliana (L.) Heyn genome. From this gene family, transcript levels of only AtPHO1, AtPHO1;H1 and AtPHO1;H10 were increased by Pi-deficiency. While the up-regulation of AtPHO1;H1 and AtPHO1;H10 by Pi deficiency followed the same rapid kinetics and was dependent on the PHR1 transcription factor, phosphite only strongly suppressed the expression of AtPHO1;H1 and had a minor effect on AtPHO1;H10. Addition of sucrose was found to increase transcript levels of both AtPHO1 and AtPHO1;H1 in Pi-sufficient or Pi-deficient plants, but to suppress AtPHO1:H10 under the same conditions. Treatments of plants with auxin or cytokinin had contrasting effect depending on the gene and on the Pi status of the plants. Thus, while both hormones down-regulated expression of AtPHO1 independently of the plant Pi status, auxin and cytokinin up-regulated AtPHO1;H1 and AtPHO1;H10 expression in Pi-sufficient plants and down-regulated expression in Pi-deficient plants. Treatments with abscisic acid inhibited AtPHO1 and AtPHO1;H1 expression in both Pi-sufficient and Pi-deficient plants, but increased AtPHO1;H10 expression under the same conditions. The inhibition of expression by abscisic acid of AtPHO1 and AtPHO1;H1, and of the Pi-starvation responsive genes AtPHT1;1 and AtIPS1, was dependant on the ABI1 type 2C protein phosphatase. These results reveal that various levels of cross talk between the signal transduction pathways to Pi, sucrose and phytohormones are involved in the regulation of expression of the three AtPHO1 homologues.