Ci-hox12 tail gradient precedes and participates in the control of the apoptotic-dependent tail regression during Ciona larva metamorphosis.

At the onset of the Ciona intestinalis metamorphosis, the first event is tail regression characterized, by a contraction, an apoptotic wave and Primordial Germ Cells (PGC) movement. All these cell behaviors originate from the posterior tail tip and progress to the anterior. Interestingly, earlier in Ciona development, the antero-posterior (A/P) patterning of the tailbud epidermis depends on two antagonist gradients, respectively FGF/MAPK at the posterior and retinoic acid (RA) at the anterior part of the tail. Fundamental genes such as Ci-hox1, Ci-hox12 and Ci-wnt5, classically involved in chordates A/P polarity and patterning, are controlled by these gradients and exhibit specific expression profiles in the tail epidermis. In this study, we first confirmed by video-microscopy that tail regression depends on a postero-anterior wave of a caspase-dependent apoptosis coupled with a contraction event. Concomitantly an apoptotic-dependent postero-anterior movement of PGC was observed for the first time. Unexpectedly, we observed that expression of the posterior hox gene, Ci-hox12, was extended from a posterior localization to the entire tail epidermis as the larvae progress from the swimming period to the settlement stage. In addition, when we disturbed FGF/MAPK or RA gradients we observed strong effects on Ci-hox12 expression pattern coupled with modulation on the subsequent tail regression dynamics. These results support the idea that Ci-hox12 expression in larval tail precedes and participates in the regulation of the postero-anterior cell behavior during the subsequent tail regression.

Ischemic gastritis: a rare but lethal consequence of celiac territory ischemic syndrome.

AIM: Ischemic gastritis is poorly known by physicians and is often fatal if not correctly diagnosed. Here, we report on the clinical, endoscopic and imaging features and treatment outcomes for five ischemic gastritis patients. METHODS: This was a retrospective, single-centre study of patients treated for ischemic gastritis between January 2009 and April 2012. All patients underwent transluminal angioplasty or open revascularization surgery. RESULTS: Five patients (4 men, 1 female) were included in the present study. The condition was diagnosed in two cases of peritonitis with gastric or duodenal perforation, two cases of acute epigastric pain and one case of gastric bleeding, profuse vomiting and hypovolemic shock. Three of the five patients had endoscopically proven gastric ulcerations or necrosis. A computed tomography scan contributed to the diagnosis in all cases. The symptoms resolved in all cases after gastric revascularization via an aortohepatic bypass (N.=1), a renohepatic bypass (N.=1), a retrograde iliosuperior mesenteric bypass (N.=2) with associated celiac artery angioplasty (N.=1) and celiac and superior mesenteric artery angioplasty (N.=1). During follow-up, three patients died of starvation due to short bowel syndrome (N.=1) or metastatic lung cancer (N.=2). CONCLUSION: Ischemic gastritis is a component of celiac territory ischemia syndrome and is closely associated with chronic or acute mesenteric ischemia. Computed tomography always informs the diagnosis. The rapid healing observed here after revascularization confirmed the ischemic nature of the condition and the inappropriateness of gastric resection in this context.

Cecal distension on non-tumoral left colonic obstacle: Management strategy in two cases.

Diastatic damage of the caecum is only described in left colon neoplastic obstructions. However, diverticular sigmoid stenosis can likely cause cecal diastatic distention. In emergency, ileo-cecal resection removing the area of diastatic damage or externalizing the cecal perforation can be an interesting alternative to subtotal colectomy. The left colonic stenosis is treated later so the colon can be spared with better long-term functional outcome than after subtotal colectomy.

Automated pulse pressure and stroke volume variations from radial artery: evaluation during major abdominal surgery.

BACKGROUND: Off-line calculation of the pulse pressure variation (PPV(ref)) has repeatedly been shown to be a reliable predictor of fluid responsiveness in mechanically ventilated patients. This study was designed to assess the ability of two algorithms for automated calculation of PPV (PPV(auto)) (Intellivue MP 70) and stroke volume variation (SVV(auto)) (FloTrac/Vigileo) to predict fluid responsiveness during abdominal surgery. METHODS: We conducted a prospective study of 56 fluid challenges given for haemodynamic instability in 11 patients undergoing major abdominal surgery. Fluid responsiveness was defined as an increase in stroke volume index (SVI) >10%. PPV(ref), PPV(auto), SVV(auto), and SVI (oesophageal Doppler) were recorded simultaneously before and after each fluid challenge. RESULTS: PPV(auto) and SVV(auto) both correlated with PPV(ref) [r(corr)=0.87 (P<0.0001) and 0.84 (P<0.0001), respectively; n=77]. All three indices measured before fluid challenges were higher in responder (n=32) than in non-responder (n=24) fluid challenges (P < or = 0.02). The mean areas under the receiver operating characteristic curves were 0.96 (PPV(ref)), 0.96 (PPV(auto)), and 0.95 (SVV(auto)), and the optimal threshold value for each variable was 13%, 13%, and 12%, respectively. All indices correlated with the fluid challenge-induced changes in SVI (PPV(ref): r(corr)=0.65; PPV(auto): r(corr)=0.58; SVV(auto): r(corr)=0.58, P<0.001 for all). CONCLUSIONS: PPV(auto) and SVV(auto) predict fluid responsiveness as accurately as off-line PPV(ref) in patients with haemodynamic instability during major abdominal surgery.

[Dermoid cyst of the diaphragm: a case report]. / Kyste dermoïde du diaphragme: un cas.

Dermoid cysts involving the diaphragm are rare and their symptomatology is non-specific. CT is the principal diagnostic tool, but it may fail to distinguish whether a cyst is located above, below, or within the diaphragm. Surgical excision of dermoid cysts is recommended because of the possibility of malignant degeneration.

Endovascular versus open revascularization for chronic mesenteric ischemia: a comparative study.

BACKGROUND: The aim of our study was to evaluate and compare short- and long-term outcomes of percutaneous angioplasty and open revascularization for chronic intestinal ischemia. MATERIALS AND METHODS: Twenty-nine consecutive patients undergoing percutaneous angioplasty (n = 14) or open revascularization (n = 15) for chronic intestinal ischemia were prospectively studied from 2000 to 2006. All patients were symptomatic with at least thrombosis or 80% stenosis of superior mesenteric artery. RESULTS: No patient was lost to follow-up. Patients were older in percutaneous angioplasty than in the open revascularization group (p = 0.0009). Open revascularization allowed to revascularize more vessels (1.4 versus 1, p = 0.01). There was no difference between groups regarding major complications, mortality, hospital length of stay, and symptomatic recurrence. Primary re-stenosis was only observed in three patients (21.4%) in the percutaneous angioplasty group. Survival at 2 years estimated by the Kaplan-Meier method was 58% in the percutaneous angioplasty group and 70% in the open revascularization group (p = NS). CONCLUSION: Percutaneous angioplasty should be preferentially offered to older patients and those unable to undergo open revascularization.

Surgical revascularization for chronic intestinal ischemia.

AIM: The aim of this study was to assess outcome after surgical revascularization for chronic intestinal ischemia (CII). METHODS: From 1980 until 2003, 34 patients underwent revascularization for CII. Records were reviewed for operative technique, perioperative mortality and long-term outcomes. CII was diagnosed on the basis of clinical, arteriographic and angio-magnetic resonance imaging (MRI) criteria. Revascularization patency was monitored by arteriography, color duplex ultrasound scanning (CDS), computed tomography (CT)-scanning or angio-MRI. RESULTS: The celiac artery (CA) was severely diseased in 26 cases and the superior mesenteric artery (SMA) in 30 cases. Four patients presented single-vessel, 15 patients two-vessel, and 15 three-vessel involvement. Revascularization was performed by either simple (N=15) or double (N=19) bypass grafting. In 2 patients bypass grafting was combined with reimplantation. One patient underwent reimplantation alone. Median follow-up was 45 months. The 30-day mortality rate was 3%; there were 22 late death (64%). Primary revascularization patency was 94% at 1 month and 79.4% at 4 years. Clinical success rates were 85% and 70% respectively at 1 month and at 4 years. CONCLUSION: To choose the most suitable intervention, the Authors distinguished isolated CII treatable by single SMA revascularization from the digestive arteritis affecting the supramesocolic level of the abdomen, which requires double CA and SMA revascularization.

Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant.

The tumour suppressor p53 plays a complex role in the regulation of apoptosis. High levels of wild type p53 potentiate the apoptotic response, while physiological range, low levels of the protein have an anti-apoptotic activity in serum starved immortalized fibroblasts. Here we report that primary fibroblast-like cells that show normal growth control are also efficiently protected from apoptosis by the endogenous p53 activity. The capacity to inhibit apoptosis is not restricted to the wild type protein: the R-->H175 p53 mutant fully retains the anti-apoptotic activity of the wild type p53, providing a possible explanation for its high oncogenicity. Using a series of point and deletion mutants of p53 under the control of tetracycline-regulated promoter we show that certain mutants, like the wild type, protect cells at low levels but lead to apoptosis when overexpressed. This latter effect is lost upon deletion of a proline-rich domain in the NH2 part of the protein. The anti-apoptotic activity can be mapped to the extreme carboxy-terminal part of the protein and is therefore independent of other well characterized p53 activities. Our results add a new level of complexity to the network of interactions mediated by p53 in normal physiology and pathology.

[Results of infrainguinal revascularization in patients with end-stage renal disease]. / Résultats des revascularisations sous-inguinales chez les malades en insuffisance rénale terminale.

OBJECTIVES: The aim of this retrospective study was to evaluate the efficacy of bypass in patients with endstage renal disease (ESRD) and to determine predictive factors and precise bypass indications. METHOD: Forty one patients with ESRD underwent 50 bypass, 6 limbs were stage II and 44 stage III or IV according to Leriche and Fontaine classification. Revascularisations procedures were 47 infrainguinal bypass and 3 miscellaneous. Median follow up was 17,0+/-15,7 months. RESULTS: Perioperative mortality rate was 12% (n = 6). Morbidity was as follow : 1 perioperative major imputation and 8 secondary ones. There were 26 secondary death (12 from cardiac events), cumulative survival rate declined to 42,9+/-7,7% and limb salvage rate to 77,2+/-7,5% at 2 years. Primary and secondary potency rates were 53,5+/-10,4% and 70,6+/-10%. Quality of life was good in 28% of revascularised patients. Among risk factors, myocardial events showed a statistical significance in predicting survival, good runoff and bypass occlusion showed a statistical significance in predicting limb salvage. CONCLUSION: Revascularisation can be performed in ESRD patients. However to improve the results full evaluation of myocardial risks, skin lesions and infection of the feet, available autologous vein and nutritional status may be needed in those patients.

[Perioperative management of asplenic patients]. / Prévention du risque infectieux postopératoire chez les patients splénectomisés.

OBJECTIVE: In 2003, asplenia had involved 250000 patients in France. These patients are at risk of severe infection, mostly with capsulated bacteria as pneumococci, meningococci and Haemophilus. The higher mortality and morbidity due to infection in asplenic patient led in June 2003 a French expert committee to propose preventive management based on vaccination and antibioprophylaxis. STUDY DESIGN: Update article. DATA SYNTHESIS: For vaccination, two vaccines against pneumococci are available. The first one, the antipolysaccharide (Pneumo 23) is recommended for adults. It is effective for the majority of the serotypes even if its efficacy can be variable. The second one a conjugated pneumococcal vaccine (Prenevar) is used for children under two years because it has higher activity on antibiotic resistant strains therefore increasing antibiotic prophylaxis efficiency. When splenectomy is required, vaccination against pneumococci, Haemophilus (b type) and C meningococci must be performed at least 15 days before surgery, in order to get better immune stimulation. In case of emergency, vaccines have to be administrated within 30 days after surgery. Antibioprophylaxis is based on cefazolin injection before splenectomy and by postoperative intravenous amoxicillin administration. As soon as oral intake is allowed, antibioprophylaxis is continued for at least two years in adults and five years in children. Both antibiotic and vaccination have been reported to reduce pneumococcus infections.

Outcome in porcine acellular dermal matrix reinforcement of infected abdominal wall defects: a prospective study.

PURPOSE: Management of infected abdominal wall defects is a subject of debate, and the use of prosthetic mesh repair is not recommended due to the dramatic rate of mesh infection. The aim of this prospective study was to determine the recurrence rate and long-term outcomes of repairing infected abdominal wall defects using the Strattice porcine acellular dermal matrix reinforcement through a single-stage surgical approach. METHODS: From August 2010 to May 2012, consecutive patients treated for infected abdominal wall defects using Strattice, a biologic prosthesis, were enrolled. All data were collected prospectively and all patients were followed for physical examination and CT scan evaluation. The primary outcome measure was the recurrence rate. RESULTS: Eighteen patients were enrolled and 14 were evaluable. Of these, eight patients had mesh infections and six had enterocutaneous fistulas. Median follow-up was 13 months (range, 3-22) and median length of hospitalization was 13 days (range, 4-56). The Strattice was placed in the intraperitoneal underlay position in 12 patients, and in the retro-rectus position for two. Post-operative complications included skin dehiscence (n = 3), wound infection (n = 2), skin necrosis (n = 1), and seroma (n = 2). At the end of follow-up, six patients (43 %) experienced abdominal wall defect recurrence. CONCLUSIONS: The utility of biologic prostheses to repair infected abdominal wall defects is controversial; however, currently, they remain the only alternative to a two-staged surgery. Prospective, randomized studies in larger populations of patients are necessary to fully determine the usefulness of biologic prostheses in this setting.

Studies on free or haptoglobin-bound hemoglobin and derivatives (semihemoglobins and porphyrinated semihemoglobins). Some aspects of their peroxidatic activity.

The peroxidatic activity of hemoglobin (Hb) is known to be enhanced when this hemoprotein is bound to haptoglobin (Hp). The peroxidatic reaction (H2O2, guaiacol as donor) has been kinetically studied (Steady-state) in the presence of free or rabbit-haptoglobin bound human hemoglobin and some of its derivatives, all in ferricyano-form. With free Hb+ CN, we observed linearity of Lineweaver and Burk plots in a wide range of concentrations, the donor's behaviour was therefore assumed to obey the Michaelis-Menten mechanism. When Hp-Hb+ CN is the enzyme, the donor's behaviour is more complicated, analysis shows the existence of two kinds of donor's binding sites. The possibility whether this behaviour might correspond to the intrinsic properties of Hb chains, as revealed after combination with Hp, was examined. The peroxidatic activity of free and Hp-bound alpha and beta chains of Hb were studied. The alpha chains of Hb combine with Hp whereas the beta chains fail to do so. In order to make useful comparisons, the peroxidatic activity of Hp-bound alpha and beta chains were studied by the use of Hp-semihemoglobin complexes where the semihemoglobins carried heme on only one type of chain (alpha or beta). Results did not show an evident correlation between the activities of the two free or bound types of chains and those of the two classes of binding sites revealed in Hp-Hb+ CN. Moreover, it appeared that the heme-free complementary chain might influence the activity of the heme-carrying alpha or beta chain in semihemoglobins and Hp-semihemoglobin complexes. The binding or protoporphyrin on free and Hp-bound semihemoglobins leads to species which exhibit structures close to that of Hb and Hp-Hb complex respectivley. Results of studies on these derivatives brought up new interesting data : when the porphyrin ring alone is bound to the heme deficient chains (alpha or beta), in Hp-semihemoglobin complexes, the same peculiar behaviour, already observed with Hp-Hb complex, is found again. The structural implications of these results are discussed.

Interactions between three pyridazinyl-GABA derivatives and central GABA and glycine receptors in the rat, an in vivo microiontophoretic study.

Three pyridazinyl-gamma-aminobutyric acid (GABA) derivatives, SR 95103, SR 42641 and SR 95531, have previously been shown to be specific, competitive and reversible GABAA antagonists. For all three compounds selectivity was claimed mainly on the basis of biochemical results. However the absence of an interaction with the binding site for strychnine does not preclude an interaction with the glycine receptor. Therefore the interaction between these compounds and GABA- and glycine-elicited responses in the rat cuneate nucleus was examined in vivo by microiontophoretic techniques using extracellular recordings. Preliminary experiments in the somesthetic cortex of the rat (18 cells) confirmed that SR 95103 (100 mM; 0-100 nA) blocked GABA-evoked responses. In the cuneate nucleus SR 95103 (100 mM), SR 42641 (5 mM), SR 95531 (5 mM) and bicuculline methochloride (BMC; 5 mM) blocked GABA-elicited responses in a dose-dependent, competitive and reversible fashion for ejection currents up to 100 nA. The compound SR 95103 appeared to be less potent than bicuculline and also antagonized glycine-induced responses. Both SR 42641 and SR 95531 appeared to be equipotent to bicuculline and selective for the GABA receptor. Based on these results, it is postulated that SR 42641 and SR 95531 are potent and reversible GABAA antagonists and could be useful tools to further characterize the GABA receptor.

Specific binding of a phenyl-pyridazinium derivative endowed with GABAA receptor antagonist activity to rat brain.

SR 95531 has been shown to be a potent, selective, reversible and competitive GABAA antagonist. In the present study we report that (3H)SR 95531 binds with high affinity and in a specific and saturable manner to rat brain membranes. Scatchard analysis revealed two binding sites (KD: 6 nM; Bmax: 0.24 pmol/mg protein and KD: 38 nM; Bmax: 0.66 pmol/mg protein). Only GABA ligands were effective displacers of (3H)SR 95531. The respective IC50 values obtained with these compounds suggests that (3H)SR 95531 labels the GABA receptor in its antagonist conformation.

Condensation of muscimol or thiomuscimol with aminopyridazines yields GABA-A antagonists.

Ten analogs of muscimol and thiomuscimol in which the amino function was delocalized in an amidinic system were prepared by N2 alkylation of 6-aryl-3-aminopyridazines with (chloromethyl)isoxazole or (chloromethyl)isothiazole derivatives. These muscimol and thiomuscimol derivatives show potent binding properties for GABA-A receptors (they displace [3H]GABA and [3H]gabazine) and provoke convulsions after iv injections. They fit well with the model pharmacophore proposed by our group for the GABA-A antagonists and show similar structure-activity profiles to that of the pyridazinyl-GABAs.

Synthesis and activity of 5-(aminomethylene)-1,3-cyclohexanediones: enolic analogues of gamma-aminobutyric acid.

Eight 1,3-cyclohexanediones with an aminoalkyl side chain in the 5-position were synthesized as rigid enolic analogues of GABA (gamma-aminobutyric acid). Biochemical investigations about their abilities to displace [3H]GABA and [3H]baclofen [beta-(p-chlorophenyl)-gamma-aminobutyric acid] in binding studies or to inhibit the high-affinity sodium-dependent GABA uptake showed that these compounds were generally devoid of affinity for the two GABA receptors and for the GABA carrier. Only compound 1 exhibited a weak affinity in the GABA-A binding experiments (IC50 = 6.5 X 10(-5) M). Graphic computer modeling was applied in an attempt to explain this activity in comparison to some reference GABA agonists. Electrophysiological studies on dorsal root ganglia (DRG) also excluded agonistic or antagonistic properties on GABA-A or GABA-B receptor models but pointed out an atypical prolongation of Ca2+-dependent action potential for compound 1.

Synthesis and activity of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines in animal models of epilepsy.

A series of 6-aryl-3-(hydroxypolymethyleneamino)pyridazines derivatives was synthesized and evaluated for anticonvulsant activity. The compounds were screened in mice for their ability to antagonize maximal electroshock- and bicuculline-induced seizures; neurotoxicity was evaluated in the rotorod test. The anticonvulsant activity of the most potent compounds in this series was also examined in kindled amygdaloid rats and in photoepileptic Papio papio baboons. Phenobarbital, diphenylhydantoin, carbamazepine, and sodium valproate were used as standard antiepileptic drugs. The structure-activity relationships in this series were examined by either varying the aryl ring in the 6-position of the pyridazine ring or by modifying the 3-amino side chain. Only the compounds with a phenyl ring in the 6-position of the pyridazine ring exhibited appreciable anticonvulsant activity. Furthermore, a 4-hydroxypiperidine side chain in the 3-position of the pyridazine ring appeared essential for anticonvulsant activity. Substituting the phenyl ring with a Cl in the 2-position led to a substantial increase of activity; disubstituting the phenyl ring with a Cl in the 2- and 4-positions yielded the most potent compounds in this series, some of which were as potent or more potent than phenobarbital. Two compounds, 6-(2-chlorophenyl)-3-(4-hydroxypiperidino)pyridazine (2) and 6-(2,4-dichlorophenyl)-3-(4-hydroxypiperidino)pyridazine (3), were selected for further studies. Clinical evaluation of these compounds is in progress.

GABA-uptake inhibitors: construction of a general pharmacophore model and successful prediction of a new representative.

A model for the pharmacophore of GABA-uptake inhibitors was established using published structure-activity data and molecular modeling. The model accounted for the activities of different classes of GABA-uptake inhibitors. Analogues of guvacine substituted at position 6 were synthesized in order to confirm the model. 6-(3,3-Di-phenylpropyl)guvacine (30f), which fit well with the pharmacophore, had an in vitro IC50 of 0.1 microM. This value is as good as those of the best GABA-uptake inhibitors known today.

A 7-phenyl substituted triazolopyridazine has inverse agonist activity at the benzodiazepine receptor site.

To investigate further the structural requirements for benzodiazepine (BZD) receptor ligands, we synthesized SR 95195, [7-phenyl-3-methyl-1,2,4-triazolo-(4,3-b) pyridazine], a positional isomer of the 6-phenyl-triazolo-pyridazines, which were the first non-BZD derivatives to exhibit high affinity for the BZD receptor and BZD-like activity in vivo. In vitro, SR 95195 displaced specifically bound [3H]-flunitrazepam from rat cerebellar and hippocampal membranes with respective IC50 values of 4 and 8 microM. In vivo, SR 95195 lacked BZD-like activity. At high doses SR 95195 induced clonic seizures in mice (threshold convulsant dose: 150 mg kg-1; CD50: 160 mg kg-1 i.p.) which were antagonized by Ro 15-1788. At non-convulsant doses (25 mg kg-1 i.p. and 100 mg kg-1 i.p.) SR 95195 significantly decreased punished responding in an operant conflict procedure in the rat, suggesting SR 95195 has intrinsic anxiogenic activity. SR 95195, in mice, reversed the anticonvulsant and myorelaxant actions of diazepam 3 mg kg-1, orally (respective ED50 values: 45 mg kg-1 i.p. and 44 mg kg-1 i.p.). In an operant-conflict test in rats, SR 95195 at non-anxiogenic doses, antagonized the disinhibitory action of diazepam 4 mg kg-1, i.p. (ED50: 8.6 mg kg-1, i.p.), but not that of pentobarbitone 15 mg kg-1, i.p. It is concluded that SR 95195 has the pharmacological profile of an inverse BZD agonist and that displacing the phenyl from the 6- to the 7-position in the triazolopyridazine series causes a shift from agonist to inverse agonist type activity at the BZD receptor site.

Arterial embolization for bleeding pseudocysts complicating chronic pancreatitis.

OBJECTIVES: To evaluate the efficacy of arterial embolization (EMB) in the management of bleeding pancreatic pseudocysts or pseudoaneurysms and to assess the possible indication for secondary surgery. DESIGN: Retrospective review with a mean follow-up of 60 months (range, 18-125 months). SETTING: Tertiary care center, university hospital. PATIENTS: The medical records of 14 patients who were referred to the hospital with bleeding pancreatic pseudocysts and/or pseudoaneurysms related to chronic pancreatitis, between 1983 and 1994, were reviewed. The clinical presentation was major bleeding in 10 patients (gastrointestinal or intraperitoneal) and chronic signs in 4. INTERVENTION: Celiac and superior mesenteric angiography with EMB attempt in all patients. MAIN OUTCOME MEASURES: The immediate effect on bleeding and the long-term safety of arterial EMB. RESULTS: Embolization failed in 3 patients and surgery was needed (1 patient died). Embolization was successful in 11 patients, but 2 complications occurred (duodenal necrosis and aortic thrombosis) (1 patient died). Among the 10 patients whose bleeding stopped, an intentional pancreatectomy was performed 4 times (all patients are alive). The 6 other patients did not undergo a further pancreatic operation due to unfavorable local or general condition. None of them had recurrent bleeding, 3 of them died later of extrapancreatic diseases. Overall, early mortality was 14%, with deaths occurring only in unsuccessful or complicated EMB cases. CONCLUSIONS: The immediate effectiveness of arterial EMB is undeniable but depends on the expertise of the radiologist. When EMB is successful, further surgery should be reserved for patients in good general condition who have other complications of chronic pancreatitis that are not amenable to minimally invasive techniques.