Cranberry Pomace Extract Exerts Antiviral Activity against Zika and Dengue Virus at Safe Doses for Adult Zebrafish

Mosquito-borne dengue virus (DENV) and zika virus (ZIKV) infections constitute a global health emergency. Antivirals directly targeting the virus infectious cycle are still needed to prevent dengue hemorrhagic fever and congenital zika syndrome. In the present study, we demonstrated that Cranberry Pomace (CP) extract, a polyphenol-rich agrifood byproduct recovered following cranberry juice extraction, blocks DENV and ZIKV infection in human Huh7.5 and A549 cell lines, respectively, in non-cytotoxic concentrations. Our virological assays identified CP extract as a potential inhibitor of virus entry into the host-cell by acting directly on viral particles, thus preventing their attachment to the cell surface. At effective antiviral doses, CP extract proved safe and tolerable in a zebrafish model. In conclusion, polyphenol-rich agrifood byproducts such as berry extracts are a promising source of safe and naturally derived nutraceutical antivirals that target medically important pathogens.     

Introduction to the Special Issue on “Promoting a Culture of Prevention: an International Perspective”

Prevention Science - The primary goal of this special issue is to showcase novel, theory-driven, creative, and rigorous contributions to our understanding of the existence and development of a...     

Methods for testing theory and evaluating impact in randomized field trials: intent-to-treat analyses for integrating the perspectives of person, place, and time

Randomized field trials provide unique opportunities to examine the effectiveness of an intervention in real world settings and to test and extend both theory of etiology and theory of intervention. These trials are designed not only to test for overall intervention impact but also to examine how impact varies as a function of individual level characteristics, context, and across time. Examination of such variation in impact requires analytical methods that take into account the trial's multiple nested structure and the evolving changes in outcomes over time. The models that we describe here merge multilevel modeling with growth modeling, allowing for variation in impact to be represented through discrete mixtures--growth mixture models--and nonparametric smooth functions--generalized additive mixed models. These methods are part of an emerging class of multilevel growth mixture models, and we illustrate these with models that examine overall impact and variation in impact. In this paper, we define intent-to-treat analyses in group-randomized multilevel field trials and discuss appropriate ways to identify, examine, and test for variation in impact without inflating the Type I error rate. We describe how to make causal inferences more robust to misspecification of covariates in such analyses and how to summarize and present these interactive intervention effects clearly. Practical strategies for reducing model complexity, checking model fit, and handling missing data are discussed using six randomized field trials to show how these methods may be used across trials randomized at different levels.     

Failing energetics in failing hearts

The perpetual and vigorous nature of heart muscle work requires efficient myocardial energetics. This depends not only on adequate ATP production, but also on efficient delivery of ATP to muscle ATPases and rapid removal of ADP and other by-products of ATP hydrolysis. Indeed, recent evidence indicates that defects in communication between ATP-producing and ATP-consuming cellular sites are a major factor contributing to energetic deficiency in heart failure. In particular, the failing myocardium is characterized by reduced catalytic activity of creatine kinase, adenylate kinase, carbonic anhydrase, and glycolytic enzymes, which collectively facilitate ATP delivery and promote removal of ADP, Pi, and H+ from cellular ATPases. Although energy transfer through adenylate kinase and glycolytic enzymes has been recognized as an adaptive mechanism supporting compromised muscle energetics, in the failing myocardium the total compensatory potential of these systems is diminished. A gradual accumulation of defects at various steps in myocardial energetic signaling, along with compromised compensatory mechanisms, precipitates failure of the whole cardiac energetic system, ultimately contributing to myocardial dysfunction. These advances in our understanding of the molecular bioenergetics in heart failure provide a new perspective toward improving the energetic balance of the failing myocardium.     

Lipid abnormalities and oxidized LDL in chronic kidney disease patients on hemodialysis and peritoneal dialysis

Dyslipoproteinemia and oxidative modification of low-density lipoprotein (oxLDL) contribute to the development of oxidative stress and atherosclerosis in chronic kidney disease (CKD). On the contrary, high-density lipoprotein cholesterol (HDL-C), especially HDL3-C subtype, has protective effect against oxidative damage. There is limited evidence referring HDL-C subclass levels in patients on dialysis. This study was designed to compare lipid abnormalities and oxLDL levels in hemodialysis (HD) and peritoneal dialysis (PD) patients. Serum lipids, HDL subclasses, and oxLDL were measured in 55 patients with CKD-stage 5 (31 patients on HD and 24 patients on PD) and in 21 normal controls (NC). The results showed that in dialysis patients, triglycerides were higher than in controls (p < 0.0001) and HDL-C was significantly lower (p < 0.0001). The HDL2-C subclass concentration did not differ significantly between patients and controls, while HDL3-C was lower in patients (11 ± 0.5 mg/dL) than in NC (23 ± 1, p < 0.0001). oxLDL levels were markedly increased in patients (1.92 ± 0.29 mg/L) compared to NC (0.22 ± 0.05, p < 0.0001). Patients on PD had higher levels of cholesterol (p < 0.001) and apolipoprotein B (p < 0.05) than patients on HD. However, HDL-C, HDL-C subclasses, and oxLDL concentrations did not differ significantly between PD and HD patients. It is concluded that patients with CKD have a nearly 10-fold elevation of oxLDL compared with NC. Patients on PD have differences in the lipid profile compared with patients on HD; however, both modalities seem to possess similar potential to atherosclerosis development.     

Brain perfusion SPECT imaging and acetazolamide challenge in vascular cognitive impairment

Cerebrovascular disease is recognized as a common cause of cognitive impairment and dementia, alone or coexisting with other neurodegenerative diseases, mostly Alzheimer's disease. Vascular cognitive impairment (VCI) is a part of the heterogenous disorders group related to cerebral vessel disease. Although age is one of the most important risk factors for VCI, other common cardiovascular risk factors are also involved. By investigating these risk factors, a high proportion of these cognitive disorders can be prevented and/or delayed. Until now, only treatment of midlife arterial hypertension has been recognized as a preventing factor of vascular dementia. Brain MRI is becoming the method of choice to investigate cerebral vascular pathologies. However, this form of morphological imaging remains inadequate and does not provide useful functional information during VCI exploration, despite which functional imaging such as brain perfusion single-photon computed tomography, performed in baseline conditions and/or after an acetazolamide challenge, is underutilized in VCI exploration. The common strategies for VCI screening have not been standardized until now, and therefore further long-term imaging studies are needed to establish early diagnostic protocols. The present review summarizes the potential benefits of brain perfusion single-photon computed tomography imaging and possible scintigraphic quantification of cerebral hemodynamic reserves in investigation of VCI.     

Anorectal malignant melanoma has a poor prognosis

Clinicopathologic features and surgical treatment of 15 patients with primary anorectal malignant melanoma were studied retrospectively. There was a female preponderance (2:1). The median age was 66 years. Common initial symptoms were rectal bleeding (87%) and/or anal pain (33%); 25% of the melanomas were amelanotic. The maximum tumor size ranged between 0.8 and 8.4 cm (median 3.0 cm). Of the tumors evaluated histologically (n=12), tumor thickness ranged from 0.9 to 11.3 mm (median 6.1 mm). All melanomas invaded at least into the subepithelial tissue (n=8) and/or the submucosa of the distal rectum (n=4), with extension into the internal anal sphincter (n=5) and lamina propria (n=3). Endoluminal ultrasound accurately demonstrated depth of invasion in 3 of 3 patients. Three (20%) patients with distant metastases at initial presentation had a mean survival of 8 mo; one of these primary melanomas measured 0.8 cm. Of 12 patients undergoing curative treatments — 4 by abdominoperineal resection (APR) and 8 by local excision (LE), the incidence of loco-regional recurrence was similar (2/4 and 5/8). All these 7 patients with loco-regional recurrence developed distant metastases within 3 months. The mean survival was similar between APR and LE in the total group (25 mo vs 20 mo), in the decreased (27 mo vs 24 mo) and in those treated with a curative intent (29 mo vs 22 mo). There was no long-term survivor but four patients remained tumor-free up to 19 mo after APR (n=1) or LE (n=3). Thus anorectal melanoma has a poor prognosis and, when technically feasible, LE appears to have similar results as APR.

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Résumé Les aspects clinico-pathologiques et le traitement chirurgical de 15 malades présentant un mélanome malin primitif ano-rectal ont été étudiés rétrospectivement. Il y avait une prépondérance féminine (2:1). L'âge moyen était de 66 ans. Le premier symptome commun était une rectorragie (87%) et ou une douleur anale (33%); 25% de ces mélanomes étaient achromiques. Le diamétre maximal de la tumeur était compris entre 0,8 et 8,4 cm (médiane 3,0 cm). Sur les tumeurs examinées histologiquement (n=12), l'épaisseur de la tumeru était comprise entre 0,9 et 11 mm (moyenne 6,1 mm). Tous ces mélanomes envahissaient au moins le tissu sub-épithélial (n=8) et/ou la sous muqueuse du rectum distal (n=4), avec une extension dans le sphincter anal interne (n=5) ou la lamina propria (n=3). L'échographie endorectale a montré de façon précise la profondeur de l'invasion chez 3 patients sur 3. Trois patients (20%), avec des métastases à distance lors de l'examen initial, ont eu une moyenne de survie de 8 mois. L'un de ces mélanomes primaires mesurait 0,8 cm. Sur les 12 patients ayant eu un traitement curatif-4 amputations abdomino-périnéales (AAP) et 8 excisions locales (LE)-l'incidence de récidive loco-régionale fut similaire (2/4 et 5/8). Tous les 7 patients avec une récidive loco-régionale ont développé des métastases à distance dans les 3 mois. La moyenne de survie était similaire après AAP ou LE dans le groupe total (25 mois versus 20 mois), chez les malades décédés (27 mois versus 24 mois), et chez ceux traités avec une intention curative (29 mois versus 22 mois). Il n'y a pas eu de survie à long terme mais 4 patients demeurent indemmes de récidive jusqu'à 19 mois après AAP (n=1) ou LE (n=3). Ainsi le mélanome ano-rectal a un pronostic défavorable et, lorsque cela est techniquement possible, l'excision locale semble avoir des résultats similaires à l'amputation abdomino-périnéales.

     

p53 expression in low grade dysplasia in Barrett's esophagus: correlation with interobserver agreement and disease progression

OBJECTIVES: The frequency of progression from low grade dysplasia (LGD) to high grade dysplasia/carcinoma (HGD/ CA) in Barrett's esophagus (BE) varies among studies. Current assessment is made more difficult because of pathologists' interobserver variability in diagnosing LGD. We recently conducted an interobserver study on LGD and reported a positive correlation between the extent of agreement among GI pathologists and progression of LGD. In the current study, we analyzed the immunohistochemical staining for p53 in patients diagnosed with LGD with known clinical outcome and interobserver agreement data. METHODS: Fixed, paraffin-embedded endoscopic biopsy specimens from 16 patients diagnosed with LGD in BE were immunostained for p53 (DO-7, Dako, Carpinteria, CA). Hematoxylin and eosin-stained and immunostained sections were examined in tandem to determine whether the LGD areas in question stained for p53. The p53 immunoreactivity was correlated with clinical progression and with the interobserver agreement among three GI pathologists. RESULTS: The overall mean follow-up was 23 months (range 2-84 months). LGD areas in seven of eight patients (88%) who progressed to HGD/CA stained positively for p53 compared to only two of eight nonprogressors (25%). A correlation with clinical progression was seen for p53 positivity (p = 0.017; log-rank test), and for either p53 positivity or complete agreement among three GI pathologists on LGD diagnosis (p = 0.014; log-rank test). The p53 staining demonstrated 88% sensitivity and 75% specificity for progression of LGD to HGD/CA. Adding complete interobserver agreement on LGD among three experienced GI pathologists to p53 positivity resulted in improved sensitivity with no change in specificity (100% and 75%, respectively). CONCLUSIONS: In conjunction with histological evaluation by GI pathologists for a diagnosis of LGD, immunohistochemical staining for p53 can be used as an adjunctive test, as it correlated with progression to HGD/CA in this series.     

Reduced Paneth cell alpha-defensins in ileal Crohn's disease

The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human alpha-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC alpha-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC alpha-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of alpha-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of alpha-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.