Functional Imaging of Pheochromocytoma with Ga-DOTATOC and C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia

Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or (11)C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of (11)C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats.

Models of hybridization during range expansions and their application to recent human evolution

Several lines of genetic, archeological and paleontological evidence suggest that anatomically modern humans (Homo sapiens) colonized the world in the last 60,000 years by a series of migrations originating from Africa (e.g. Liu et al., 2006; Handley et al., 2007; Prugnolle, Manica, and Balloux, 2005; Ramachandran et al. 2005; Li et al. 2008; Deshpande et al. 2009; Mellars, 2006a, b; Lahr and Foley, 1998; Gravel et al., 2011; Rasmussen et al., 2011). With the progress of ancient DNA analysis, it has been shown that archaic humans hybridized with modern humans outside Africa. Recent direct analyses of fossil nuclear DNA have revealed that 1–4 percent of the genome of Eurasian has been likely introgressed by Neanderthal genes (Green et al., 2010; Reich et al., 2010; Vernot and Akey, 2014; Sankararaman et al., 2014; Prufer et al., 2014; Wall et al., 2013), with Papua New Guineans and Australians showing even larger levels of admixture with Denisovans (Reich et al., 2010; Skoglund and Jakobsson, 2011; Reich et al., 2011; Rasmussen et al., 2011). It thus appears that the past history of our species has been more complex than previously anticipated (Alves et al., 2012), and that modern humans hybridized several times with local hominins during their expansion out of Africa, but the exact mode, time and location of these hybridizations remain to be clarifi ed (Ibid.; Wall et al., 2013). In this context, we review here a general model of admixture during range expansion, which lead to some predictions about expected patterns of introgression that are relevant to modern human evolution.

Effect sizes and standardization in neighbourhood models of forest stands: potential biases and misinterpretations

Effects of conspecific neighbours on survival and growth of trees have been found to be related to species abundance. Both positive and negative relationships may explain observed abundance patterns. Surprisingly, it is rarely tested whether such relationships could be biased or even spurious due to transforming neighbourhood variables or influences of spatial aggregation, distance decay of neighbour effects and standardization of effect sizes. To investigate potential biases, communities of 20 identical species were simulated with log-series abundances but without species-specific interactions. No relationship of conspecific neighbour effects on survival or growth with species abundance was expected. Survival and growth of individuals was simulated in random and aggregated spatial patterns using no, linear, or squared distance decay of neighbour effects. Regression coefficients of statistical neighbourhood models were unbiased and unrelated to species abundance. However, variation in the number of conspecific neighbours was positively or negatively related to species abundance depending on transformations of neighbourhood variables, spatial pattern and distance decay. Consequently, effect sizes and standardized regression coefficients, often used in model fitting across large numbers of species, were also positively or negatively related to species abundance depending on transformation of neighbourhood variables, spatial pattern and distance decay. Tests using randomized tree positions and identities provide the best benchmarks by which to critically evaluate relationships of effect sizes or standardized regression coefficients with tree species abundance. This will better guard against potential misinterpretations.

Endovascular treatment of patients with types A and B thoracic aortic dissection using Relay thoracic stent-grafts: results from the RESTORE Patient Registry

To evaluate the safety and performance of Relay stent-grafts in patients with acute or chronic aortic dissections.

Clinical Characteristics of Children with Viral Single- and Co-Infections and a Petechial Rash

BACKGROUND:: Children with petechial rash are more likely to undergo invasive diagnostics, to be treated with antibiotics for potential bacterial infection and to be hospitalized. However, viruses have also been associated with petechial rash. Nonetheless, a systematic analysis of viral infections with modern available techniques as quantitative real time polymerase chain reaction (q-PCR) in the context of petechial rash is lacking. The purpose of this pediatric study was to prospectively uncover viral pathogens that may promote the emergence of petechiae and to analyze the correlation with the clinical characteristics and course. METHODS:: We conducted a prospective study in children (0 to 18 years) presenting with petechiae and signs or symptoms of infection at the emergency department between November 2009 and March 2012. In nasopharyngeal aspirates the following viruses were analyzed by q-PCR: Cytomegalovirus, Epstein-Barr virus, parvovirus B19, Influenza A and B, parainfluenza viruses, human respiratory syncytial virus A and B, human metapneumovirus, rhinovirus, enterovirus, adenovirus, human coronavirus OC43, 229E, NL63 and human bocavirus. RESULTS:: A viral pathogen was identified in 67% of the analyzed 58 cases with petechial rash. Virus positive patients showed a significantly higher incidence of lower respiratory tract infections. Forty-one percent were viral co-infections, which were significantly younger than virus negative patients, had a higher leukocyte count and were hospitalized for a longer time. CONCLUSIONS:: A petechial rash is frequently associated viral single- and co-infections and can rapidly be identified via q-PCR.

Initial clinical experience with the 4-F self-expanding XPERT stent system for infrapopliteal treatment of patients with severe claudication and critical limb ischemia

PURPOSE: To evaluate the primary success and short-term patency associated with a new 4-F sheath-compatible self-expanding nitinol stent after failed conventional angioplasty of distal popliteal and infrapopliteal lesions in severe lifestyle-limiting claudication (LLC) and chronic critical limb ischemia (CLI). MATERIALS AND METHODS: Between May 2003 and July 2005, 35 patients with Rutherford category 3-5 disease (16 patients with CLI, 19 patients with LLC) underwent percutaneous transluminal angioplasty (PTA) and stent implantation. Indications for stent placement were residual stenosis, flow-limiting dissections, or elastic recoil after PTA. Before and after the intervention and during the 6-month follow-up, clinical investigation, color-flow and duplex Doppler ultrasonography, and digital subtraction angiography were performed. Technical success, primary patency at 6 months, clinical improvement as defined by Rutherford with clinical and hemodynamic measures, and complications were evaluated. RESULTS: A total of 22 patients underwent distal popliteal artery stent placement and 13 underwent tibioperoneal artery stent placement. Stent implantation was successfully performed in all patients. After stent placement, the primary cumulative patency rate for the study group at 6 months was 82%. The mean resting ankle-brachial index at baseline was 0.50 +/- 0.16 and significantly increased to 0.90 +/- 0.17 at 12-24 hours after intervention and 0.82 +/- 0.24 at latest follow-up (P < .001 for both). The sustained clinical improvement rate was 80% at the 6-month follow-up. The 6-month limb salvage rate regarding major amputation was 100%. The rate of major complications was 17%. CONCLUSIONS: Infrapopliteal application of the new nitinol stent is a safe, feasible, and effective method with good short-term patency rate in the treatment of severe LLC and chronic CLI.

Interactions of nanoparticles with pulmonary structures and cellular responses

Combustion-derived and synthetic nano-sized particles (NSP) have gained considerable interest among pulmonary researchers and clinicians for two main reasons: 1) Inhalation exposure to combustion-derived NSP was associated with increased pulmonary and cardiovascular morbidity and mortality as suggested by epidemiological studies. Experimental evidence has provided a mechanistic picture of the adverse health effects associated with inhalation of combustion-derived and synthetic NSP. 2) The toxicological potential of NSP contrasts with the potential application of synthetic NSP in technological as well as medicinal settings with the latter including the use of NSP as diagnostics or therapeutics. In order to shed light on this paradox, this article aims to highlight recent findings about the interaction of inhaled NSP with the structures of the respiratory tract including surfactant and alveolar macrophages and epithelial cells. Cellular responses to NSP exposure include the generation of reactive oxygen species and the induction of an inflammatory response. Furthermore, this review places special emphasis on methodological differences between experimental studies and the caveats associated with the dose metrics and points out ways to overcome inherent methodological problems. Key words: electron tomography, surfactant, translocation, oxidative stress, inflammation.

Dual induction of PKR with E2F-1 and IFN-alpha to enhance gene therapy against hepatocellular carcinoma

Overexpression of the transcription factor E2F-1 induces apoptosis in tumor cells. This apoptotic effect is partly mediated through the induction of the double-stranded RNA-activated protein kinase (PKR). Here, we investigate if agents that upregulate PKR could enhance the apoptotic effect of E2F-1 overexpression in liver tumors. In human hepatocellular carcinoma (HCC) cells (Hep3B, HepG2, Huh7), adenovirus-mediated overexpression of E2F-1 (AdCMV-E2F) transcriptionally increased PKR mRNA. The subsequent increase of total and phosphorylated PKR protein was followed by induction of apoptosis. When AdCMV-E2F was combined with the PKR modifier interferon alpha (IFNalpha), PKR was additionally upregulated and both PKR activation and apoptosis were increased. Subcutaneous xenograft tumors were selectively targeted using an adenoviral vector expressing E2F-1 under the control of the human telomerase reverse transcriptase (hTERT) promoter (AdhTERT-E2F). Weekly systemic administration of AdhTERT-E2F inhibited tumor growth. The tumor suppressive effect of AdhTERT-E2F therapy was further enhanced in combination with IFNalpha.Our results demonstrate that PKR activating agents enhance the anti-tumor effect of E2F-1 overexpression in HCC in-vitro and in-vivo. Hence, modulation of PKR is a potential strategy to increase the efficacy of PKR-dependent anti-tumor therapies.

Interaction of Plectin with Keratins 5 and 14: Dependence on Several Plectin Domains and Keratin Quaternary Structure.

Plectin, a cytolinker of the plakin family, anchors the intermediate filament (IF) network formed by keratins 5 and 14 (K5/K14) to hemidesmosomes, junctional adhesion complexes in basal keratinocytes. Genetic alterations of these proteins cause epidermolysis bullosa simplex (EBS) characterized by disturbed cytoarchitecture and cell fragility. The mechanisms through which mutations located after the documented plectin IF-binding site, composed of the plakin-repeat domain (PRD) B5 and the linker, as well as mutations in K5 or K14, lead to EBS remain unclear. We investigated the interaction of plectin C terminus, encompassing four domains, the PRD B5, the linker, the PRD C, and the C extremity, with K5/K14 using different approaches, including a rapid and sensitive fluorescent protein-binding assay, based on enhanced green fluorescent protein-tagged proteins (FluoBACE). Our results demonstrate that all four plectin C-terminal domains contribute to its association with K5/K14 and act synergistically to ensure efficient IF binding. The plectin C terminus predominantly interacted with the K5/K14 coil 1 domain and bound more extensively to K5/K14 filaments compared with monomeric keratins or IF assembly intermediates. These findings indicate a multimodular association of plectin with K5/K14 filaments and give insights into the molecular basis of EBS associated with pathogenic mutations in plectin, K5, or K14 genes.Journal of Investigative Dermatology advance online publication, 10 July 2014; doi:10.1038/jid.2014.255.

Esthetic, Functional, and Everyday Life Assessment of Individuals with Cleft Lip and/or Palate

OBJECTIVES To evaluate the level of satisfaction of individuals with cleft lip and/or palate (CLP) and their parents concerning the esthetic and functional treatment outcomes, the impact of the cleft on everyday life, and potential associations with treatment outcome satisfaction. SUBJECTS AND METHODS The sample consisted of 33 patients (7 CP, 20 unilateral CLP, and 6 bilateral CLP; median age: 17.1, range: 9.0-33.1 years) and 30 parents, who responded to a questionnaire in an interview-guided session. All participants received their orthodontic treatment at the Department of Orthodontics in the University of Athens. RESULTS Patients and their parents were quite satisfied with esthetics and function. Patients with UCLP primarily were concerned about nose esthetics (BCLP about lip esthetics and CP about speech). Increased satisfaction was associated with decreased influence of the cleft in everyday life (0.35 < rho < 0.64, P < 0.05). Parents reported significant influence of the cleft on family life, while patients did not. CONCLUSIONS Despite the limited sample size of subgroups, the main concerns of patients with different cleft types and the importance of satisfying lip, nose, and speech outcomes for an undisturbed everyday life were quite evident. Thus, the need for targeted treatment strategies is highlighted for individuals with cleft lip and/or palate.