One-Week Elderberry Juice Treatment Increases Carbohydrate Oxidation after a Meal Tolerance Test and Is Well Tolerated in Adults: A Randomized Controlled Pilot Study.

Obesity in the United States continues to worsen. Anthocyanin-rich fruits and vegetables provide a pragmatic dietary approach to slow its metabolic complications. Given American diet patterns, foods with high anthocyanin content could address dose-response challenges. The study objective was to determine the effect of 100% elderberry juice on measures of indirect calorimetry (IC) and insulin sensitivity/glucose tolerance in a placebo-controlled, randomized, crossover pilot study. Overweight and obese adults were randomized to a 5-week study which included 2 1-week periods of twice-daily elderberry juice (EBJ) or sugar-matched placebo consumption separated by a 3-week washout period. Following each 1-week test period, IC and insulin sensitivity/glucose tolerance was measured with a 3 h meal tolerance test (MTT). Treatment differences were tested with linear mixed modeling. A total of 22 prospective study volunteers (18 F/4 M) attended recruitment meetings, and 9 were analyzed for treatment differences. EBJ was well tolerated and compliance was 99.6%. A total of 6 IC measures (intervals) were created, which coincided with 10-20 min gaseous samplings in-between MTT blood samplings. Average CHO oxidation was significantly higher during the MTT after 1-week EBJ consumption (3.38 vs. 2.88 g per interval, EBJ vs. placebo, p = 0.0113). Conversely, average fat oxidation was significantly higher during the MTT after 1-week placebo consumption (1.17 vs. 1.47 g per interval, EBJ vs. placebo, p = 0.0189). This was in-line with a significantly lower average respiratory quotient after placebo treatment (0.87 vs. 0.84, EBJ vs. placebo, p = 0.0114). Energy expenditure was not different. There was no difference in serum glucose or insulin response between treatments. This pilot study of free-living volunteers describes significant change in IC but not insulin sensitivity with an EBJ intervention. Controlled feeding and increased sample size will help determine the utility of EBJ on these outcomes.

Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome.

The relationships between psychological stress and cognitive functions are still to be defined despite some recent progress. Clinically, we noticed that patients with Down syndrome (DS) may develop rapid neurocognitive decline and Alzheimer's disease (AD) earlier than expected, often shortly after a traumatic life event (bereavement over the leave of a primary caregiver, an assault, modification of lifestyle, or the loss of parents). Of course, individuals with DS are naturally prone to develop AD, given the triplication of chromosome 21. However, the relatively weak intensity of the stressful event and the rapid pace of cognitive decline after stress in these patients have to be noticed. It seems DS patients react to stress in a similar manner normal persons react to a very intense stress, and thereafter develop a state very much alike post-traumatic stress disorders. Unfortunately, only a few studies have studied stress-induced regression in patients with DS. Thus, we reviewed the biochemical events involved in psychological stress and found some possible links with cognitive impairment and AD. Interestingly, these links could probably be also applied to non-DS persons submitted to an intense stress. We believe these links should be further explored as a better understanding of the relationships between stress and cognition could help in many situations including individuals of the general population.

Correction to: Mothers screening for malnutrition by mid-upper arm circumference is non-inferior to community health workers: results from a large-scale pragmatic trial in rural Niger.

[This corrects the article DOI: 10.1186/s13690-016-0149-5.].

Thyroid hormone and folinic acid in young children with Down syndrome: the phase 3 ACTHYF trial.

PURPOSE: To determine whether folinic acid (FA) and thyroxine, in combination or alone, benefit psychomotor development in young patients with Down syndrome (DS). METHODS: The Assessment of Systematic Treatment With Folinic Acid and Thyroid Hormone on Psychomotor Development of Down Syndrome Young Children (ACTHYF) was a single-center, randomized, double-blind, placebo-controlled phase 3 trial in DS infants aged 6-18 months. Patients were randomly assigned to one of four treatments: placebo, folinic acid (FA), L-thyroxine, or FA+L-thyroxine, administered for 12 months. Randomization was done by age and sex. The primary endpoint was adjusted change from baseline in Griffiths Mental Development Scale global development quotient (GDQ) after 12 months. RESULTS: Of 175 patients randomized, 143 completed the study. The modified intention-to-treat (mITT) population included all randomized patients who did not prematurely discontinue due to elevated baseline thyroid stimulating hormone (TSH). Baseline characteristics in the mITT were well balanced between groups, with reliable developmental assessment outcomes. Adjusted mean change in GDQ in the mITT showed similar decreases in all groups (placebo: -5.10 [95% confidence interval (CI) -7.84 to -2.37]; FA: -4.69 [95% CI -7.73 to -1.64]; L-thyroxine: -3.89 [95% CI -6.94 to -0.83]; FA+L-thyroxine: -3.86 [95% CI -6.67 to -1.06]), with no significant difference for any active treatment group versus placebo. CONCLUSION: This trial does not support the hypotheses that thyroxine and/or folinic acid improve development of young children with DS or are synergistic. This trial is registered with ClinicalTrials.gov number, NCT01576705.

Focus on 1,25-Dihydroxyvitamin D3 in the Peripheral Nervous System.

In this review, we draw attention to the roles of calcitriol (1,25-dihydroxyvitamin D3) in the trophicity of the peripheral nervous system. Calcitriol has long been known to be crucial in phosphocalcium homeostasis. However, recent discoveries concerning its involvement in the immune system, anti-cancer defenses, and central nervous system development suggest a more pleiotropic role than previously thought. Several studies have highlighted the impact of calcitriol deficiency as a promoting factor of various central neurological diseases, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Based on these findings and recent publications, a greater role for calcitriol may be envisioned in the peripheral nervous system. Indeed, calcitriol is involved in myelination, axonal homogeneity of peripheral nerves, and neuronal-cell differentiation. This may have useful clinical consequences, as calcitriol supplementation may be a simple means to avoid the onset and/or development of peripheral nervous-system disorders.

Cost-effectiveness of the treatment of uncomplicated severe acute malnutrition by community health workers compared to treatment provided at an outpatient facility in rural Mali.

BACKGROUND: The Malian Nutrition Division of the Ministry of Health and Action Against Hunger tested the feasibility of integrating treatment of severe acute malnutrition (SAM) into the existing Integrated Community Case Management package delivered by community health workers (CHWs). This study assessed costs and cost-effectiveness of CHW-delivered care compared to outpatient facility-based care. METHODS: Activity-based costing methods were used, and a societal perspective employed to include all relevant costs incurred by institutions, beneficiaries and communities. The intervention and control arm enrolled different numbers of children so a modelled scenario sensitivity analysis was conducted to assess the cost-effectiveness of the two arms, assuming equal numbers of children enrolled. RESULTS: In the base case, with unequal numbers of children in each arm, for CHW-delivered care, the cost per child treated was 244 USD and cost per child recovered was 259 USD. Outpatient facility-based care was less cost-effective at 442 USD per child and 501 USD per child recovered. The conclusions of the analysis changed in the modelled scenario sensitivity analysis, with outpatient facility-based care being marginally more cost-effective (cost per child treated is 188 USD, cost per child recovered is 214 USD), compared to CHW-delivered care. This suggests that achieving good coverage is a key factor influencing cost-effectiveness of CHWs delivering treatment for SAM in this setting. Per week of treatment, households receiving CHW-delivered care spent half of the time receiving treatment and three times less money compared with those receiving treatment from the outpatient facility. CONCLUSIONS: This study supports existing evidence that the delivery of treatment by CHWs is a cost-effective intervention, provided that good coverage is achieved. A major benefit of this strategy was the lower cost incurred by the beneficiary household when treatment is available in the community. Further research is needed on the implementation costs that would be incurred by the government to increase the operability of these results.

Quality of care for treatment of uncomplicated severe acute malnutrition delivered by community health workers in a rural area of Mali.

An alternative Community-based Management of Acute Malnutrition model with community health workers (CHWs) delivering treatment for uncomplicated severe acute malnutrition (SAM) was piloted in Mali. The capacity of the CHWs to evaluate, classify, and treat cases of uncomplicated SAM, to provide nutritional counselling to caretakers of children receiving treatment for SAM, malaria, pneumonia or diarrhoea and to correctly refer cases of complicated SAM, was assessed. This was done using direct observation by trained enumerators of the management of SAM cases using checklists, re-diagnosing the cases admitted for treatment and reviewing admissions cards and registers. One hundred twenty-five cases, assessed and treated by the CHWs, were observed. The majority of children were correctly assessed for the presence of major clinical signs (cough, diarrhoea, fever, and vomiting; 97.6%), and similarly most children were checked for the presence of danger signs (95.2%). Mid-upper arm circumference was correctly assessed in 96.8% of children and oedema was correctly assessed in 78.4% (The composite indicator, which includes all essential tasks to provide high-quality treatment, was achieved in 79.5% of cases. This paper concludes that well-trained and supervised CHWs are capable of managing cases of uncomplicated SAM. This suggests that such a strategy is an opportunity to increase access to quality treatment in Mali for SAM cases. However, further evidence is required to ensure that this level of care can be achieved at scale.

Temporal dynamics of the gut microbiota in people sharing a confined environment, a 520-day ground-based space simulation, MARS500.

BACKGROUND: The intestinal microbial communities and their temporal dynamics are gaining increasing interest due to the significant implications for human health. Recent studies have shown the dynamic behavior of the gut microbiota in free-living, healthy persons. To date, it is not known whether these dynamics are applicable during prolonged life sharing in a confined and controlled environment. RESULTS: The MARS500 project, the longest ground-based space simulation ever, provided us with a unique opportunity to trace the crew microbiota over 520 days of isolated confinement, such as that faced by astronauts in real long-term interplanetary space flights, and after returning to regular life, for a total of 2 years. According to our data, even under the strictly controlled conditions of an enclosed environment, the human gut microbiota is inherently dynamic, capable of shifting between different steady states, typically with rearrangements of autochthonous members. Notwithstanding a strong individuality in the overall gut microbiota trajectory, some key microbial components showed conserved temporal dynamics, with potential implications for the maintenance of a health-promoting, mutualistic microbiota configuration. CONCLUSIONS: Sharing life in a confined habitat does not affect the resilience of the individual gut microbial ecosystem, even in the long term. However, the temporal dynamics of certain microbiota components should be monitored when programming future mission simulations and real space flights, to prevent breakdowns in the metabolic and immunological homeostasis of the crewmembers.

Do biofilm communities respond to the chemical signatures of fracking? A test involving streams in North-central Arkansas.

BACKGROUND: Unconventional natural gas (UNG) extraction (fracking) is ongoing in 29 North American shale basins (20 states), with ~6000 wells found within the Fayetteville shale (north-central Arkansas). If the chemical signature of fracking is detectable in streams, it can be employed to bookmark potential impacts. We evaluated benthic biofilm community composition as a proxy for stream chemistry so as to segregate anthropogenic signatures in eight Arkansas River catchments. In doing so, we tested the hypothesis that fracking characteristics in study streams are statistically distinguishable from those produced by agriculture or urbanization. RESULTS: Four tributary catchments had UNG-wells significantly more dense and near to our sampling sites and were grouped as 'potentially-impacted catchment zones' (PICZ). Four others were characterized by significantly larger forested area with greater slope and elevation but reduced pasture, and were classified as 'minimally-impacted' (MICZ). Overall, 46 bacterial phyla/141 classes were identified, with 24 phyla (52%) and 54 classes (38%) across all samples. PICZ-sites were ecologically more variable than MICZ-sites, with significantly greater nutrient levels (total nitrogen, total phosphorous), and elevated Cyanobacteria as bioindicators that tracked these conditions. PICZ-sites also exhibited elevated conductance (a correlate of increased ion concentration) and depressed salt-intolerant Spartobacteria, suggesting the presence of brine as a fracking effect. Biofilm communities at PICZ-sites were significantly less variable than those at MICZ-sites. CONCLUSIONS: Study streams differed by Group according to morphology, land use, and water chemistry but not in biofilm community structure. Those at PICZ-sites covaried according to anthropogenic impact, and were qualitatively similar to communities found at sites disturbed by fracking. The hypothesis that fracking signatures in study streams are distinguishable from those produced by other anthropogenic effects was statistically rejected. Instead, alterations in biofilm community composition, as induced by fracking, may be less specific than initially predicted, and thus more easily confounded by agriculture and urbanization effects (among others). Study streams must be carefully categorized with regard to the magnitude and extent of anthropogenic impacts. They must also be segregated with statistical confidence (as herein) before fracking impacts are monitored.

Histopathological tumor invasion of the mesenterico-portal vein is characterized by aggressive biology and stromal fibroblast activation.

BACKGROUND: Mesenterico-portal vein resection (PVR) during pancreatoduodenectomy for pancreatic head cancer was established in the 1990s and can be considered a routine procedure in specialized centers today. True histopathologic portal vein invasion is predictive of poor prognosis. The aim of this study was to examine the relationship between mesenterico-portal venous tumor infiltration (PVI) and features of aggressive tumor biology. METHODS: Patients receiving PVR for pancreatic ductal adenocarcinoma of the pancreatic head were identified from a prospectively maintained database. Immunohistochemical staining of tumor tissue was performed for the markers of epithelial-mesenchymal transition (EMT) E-Cadherin, Vimentin and beta-Catenin. Morphology of cancer-associated fibroblasts (CAFs) was assessed as inactive or activated. Statistical calculations were performed with MedCalc software. RESULTS: In total, 41 patients could be included. Median overall survival was 25 months. PVI was found in 17 patients (41%) and was significantly associated with loss of membranous E-Cadherin in tumor buds (p = 0.020), increased Vimentin expression (p = 0.03), activated CAF morphology (p = 0.046) and margin positive resection (p = 0.005). CONCLUSION: Our findings suggest that PVI is associated with aggressive tumor biology and disseminated growth less amenable to margin-negative resection.

Mothers screening for malnutrition by mid-upper arm circumference is non-inferior to community health workers: results from a large-scale pragmatic trial in rural Niger.

BACKGROUND: Community health workers (CHWs) are recommended to screen for acute malnutrition in the community by assessing mid-upper arm circumference (MUAC) on children between 6 and 59 months of age. MUAC is a simple screening tool that has been shown to be a better predictor of mortality in acutely malnourished children than other practicable anthropometric indicators. This study compared, under program conditions, mothers and CHWs in screening for severe acute malnutrition (SAM) by color-banded MUAC tapes. METHODS: This pragmatic interventional, non-randomized efficacy study took place in two health zones of Niger's Mirriah District from May 2013 to April 2014. Mothers in Dogo (Mothers Zone) and CHWs in Takieta (CHWs Zone) were trained to screen for malnutrition by MUAC color-coded class and check for edema. Exhaustive coverage surveys were conducted quarterly, and relevant data collected routinely in the health and nutrition program. An efficacy and cost analysis of each screening strategy was performed. RESULTS: A total of 12,893 mothers and caretakers were trained in the Mothers Zone and 36 CHWs in the CHWs Zone, and point coverage was similar in both zones at the end of the study (35.14 % Mothers Zone vs 32.35 % CHWs Zone, p = 0.9484). In the Mothers Zone, there was a higher rate of MUAC agreement (75.4 % vs 40.1 %, p <0.0001) and earlier detection of cases, with median MUAC at admission for those enrolled by MUAC <115 mm estimated to be 1.6 mm higher using a smoothed bootstrap procedure. Children in the Mothers Zone were much less likely to require inpatient care, both at admission and during treatment, with the most pronounced difference at admission for those enrolled by MUAC < 115 mm (risk ratio = 0.09 [95 % CI 0.03; 0.25], p < 0.0001). Training mothers required higher up-front costs, but overall costs for the year were much lower ($8,600 USD vs $21,980 USD.). CONCLUSIONS: Mothers were not inferior to CHWs in screening for malnutrition at a substantially lower cost. Children in the Mothers Zone were admitted at an earlier stage of SAM and required fewer hospitalizations. Making mothers the focal point of screening strategies should be included in malnutrition treatment programs. TRIAL REGISTRATION: The trial is registered with clinicaltrials.gov (Trial number NCT01863394).

Reduction of Acute Shoulder Dislocations in a Remote Environment: A Prospective Multicenter Observational Study.

OBJECTIVE: Acute dislocations of the glenohumeral joint are common in wilderness activities. Emergent reduction should take place at the site of trauma to reduce the patient's pain and the risk of vascular and neurological complications. A limited number of reduction methods are applicable in remote areas. The aim of this study is to present our method of reduction of anterior shoulder luxation that is easily applicable in remote areas without medication, adjuncts, and assistants and is well tolerated by patients. METHODS: A prospective observational study was conducted during a 5-year period. The patients included underwent closed manual reduction with our technique. After each reduction, the physician who performed the reduction completed a standardized detailed history, and reexamined the patient (for acute complications). The patients were contacted 6 months after the trauma to investigate long-term postreduction complications. RESULTS: Reduction was achieved with our method in 39 (100.0%) of 39 patients. The mean pain felt during our reduction procedure was rated 1.7 ± 1.4 (on a scale of 10) using the visual analog scale scoring system. No complications were noted before or after the reduction attempts. We did not find any long-term complications. CONCLUSIONS: The reduction method presented in the present study is an effective method for the reduction of acute shoulder luxations in remote places. Our data suggest that this method could be applied for safe and effective reduction of shoulder dislocation.

Postoperative ulnar neuropathy is not necessarily iatrogenic: a prospective study on dynamic ulnar nerve dislocation at the elbow.

BACKGROUND: Patients who undergo surgery may develop ulnar neuropathy. Although the mechanism of ulnar neuropathy is still not clear, ulnar neuropathies are common causes of successful lawsuits against surgeons. Recently, the concept developed that endogenous patient factors can lead to postoperative peripheral neuropathies. We hypothesize that dynamic ulnar nerve dislocation at the elbow (DUNDE) may be a predisposing factor for ulnar irritation (i.e., neuropathy) in normal subjects. METHODS: In a prospective investigation, patients aged 20 years and older presenting in our emergency department were asked to participate. Three physicians examined both elbows of subjects included in our study for evidence of DUNDE (through clinical and sonographic examination) and for clinical symptoms related to ulnar neuropathy. RESULTS: Dynamic ulnar nerve dislocation was observed in 29.3% of examined subjects. No significant difference in its occurrence was observed in relation to gender or dominant side. Physical examination with provocation tests demonstrated significantly more positive Tinel tests and spontaneous signs of neuropathy in patients with dynamic dislocating ulnar nerves (14.7 vs. 1.1%). CONCLUSION: Dynamic ulnar nerve dislocation may be linked to ulnar nerve irritability (i.e., ulnar neuropathy) in normal subjects without history of trauma, surgical procedure, or anesthesia. Considering the high incidence of this variant in the general population, our study supports previous investigations suggesting that many postoperative ulnar nerve deficits are traceable to chronic patient conditions. Our study suggests that dynamic ulnar nerve dislocation is a predisposing factor in the development of ulnar neuropathy in the postoperative period. NOTES: (1) neuropathy should be viewed as a broad definition as signs of nerve irritation/inflammation, and independently of the pathophysiology and etiology; (2) because no specific term exists in the international anatomic nomenclature (Nomina Anatomica) to designate this variant, several synonyms have been used in the literature, leading to confusion and misleading conclusions concerning its traumatic etiologies and their consequences: (a) recurrent or habitual ulnar nerve luxation (or subluxation); (b) recurrent or habitual ulnar nerve dislocation; (c) ulnar nerve instability; (d) laxity of the ulnar nerve; and (e) ulnar nerve hypermobility.

In vitro 3D angiogenesis assay in egg white matrix: comparison to Matrigel, compatibility to various species, and suitability for drug testing.

In vitro angiogenesis assays are commonly used to assess pro- or anti-angiogenic drug properties. Extracellular matrix (ECM) substitutes such as Matrigel and collagen gel became very popular in in vitro 3D angiogenesis assays as they enable tubule formation by endothelial cells from culture or aortic rings. However, these assays are usually used with a single cell type, lacking the complex cellular interactions occurring during angiogenesis. Here, we report a novel angiogenesis assay using egg white as ECM substitute. We found that, similar to Matrigel, egg white elicited prevascular network formation by endothelial and/or smooth muscle cell coculture. This matrix was suitable for various cells from human, mouse, and rat origin. It is compatible with aortic ring assay and also enables vascular and tumor cell coculture. Through simple labeling (DAPI, Hoechst 33258), cell location and resulting prevascular network formation can easily be quantified. Cell transfection with green fluorescent protein improved whole cell visualization and 3D structure characterization. Finally, egg-based assay dedicated to angiogenesis studies represents a reliable and cost-effective way to produce and analyze data regarding drug effects on vascular cells.

Effect of advanced trauma life support (ATLS) on the time needed for treatment in simulated mountain medicine emergencies.

OBJECTIVE: The number of tourists exploring mountainous areas continues to increase. As a consequence, rescue operations are increasing, especially for trauma and polytrauma victims. The outcome of such patients depends greatly on the duration of the prehospital stabilization. Limited medical training of mountain rescuers may adversely affect the outcome of patients. There is no study investigating high altitude trauma treatment. The aim of this study is to analyze the impact of advanced trauma life support (ATLS) principles in mountain trauma, and to discuss a possible role of ATLS in mountain medicine education programs. METHODS: We designed 5 tasks representing life-threatening trauma problems encountered in mountain rescue. They were used to evaluate the physician's ability to adequately diagnose and react to trauma situations. We created 2 groups: 1) the ATLS group, consisting of physicians who passed the ATLS course and the mountain medicine course, and 2) the non-ATLS group, consisting of physicians who did not obtain the ATLS training but who did pass the mountain medicine course. We compared the time spent to complete the tasks in both groups. RESULTS: In 4 of the 5 tasks (airway, breathing, circulation, and combination), the ATLS group completed the task significantly faster. In the environment task, however, the ATLS group was slower. This was the only not significant result. CONCLUSIONS: ATLS principles adapted and implemented for high altitude medicine education may have a positive impact on high altitude trauma treatment and outcomes.

Fingolimod inhibits PDGF-B-induced migration of vascular smooth muscle cell by down-regulating the S1PR1/S1PR3 pathway.

Platelet Derived Growth Factor (PDGF) and sphingosine-1-phosphate (S1P) pathways play a key role in mural cell recruitment during tumor growth and angiogenesis. Fingolimod, a S1P analogue, has been shown to exert antitumor and antiangiogenic properties. However, molecular targets and modes of action of fingolimod remain unclear. In this study, we confirmed the antagonizing action of S1P and PDGF-B on rat vascular smooth muscle cell (VSMCs) growth and migration. We then compared siRNA and/or fingolimod (100 nM) treatments on PDGFR-ß, S1PR1 S1PR2 and S1PR3 expression. Fingolimod induced a 50% reduction in S1PR3 protein expression which was cumulative with that obtained with anti-S1PR3 siRNA. We found that siRNA-induced inhibition of both PDGFR-ß and S1PR3 was the most effective means to block VSMC migration induced by PDGF-B. Finally, we observed that fingolimod treatment associated with anti-S1PR1 siRNA principally inhibited VSMC growth while in combination with anti-S1PR3 siRNA it strongly inhibited VSMC migration. These results suggest that for rat VSMCs, the PDGFR-S1PR1 pathway is predominantly dedicated to cell growth while PDGFR-S1PR3 stimulates cell migration. As an S1P analogue, fingolimod is considered a potent activator of S1PR1 and S1PR3. However, its action on the PDGFR-S1PR platform appears to be dependent on S1PR1 and S1PR3 specific downregulation. Considering that the S1P pathway has already been shown to exert various crosstalks with tyrosine kinase pathways, it seems of great interest to evaluate fingolimod potential in combination with the numerous tyrosine kinase inhibitors used in oncology.

Homozygous deletion of an EGR2 enhancer in congenital amyelinating neuropathy.

The transcription factor EGR2 is expressed in Schwann cells, where it controls peripheral nerve myelination. Mutations of EGR2 have been found in patients with congenital hypomyelinating neuropathy or Charcot-Marie-Tooth disease type 1D. In a patient with congenital amyelinating neuropathy, we observed pathological abnormalities recapitulating the peripheral nervous system phenotype of homozygous Egr2-null mice. This patient, born from consanguineous parents, showed no EGR2 immunoreactivity in Schwann cells and harbored a homozygous 10.7-kilobase-long deletion encompassing a myelin-specific enhancer of EGR2. This regulatory mutation is the first genetic abnormality associated with congenital amyelinating neuropathy in humans.

Fingolimod potentiates the effects of sunitinib malate in a rat breast cancer model.

Most of the antiangiogenic strategies used in oncology principally target endothelial cells through the vascular endothelial growth factor (VEGF) pathway. Multiple kinase inhibitors can secondarily reduce mural cell stabilization of the vessels by blocking platelet-derived growth factor receptor (PDGFR) activity. However, sphingosine-1-phosphate (S1P), which is also implicated in mural cell recruitment, has yet to be targeted in clinical practice. We therefore investigated the potential of a simultaneous blockade of the PDGF and S1P pathways on the chemotactic responses of vascular smooth muscle cells (VSMCs) and the resulting effects of this blockade on breast tumor growth. Due to crosstalk between the S1P and PDGF pathways, we used AG1296 and/or VPC-23019 to inhibit PDGFR-ß and S1PR1/S1PR3 receptors, respectively. We showed that S1PR1 and S1PR3 are the principal receptors that mediate the S1P chemotactic signal on rat VSMCs and that they act synergistically with PDGFR-ß during PDGF-B signaling. We also showed that simultaneous blockade of the PDGFR-ß and S1PR1/S1PR3 signals had a synergistic effect, decreasing VSMC migration velocity toward endothelial cell and breast carcinoma cell-secreted cytokines by 65-90%. This blockade also strongly decreased the ability of VSMCs to form a three-dimensional cell network. Similar results were obtained with the combination of sunitinib malate (a VEGFR/PDGFR kinase inhibitor) and fingolimod (an S1P analog). Sunitinib malate is a clinically approved cancer treatment, whereas fingolimod is currently indicated only for treatment of multiple sclerosis. Orally administered, the combination of these drugs greatly decreased rat breast tumor growth in a syngeneic cancer model (Walker 256). This bi-therapy did not exert cumulative toxicity and histological analysis of the tumors revealed normalization of the tumor vasculature. The simultaneous blockade of these signaling pathways with sunitinib malate and fingolimod may provide an effective means of reducing tumor angiogenesis, and may improve the delivery of other chemotherapies.

How can grafted breast cancer models be optimized?

Breast cancer is the most frequent spontaneous malignancy diagnosed in women and is characterized by a broad histological diversity. Progression of the disease has a metastasizing trend and can be resistant to hormonal and chemotherapy. Animal models have provided some understanding of these features and have allowed new treatments to be proposed. However, these models need to be revised because they have some limitations in predicting the clinical efficacy of new therapies. In this review, we discuss the biological criteria to be taken into account for a realistic animal model of breast cancer graft (tumor implantation site, animal immune status, histological diversity, modern imaging). We emphasize the need for more stringent monitoring criteria, and suggest adopting the human RECIST (Response Evaluation Criteria in Solid Tumors) criteria to evaluate treatments in animal models.

A new rat model of prenatal bowel obstruction: development and early assessment.

PURPOSE: Although intestinal motility disorders often complicate the postoperative surgical management of newborns with congenital intestinal atresia, their pathogenesis remains unclear. Animal models of prenatal intestinal obstruction have been mainly developed in the lamb and the chicken. Despite new insights brought by these models, they have one or more limitations, such as high fetal mortality rates, high costs, long gestation periods, and an insufficient number of fetuses per litter. Moreover, some species are phylogenetically distant from mammals. METHODS: We developed a reproducible model of prenatal intestinal obstruction in the rat to study the histologic changes induced by the obstruction. We report, the technical devices and the first assessment of this atresia model in a didactic way to allow other researchers to easily reproduce the model. RESULTS: Prenatal intestinal obstructions in this study fulfilled all the macroscopic and histologic criteria usually listed by other models of prenatal intestinal obstruction that have been developed in other species. Furthermore with our model, we obtained a high success rate at a low cost. CONCLUSIONS: We presented in this study a reproducible model of prenatal intestinal obstruction in the rat with the macroscopical and histologic features of prenatal intestinal obstruction.