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Upon its implantation in the uterus of the mother in mammals, the embryo is composed by three morphologically distinct tissues: the Epiblast (Epi), the Trophectoderm (TE) and the Primitive Endoderm (PrE). Both Epi and PrE are formed from the same cell homogeneous population called the Inner Cell Mass (ICM). Based on our studies, we discuss in this review what molecular interactions are necessary for the specification of these two lineages. For this, we have combined a biological approach with mathematical modeling. We have shown the central role of the gene regulation group composed by NANOG, FGF4, GATA6 and FGFR2 for Epi/PrE cell specification., (© 2016 médecine/sciences – Inserm.)

Primary open-angle glaucoma is a progressive ocular disease affecting adults and associated with visual field defect. The aim of its treatment is to lower the ocular pressure by means of ocular drops, laser or surgery. To date, traditional surgical techniques still remain quite invasive, but recent research efforts have been made with a view to develop minimally invasive techniques. The Xen Gel Stent is one of them. It allows a safe and efficient lowering of ocular pressure by creating a sub-conjunctival flow, following an ab interno procedure that highly preserves the architecture of the treated eye.

In many cell types, specific and robust signalling relies on a high level of spatiotemporal organization of Ca(2+) dynamics. In response to external stimulation, Ca(2+) signals ranging from a small increase of a few tens of nanomolar concentrations at the mouth of an inositol 1, 4, 5-trisphosphate receptor to the periodic propagation of waves invading an organ or a tissue, can be observed. Here, we review our combined experimental and computational approach of Ca(2+) dynamics, which has been mainly carried out on liver hepatocytes. We focus in particular on the understanding of the relationship between elementary Ca(2+) increases, Ca(2+) oscillations and intra- or intercellular Ca(2+) waves. The physiological impact of such signalling on liver function is also discussed., (© 2011 médecine/sciences - Inserm / SRMS.)

The exsudative form of age-related macular degeneration (AMD) is characterized by the development of choroidal neovascularization (CNV) under the retina driven in part by the vascular endothelial growth factor. Several VEGF inhibitors have recently been produced for ocular administration. This review will focus on ranibizumab which is a specific antibody neutralizing all VEGF isoforms. The development, pharmacokinetics, clinical efficacy, current and future indications of ranibizumab are discussed.

On January 16, 1793, seven hundred aud forty nine deputies of the National Convention are called on to express their opinion by word of mouth about this question: "What penalty Louis, former king of the French, brought upon himself ?" Among these deputies, 47 are or were physicians : 22 vote for death without delay, 3 for suspended death sentence, 20 for indulgence (imprisonment till the peace and banishment thereafter), and 2 refuse to vote. This paper aims at summarizing the attitude of the physicians-deputies, and more specifically those of Pierre-Joseph Duhem, at the time of one of the most famous trials of the history of France.

Inflammatory processes are the physiological response of the organism to different stimuli such as trauma, infections or immunological reactions. The events leading to inflammation are characterized by leukocytes adhesion to the endothelium, diapedesis and migration, cells activation and tissue remodelling. These processes are initiated and regulated by a great variety of inflammatory mediators including cytokines, prostanoids, leukotrienes, neuropeptides, reactive oxygen and nitrogen species, complement components, coagulation factors and metalloproteases. This paper is devoted to the description of the major local effects of these mediators in the inflammatory reaction.

Background: Marchiafava-Bignami disease or corpus callosum necrosis, is an uncommon complication of chronic alcoholism. Prognosis is severe., Case Reports: Two young adults with chronic alcoholism who developed Marchiafava-Bignami disease initially improved clinically., Discussion: Diagnosis has been facilitated with MRI. An MRI exploration should be performed in chronic alcoholic patients presenting chronic encephalopathy with dementia, dysarthria, hypertonia, and ataxia, or acute encephalopathy with confusion, dumbness, seizures, and hypertonia. Necrosis of the corpus callosum gives the diagnosis of Marchiafava-Bignami disease.

We studied the effect of oral contraceptives and smoking on the lipid profile of 251 women and 72 men, 20-29-year-old. In women, taking estroprogestatives, cholesterol, triglycerides, apoproteins AI and B were higher than in controls; HDL-cholesterol was not modified. Lipoprotein analyses in polyacrylamide gradient gel exhibited an increase of the HDL3 fraction at the expense of the HDL2 fraction, with a reduced LDL size. Smoking in addition to estroprogestative absorption accentuated these modifications and led to a decreased HDL-cholesterol (HDL2 fraction essentially), with an increased LDL-cholesterol. In men, smoking resulted in higher levels of total cholesterol, apoprotein B and LDL-cholesterol, without any significant change in LDL size, higher levels of triglycerides and lower level of the HDL2 fraction without any change in HDL-cholesterol. In women, smoking led only to an increase in triglycerides. In summary, analysis of the distribution of HDL subclasses and of LDL size showed an evolution towards a supposed more atherogenic lipid profile in women taking oral contraceptives associated or not with smoking, and in male smokers.

Objective: To review the current data on perfluorocarbon (PFC) emulsions and haemoglobin (Hb) solutions., Data Sources: For this paper we analysed the literature using Medline search along with major review articles., Data Selection and Extraction: The collected articles were reviewed and selected according to their quality and originality., Data Synthesis: PFCs are synthetic fluorinated hydrocarbons capable of dissolving, at increased FIO2, large amounts of oxygen. They deliver oxygen at tissular level, and are administered as emulsions containing particles of around 0.1 micron, reaching the smallest vessels. They are exhaled unchanged by the lungs within 7 days. The first clinically used PFC was Fluosol-DA 20%. Currently, Oxyfluor 40% and Oxygent 60% are under evaluation. PFCs are not true blood substitutes, but rather a means to support tissue oxygenation during extreme haemodilution. Solutions of free Hb do not require compatibility testing and are fully saturated with oxygen at ambient FIO2. Hb is either human, bovine or recombinant Hb. In order to maintain adequate intravascular half-life and affinity for oxygen, the Hb molecules are modified by internal cross-linking, polymerisation and encapsulation. After promising results using animal models, some of these modified Hb solutions are now undergoing phase III clinical trials. Among these, diaspirin cross-linked haemoglobin (DCLHb) has been tested in cardiac and orthopaedic surgery, as well as in trauma patients. The initial results of these multicentre trials are currently being analysed.

Anoxia-reoxygenation leads to severe metabolic alterations, which result in a generalized inflammatory reaction and multiple organ dysfunction. Direct blood transfusion limits these alterations, but is accompanied by risk of transmission of infections or viral diseases. To avoid these risks, "blood substitutes" have been designed. The modified hemoglobins are not true blood substitutes because they do not possess the complex functions of erythrocytes. They are only oxygen carriers, with a short intravascular life, adapted for temporary use. They are stable, devoid of toxicity and antigenicity, and are able to carry and deliver O2 without regulation of this oxygen transport and without chemical reaction with O2. They possess rheologic properties and an oncotic pressure like those of blood. The use of natural hemoglobin solutions, obtained after lysis of erythrocytes, remains "at risk" because these solutions easily form methemoglobin, increase the oncotic pressure, present renal toxicity, and possess a too high affinity for O2. For these reasons, 5 types of modified hemoglobin solutions have been designed, prepared from human or bovine hemoglobin or by genetic engineering. These hemoglobins are highly purified to eliminate trace amounts of stroma, lipids and endotoxins, which are responsible for acute toxicity. They are modified by internal cross-linking between the monomers, or by binding to macromolecules. Afterwards, they can be polymerized or encapsulated in liposomes. The purpose of these modifications is to modulate the affinity for O2 (by decreasing the binding of O2 and increasing its delivery to tissue), to reduce the dissociation into monomers and to guard against oxidation into methemoglobin. Encapsulation in liposomes allows co-encapsulation of effector molecules and protective substances. Genetic engineering allows the production of recombinant hemoglobin with selective modifications. The modified hemoglobin solutions are essentially used in hemorrhagic shock and perioperative hemodilution. Experimental work in animals has afforded good results: restoration of normal O2 pressure and no toxicity. These assays allow frequent observation of an unexpected rapid hypertensive effect, transient, reversible, and that could be controlled by antihypertensive drugs. The mechanisms of this hypertensive effect remain controverted (stimulation of endothelin production, inhibition of nitric oxide effects, etc.). In humans, studies with healthy volunteers have been completed, while phase II clinical studies are under way in hypovolemic shock, in major abdominal, orthopedic and cardiac surgery, in stroke and in intensive care patients after surgery. The detailed results are awaited, but the modified hemoglobin solutions already appear to be without toxicity and present the same hypertensive effect as observed in animals. However, until now only low doses have been used, and the catabolism of these solutions remains largely unknown.

This preliminary study demonstrated the existence of a free radical generation during an experimental postischemic muscular reperfusion in a halothane anesthetized horse. The authors used alpha-phényl-N-tert-butylnitrone as a spin trap agent and the electronic paramagnetic resonance method to observe in vivo a free radical generation.

During sepsis, the systemic inflammatory response is characterized by the release of numerous mediators supporting and dispersing inflammation. In Gram negative sepsis, the endotoxins play a starting role, while in other sepsis, the triggering mediators or mechanisms are unknown but lead to a similar inflammatory reaction. Coagulation and complement cascades are activated, with the release of chemoattractive substances, mediators and proteases and the activation of phagocytic cells. Macrophages/monocytes and polymorphonuclear leucocytes produce then active oxygen species and cytokines; they degranulate (releasing active enzymes such as myeloperoxidase), they express an increasing number of membrane receptors able to interact with endothelial cells and release a supplementary lot of inflammatory mediators (prostanoids, platelet activating factor, leukotrienes ... ). Platelets, also activated, produce the same mediators (TXA2, PAF ...) or specific ones such as serotonine, platelet factor 4, growth factors. Last, but not least, the endothelial cells are stimulated, directly (by endotoxins) or undirectly (by cytokines, C5a, PAF ...). These cells play then a main role by their own phagocytic activity, by alteration of their antithrombotic and fibrinolytic potential, by their secretion of inflammatory mediators and by an increased expression of receptors of adhesivity for the activated phagocytes or platelets, what leads to endothelium injury with membrane permeability alterations. These cascades of activation, these extensions of the inflammatory reaction by the mediators and by the phagocytes and platelets can explain the frequency of multiple organ failure during sepsis as well as the difficulty of an adequate pharmacological therapy.

Increase of blood leucocytes induced by a dynamic exercise has been studied in 10 adult male subjects (age: 22 +/- 2 years; body weight 73 +/- 10 kg; VO2max: 54 +/- 8 ml O2/kg.min. The exercise consisted of a 20 minutes test on a cycle ergometer at a work rate eliciting a total energy expenditure roughly equal to 80% of the maximal aerobic power (80% VO2max). During exercise the absolute number of circulating leucocytes (n Leu) increased significantly toward a maximal value reached in most cases at the end of exercise. The maximal values of n Leu--expressed as percentage of n Leu measured at rest--in the different blood leucocyte types (monocytes:n Mono; granulocytes:n GR; natural killer cells:n NK) and lymphocyte subsets (lymphocytes:n LY; lymphocytes T:n T; lymphocytes B:n B; lymphocytes T helper:n T4; lymphocytes T suppressor:n T8)--were as follows:n Mono:240%; n GR:170%; n NK:490%; n LY:220%; n T:200%; n B:190%; n T4:140%; n T8:190%. With the exception of n GR, n Leu decreased during recovery at a rate depending on the leucocyte type. The n T4/n T8 ratio, equal to 1 at rest, was reduced by about 40% during exercise. This ratio rose after exercise and reached a value equal to that measured at rest after 20 minutes recovery. In agreement with FERRY (1989), we concluded that exercise is accompanied by a selective mobilization of the different leucocyte types. The magnitude of this phenomenon and the kinetics of n Leu recuperation depend on cell types.

The two basic mechanisms underlying most of the pleuropulmonary complications of severe acute pancreatitis include pulmonary atelectasis and alveolar flooding. Like in any abdominal catastrophe, pleural effusion and limited diaphragmatic excursion due to pain and intestinal atony are the main factors responsible for alveolar collapse and secondary infection. Physical therapy and needle pleural evacuation are the cornerstones of management. Owing to its pathophysiologic mechanisms adult respiratory distress syndrome is peculiar to acute pancreatitis. Alveolar capillary membrane injury is related to pancreatic necrosis, to its regional extent and to the subsequent over-amplification of the inflammatory reaction. Diversion of those potential mediators of the syndrome either surgically or by thoracic duct drainage is essential in order to improve survival in these patients.

The polyene antibiotic "Amphotericin B" can interact with sterols, cholesterol or ergosterol in aqueous and hydroalcoholic media and a correlative striking spectral change appears between 300 and 420 nm in the CD and absorption spectra. Using these spectroscopic methods we have determined that the influence of temperature between 4 and 80 degrees C is very important. The higher the temperature the most rapid is the modification of the spectra. Thus, the "Amphotericin B"-sterol complex is more easily formed when heating. We have not found any reversibility at 80 degrees C.

5 micrograms of human beta-endorphin were labelled with 2 mCi 125I by the chloramine T technique. After two gel filtrations on Sephadex G-15 and on Sephadex G-50 in phosphate buffer with EDTA, Trasylol and mercapto-ethanol, a pure tracer was obtained with a specific activity about 150 microCi/ug. Kept at + 4 degrees C, the tracer remained utilizable for 30 days without loss of immunoreactivity. The labelling with lactoperoxydase and the use of another gel filtration method (filtration on Aca 202) gave a 125I beta-END tracer with the same immunoreactivity. The binding of this tracer to the antibody of an anti-beta-END antiserum diluted at 1/8000 was 32% with a non specific binding of 2%. 5 micrograms of human beta-lipotropin were labelled with 0.5 mCi 125I by the lactoperoxydase method. After two gel filtrations on Sephadex G-25 and on Sephadex G-75 in phosphate buffer with EDTA, Trasylol and mercapto-ethanol, a pure tracer with a specific activity of 140 microCi/micrograms was obtained. It remained utilizable for 30 days when kept at + 4 degrees C. Gel filtration on Aca 202 did not give good purification, while gel filtration on Aca 54 was good but slower than on Sephadex G-75. The binding to antibody in absence of unlabelled beta-LPH was 32% for an anti-beta-LPH antiserum diluted at 1/4000. The non specific binding was 2.5%.

Blood plasma lipids of women about seventy years old who had suffered from cardiovascular diseases (AVC) were studied and compared with the plasma lipids of women of about the same age without cardiac troubles. A great difference appears in the unesterified fatty acids of the phospholipids from cardiac women: we have observed a decreasing level of polyunsaturated fatty acids with a carbon chain of more than 18 carbons, and a decreasing ratio between the total concentration of the two precursors (linoleic acid omega and alpha-linolenic acid omega 3) and the total concentration of their long chain polyunsaturated derived fatty acids. On the contrary, we did not observe any significant variation of the unesterified fatty acid level in the plasma. The triglyceride and cholesterol levels also were not different between the two groups of patients. The hypothesis of a lack of elongation and of desaturation of linoleic and alpha-linolenic acids by competitive inhibition with oleic acid seems improbable, since the plasmatic concentration of oleic acid was not statistically different.

Cicletanine is a new antihypertensive agent known for being able to stimulate prostaglandin synthesis in vivo and in endothelial cell cultures. The drug was administered to spontaneously hypertensive rats (SHP-SP) whose hypertension was enhanced by a high sodium content diet. Cicletanine prolonged the animals' survival and reduced the severity of histological renal lesions. PGE2, PGI2 and thromboxane A2 assays performed in renal tissues showed a highly significant increase of PGE2 (a prostaglandin involved in the regulation of renin synthesis) in SHR-SP rats treated with oral cicletanine in daily doses of 30 mg/kg. A less significant increase of PGI2 was found in renal tissues, whereas only slight variations in thromboxane concentrations were observed. The favourable therapeutic effect obtained with cicletanine in the treatment of hypertension may be due, at least in part, to the stimulation of PGE2 and PGI2 production in renal tissue.

Normal serum prolactin levels range from 5 to 20 ng/ml (circadian rhythm, effect of stress, relation with estrogen secretion). Neuroleptics increase serum prolactin levels. Normal concentrations are restored within 24 to 48 hours of discontinuation of the drug. When neuroleptics are given for a long period of time, serum prolactin concentrations fall gradually to low levels. There is no conclusive evidence that prolactin plays a role in breast tumors in women. Epidemiologic studies have shown that neuroleptics are not responsible for increased incidences of these tumors.

The wash fluid of the peritoneal cavity of the rat contains large amounts of 6-oxo PGF1 alpha. The peritoneal exudate induced two hours previously by iota carrageenan contains thromboxane B2 but its level in 6-oxo PGF1 alpha is not increased.

Blood glucose levels were assessed in 49 neonates, using 2 blood glucose test strips. Results were compared to blood glucose levels. Correlations between values from the test strips and values from the laboratory were better using the Haemo-Glukotest (r = 0.91) than using the Dextrostix (r = 0.82). As compared to values from the laboratory, however, both glucose test strips gave higher values and did not properly identify all cases of hypoglycemia.

The hypotensive effect of arachidonic acid in the rabbit increases simultaneously with the fall of the plasmatic unesterified fatty acids (NEFA), after treatment with nicotinic acid or heparin. In the case of nicotinic acid sensitization, which occurs in 10 minutes, the fall of NEFA occurs immediately. The sensitization by heparin appears only after 40 minutes following the injection; during this latency, the NEFA are enhanced; after the fall of NEFA, the rabbit becomes more sensitive to arachidonic acid. Mechanisms of heparinic sensitization are discussed.

The natural course of severe acute pancreatitis can be divided into two successive phases. The initial phase is characterized by the systemic manifestations resulting from the acute inflammatory response that takes place in the pancreas. The second stage reflects the progression of pancreatic necrosis towards spontaneous resolution, pseudocyst formation or secondary infection. While the treatment of these latter complications mainly consists of surgery (drainage of pseudocyst/infected necrosis) prevention and management of the initial systemic complications of acute pancreatitis is essentially involves medical therapy (empirical treatment, percutaneous peritoneal dialysis and thoracic duct drainage). Only the simultaneous and appropriate use of these various therapeutic modalities can ensure a substantial reduction in the mortality of severe acute pancreatitis. The place of these therapeutic approaches is discussed.