[18F]FDG-PET/CT and long-term responses to everolimus in advanced neuroendocrine neoplasia.

PURPOSE: This study aims to identify in patients with neuroendocrine neoplasia (NEN) the potential correlation between FDG-PET findings and responses to everolimus therapy to identify predictors of long-term efficacy. METHODS: Retrospective analysis of patients with sporadic, advanced, progressive NEN treated with everolimus was performed based on the available data on FDG-PET patients obtained before commencing therapy. Data are expressed as the median (25-75th IQR). Risk factor analysis and survival analysis were performed by logistic regression and Cox proportional hazard regression and the determination of Kaplan-Meier curves, as appropriate. RESULTS: Sixty-six patients were evaluated (NET G1 19.7%, NET G2 75.7%, and NET G3 4.6%), including 45.4% with positive FDG-PET findings. Overall, disease stabilization and a partial response were achieved for 71.2% and 6% of patients, respectively. A long-term response (> 24 months) was observed in 33% of patients. Ki67 was the only predictor of tumor progression (p = 0.03). No significant difference in clinical outcomes was observed between patients with positive or negative FDG-PET findings (median PFS was 24 months and 18 months, respectively, p = 0.337; the disease control rate was 83.3% and 70%, respectively, p = 0.245). CONCLUSIONS: Everolimus is a valid therapeutic option for advanced, progressive, well-differentiated NEN, even in patients with positive FDG-PET findings.

Assessing effects of dietary and milking frequency changes and injection of cabergoline during dry-off on hunger in dairy cows using 2 feed-thwarting tests.

We investigated the single and combined effects of 2 feeding levels (normal lactation diet vs. energy-reduced diet, both fed for ad libitum intake) and 2 daily milking frequencies (twice vs. once) during 1 wk before the dry-off day (d 0), as well as an intramuscular injection of either a dopamine agonist (cabergoline; Velactis, Ceva Santé Animale; labeled for use only with abrupt dry-off, e.g., no reduction in feeding level or milking frequency before the last milking) or saline after the last milking on d 0 on the feeding motivation of clinically healthy, loose-housed, pregnant, lactating Holstein cows. From d 0, all cows were fed the same dry-cow diet for ad libitum intake. Cows were subjected to 2 feed-thwarting tests, a test in the home pen using their diets (test A: d -6, -1, and 1; during 35 min when the feed bins were filled, but locked) and another test carried out in an adjacent pen in which access to concentrate provided in a familiar plastic box was blocked by a wire-mesh lid (test B: d -5 and 2). In test A, we recorded how often cows attempted to feed per 35 min, whether cows vocalized during the 35-min period, and latency to feed within 300 s after feed bins were unlocked. In test B, we recorded latency to approach either of 2 familiar boxes (the wire-mesh box and an identical open box with a small portion of concentrate) within 600 s and how often cows directed behaviors toward the wire-mesh box (number of occurences/5 min). On d -6 (test A), no clear differences in feeding motivation among treatments were found. On d -5 and -1, cows fed the energy-reduced diet displayed a higher probability of vocalizing (test A), were more than 50% quicker to feed (test A), were approximately 5× quicker to approach a box (test B), and directed 60% more behavior toward the wire-mesh box (test B) than cows fed the normal diet. Moreover, cows fed the energy-reduced diet attempted to feed approximately 75% more on d -1 compared with d -6 (test A). On d 2 (test B), cows previously fed the normal diet directed 40% more behavior toward the wire-mesh box than cows previously fed the energy-reduced diet. Reducing feeding level, either before or on the dry-off day, resulted in consistently increased feeding motivation, interpreted as a sign of hunger. No clear effects of change in milking frequency, singly or combined with reduced diet energy density, on feeding motivation were found before d 0. Whereas, on d 2, cows previously milked twice daily were quicker to approach a box than cows previously milked once daily. Cows injected with cabergoline attempted to feed more, but showed lower probability of vocalizing compared with saline-injected cows (d 1; test A), irrespective of treatment before d 0. The effects of cabergoline on feeding motivation are not easily interpreted and warrant further investigation. From a hunger perspective, reducing milking frequency rather than diet energy density seems to be a less negative management to reduce milk production before dry-off.

[Secondary nasal surgery with cleft palates]. / Les rhinoseptoplasties secondaires des fentes labiopalatines.

Residual nasal deformity in patients with cleft palate remains the main demand of these patients. Performing primary nasal surgery has significantly improved the results. However, it is still often necessary to improve the nasal morphology. Respect of tissues during primary surgery is essential and allows easier secondary corrections. Anatomical reconstruction greatly facilitates the treatment of secondary deformities. Do not hesitate in case of major labionasales sequelae, to make revision, according to the rules of primary surgery, of the entire lip and nose.

Enhanced EDX images by fusion of multimodal SEM images using pansharpening techniques.

The goal of this paper is to explore the potential interest of image fusion in the context of multimodal scanning electron microscope (SEM) imaging. In particular, we aim at merging the backscattered electron images that usually have a high spatial resolution but do not provide enough discriminative information to physically classify the nature of the sample, with energy-dispersive X-ray spectroscopy (EDX) images that have discriminative information but a lower spatial resolution. The produced images are named enhanced EDX. To achieve this goal, we have compared the results obtained with classical pansharpening techniques for image fusion with an original approach tailored for multimodal SEM fusion of information. Quantitative assessment is obtained by means of two SEM images and a simulated dataset produced by a software based on PENELOPE.

[Facial injections of hyaluronic acid-based fillers for malformations. Preliminary study regarding scar tissue improvement and cosmetic betterment]. / Injections d'acides hyaluroniques au niveau de visages atteints de malformations faciales. Étude préliminaire de l'assouplissement des zones cicatricielles et de l'amélioration esthétique.

BACKGROUND: Cross-linked hyaluronic acid-based fillers have gained rapid acceptance for treating facial wrinkles, deep tissue folds and sunken areas due to aging. This study evaluates, in addition to space-filling properties, their effects on softness and elasticity as a secondary effect, following injection of 3 commercially available cross-linked hyaluronic acid-based fillers (15mg/mL, 17,5mg/mL and 20mg/mL) in patients presenting with congenital or acquired facial malformations. PATIENTS ET METHODS: We started injecting gels of cross-linked hyaluronic acid-based fillers in those cases in 2013; we performed 46 sessions of injections in 32 patients, aged from 13-32. Clinical assessment was performed by the patient himself and by a plastic surgeon, 15 days after injections and 6-18 months later. RESULTS: Cross-linked hyaluronic acid-based fillers offered very subtle cosmetic results and supplemented surgery with a very high level of satisfaction of the patients. When injected in fibrosis, the first session enhanced softness and elasticity; the second session enhanced the volume. Cross-linked hyaluronic acid-based fillers fill sunken areas and better softness and elasticity of scar tissues. CONCLUSION: In addition to their well-understood space-filling function, as a secondary effect, the authors demonstrate that cross-linked hyaluronic acid-based fillers improve softness and elasticity of scarring tissues. Many experimental studies support our observations, showing that cross-linked hyaluronic acid stimulates the production of several extra-cellular matrix components, including dermal collagen and elastin.

[Orbital congenital nevi: Principles of treatment about 51 cases]. / Nævi orbitaires congénitaux: principes de prise en charge thérapeutique à propos de 51 cas.

INTRODUCTION: The incidence of congenital nevi is one over 20,000 newborns per year, 14 % of them are located in the head and neck area. Nevi of the orbital region are particularly difficult to handle on the aesthetic and functional side. The objectives of this study were to conduct an analysis of different clinical presentations of congenital nevi of the eyelid orbital region in children to establish a treatment algorithm. MATERIEL AND METHODS: We realised a bi-centric retrospective study including 51 children with orbito-palpebral congenital nevi. We analysed the different clinical presentations, their treatments and their results. RESULTS: Nineteen underwent direct suture excision; three a total skin graft; 15 a combination of treatments, among them four underwent tissular expansion and 14 patients were not operated and clinically followed-up. The average follow-up time was 6.6 years. In 33 cases residual nevic area was still present. The postoperative sequelae were: dyschromia (n=17), anatomical deformation of the eye (n=10), nevi outbreaks (n=8), internal canthus deformation (n=5) and ectropion (n=1). CONCLUSION: The results of our study show that therapeutic abstention is preferred when the aesthetic wrong is accepted by the patient and when there is not a higher risk of malignant degeneration. In order to minimise the risk of postoperative sequelae, we propose a therapeutic algorithm for the management of congenital orbital nevi.

[Tissular expansion in giant congenital nevi treatment]. / Nævus pigmentaires congénitaux géants : quelle place pour l'expansion cutanée.

UNLABELLED: Surgical management of giant melanotic naevi remains a surgical challenge. Tissue expansion provides tissue of the same quality for the repair of defects. The aim of this study is to review tissular expansion for giant melanotic naevi. MATERIALS AND METHODS: We conducted a retrospective study from 2000 to 2012. All children patients who underwent a tissular expansion for giant congenital naevi had been included. Epidemiological data, surgical procedure, complication rate and results had been analysed. RESULTS: Thirty-tree patients had been included; they underwent 61 procedures with 79 tissular-expansion prosthesis. Previous surgery, mostly simple excision had been performed before tissular expansion. Complete naevus excision had been performed in 63.3% of the cases. Complications occurred in 45% of the cases, however in 50% of them were minor. Iterative surgery increased the complication rate. CONCLUSION: Tissular expansion is a valuable option for giant congenital naevus. However, complication rate remained high, especially when iterative surgery is needed.

Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.

BACKGROUND: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. AIM: To investigate epidemiology, clinical presentation, and natural history of NET. DESIGN AND SETTING: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0 ± 16.4 yr, significantly anticipated in MEN1 patients (47.7 ± 16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hypersecretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1-associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.

Depression, pathological dependence, and risky behaviour in adolescence.

During adolescence, there is an increased chance of increased incidence of depression and the development of addictive/dependent behaviours such as pathological gambling, excessive Internet use and compulsive shopping, Here we present a psychoeducational approach in the schools of Pescara and Penne to identify and treat these problems.

Effects of dietary and milking frequency changes and administration of cabergoline on clinical udder characteristics in dairy cows during dry-off.

We investigated the effects of 2 diet energy densities [normal lactation diet (NORM) vs. energy-reduced diet (REDU), both fed for ad libitum intake] and 2 daily milking frequencies [twice (2×) vs. once (1×)] during 1 week before the dry-off day, as well as effects of an injection of either a dopamine agonist [cabergoline (CAB); Velactis, Ceva Santé Animale, Libourne, France; labelled for use only with abrupt dry-off, e.g. no reduction in diet energy density or milking frequency before the last milking] or saline (SAL) following the last milking, on clinical udder characteristics of Holstein cows. During a week before and after the last milking, the following measures were recorded: palpation-based udder firmness and soreness; image-based hock-hock distance; responsiveness to mechanical udder stimulation and degree of udder fill measured with a dynamometer. Before the last milking, REDU cows displayed lower odds of having a firm udder and lower degree of udder fill, as well as lower responsiveness to mechanical udder stimulation, than NORM cows. After the last milking, REDU cows displayed shorter hock-hock distance compared with NORM cows. The effects of milking frequency on the clinical udder characteristics were unclear. Within 24 h following injection, CAB cows showed lower odds of having a firm udder, shorter hock-hock distance, and lower degree of udder fill than SAL cows, irrespective of treatment group before dry-off. In this study, reducing diet energy density prior to dry-off, and to some extent administering the dopamine agonist cabergoline after the last milking, resulted in fewest clinical udder changes.

Effects of changes in diet energy density and milking frequency and a single injection of cabergoline at dry-off on feeding behavior and rumination time in dairy cows.

Dry-off is a typical management practice, but research on the effects of dry-off on feeding behavior in high-yielding cows is limited. The present study investigated the effects of 2 diet energy densities: lactation diet (normal energy density, NORM) versus a lactation diet diluted with 30% straw (reduced energy density, REDU), both offered ad libitum, and 2 daily milking frequencies (2× vs. 1×) during the 7 d before dry-off day (d 0), and the effects of an injection of either a dopamine agonist [cabergoline (CAB); Velactis, Ceva Santé Animale; labeled for use only with abrupt dry-off; i.e., no reduction in feeding level or milking frequency before the last milking] or saline (SAL) following the last milking on d 0 (2 × 2 × 2 factorial arrangement), on automatically monitored feeding behavior and rumination time in 119 clinically healthy, loose-housed, pregnant, lactating Holstein cows during the week before and after d 0. From d 0, all cows were fed the same dry-cow diet ad libitum. Data were analyzed in R using mixed-effects models. Over the days before d 0, REDU cows spent 30% more time feeding at a 50% lower feeding rate, visited both assigned and unassigned feed bins more frequently, and spent more time ruminating than NORM cows. No clear behavioral effects of reduced milking frequency were found. Within 24 h following injection, CAB cows spent approximately 40% less time feeding at a lower feeding rate, visited their feed bin 28% less often, and spent 40% less time ruminating than SAL cows, irrespective of treatment before dry-off. The current study demonstrates that reducing diet energy density for 1 wk before dry-off led to clear behavioral changes in high-yielding cows. Administering CAB after the last milking induced decreased feeding behavior lasting approximately 24 h, indicating collateral effects other than reduced prolactin secretion.

Pollen and seed desiccation tolerance in relation to degree of developmental arrest, dispersal, and survival.

In most species, arrest of growth and a decrease in water content occur in seeds and pollen before they are dispersed. However, in a few cases, pollen and seeds may continue to develop (germinate). Examples are cleistogamy and vivipary. In all other cases, seeds and pollen are dispersed with a variable water content (2-70%), and consequently they respond differently to environmental relative humidity that affects dispersal and maintenance of viability in time. Seeds with low moisture content shed by the parent plant after maturation drying can generally desiccate further to moisture contents in the range of 1-5% without damage and have been termed 'orthodox'. Pollen that can withstand dehydration also was recently termed orthodox. Seeds and pollen that do not undergo maturation drying and are shed at relatively high moisture contents (30-70%) are termed 'recalcitrant'. Since recalcitrant seeds and pollen are highly susceptible to desiccation damage, they cannot be stored under conditions suitable for orthodox seeds and pollen. Hence, there are four types of plants with regard to tolerance of pollen and seeds to desiccation. Orthodoxy allows for dispersal over greater distances, longer survival, and greater resistance to low relative humidity. The advantage of recalcitrance is fast germination. Orthodoxy and recalcitrance are often related to environment rather than to systematics. It has been postulated that certain types of genes are involved during presentation and dispersal of pollen and seeds, since molecules (sucrose, polyalcohols, late embryogenic abundant proteins, antioxidants, etc.) that protect different cell compartments during biologically programmed drying have been detected in both.

Distribution and genesis of the RFRP-producing neurons in the rat brain: comparison with melanin-concentrating hormone- and hypocretin-containing neurons.

Prepro-RFRP-containing neurons have recently been described in the mammalian brain. These neurons are only found in the tuberal hypothalamus. In this work, we have provided a detailed analysis of the distribution of cells expressing the RFRP mRNA, and found them in seven anatomical structures of the tuberal hypothalamus. No co-expression with melanin-concentrating hormone (MCH) or hypocretin (Hcrt), that are also described in neurons of the tuberal hypothalamus, was observed. Using the BrdU method, we found that all RFRP cell bodies are generated between E13 and E14. Thus, RFRP neurons form a specific cell population with a complex distribution pattern in the tuberal hypothalamus. However, they are generated in one peak. These observations are discussed with data concerning the distribution and genesis of the MCH and Hcrt cell populations that are also distributed in the tuberal hypothalamus.

The rostromedial zona incerta is involved in attentional processes while adjacent LHA responds to arousal: c-Fos and anatomical evidence.

Neurons producing melanin-concentrating hormone (MCH) are located in the tuberal lateral hypothalamus (LHA) and in the rostromedial part of the zona incerta (ZI). This distribution suggests that rostromedial ZI shares some common features with the LHA. However, its functions with regard to arousal or feeding, which are often associated with the LHA, have not been thoroughly investigated. This study analyses the responses in the tuberal LHA and adjacent rostromedial ZI after experiments related to arousal, exploration, food teasing and ingestive behavior. Specific aspects of the connections of the rostromedial ZI were also studied using retrograde and anterograde tract-tracing approaches. The rostromedial ZI is activated during exploratory and teasing experiments. It receives specific projections from the frontal eye field and the anterior pole of the superior colliculus that are involved in gaze fixation and saccadic eye movements. It also receives projections from the laterodorsal tegmental nucleus involved in attention/arousal. By contrast, the tuberal LHA is activated during wakefulness and exploratory behavior and reportedly receives projections from the medial prefrontal and insular cortex, and from several brainstem structures such as the periaqueductal gray. We conclude that the rostromedial ZI is involved in attentional processes while the adjacent tuberal LHA is involved in arousal.

Ontogenetic expression of CART-peptides in the central nervous system and the periphery: a possible neurotrophic role?

Little attention has been devoted to the expression of CART during development. However, a few studies in the central nervous system and periphery provide a clear indication that these peptides may play significant roles during histogenesis, and may have trophic actions.

Orbital soft tissue surgery for patients with Treacher-Collins or Nager syndrome. A new surgical approach with early correction of soft tissue: prospective study.

Orbitopalpebral anomalies in mandibulofacial dysostosis (Treacher-Collins syndrome) can be difficult to correct surgically and most authors recommend correction of the malar bone after the age of 8 years. We propose a new, early surgical approach for periorbital defects that involves initial implantation of autologous fat and subperiosteal malar lift with a pedicled upper eyelid flap. We prospectively studied 5 children, 3 of whom had previously had orbital reconstruction. Initial fat graft into the periorbital area was followed by a subperiosteal malar lift with lateral canthopexy, and a pedicled upper eyelid flap if needed. Two surgeons independently assessed the patients' characteristics including scleral show before and after operation, antimongoloid palpebral fissures, canthal dystopia, number 6 cleft (Tessier classification), skin quality, and surgical and ophthalmic complications. Before operation 3 patients had had ophthalmic problems. Postoperative evaluation showed improvements in scleral show, canthal dystopia, and skin quality, and correction of antimongoloid palpebral fissures and subcutaneous number 6 clefts. There were no postoperative complications. The proposed protocol gave satisfactory aesthetic and functional results in children with Treacher-Collins syndrome. We recommend that it is considered for periorbital reconstruction in all patients with a mandibulofacial deformity.

Effects of calcium antagonists on serotonin and noradrenaline venoconstriction in humans.

The activity of some calcium antagonists on 5-hydroxytryptamine (5HT) and noradrenaline-induced venoconstriction has been evaluated in humans. Oral doses of nimodipine, 30 mg, and nifedipine, 10 mg, but not of verapamil, 80 mg, and flunarizine, 10 mg, inhibit 5HT-induced venoconstriction of the dorsal hand vein. Nimodipine, but not verapamil and flunarizine, inhibit noradrenaline-induced venoconstriction as well. Verapamil, locally administered into the hand vein, inhibits 5HT and noradrenaline-induced venoconstriction. These results suggest that only calcium antagonists of the dihydropyridine type have antivenoconstrictive activity in the hand vein at oral clinical doses, whereas verapamil is active only if administered by the intravenous route, which probably produces local plasma concentrations higher than those reached with the oral clinical doses.

Active oxygen forms in photoreaction between DNA and furanochromones khellin and visnagin.

The two furanochromones khellin and visnagin react with DNA under irradiation by 365 nm light, forming photoadducts. Recently, the use of khellin as therapeutic agent for skin diseases has been proposed. It is well known that during the formation of photoadducts toxic active oxygen forms are produced. We studied therefore the behaviour of the two furanochromones as producers of 1O-2 and O-2. Our results indicate that visnagin is a strong generator of both superoxide radicals and singlet oxygen, while khellin does not exhibit strong production of OO-2, which is promptly quenched by superoxide dismutase.

Synthesis and anticancer activity of 5-diethylaminomethyl derivatives and nitrogen mustards of uracil and 2-thiouracils.

Several 5-diethylaminomethyl derivatives and nitrogen mustards of uracil and 2-thiouracil have been synthesized and tested for their potential anticancer activity in vitro on KB cells and in vivo on Ehrlich carcinoma. Among the alkylating derivatives tested several showed cytotoxic activity in vitro and compound V [5-[bis(2-chloroethyl) amino] methyl-6-propyluracil hydrochloride] showed both in vitro and in vivo anticancer activity.