Evaluation of antioxidant properties of major dietary polyphenols and their protective effect on 3T3-L1 preadipocytes and red blood cells exposed to oxidative stress.

Obesity has been associated with a marked risk of metabolic diseases and requires therapeutic strategies. Changes in redox status with increased oxidative stress in adipose tissue have been linked with obesity-related disorders. Thus, the biological effect of antioxidants such as polyphenols is of high interest. We aimed to measure antioxidant capacities of 28 polyphenols representative of main dietary phenolic acids, flavonoids, stilbenes and curcuminoids. Then, 14 molecules were selected for the evaluation of their effect on 3T3-L1 preadipocytes and human red blood cells exposed to oxidative stress. Analysis of reducing and free radical-scavenging capacities of compounds revealed antioxidant properties related to their structure, with higher activities for flavonoids such as quercetin and epicatechin. Their effects on preadipocytes' viability also depended on their structure, dose and time of exposure. Interestingly, most of the compounds exhibited a protective effect on preadipocytes exposed to oxidative stress, by reversing H2O2-induced anti-proliferative action and reactive oxygen species production. Polyphenols also exerted an anti-inflammatory effect on preadipocytes exposed to H2O2 by reducing IL-6 secretion. Importantly, such antioxidant and anti-inflammatory effects were observed in co-exposition (polyphenol and prooxidant during 24 h) or pretreatment (polyphenol during 24 h, then prooxidant for 24 h) conditions. Moreover, compounds protected erythrocytes from AAPH radical-induced lysis. Finally, these results led to demonstrate that antioxidant and anti-inflammatory properties of polyphenols may depend on structure, dose, time of exposure and cell conditioning with oxidative stress. Such findings should be considered for a better understanding of polyphenols' benefits in strategies aiming to prevent obesity-related diseases.

[Conjunctival Kaposi sarcoma]. / Sarcome conjonctival de Kaposi.

Kaposi sarcoma is rare and occurs in four forms (classic, endemic, post-transplant and epidemic), which all have the same histological appearance associated with the same viral agent: human herpes virus type 8 (HHV-8). Conjunctival and palpebral locations are, however, rare, and only 30 cases have been described in the literature. We present the case of a 34-year-old woman with conjunctival Kaposi angiosarcoma, with rare bulbar location associated with superior palpebral telangiectases against a rare immunodepression syndrome (common variable immunodeficiency). The treatment consisted of an excision biopsy with an over-and-over suture of a conjunctival rotation flap, combined with anti-HHV-8 chemotherapy to effect a regression of the palpebral lesion. However, the reappearance of a conjunctival lesion on the rim of the excision site required local radiotherapy of approximately 30 Gy, with no recurrence after 1 month.

Role and regulation of acylethanolamides in energy balance: focus on adipocytes and beta-cells.

The endocannabinoid, arachidonoylethanolamide (AEA), and the peroxisome proliferator-activated receptor (PPAR)-alpha ligand, oleylethanolamide (OEA) produce opposite effects on lipogenesis. The regulation of OEA and its anti-inflammatory congener, palmitoylethanolamide (PEA), in adipocytes and pancreatic beta-cells has not been investigated. We report here the results of studies on acylethanolamide regulation in these cells during obesity and hyperglycaemia, and provide an overview of acylethanolamide role in metabolic control. We analysed by liquid chromatography-mass spectrometry OEA and PEA levels in: 1) mouse 3T3F442A adipocytes during insulin-induced differentiation, 2) rat insulinoma RIN m5F beta-cells kept in 'low' or 'high' glucose, 3) adipose tissue and pancreas of mice with high fat diet-induced obesity (DIO), and 4) in visceral fat or blood of obese or type 2 diabetes (T2D) patients. In adipocytes, OEA levels remain unchanged during differentiation, whereas those of PEA decrease significantly, and are under the negative control of both leptin and PPAR-gamma. PEA is significantly downregulated in subcutaneous adipose tissue of DIO mice. In RIN m5F insulinoma beta-cells, OEA and PEA levels are inhibited by 'very high' glucose, this effect being enhanced by insulin, whereas in cells kept for 24 h in 'high' glucose, they are stimulated by both glucose and insulin. Elevated OEA and PEA levels are found in the blood of T2D patients. Reduced PEA levels in hypertrophic adipocytes might play a role in obesity-related pro-inflammatory states. In beta-cells and human blood, OEA and PEA are down- or up-regulated under conditions of transient or chronic hyperglycaemia, respectively.

[Evaluation of transcutaneous bilirubin measurement and agreement with bilirubinemia]. / Evaluation de la mesure transcutanée de la bilirubine et concordance avec la mesure sur sang total et plasma.

Evaluation of the neonates for jaundice and kernicterus is indispensable when early hospital discharge has become standard practice. Transcutaneous bilirubin (TcB) measurement is an advantageous option because of its non-invasive nature and the possibility of its use near the patient. The point of care device BiliCheck has been compared in numerous instances to serum bilirubin. However, its clinical utility remains a subject of discussion. We have compared total blood bilirubin (TBB) concentrations to TcB values using the BiliCheck in newborns at 48 +/- 12 hours of life, at the time of discharge when they have lost weight. One hundred and ninety-six term neonates were initially included into the study. Transcutaneous bilirubin could be compared to whole blood bilirubin for 178 of them. Methods were compared by linear regression analysis and by the non-parametric Bland and Altman method. The correlation between BiliCheck and whole blood bilirubin was adequate (r(2): 0.7768). However, the Bland-Altman analysis revealed a 95% CI of -50.4 to 47.5 micromol/L. Transcutaneous bilirubin was also compared to a measure on plasma in a sub-group of 53 infants, the correlation was 0.7749 with a 95% CI of -35.8 to 46.5 micromol/L. Comparing total blood bilirubin with plasma bilirubin in 35 patients, we observed a similar results with a correlation of 0.7583 and a 95% CI of -34.6 to 40.7 micromol/L. Finally, the extent of weight loss observed in our group of patients had little influence and did not affect the agreement between the 2 approaches. We conclude that the BiliCheck may be used to monitor bilirubin in term neonates at 48 hours of life even with a weight loss. Clinicians have however to be conscious of the limit of the precision of the measures both for the BiliCheck and the laboratory methods.

Microbial metabolism of caffeic acid and its esters chlorogenic and caftaric acids by human faecal microbiota in vitro.

Caffeic acid and its esters, chlorogenic and caftaric acids, are major dietary polyphenols present in various foods and beverages. Although caffeic acid is easily absorbed in the small intestine, its esterification with quinic acid, as in chlorogenic acid, decreases its gut absorption and increases the quantities reaching the colon and its microbiota. The microbial conversion of caftaric acid, the tartaric acid ester of caffeic acid, has not been studied earlier. In this work we compared the direct action of a human faecal microbiota on the metabolism of caffeic, chlorogenic and caftaric acids in an in vitro fermentation model. All substrates disappeared quickly and none of the free acids (caffeic, quinic or tartaric acids) were detected after 2 hours of incubation. Two major microbial metabolites were identified by HPLC-ESI-MS-MS as 3-hydroxyphenylpropionic (3-HPP) and benzoic acids (BA). Maximal levels of 3-HPP were reached after 2 h of fermentation and accounted for 9-24% of the dose of caffeic acid and its esters. BA was formed steadily throughout the incubation, accounting for 4-5% of the initial dose of the substrates after 24 h of incubation. The similarities in the metabolic patterns observed for caffeic, chlorogenic and caftaric acids suggest that esterification does not influence the metabolism of caffeic acid by the gut microbiota.

Natremia of healthy term newborns at 48 h of life: influence of feeding patterns.

OBJECTIVES: To describe natremia in healthy term newborns and determine whether there is a relationship between blood sodium and feeding patterns. METHODS: All normal newborns, admitted to the nursery between January and March 2004 were eligible for this prospective cohort study. Inclusion criteria were: > or =37 weeks of gestational age, birth weight > or =2500 g, Apgar scores > or =7 at 5 and 10 min and normal physical examination. A capillary blood sample was taken at 48+/-12 h of life. RESULTS: Blood samples from 126 newborns were analyzed. Mean gestational age was 39.6 weeks, birth weight was 3414 g and weight loss at 48 h of life was 6.5% of birth weight. Mean capillary blood sodium was 141 mmol/L (SD 3.4). Exclusively, breast-fed newborns had statistically higher mean blood sodium (141 mmol/L, SD 3.0) than the non-exclusively breast-fed+formula fed group (139 mmol /L, SD 3.7). There was a significant linear association between blood sodium and the quantity of milk supplements received as well as between blood sodium and weight loss. CONCLUSIONS: Most newborns have blood sodium values within a narrower range than previously described in the literature. We also demonstrate that the exclusively breast-fed infants appear to have marginally but statistically higher values of blood sodium than non-exclusively breast-fed and formula-fed infants.

Performance of multilayered particles: influence of a thin cushioning layer.

Nowadays, oral dosage forms with controlled release kinetics have known an increasing interest. The polymer coating of drug-loaded particles is one of the most common methods used for controlling drug delivery. Such multilayered particles could be either filled into capsules or compressed into tablets for their oral administration. However, many studies have noticed that coating films are damaged during the compression process, leading to significant changes in drug release profiles. The aims of this study were to investigate the effects of a thin cushioning layer [made of HydroxyPropylMethyl Cellulose (HPMC)] applied on coated theophylline particles upon particle characteristics, tablet properties, and then upon their dissolution performance. If no significant effect was shown with particles, this thin HPMC layer played an important role in the tablets. Tablet cohesiveness was decreased due to HPMC cushioning properties and moreover, the theophylline release rate was increased, as HPMC is a water-soluble polymer creating channels in polymer film for dissolution medium. Therefore, a cushioning layer helped to protect polymer coats from fracture during compression but could also affect drug release and so, both effects must be checked in such a drug delivery system.

Influence of cryogenic grinding on properties of a self-emulsifying formulation.

Recently, self-emulsifying drug delivery systems (SEDDS) have been developed as a method to deliver lipophilic drugs. Gelucire 44/14 is an excipient, from the lauroyl macrogolglycerides family, producing a fine oil-in-water emulsion when introduced into an aqueous phase under gentle agitation as SEDDS, improving thereby solubility of poorly water-soluble drugs and their bioavailability. The aims of this study were to process Gelucire 44/14 into a powder by cryogenic grinding to produce solid oral dosage forms and to investigate influence of this process on different properties of a formulation made of Gelucire 44/14 and ketoprofen (90/10). Cryogenic grinding produced Gelucire 44/14 in a powder form and this process did not change its physical properties, emulsification capacities and dissolution performances of the formulation tested. However, interactions took place between ketoprofen and Gelucire 44/14 with a decrease of the melting peak and a reduction of the droplet size of the formed emulsion. The influence of drug-Gelucire 44/14 interactions must be investigated case by case in any formulations.

Effects of different cellulose derivatives on drug release mechanism studied at a preformulation stage.

As a matter of fact, in vitro dissolution is well known to be the method of choice for the pharmaceutical industry to develop effective medicines. However, many experiments must be performed all along a new product life and they represent an overcharge of work for researchers. The purpose of this paper was to assess the relevance of new parameters obtained during preformulation stage by Nuclear Magnetic Resonance (NMR) experiments to better understand drug release mechanism. This study was carried out with three cellulose derivatives currently used as carrier matrices (Microcrystalline cellulose (MCC), Hydroxypropylmethyl cellulose (HPMC) and Ethyl cellulose (EC)). Granules and tablets were produced with these three excipients (60% w/w) and theophylline as drug model (40%). On the one hand, in vitro dissolution studies were performed with the rotating paddle method displaying the different release behaviour of these three matrices (immediate release for MCC, steady release for HPMC and sustained release for EC). On the other hand, the evolution of the T2m spin-spin relaxation time in NMR experiments during granules hydration was recorded. NMR findings shore up dissolution data, both depending on interactions between the matrix and water. NMR spectroscopy appears to be a valuable tool for obtaining, at an earlier stage of drug development, more information about drug release mechanism.

Dry adsorbed emulsion: 2. Dissolution behaviour of an intricate formulation.

The behaviour of a pharmaceutical form, called dry adsorbed emulsion (DAE), containing a sparingly soluble drug (i.e. theophylline) was studied for dissolution drug release kinetic, in relation with DAE structure characterisation. In vitro dissolution testings were performed under different experimental conditions (medium at pH 1.2 and 7.4, medium with or without surfactant addition, different particle sizes, discrete or densified particles). Discrete DAE particles showed an extended release, in comparison with the native drug powder, depending on both drug solubility in the medium and particle size. The relevance of dissolution data was not improved by surfactant addition (0.1% sodium lauryl sulfate: SLS). After an initial release due to theophylline of the DAE superficial layer, the dissolution followed the Higuchi model. This suggested that DAE behaved as an inert matrix, which controlled drug release by diffusion through the hydrophobic part of the DAE. Densified DAE particles showed a slower dissolution rate than discrete DAE particles, because of their weak wettability and their poor disintegrant properties due to the particulate rearrangement under pressure. Lastly in a technological point of view, DAE could be considered as a potential drug delivery system in capsules or tablets to better control bioavailability of drugs.

Dry adsorbed emulsion: 1. Characterization of an intricate physicochemical structure.

A recent solid pharmaceutical form called "Dry Adsorbed Emulsion" (DAE) was characterized in morphological and structural fields. A DAE is an intricate system initiated by a water-in-oil emulsion including the active drug (i.e., theophylline). Each emulsion phase is adsorbed on pulverulent adsorbents with a suitable polarity (silica) to obtain a free-flowing powder with nonporous particles of size from 125 to 710 microm, with small specific surface area and a spherical shape. Different methods, such as scanning electron microscopy combined with chemical microanalysis, dying tests, and electron spin resonance studies, allow the formulator to follow the behavior of DAE aqueous and oily phases during the manufacturing process and then to set up a structural model for DAE particles. These DAE particles appear to be made up of a random pack of hydrophilic and hydrophobic particles, containing a liquid phase adsorbed on silica by weak bonds.

Overexpression of stathmin in breast carcinomas points out to highly proliferative tumours.

We recently discovered that stathmin was overexpressed in a subgroup of human breast carcinomas. Stathmin is a cytosolic phosphoprotein proposed to act as a relay integrating diverse cell signalling pathways, notably during the control of cell growth and differentiation. It may also be considered as one of the key regulators of cell division for its ability to destabilize microtubules in a phosphorylation-dependent manner. To assess the significance of stathmin overexpression in breast cancer, we evaluated the correlation of stathmin expression, quantified by reverse transcription polymerase chain reaction, with several disease parameters in a large series of human primary breast cancer (n = 133), obtained in strictly followed up women, whose clinico-pathological data were fully available. In agreement with our preliminary survey, stathmin was found overexpressed in a subgroup of tumours (22%). In addition, overexpression was correlated to the loss of steroid receptors (oestrogen, P = 0.0006; progesterone, P = 0.008), and to the Scarff-Bloom-Richardson histopathological grade III (P= 0.002), this latter being ascribable to the mitotic index component (P= 0.02). Furthermore studies at the DNA level indicated that stathmin is overexpressed irrespective of its genomic status. Our findings raise important questions concerning the causes and consequences of stathmin overexpression, and the reasons of its inability to counteract cell proliferation in the overexpression group.

Preformulation: effect of moisture content on microcrystalline cellulose (Avicel PH-302) and its consequences on packing performances.

This study evaluates the influence of moisture content on the packing performances of a new grade of microcrystalline cellulose (MCC) (Avicel PH-302) either by classical method or by an unconventional compression technique (constant volume reduction of powder bed). An increase in moisture content decreases the apparent density of the powder bed, resulting from interparticulate friction enhancement. This modification of apparent density seems to be the main effect caused by the presence of humidity, which explains the variations of compression properties, like an increase of powder plasticity generally observed in the experimental conditions.

Compared randomized roles and pain factor by Vabra and Wallach Endocell in endometrial evaluation.

This randomized study was carried out to compare pain factors of Vabra and Endocell by an ordered classification of one to ten to evaluate the respective pathological yield and to establish the clinical acceptability. Patients had endometrial evaluation either for abnormal bleeding, abnormal endometrial line as demonstrated by echography or abnormal endometrial cells in the Pap smear. Age, gravidity, parity and hysterometry were similar in both groups, with abnormal bleeding being the most frequent indication (250/370 patients, 67.5%). Both techniques yielded equal results for insufficient tissue retrieval at 46/184 (25.0%) for Vabra and at 50/183 (27.3%) for Endocell. The pain score differed significantly in favor of Wallach Endocell at 4.36+/-2.38 versus Vabra at 5.65+/-2.41 (p=0.001). Vabra and Endocell give similar pathological results; however, Endocell is significantly less painful and easier to manipulate and carry because of its weight (1.69 g vs. 37.80 g).

Pancreatic injury in the hemolytic-uremic syndrome.

In a retrospective review of 241 cases with hemolytic-uremic syndrome, there was evidence of pancreatic involvement in 2 patients, abnormal ultrasounds in 4 patients, and pancreatic injury in 3 of 8 patients undergoing autopsy. Pancreas ultrasound examination, available in 134 cases, was very valuable in identifying those with pancreatic injury.

[Methodologic study of the stability of intravenous nutritive emulsions]. / Méthodologie d'étude de la stabilité des émulsions nutritives intraveineuses.

Stability studies are one of the main steps of emulsion development, since emulsions are thermodynamically unstable systems. This is even more critical for drugs, and especially for nutritive parenteral emulsions considering the large volumes which are infused to patients. Physico-chemical stability of emulsions can be estimated, either under real storage conditions, or using accelerated testing that are of great interest in formulation. After a literature review of stability testing applied to emulsions, we give an example of procedure which is especially useful for intravenous nutritive emulsions.

[Primary palpebral localization of a trabecular Merkel cell carcinoma (1 case)]. / Localisation palpébrale primitive du carcinome trabéculaire à cellules de Merkel (1 cas).

We report one case of Merkel cell carcinoma. They commonly arise on the eyelids of elderly patients. Others localisations are on the skin of the pelvis. Clinical aspects, histological study, associating morphological aspect, ultra-structural and immuno-histo-chemical studies are characteristics enough to differentiate this tumor others tumors of the skin like cutaneous malignant lymphoma. The origin of this tumor is still discussed, but sure neuro-endocrinal. Possibility of visceral metastases on a small number of cases (6 to 8%) must be consider when treated. Total surgical ablation should be obtained.

Kinetic comparison of the 3 beta-hydroxysteroid dehydrogenase activity in human placenta, chorion laeve, and ovary.

Recent studies from our laboratory and others have shown that Km values for steroid substrates of the 3 beta-hydroxysteroid dehydrogenase in the human placenta were in the nanomolar range compared with micromolar values previously described. The purpose of the present study was to measure the kinetic parameters of the 3 beta-hydroxysteroid dehydrogenase in other human tissues, namely the ovary and chorion laeve, and to determine whether they were similar to those of the placental enzyme. In chorion laeve microsomes the 3 beta-hydroxysteroid dehydrogenase had Km values for dehydroepiandrosterone and pregnenolone similar to those found in placenta. Microsomes from human ovaries, on the other hand, had Km values for both substrates 10- to 20-fold higher. However, the ability of various steroids to inhibit the ovarian enzyme was similar to that previously described from the placenta and the chorion laeve.

The significance of pregnancy among adolescents choosing abortion as compared to those continuing pregnancy.

The significance of pregnancy for adolescent women is usually related to unconscious motivations. Some teenagers faced with the problem choose to abort, and others do not. Psychosocial status, contraceptive and sexual habits, attitudes towards pregnancy and environmental influences were studied in 50 teenagers who chose abortion. These young women were matched for age and parity with a control group of 50 who elected to carry their pregnancies to term. The results point to significant differences between the two groups, particularly as to the meaning of pregnancy and the decision-making process.

PIP: The significance of pregnancy for adolescent women is usually related to unconscious motivations. Some teenagers faced with the problem choose to abort, and others do not. Psychological status, contraceptive and sexual habits, attitudes towards pregnancy and environmental influences were studied in 50 teenagers who chose abortion. These young women were matched for age and parity with a control group of 50 who elected to carry their pregnancies to term. The results point to significant differences between the 2 groups, particularly as to the meaning of pregnancy and the decision-making process. The teenagers who chose abortion seemed more independent and self-assured, made their decisions basically by themselves and had a more realistic view of pregnancy. The teenagers who chose to carry their pregnancies to term appeared more submissive and less capable of integrating various elements of reality into their decision making. Their choices seemed strongly influenced by the partner, family and friends. Because of these outside influences, the patient may perceive her decision to be externally determined, leaving her more susceptible to guilt feelings and allowing her to avoid full consideration of the implications of immediate child-bearing. Interpersonal relationships and the patient's personality were viewed as the major influences on pregnancy resolution. Future studies should shed light on the meaning of adolescent pregnancy as a contemporary sociologic phenomenon and address the following questions: How can adolescents' needs be met in ways other than pregnancy? What are their needs and the fears, anxieties and feelings of loneliness and depression that early sexual activity has not been able to allay?

[Painful sciatic rubbing caused by benign synovioma of the spinal joints. Apropos of 4 cases]. / Conflits mécaniques sciatalgiques par synovialome bénin des articulations rachidiennes. A propos de quatre cas.

Synovioma, a benign neoplasm arising from pigmented villonodular synovium or synovitis, is uncommon. It involves the tendons and joints of the finger, ankle and foot. In this study four cases of villonodular synovioma of spinal joints are reported. The authors studied 555 cases of patients operated for sciatica due to herniated disk. Histopathology showed that in four out of 555 cases sciatica was found to be due to synoviomas of the spinal joints. The patients, three women and one man, were between 54 and 70 years of age and each had had a long history of low back pain with episodes of sciatica. Clinical evaluation at the time of surgery showed moderate severity of signs and symptoms. Roentgenographic studies of all four cases revealed osteoarthritic changes of vertebral apophyses, with two cases of spondylolisthesis. The pathogenesis of synovioma remains controversial and its histopathological characterization -hyperplasia VS/true tumours- has not yet been determined. It is possible that the number of recorded cases of sciatica due to synoviomas is small because surgical and pathological studies in patients with sciatica associated with osteoarthritic changes have not been adequately performed. Surgery consists of a large resection of the capsule and ligament including resection of intraspinal extension. Because this study involves only four cases, the first of which occurred in 1977, the possibility of recurrence cannot be evaluated.