Of logos and men: semantic memory impairment for unique entities in a case of semantic variant of primary progressive aphasia.

In this study, an individual (NG) with the semantic varient of primary progressive aphasis (svPPA) was assessed with tasks designed to investigate the recognition and activation of semantic knowledge about unique entities. NG had significant difficulties in the recognition of brand names and famous names but was largely unimpaired in the recognition of logos and famous faces. However, she was impaired in tasks requiring the activation of semantic representations of logos, brand names, famous faces, and famous names. These results suggest that the recognition of unique entities results from the interaction of perceptual and conceptual processes and, that the ability to activate semantic information about these entities can be affected in svPPA.

Texture analysis on MR images helps predicting non-response to NAC in breast cancer.

BACKGROUND: To assess the performance of a predictive model of non-response to neoadjuvant chemotherapy (NAC) in patients with breast cancer based on texture, kinetic, and BI-RADS parameters measured from dynamic MRI. METHODS: Sixty-nine patients with invasive ductal carcinoma of the breast who underwent pre-treatment MRI were studied. Morphological parameters and biological markers were measured. Pathological complete response was defined as the absence of invasive and in situ cancer in breast and nodes. Pathological non-responders, partial and complete responders were identified. Dynamic imaging was performed at 1.5 T with a 3D axial T1W GRE fat-suppressed sequence. Visual texture, kinetic and BI-RADS parameters were measured in each lesion. ROC analysis and leave-one-out cross-validation were used to assess the performance of individual parameters, then the performance of multi-parametric models in predicting non-response to NAC. RESULTS: A model based on four pre-NAC parameters (inverse difference moment, GLN, LRHGE, wash-in) and k-means clustering as statistical classifier identified non-responders with 84 % sensitivity. BI-RADS mass/non-mass enhancement, biological markers and histological grade did not contribute significantly to the prediction. CONCLUSION: Pre-NAC texture and kinetic parameters help predicting non-benefit to NAC. Further testing including larger groups of patients with different tumor subtypes is needed to improve the generalization properties and validate the performance of the predictive model.

Inflammatory myofibroblastic tumor of the pancreatic head.

Inflammatory myofibroblastic tumors are rare, especially in the pancreas. It is sometimes difficult to obtain a definitive diagnosis with radiological imaging and there is not yet consensus about treatment. We report a case of a 56-year-old man with recurrent abdominal pain particularly in the right upper quadrant without other symptoms. The imaging results showed a pancreatic hypovascularized mass with stenosis of the main pancreatic duct and the common bile duct without metastasis. The FDG PET scanner showed two hypermetabolic foci in the head of the pancreas. The biopsies of the mass were not diagnostic. The therapy adopted was Whipple's pancreaticoduodenectomy with a histological diagnosis of the inflammatory myofibroblastic tumor.

Intravenous nitroglycerin for prevention of pancreatitis after therapeutic endoscopic retrograde cholangiography: a randomized, double-blind, placebo-controlled multicenter trial.

BACKGROUND AND STUDY AIMS: Several studies have suggested that nitroglycerin promotes pancreatic drainage and thereby helps to prevent pancreatitis occurring after endoscopic retrograde cholangiography (ERC). We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of intravenous nitroglycerin for preventing acute pancreatitis in moderate- to high-risk patients undergoing ERC. PATIENTS AND METHODS: The patients underwent therapeutic ERC for gallstone removal, bile duct stenosis, or sphincter of Oddi dysfunction (SOD). They were randomly allocated to receive an intravenous nitroglycerin bolus of 0.1 mg, then 35 microg/kg per minute intravenously (maximum dose 9 mg) for 6 h, or an identical placebo regimen. Serum amylase and lipase levels were determined before and 24 h after ERC. RESULTS: The study was terminated after the interim analysis. The intention-to-treat population consisted of 208 patients enrolled in 20 centers, of whom 105 received nitroglycerin and 103 placebo therapy. Post-ERC pancreatitis (mild/moderate/severe) occurred in 25 patients, comprising 10 (3/5/2) in the nitroglycerin arm and 15 (5/6/4) in the placebo arm (OR 0.62, 95 % CI 0.26 - 1.45; P = 0.26). Pancreatitis-related hospital stays were similar in the two groups (median 4 days, range 2 - 13 days in the nitroglycerin group; median 5 days, range 2 - 20 days in the placebo group). The incidence of pancreatitis in patients with SOD did not differ between the groups (4/11 in the nitroglycerin arm, and 4/15 in the placebo arm). Adverse events were more frequent in the nitroglycerin group and led to cessation of drug infusion in 10 patients in the nitroglycerin arm and in 2 patients in the placebo arm ( P = 0.019). CONCLUSION: In this study, nitroglycerin offered a limited and clinically nonsignificant benefit for the prevention of post-ERC pancreatitis. Its use did not improve the technical success rate of ERC.

Heart rate variability, training variation and performance in elite swimmers.

The aim of the present study was to investigate the relationships between heart rate variability (HRV) changes and both training variations and performances in elite swimmers. A secondary purpose was to measure catecholamine urinary excretion in elite swimmers to validate the HRV indices of sympathetic activity during training. Thirteen swimmers (4 females and 9 males) were tested before and after 4 weeks of intense training (IT) and 3 weeks of reduced training (RT). At the end of each period, the swimmers participated in an official competition of their best event. Individual performances were expressed as percentage of the previous season's best performance. Spectral analysis was used to investigate RR interval variability. HRV indices failed to show any significant changes between the study periods (p>0.05). Pre-IT HF was correlated with performance (r=0.45; p=0.05) and HFnu (r=0.59; p<0.05) during RT. On the other hand, once RT was completed, HFnu was correlated positively to performance (r=0.81; p<0.01) and negatively to fatigue (r=- 0.63; p<0.03). Conversely, the indices of sympathetic activity, i.e., LFnu and LF/HF ratio were inversely related to performance (both r=- 0.81; p<0.01); total fatigue score was correlated to the changes in HFnu (r=- 0.63; p<0.03) and in the LF/HF ratio (r=0.58; p<0.05). Changes in the adrenaline/noradrenaline ratio over the follow-up period were related to the changes in the LF/HF ratio (r=0.45; p<0.03). In highly trained swimmers coping well with a training program, including 4 weeks of IT followed by 3 weeks of RT, HRV indices were unaltered. On the other hand, after the 3 weeks of RT, HFnu was positively related to performance and inversely related to the fatigue score. Thus, elevated initial HF levels could be important in the parasympathetic activity increases during taper and, hence, in swimming performance improvement.

24-hr urinary catecholamine excretion, training and performance in elite swimmers.

The aim of the present study was to investigate the effects of training variations on 24-hr urinary noradrenaline (NA) and adrenaline (Ad) levels and the adrenaline/noradrenaline (Ad/NA) ratio to search for a possible relationship between catecholamine excretion, training, and performance in highly trained swimmers. Fourteen swimmers (5 female and 9 male) were tested after 4 weeks of intense training (IT), 3 weeks of reduced training (RT), and 5 weeks of low training (LT). At the end of each period, the swimmers performed their best event at an official competition. Individual performances were expressed as percentage of the previous season's best performance. The changes in NA levels after 4 weeks of IT were negatively related to changes in training volume (r=-0.70, p<0.01) and total training load (r=-0.68, p<0.02). NA levels measured at the end of IT were positively related to changes in performance after three weeks of RT (r=0.77, p<0.01). The percentage changes in performance between RT and LT were related to NA levels at the end of RT (r=0.60; p<0.04). Ad/NA ratios and Ad were related to performance (r=0.58, p<0.01; r=52, p<0.01; respectively). The differences in Ad/NA ratios and Ad between two consecutive competitions were related to the differences in performance (r=0.59, p<0.01; r=0.49, p<0.01; respectively). 24-hr NA and the Ad/NA excretion ratio were related to both training variations and performance. Thus, 24-hr NA levels and Ad/NA ratio may provide useful markers for monitoring training stress in elite swimmers.

Pigs are not a reliable experimental model in the study of the haemodynamic and respiratory effects of CO2 pneumoperitoneum.

BACKGROUND: Haemodynamic and respiratory effects of a CO2 pneumoperitoneum (intra-abdominal pressure = 12 mmHg) associated to a head-up position(15 degrees ) were studied in 20 pigs using a Swan-Ganz catheter and the Single Breath Test for CO2. The pneumoperitoneum induced a moderate rise in mean arterial pressure (+17%) (P<0.001) without any variation in heart rate, cardiac output and systemic vascular resistances. RESULTS: The following respiratory effects were observed: an increase in PaCO2 (+20%) (P<0.001), PE'CO2 (+31%) (P<0.001), expired volume of CO2 (+28%) (P<0.001), arterial to end-tidal CO2 gradient (+80%) (P<0.001) and alveolar dead space (+40%) (P<0.001) occured. Alveolar ventilation remained stable. Finally and contrary to healthy human patient, intraperitoneal CO2 insufflation in pig induced slight haemodynamic changes and major respiratory modifications. CONCLUSION: Thus, our data do not support the conclusion that the pig is a reliable experimental model for studying the pathophysiology of CO2 pneumoperitoneum-induced changes in haemodynamic and respiratory parameters, in human patients.

Comparative biosynthetic pathway of androstenol and androgens.

It has been shown recently that androstenol and androstanol could modulate gene expression through the nuclear orphan receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor). Although, in the pig, androstenol is produced in high amounts and is active as a pheromone, its role in the human is ill defined. Androstenol possesses a structure similar to that of androgens, with the exception that it does not possess an oxygen at position 17 that is crucial for androgenic and estrogenic activity. It has been shown that human and boar testis homogenates could produce androstenol, but details of the biosynthetic pathway had not yet been elucidated. It has also been shown recently that androstenol could modulate the activity of CAR and PXR and the expression of some cytochrome P450 drug-metabolizing enzymes. We wanted to determine the precise biosynthetic pathway of androstenol and other closely related steroids. Using transformed human embryonic kidney (HEK-293) cells that stably express 3 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase, we have shown that these enzymes are able to efficiently transform the precursor 5,16-androstadien-3 beta-ol into androstenol. We thus provided evidence that androstenol, the ligand for CAR and PXR, is produced by the biosynthetic pathway of sex steroids.

High metabolization of catecholestrogens by type 1 estrogen sulfotransferase (hEST1).

Recently, two types of estrogen sulfotransferase, chronologically named types 1 and 2 estrogen sulfotransferase (hEST1 and hEST2), have been described. Since hEST2 selectively catalyzes the sulfonation of ethinyl estradiol as well as that of estrone (E1) and estradiol (E2), but poorly the sulfonation of catecholestrogens, we wanted to assess the ability of hEST1 to metabolize these compounds. We overexpressed hEST1 in Escherichia coli in fusion with GST, then purified the enzyme using a glutathione affinity column, and obtained GST-free enzyme by digestion with thrombin. Using [35S]-phosphosadenosine phosphosulfate (PAPS) as cofactor, we showed that hEST1 efficiently metabolizes the transformation of 2-OH-E2 and 2-OH-E1. However, the transformation of 4-OH-E1 and 4-OH-E2 is much less efficient. Our results also show that hEST1 metabolizes more efficiently E2 than E1. Since hEST1 mRNA is produced from the same gene as MPST using different alternative promoters and since it is expressed in most breast cancer cells (MCF-7, ZR-75-1, T47-D, MDA-231, and MDA-418), studies of the expression and activity of hEST1 will be most important to have a better knowledge about its involvement in the control of the genotoxicity of estrogens and catecholestrogens.

Acute and delayed antithrombotic effects of alcohol in humans.

Alcohol intake, especially in the form of red wine, has been shown to inhibit platelet function. However, whether alcohol in spirits may inhibit platelet-dependent thrombosis in humans up to 6 hours after ingestion is unknown and was assessed in this study. Platelet thrombus that is formed on exposure of an aortic media (simulating deep arterial injury or plaque rupture) to flowing blood was assessed in an ex vivo Badimon's superfusion chamber at shear rates of 754 or 2,546 seconds(-1) (simulating flow in normal or stenosed arteries). Twelve healthy subjects were studied before and at 20 minutes and 6 hours after consumption of 2 ounces of 40% alcohol. Blood alcohol level was 1.1+/-0. 1, 8.2+/-0.7, and 1.3+/-0.2 mmol/L at baseline, 20 minutes and 6 hours, respectively, after alcohol consumption (analysis of variance [ANOVA] p = 0.0001). Compared with baseline, platelet thrombus formation at the low shear rate flow was significantly decreased by 57% and 61% at 20 minutes and 6 hours, respectively, after alcohol intake (ANOVA p = 0.0001). Platelet thrombus deposition at the high shear rate was similarly inhibited to 68% and 64% of baseline values at 20 minutes and 6 hours, respectively (ANOVA p = 0.003). Men and women showed equal benefit. Thus, moderate alcohol intake in humans significantly inhibited platelet thrombus deposition under low and high shear rates of arterial flow conditions. This antithrombotic effect of a single alcohol drink, persisting for 6 hours and even after blood alcohol level has returned to baseline, may be clinically relevant to the cardioprotective effects of alcohol in men and women.

Intranasal midazolam in piglets: pharmacodynamics (0.2 vs 0.4 mg/kg) and pharmacokinetics (0.4 mg/kg) with bioavailability determination.

Intranasal midazolam was studied in two series of piglets: series 1, n = 20 (18 +/- 3 kg), a randomized double blind pharmacodynamic study to compare doses of 0.2 mg/kg and 0.4 mg/kg; series 2, n = 9 (42 +/- 8 kg), a pharmacokinetic study with a 0.4 mg/kg dose administered either intravenously (i.v.) or intranasally (i.n.) in a cross-over protocol with a one-week wash-out period between each. In series 1, midazolam caused significant anxiolysis and sedation within 3 to 4 min, without a significant difference between 0.2 and 0.4 mg/kg doses for any of the studied parameters. In series 2, after intranasal midazolam administration of 0.4 mg/kg, plasma concentrations attained a maximum (Cmax) of 0.13 +/- 0.04 mg/l at 5 min (median Tmax) and remained higher than 0.04 mg/l until 60 min. The bioavailability factor (F) in this study was F = 0.64 +/- 0.17 by the intranasal route. The terminal half-life (T1/2 lambda z) = 145 +/- 138 min was comparable with the i.v. administration half-life (158 +/- 127 min). In conclusion, optimal intranasal midazolam dose in piglets was 0.2 mg/kg, which procures rapid and reliable sedation, adapted to laboratory piglets.

Early transitory rise in intracellular pH leads to Bax conformation change during ceramide-induced apoptosis.

Ceramide can induce apoptosis through a caspase independent pathway. Bax has been described as able to kill cells in the absence of caspase activity, therefore we measured Bax in situ during ceramide-induced apoptosis using anti-Bax antibodies and flow cytometry analysis. An early (<30 min) increase in Bax labeling was observed after the addition of several ceramide species to several hemopoietic-related cell types. On U937, this increase was not due to antigens synthesis or processing, but rather an increased accessibility or reactivity of Bax antigens for antibodies. This increased immuno-reactivity of Bax was not inhibited by Z-VAD-fmk nor leupeptin, and preceded nuclear fragmentation by several hours. Such an increase in immuno-reactivity was also observed after Fas ligation, but it occurred later (>2 h) accompanying nuclear apoptosis, and was inhibited by Z-VAD-fmk. Bax immuno-reactivity was found to be related to intracellular pH (pHi), and C2-Ceramide (C2-Cer) induced a very early (<10 min) transitory increase in pHi. Both Bax immunoreactivity and pHi increases were dependent on the mitochondrial permeability transition pore (PTP) status. It was concluded from these results that C2-Cer induced a transitory increase in pHi in relation to the PTP. This rise in pHi led to conformational changes in Bax which could be responsible for further apoptosis in the C2-Cer pathway while it was a consequence of caspase activation in the Fas pathway.

Automated reticulocyte counting and immature reticulocyte fraction measurement. Comparison of ABX PENTRA 120 Retic, Sysmex R-2000, flow cytometry, and manual counts.

We evaluated reticulocyte counting and measurement of immature reticulocyte fraction (IRF) with the ABX PENTRA 120 Retic blood analyzer on 300 blood samples. Reticulocyte counts were compared with those obtained by visual counting of 2,000 RBCs, by the TOA (Kobe, Japan) Sysmex R-2000 and a flow cytometry method. The parameters analyzed were the percentages of reticulocytes on all analyzers and the IRF with different modalities. The Retic Count kit (Becton Dickinson, San Jose, CA) was used with the Coulter (Hialech, FL) XL, and a mean channel of fluorescence (MCF) was calculated to fit the reticulocyte maturation. Reticulocyte counting with the ABX (Montpellier, France) PENTRA 120 Retic showed excellent precision and linearity with no significant carryover. Reticulocyte counts were stable after blood storage for 72 hours at 4 degrees C but not at room temperature (RT). IRF parameters values were stable for only 8 hours at 4 degrees C and 6 hours at RT. Comparisons of the methods showed good intraclass correlation (RI) for reticulocyte percentages between ABX PENTRA 120 Retic and Sysmex R-2000, ABX PENTRA 120 Retic and flow cytometry, Sysmex R-2000 and flow cytometry, and ABX PENTRA 120 Retic and manual counting. IRF values were correlated between fluorescence rates and RNA content, but in each case, low RI values were found, showing that Sysmex and ABX IRF values were not concordant. We obtained a significant correlation between mean fluorescence index and the MCF measured by flow cytometry, but the 2 methods were not concordant using the RI. The ABX PENTRA 120 Retic is a good instrument for analyzing reticulocyte count and percentage and allows a good analysis of IRF with several modalities.

Comedolytic effect of topical retinaldehyde in the rhino mouse model.

BACKGROUND: Retinaldehyde is a key molecule in the metabolism of vitamin A by keratinocytes. In order to evaluate its range of topical activity in acne, its comedolytic effect was compared to that of retinoic acid in the same vehicle, in the rhino mouse model. METHODS: The animals were treated on the back daily for 5 consecutive days per week for 3 weeks. At the end of this period, histological slides were analyzed in order to quantify the features of comedones and epidermal thickness. RESULTS: Topical treatment with a retinaldehyde (0.05% w/w) and a retinoic acid formulation (0. 025% w/w) induced comedolysis and increased the epidermal thickness with the same intensity. CONCLUSION: These data indicate that retinaldehyde exerts a significant comedolytic activity.

Renoprotective effects of trimetazidine against ischemia-reperfusion injury and cold storage preservation: a preliminary study.

BACKGROUND: Initial ischemia-reperfusion injury is associated with organ retrieval, storage, and transplantation adversely affects early graft function and influences the development of chronic graft dysfunction. We have recently shown that the protective agent trimetazidine (TMZ) added to preservation solutions: Euro-collins (EC) and University of Wisconsin (UW) was efficient to protect kidneys from ischemia-reperfusion injury in an isolated perfused kidney model. We extended these observations to investigate the role of this drug in the development and progression of organ dysfunction in the autotransplant pig kidney model. METHODS: Five experimental groups were studied. After 48-hr cold preservation, autotransplantation and immediate controlateral nephrectomy was then performed in group EC (EC+placebo (n=8), EC+TMZ (n=8), UW+placebo (n=7), and (UW+TMZ) (n=7) and compared with control group (uninephrectomized, n=4) during 14 days. Blood and urine samples were collected for the measurement of creatinine and blood urea nitrogen on postoperative days 1, 3, 5, 7, 11, and 14. Histological analysis was performed after reperfusion and at day 14. RESULTS: Survivals were 100% in group B and D versus 42% in group A and 57% in group C. Urine production occurred earlier after autotransplantation from TMZ preserved kidneys than in placebo preserved groups. Peak creat and blood urea nitrogen was significantly greater in groups B and D than in groups A and C. TMZ was also efficient both to reduce ischemia-reperfusion injury and to decrease cellular infiltration. CONCLUSION: These results support the beneficial effect of TMZ against ischemia-reperfusion injury and its early effects on grafts in the form of delayed graft function and decreased graft survival. In addition, TMZ reduces inflammatory cellular infiltration in the renal parenchyma.

Overproduction of the Bacillus subtilis glutamyl-tRNA synthetase in its host and its toxicity to Escherichia coli.

The Bacillus subtilis glutamyl-tRNA synthetase (GluRS), encoded by the gltX gene, aminoacylates its homologous tRNA(Glu) and tRNA(Gln) with glutamate. This gene was cloned with its sigma A promoter and a downstream region including a rho-independent terminator in the shuttle vector pRB394 for Escherichia coli and B. subtilis. Transformation of B. subtilis with this recombinant plasmid (pMP411) led to a 30-fold increase of glutamyl-tRNA synthetase specific activity in crude extracts. Transformation of E. coli with this plasmid gave no recombinants, but transformation with plasmids bearing an altered gltX was successful. These results indicate that the presence of B. subtilis glutamyl-tRNA synthetase is lethal for E. coli, probably because this enzyme glutamylates tRNA1(Gln) in vivo as it does in vitro.

Caspase activation is an early event in anthracycline-induced apoptosis and allows detection of apoptotic cells before they are ingested by phagocytes.

An increasing number of methods are being described to detect apoptotic cells. However, attempts to detect apoptotic cells in clinical samples are rarely successful. A hypothesis is that apoptotic cells are cleared from the circulation by phagocytosis before they become detectable by conventional morphological or cytometric methods. Using LR73 adhering cells as phagocytes in a model of in vitro phagocytosis, we found that phagocytosis of daunorubicin (DNR)-treated U937, HL60, or K562 leukemia cell lines occurred prior to phosphatidylserine externalization, DNA hydrolysis, chromatin condensation, nuclear fragmentation, or mitochondrial potential alteration. Moreover DNR-treated K562 cells were eliminated by phagocytes while apoptosis was never observed by any of the above methods. By contrast, using a fluorometric batch analysis assay to detect caspase activity in ceramide- or DNR-treated cells (fluorogenic substrate for caspase), we found that caspase activity increased in apoptosis-committed cells before they were detected by flow cytometry or recognized by phagocytes. Similarly a caspase activity increase was detected in circulating mononuclear cells of luekemic patients 15 h after the beginning of anthracyclin treatment. We suggest that recent findings on enzymatic events (caspase activation) occurring in the early events of apoptosis must now allow the development of new markers for apoptosis, irrespective of the morphological features or internucleosomal fragmentation which are late events in apoptosis.

Sacrococcygeal and transsacral epidural anesthesia in the laboratory pig: a model for experimental surgery.

The laboratory piglet is currently the preferred animal for experimental digestive surgery. In order to ensure optimal perioperative analgesic control with motor blockade during surgery together with rapid postoperative recovery, epidural anesthesia techniques were developed in this animal. We report the anatomo-radiologic studies (10 animals) and clinical experiments (51 transplantations of the liver and the small intestine) which led to the refinement of this anesthesia. In laboratory piglets, epidural anesthesia by distal transsacral (S4-S5) or sacrococcygeal approach is possible in a reproducible manner. The localization of the injection site is simple and epidural space catheterisation is easy without risk for the dural sac which ends at S1-S2.