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PubMed2000

The role of frozen section, gender, age, and tumor size in the differentiation of follicular adenoma from carcinoma: a meta-analysis.

BACKGROUND: The purpose of this study was to reanalyze modern trials and use meta-analysis to determine how well frozen section gender, age, and tumor size could differentiate follicular adenoma from follicular carcinoma. METHOD: Inclusion criteria were studies where patients had a permanent pathologic diagnosis of follicular adenoma or follicular carcinoma and underwent frozen section or had clinical features recorded. Data were pooled, and the random effects model of meta-analysis was used. A probability value of less than.05 was considered significant. RESULTS: Nineteen studies were included (n = 3486 patients). Frozen section was evaluated in 11 studies (n = 2204 patients). Frozen section had an 87% sensitivity, a 48% specificity, a 92% and 35% positive and negative predictive value, respectively, an 82% accuracy, an odds ratio of 0.181, a 95% confidence interval (CI) of 0.07 to 0.49, and a probability value of.001. Clinical features were evaluated in 10 studies (n = 1954 patients). Of the patients with follicular carcinoma, 27.5% were male compared with patients with follicular adenoma, of whom 17.7% were male (P <.01; odds ratio, 2.17; CI 1.3-3.6; P =.003). Of the patients with follicular carcinoma, 52.2% were older than 50 years (52.2%) compared with patients with follicular adenoma, of whom 28.5% were older than 50 years (P <.001). Of patients with follicular carcinoma, 36.8% had tumors larger than 3 to 5 cm compared with patients with follicular adenoma, of whom 14.7% had tumors larger than 3 to 5 cm (P <.001; odds ratio, 3.99; CI 1.5-10.8; P =.006). CONCLUSIONS: Meta-analysis suggests that frozen section is not a specific test and cannot be used to confidently rule out follicular carcinoma. Male gender and large tumor size are significantly associated with carcinoma.

Adenoma↗
PubMed2004

Forces generated during actin-based propulsion: a direct measurement by micromanipulation.

Dynamic actin networks generate forces for numerous types of movements such as lamellipodia protrusion or the motion of endocytic vesicles. The actin-based propulsive movement of Listeria monocytogenes or of functionalized microspheres have been extensively used as model systems to identify the biochemical components that are necessary for actin-based motility. However, quantitative force measurements are required to elucidate the mechanism of force generation, which is still under debate. To directly probe the forces generated in the process of actin-based propulsion, we developed a micromanipulation experiment. A comet growing from a coated polystyrene bead is held by a micropipette while the bead is attached to a force probe, by using a specially designed "flexible handle." This system allows us to apply both pulling and pushing external forces up to a few nanonewtons. By pulling the actin tail away from the bead at high speed, we estimate the elastic modulus of the gel and measure the force necessary to detach the tail from the bead. By applying a constant force in the range of -1.7 to 4.3 nN, the force-velocity relation is established. We find that the relation is linear for pulling forces and decays more weakly for pushing forces. This behavior is explained by using a dimensional elastic analysis.

Actins↗
PubMed2004

Cooperative extraction of membrane nanotubes by molecular motors.

In eukaryotic cells, nanotubes represent a substantial fraction of transport intermediates between organelles. They are extracted from membranes by molecular motors walking along microtubules. We previously showed that kinesins fixed on giant unilamellar vesicles in contact with microtubules are sufficient to form nanotubes in vitro. Motors were attached to the membrane through beads, thus facilitating cooperative effects. Koster et al. proposed that motors could dynamically cluster at the tip of tubes when they are individually attached to the membrane. We demonstrate, in a recently designed experimental system, the existence of an accumulation of motors allowing tube extraction. We determine the motor density along a tube by using fluorescence intensity measurements. We also perform a theoretical analysis describing the dynamics of motors and tube growth. The only adjustable parameter is the motor binding rate onto microtubules, which we measure to be 4.7 +/- 2.4 s(-1). In addition, we quantitatively determine, for a given membrane tension, the existence of a threshold in motor density on the vesicle above which nanotubes can be formed. We find that the number of motors pulling a tube can range from four at threshold to a few tens away from it. The threshold in motor density (or in membrane tension at constant motor density) could be important for the understanding of membrane traffic regulation in cells.

Animals↗
PubMed2002

A minimal system allowing tubulation with molecular motors pulling on giant liposomes.

The elucidation of physical and molecular mechanisms by which a membrane tube is generated from a membrane reservoir is central to the understanding of the structure and dynamics of intracellular organelles and of transport intermediates in eukaryotic cells. Compelling evidence exists that molecular motors of the dynein and kinesin families are involved in the tubulation of organelles. Here, we show that lipid giant unilamellar vesicles (GUVs), to which kinesin molecules have been attached by means of small polystyrene beads, give rise to membrane tubes and to complex tubular networks when incubated in vitro with microtubules and ATP. Similar tubes and networks are obtained with GUVs made of purified Golgi lipids, as well as with Golgi membranes. No tube formation was observed when kinesins were directly bound to the GUV membrane, suggesting that it is critical to distribute the load on both lipids and motors by means of beads. A kinetic analysis shows that network growth occurs in two phases: a phase in which membrane-bound beads move at the same velocity than free beads, followed by a phase in which the tube growth rate decreases and strongly fluctuates. Our work demonstrates that the action of motors bound to a lipid bilayer is sufficient to generate membrane tubes and opens the way to well controlled experiments aimed at the understanding of basic mechanisms in intracellular transport.

Adenosine Triphosphate↗
PubMed2002

Bidirectional cooperative motion of molecular motors.

Recently, in a beautiful set of experiments, it has been shown that a Ncd mutant, NK11, which lacks directionality in its individual motion, was able to exhibit a new kind of directed motion in motility assays (Endow, S. A. & Higuchi, H. (2000) Nature (London) 406, 913-916): the filaments keep a given velocity for a while and then suddenly move in the opposite direction with similar velocity. We show that these observations nicely illustrate the concept of dynamic transitions in motor collections introduced earlier in the case of an infinite number of motors. We investigate the experimentally relevant case of a finite number of motors both when directionality is present (kinesins, myosins, Ncd) and absent (NK11). Using a symmetric two-state model, we demonstrate that bidirectional motion is the signature of a dynamic transition that results from the collective behavior of many motors acting on the same filament. For motors exhibiting directional bias individually, an asymmetric two-state model is appropriate. In that case, dynamic transitions exist for motor collections in the presence of an external force. We give predictions for the dependence of motion on ATP concentration, external forces, and the number of motors involved. In particular, we show that the reversal time grows exponentially with the number of motors per filament.

Computer Simulation↗
PubMed1991

Free-flow electrophoresis with trapping by a transverse inhomogeneous field.

We propose an electrophoretic technique combining the use of a series of dielectric traps controlled by an ac electric field and conventional continuous field free-flow electrophoresis. From the theoretical model that we describe, one can expect, for DNA electrophoresis, an improvement of one to two orders of magnitude in the selectivities or experimental durations.

Chemical Phenomena↗
PubMed1999

Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP.

The pharmacological phenotype of ATP-sensitive potassium (K(ATP)) channels is defined by their tissue-specific regulatory subunit, the sulfonylurea receptor (SUR), which associates with the pore-forming channel core, Kir6.2. The potassium channel opener diazoxide has hyperglycemic and hypotensive properties that stem from its ability to open K(ATP) channels in pancreas and smooth muscle. Diazoxide is believed not to have any significant action on cardiac sarcolemmal K(ATP) channels. Yet, diazoxide can be cardioprotective in ischemia and has been found to bind to the presumed cardiac sarcolemmal K(ATP) channel-regulatory subunit, SUR2A. Here, in excised patches, diazoxide (300 microM) activated pancreatic SUR1/Kir6.2 currents and had little effect on native or recombinant cardiac SUR2A/Kir6.2 currents. However, in the presence of cytoplasmic ADP (100 microM), SUR2A/Kir6.2 channels became as sensitive to diazoxide as SUR1/Kir6. 2 channels. This effect involved specific interactions between MgADP and SUR, as it required Mg(2+), but not ATP, and was abolished by point mutations in the second nucleotide-binding domain of SUR, which impaired channel activation by MgADP. At the whole-cell level, in cardiomyocytes treated with oligomycin to block mitochondrial function, diazoxide could also activate K(ATP) currents only after cytosolic ADP had been raised by a creatine kinase inhibitor. Thus, ADP serves as a cofactor to define the responsiveness of cardiac K(ATP) channels toward diazoxide. The present demonstration of a pharmacological plasticity of K(ATP) channels identifies a mechanism for the control of channel activity in cardiac cells depending on the cellular ADP levels, which are elevated under ischemia.

Adenosine Diphosphate↗
PubMed2000

Auditory sensitivity provided by self-tuned critical oscillations of hair cells.

We introduce the concept of self-tuned criticality as a general mechanism for signal detection in sensory systems. In the case of hearing, we argue that active amplification of faint sounds is provided by a dynamical system that is maintained at the threshold of an oscillatory instability. This concept can account for the exquisite sensitivity of the auditory system and its wide dynamic range as well as its capacity to respond selectively to different frequencies. A specific model of sound detection by the hair cells of the inner ear is discussed. We show that a collection of motor proteins within a hair bundle can generate oscillations at a frequency that depends on the elastic properties of the bundle. Simple variation of bundle geometry gives rise to hair cells with characteristic frequencies that span the range of audibility. Tension-gated transduction channels, which primarily serve to detect the motion of a hair bundle, also tune each cell by admitting ions that regulate the motor protein activity. By controlling the bundle's propensity to oscillate, this feedback automatically maintains the system in the operating regime where it is most sensitive to sinusoidal stimuli. The model explains how hair cells can detect sounds that carry less energy than the background noise.

Animals↗
PubMed1996

Elevated cyclic AMP inhibits NF-kappaB-mediated transcription in human monocytic cells and endothelial cells.

The NF-kappaB/Rel family of transcription factors regulates the inducible expression of many genes in activated human monocytes and endothelial cells. In this study, we examined the molecular mechanism by which agents that elevate intracellular cAMP inhibit the expression of the tumor necrosis factor alpha (TNFalpha), tissue factor, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 genes. Both forskolin and dibutyryl cAMP, which elevate intracellular cAMP by independent mechanisms, inhibited TNFalpha and tissue factor expression at the level of transcription. Induction of NF-kappaB-dependent gene expression in transiently transfected human monocytic THP-1 cells and human umbilical vein endothelial cells was inhibited by elevated cAMP and by overexpression of the catalytic subunit of protein kinase A (PKA). Elevated cAMP did not prevent nuclear translocation of p50/p65 and c-Rel/p65 heterodimers, decrease nuclear translocation of p65, or significantly modify TNFalpha-induced phosphorylation of p65. Functional studies demonstrated that transcriptional activation of a plasmid containing multimerized kappaB sites by p65 was inhibited by agents that elevate cAMP and by overexpression of the catalytic subunit of PKA. This study indicates that activation of PKA reduces the induction of a distinct set of genes in monocytes and endothelial cells by inhibiting NF-kappaB-mediated transcription.

Biological Transport↗
PubMed1998

Hepatitis B x protein inhibits p53-dependent DNA repair in primary mouse hepatocytes.

The mechanisms by which the hepatitis B x protein (HBx) contributes to hepatocarcinogenesis remain unclear. However, interaction with the tumor suppressor gene p53 and inhibition of p53-dependent cellular functions, including nucleotide excision repair, could be central to this process. We studied the levels of global repair (removal of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts) and transcription-coupled repair (removal of CPDs in both strands of the dihydrofolate reductase gene) in primary wild-type and p53-null mouse hepatocytes. We show that global repair of CPDs appears to be more efficient in mouse hepatocytes than in other commonly studied rodent cells and approaches the levels of human cells and that p53 is required for global genomic DNA repair of CPDs but not for transcription-coupled repair. We then investigated the effect of HBx expression on hepatocyte nucleotide excision repair. We demonstrate that HBx expression affects DNA repair in a p53-dependent manner. Transient HBx expression reduces global DNA repair in wild-type cells to the level of p53-null hepatocytes and has no effect on the repair of a transfected damaged plasmid. Therefore, in viral hepatitis, the hepatitis B virus could inhibit the p53-dependent component of global repair leading, over time, to accumulation of genetic defects and fostering carcinogenesis.

Animals↗
PubMed2001

Reduced expression of the epithelial adhesion ligand laminin 5 in the skin causes intradermal tissue separation.

Laminin 5, the major keratinocyte adhesion ligand, is found in the lamina lucida subregion of the epidermal basement membrane of the skin, where it colocalizes with the anchoring filaments. Mutations in the genes encoding laminin 5 cause junctional epidermolysis bullosa, an inherited skin blistering disease characterized by abnormal hemidesmosomes and cleavage of the lamina lucida leading to epidermal detachment. In this work we describe the genetic basis of a new subtype of lethal inherited epidermolysis bullosa associated with reduced skin reactivity to laminin 5, presence of mature hemidesmosomes, and intradermal cleavage of the skin. The epidermolysis bullosa patients were heterozygous for a nonsense mutation (Q896X) and a splice site mutation (764-10T-->G) in the gene (LAMC2) for the gamma2 chain of laminin 5. The nonsense mutation causes accelerated decay of the corresponding mRNA, while the splice site mutation results in maturation of a cryptic wild-type gamma2 mRNA leading to reduced expression of wild-type laminin 5. In vitro studies using the probands' keratinocytes showed that secretion of reduced amounts of functional laminin 5 in the patient, although permitting formation of hemidesmosomes, fail to restore efficient cell adhesion. Our results provide the first evidence that laminin 5 contributes to the firm adhesion of the epithelial basement membrane to the underlying stroma. They also show that a low expression level of laminin 5 induces assembly of mature hemidesmosomes in vivo but fails to assure a stable cohesion of the dermal-epidermal junction.

3T3 Cells↗
PubMed1988

Effects of age, and protein malnutrition followed by a balanced diet on the non-parallel change in digestive enzymes in the pancreas and their secretion in the rat.

1. Ninety male Wistar rats were divided into two groups. A control group (C) was fed on a balanced diet, containing 200 g protein/kg for 51 d. An experimental group (E) was fed on a low-protein diet containing 50 g protein/kg for 28 d (PM), and then on a balanced diet for 23 d (BR). At different days of PM and BR, the pancreas and the pancreatic juice were collected 40 min after injection of 0.1 mCi [3H]leucine. The amounts of amylase (EC 3.2.1.1), trypsinogen 2 (EC 3.4.21.4), chymotrypsinogen 1 (EC 3.4.21.1) and lipase (EC 3.1.1.3) were determined after separation by the isoelectric focussing technique. Incorporation of [3H]leucine into the four hydrolases of pancreatic juice and pancreas was also determined. 2. In control rats a progressive increase in the concentration of digestive enzymes and the amounts secreted were observed with age. Maturation was reached when the rats were 9 weeks old. In rats E, PM inhibited maturation of the pancreas. However, individual enzymes were not affected to the same extent and at the same time. As soon as re-feeding was initiated, pancreas maturation took place and a significant increase in these variables was observed. The increases varied according to the hydrolase and did not appear at the same time. 3. In control rats, a preferential secretion of newly synthesized enzymes was observed in young rats, whereas with age, the proportion of newly synthesized enzymes excreted decreased slowly. In group E rats, at the beginning of PM, the proportion of newly synthesized enzymes secreted was very low and increased with time. 4. In rats C and E, our results indicated a non-parallelism between pancreatic enzyme levels and amounts secreted. This non-parallelism was different in both groups, it was changed with age and pancreas maturation in group C, and according to nutritional state in group E.

Aging↗
PubMed1993

Comparative changes between pancreas and pancreatic juice digestive enzyme contents during nutritional rehabilitation following severe protein malnutrition in the rat.

The relationship between digestive enzyme activities in the pancreas and pancreatic juice was studied in post-weaning rats fed on a low-protein diet (30 g cereal protein/kg) for 1 month and a refeeding balanced diet (235 g mixed protein/kg) for the following 3 months. A control group was fed on the balanced diet for 4 months. At the end of malnutrition and at various times of refeeding, activities of amylase (EC 3.2.1.1), trypsin (EC 3.4.21.4), chymotrypsin (EC 3.4.21.1), lipase (EC 3.1.1.3), phospholipase A2 (EC 3.1.1.4) and cholesterolesterase (EC 3.1.1.13) in pancreas and pancreatic juice were measured. Recovery of body and pancreas weights was obtained after 3 months of refeeding. Pancreas offered a higher resistance to the low-protein diet; a quicker recovery than that of the whole organism was observed during refeeding. Protein and RNA contents of pancreatic cells were depressed by protein depletion. At the end of refeeding, pancreatic and cell RNA contents were still depressed. In pancreas and pancreatic juice, protein depletion produced a decrease in enzyme activities, with the exception of phospholipase A2 and cholesterolesterase. During refeeding, activities were increased to various levels in pancreatic juice and pancreas. In pancreatic juice, a deficit in enzyme activities still prevailed at the end of refeeding. The retention thresholds (total activity in pancreas v. activity per h in pancreatic juice) of hydrolases were increased by malnutrition. They were all decreased by refeeding at various rates, but after 3 months of refeeding the thresholds were still markedly increased for all enzymes studied. After malnutrition and during refeeding, the dissociated enzyme activities in pancreas and pancreatic juice could be the expression of an alteration at different stages: synthesis, intracellular transport, storage mechanisms and secretion.

Amylases↗
PubMed1994

Pancreatic digestive hydrolase activities in growing rats fed alternately on raw and heated soya-bean flour.

The time-course effects of two diets containing raw (RSF) or heated (HSF) soya-bean flour on the digestive enzyme levels in the pancreas and in pancreatic juice were investigated in growing rats fed, alternately, on RSF or HSF diets for two 4-week periods. These values were compared with those obtained in a control group fed on a casein diet. RSF and HSF diets lowered N balance (84.8 (SE 0.9), 82.6 (SE 0.8) and 79.9 (SE 0.8)% with control, HSF and RSF diets respectively, at the third week). However, they increased protease activities compared with the control diet (3-fold for trypsin (EC 3.4.21.4) and chymotrypsin (EC 3.4.21.1) activities in pancreas contents and outputs with the RSF diet; 2-fold for trypsin in pancreas contents and outputs and by 60% for chymotrypsin contents with the HSF diet). The poorer nutritional N utilization might be attributable to soya-bean flour heat-stable (lectins) and heat-labile components (trypsin inhibitors). The decrease in lipid apparent digestibilities in RSF and HSF diets (97.0 (SE 0.8), 91.1 (SE 0.9) and 90.4 (SE 0.7)% with control, RSF and HSF diets at the seventh week) were correlated with a diminution in apparent lipase (EC 3.1.1.3; measured without addition of exogenous colipase), potential lipase (measured with addition of saturated amounts of exogenous colipase) and colipase activities. Compared with control values, gains in potential and apparent lipase outputs were diminished by nearly 40% and gain in colipase outputs by 60% with RSF and HSF diets. These results show clearly that heated or raw soya-bean flours have a significant inhibitory effect on lipase digestive enzyme activities in the pancreas and in its secretion, which might explain impaired lipid digestibility.

Animals↗
PubMed1994

Changes in fatty acid compositions of total serum and lipoprotein particles, in growing rats given protein-deficient diets with either hydrogenated coconut or salmon oils as fat sources.

The present study examines the effects of dietary saturated (hydrogenated coconut oil) and polyunsaturated (salmon oil) fats on the composition and metabolism of lipoproteins in growing rats fed on protein-deficient diets. Four groups of rats were fed on the following diets for 28 d: 200 g casein + 50 g coconut oil (COC)/kg, 20 g casein + 50 g coconut oil (COd)/kg, 200 g casein + 50 g salmon oil (SAC)/kg, 20 g casein + 50 g salmon oil (SAd)/kg. Both protein-deficient groups exhibited low concentrations of protein and triacylglycerol (in serum, very-low-density lipoprotein (VLDL), low-density lipoprotein-high-density lipoprotein, (LDL-HDL1) and HDL2-3), of cholesterol (in LDL-HDL1) and of phospholipids (in VLDL). Furthermore, serum and VLDL cholesterol concentrations were also reduced in the SAd group. Compared with rats given 200 g casein/kg diets, those fed on low-protein diets presented lower linoleic and arachidonic acid levels, in serum phospholipids and a dramatic decrease in the polyunsaturated: saturated fatty acid value. Relative amounts of linoleic and arachidonic acids in phospholipids of VLDL and HDL2-3 were also lowered in the COd group but not in the SAd group. However, proportions of 22:5n-6 and 22:6n-3 in VLDL and HDL2-3 phospholipid fractions were enhanced in the COd and SAd groups respectively. The most affected apolipoproteins (apo) were apo B100 and apo B48 in rats fed on protein-deficient diets, apo AI and apo E in the COd group, and apo AIV in the SAd group. Compared with rats fed hydrogenated coconut oil diets, those fed salmon oil diets had enhanced LDL-HDL1 and HDL2-3 but lower VLDL total apolipoproteins (mainly due to a fall in apo B100 and apo B48). Arachidonic and eicosapentaenoic acids, which are impaired by protein deficiency, are the precursors of prostaglandins, thromboxanes and leukotrienes which are implicated in a number of regulatory processes. Our results demonstrate that protein malnutrition is associated with impaired metabolism of arachidonic and eicosapentaenoic acids. Protein malnutrition and essential fatty acid (EFA) deficiency are characterized by many common clinical features and the link between the two may be an impaired production of eicosanoids, since arachidonic and eicosapentaenoic acids are the precursors of these important metabolic regulators. Because of the apparent involvement of EFA deficiency in the aetiology of protein malnutrition, it may be prudent to include adequate amounts of EFA in diets of infants suffering from kwashiorkor.

Animals↗
PubMed2000

Impact of the development of agricultural land on the transmission of sleeping sickness in Daloa, Côte d'Ivoire.

Although tools to control sleeping sickness do exist, their use is difficult; areas where intervention is most required often cannot be targeted for lack of appropriate risk indicators. The importance of human behaviour and habits in the manifestation of the disease is clear. In the development of effective new approaches to the control of the disease, information must be gathered about human populations, and their interaction with the environment, in rural as well as in urban and peri-urban areas. The results of a study carried out in Daloa show that use of some methods for the development of agricultural land leads to increased human-vector contact and, as a result, increased risk of sleeping sickness. Such land-management methods may therefore be useful as risk indicators for transmission. Transmission does not occur in the town of Daloa itself but in surrounding areas under cultivation. The use of the epidemiological risk index seems to be inappropriate in urban (and perhaps peri-urban) areas. The results emphasise not only the importance of environmental and demographic data in elucidating the epidemiology of human trypanosomiasis but also the need for further investigations in peri-urban areas.

Adolescent↗
PubMed1983

Response to tetanus immunization in onchocerciasis patients.

Fifty-five people were examined for tetanus antitoxin level two months after immunization with a single 0.5 ml dose of concentrated tetanus toxoid vaccine; only 7.1% of patients infected with onchocerciasis became immunized, whereas 44.5% were immunized in the control group. These results are consistent with previous observations of a reduced level of both cell-mediated and humoral immunity in patients heavily infected with parasitic diseases, especially onchocerciasis. This study raises doubts about the efficacy of immunization in young adult age groups and re-emphasizes the need for immunization in infancy.

Adolescent↗