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PubMed1998

Spatio-temporal receptive fields in carp retinal horizontal cells.

1. The dynamics of the receptive fields of retinal horizontal cells were examined by applying a spatio-temporal modulated light signal to the retina. 2. The spatio-temporal receptive fields of both cone- and rod-driven horizontal cells, estimated through cross-correlation between the modulated light signal and the cells' responses, showed their receptive fields (the space-dependent component) to be reduced in size with time. 3. In cone-driven horizontal cells, the reduction in receptive field size was initially small but then rapidly became prominent with time. The time to peak of the time-dependent component of spatio-temporal receptive fields did not depend on the distance from the centre. 4. Application of a small amount of Co2+, an agent blocking the cone-driven horizontal cells' feedback action on cones, or GABA, resulted in a reversal of the time-dependent shrinkage of receptive fields to time-dependent expansion. 5. In rod-driven horizontal cells, the receptive field shrinkage was slow. The time to peak of the time-dependent component decreased with the distance from the centre. 6. Image processing experiments examining the response pattern in the horizontal cell layer (neural image) to a moving square of light showed smudging of the neural image when the time-dependent receptive field expansion was present, while there was essentially no smudging under conditions of receptive field shrinkage.

Animals↗

PubMed1999

Comparison of cortical bone ablations by using infrared laser wavelengths 2.9 to 9.2 microm.

BACKGROUND AND OBJECTIVE: The purpose of this study was to compare the ablation of cortical bone at wavelengths across the near and midinfrared region. STUDY DESIGN/MATERIALS AND METHODS: An free electron laser generating 4-micros macropulses at specific wavelengths between 2.9 and 9.2 microm was used to ablate cortical bone. The same pulse intensity, repetition rate, radiant exposure, number of pulses, and delivery was used for each wavelength. Tissue removal, collateral thermal injury, and morphologic characteristics of the ablation sites were measured by light and scanning electron microscopy, and compared with the infrared absorption characteristics of cortical bone. RESULTS: Within the parameters used, bone ablation was found to be wavelength dependent. Incisions were deepest where protein has strong absorption, and were most shallow where mineral is a strong absorber. No char was observed on ablation surfaces where 3.0, and 5.9-6.45 microm wavelengths were used. CONCLUSIONS: The use of wavelengths in the 6.1-microm amide I to 6.45-microm amide II region, with the pulse characteristics described, were the most efficient for cutting cortical bone and produced less collateral thermal injury than cutting with a surgical bone saw. This study confirms previous observations that the ablation mechanism below plasma threshold is consistent with an explosive process driven by internal vaporization of water in a confined space and demonstrates that ablation is enhanced by using wavelengths that target the protein matrix of cortical bone.

Absorption↗

PubMed1995

Acidic receptor domains on both sides of the outer membrane mediate translocation of precursor proteins into yeast mitochondria.

Mitochondrial precursor proteins made in the cytosol bind to a hetero-oligomeric protein import receptor on the mitochondrial surface and then pass through the translocation channel across the outer membrane. This translocation step is accelerated by an acidic domain of the receptor subunit Mas22p, which protrudes into the intermembrane space. This 'trans' domain of Mas22p specifically binds functional mitochondrial targeting peptides with a Kd of < 1 microM and is required to anchor the N-terminal targeting sequence of a translocation-arrested precursor in the intermembrane space. If this Mas22p domain is deleted, respiration-driven growth of the cells is compromised and import of different precursors into isolated mitochondria is inhibited 3- to 8-fold. Binding of precursors to the mitochondrial surface appears to be mediated by cytosolically exposed acidic domains of the receptor subunits Mas20p and Mas22p. Translocation of a precursor across the outer membrane thus appears to involve sequential binding of the precursor's basic and amphiphilic targeting signal to acidic receptor domains on both sides of the membrane.

Amino Acid Sequence↗

PubMed2003

Potent side-chain to side-chain cyclized dermorphin analogues containing a carbonyl bridge.

A new family of cyclic opioid peptide analogues related to the 1-4 sequence of dermorphin/deltorphin (Tyr-D-Aaa2-Phe-Aaa4-NH2) has been synthesized. The synthesis of the linear precursor peptides was accomplished by the solid-phase method and ring formation was achieved via a ureido group incorporating the side chain amino functions of D-Aaa2 (D-Lys, D-Orn) and Aaa4 (Lys, Orn, Dab, Dap). The peptides were tested in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays. Most showed very high agonist potency in the GPI assay. The peptide containing D-Lys in position 2 and Dab in position 4 was 210 times more active than enkephalin, and that containing Orn and Dab, respectively, was 150 times more active than enkephalin. The latter peptide was also very active in the MVD assay, and showed an IC50 MVD/GPI ratio of 0.816. NMR spectra of selected peptides were recorded, and structural parameters were determined. The conformational space of the peptides was examined using the electrostatically driven Monte Carlo method. With the help of the NMR spectra each peptide was described as an ensemble of conformations. The conformations have been interpreted with regard to the opioid activities, and comparisons have been made with a model proposed earlier for enkephalin analogues.

Analgesics, Opioid↗

PubMedDate not supplied

Left-side infant holding: a test of the hemispheric arousal-attentional hypothesis.

When asked to hold a young infant in their arms, most adults hold on the left side (Harris, 1997). In a prior study, we found the same bias when we asked adults merely to imagine holding an infant in their arms (Harris, Almerigi, & Kirsch, 1999). It has been hypothesized that the left-side bias is the product of right-hemisphere arousal accompanying certain aspects of the act, causing attention to be driven to the contralateral, or left, side of personal space. Left-side holding, whether actual or imagined, thus would be consistent with the direction to which the holder's attention has been endogenously directed. We tested this hypothesis by giving 250 college students the "imagine-holding" task and then, as an independent measure of lateralized hemispheric arousal, a 34-item Chimeric Faces Test (CFT). On the "imagine" test, a significant majority reported a left-side hold, and, on the CFT, left-side holders had a significantly stronger left-hemispace bias than right-side holders, although both left- and right side holders had left-hemispace CFT biases. The results thus support the attentional-arousal hypothesis but indicate that other factors are contributing as well.

Adult↗

PubMed2026

A serpin-myeloid axis in pancreatic cancer heterogeneity and immune evasion.

Pancreatic ductal carcinoma (PDAC) is characterized by a highly immunosuppressive, extracellular matrix-rich microenvironment, yet tumours display marked heterogeneity1-4. This raises the question of whether immune resistance is a global tumour property or is organized within spatially restricted niches. Here, using Perturb-map spatial functional genomics, we determine how different genes shape the growth and cellular environments of PDAC clones across space and time. This analysis revealed early gene-driven remodelling of local immune neighbourhoods preceding late-stage spatial clonal dominance. We identify SERPINE1 (encoding plasminogen activator inhibitor 1 (PAI1)) and SERPINB2 (encoding PAI2) as dominant regulators of tumour microenvironment control and immune evasion. These serpins promote stabilization of fibrin-rich extracellular matrix niches that spatially retain and programme macrophages towards immunosuppressive states while excluding cytotoxic T cells. Loss of Serpine1 or Serpinb2, or pharmacological inhibition of PAI1 or CD18, improves tumour control in mice and synergizes with anti-PD-1. Multimodal spatial analysis of patient tumours revealed that immunosuppressive niches form around rare SERPINB2- and SERPINE1-expressing PDAC subpopulations, dominated by SPP1+/MARCO+ macrophages. These findings identify cancer-derived SERPINE1 and SERPINB2 as local spatial organizers of immune suppression, linking tumour-intrinsic heterogeneity to local microenvironmental control and immunotherapy resistance in PDAC.

Journal Article↗

PubMed2003

The inflammation-induced down-regulation of plasma Fetuin-A (alpha2HS-Glycoprotein) in liver results from the loss of interaction between long C/EBP isoforms at two neighbouring binding sites.

Fetuin-A is an hepatic protein whose mRNA transiently falls during the inflammatory acute phase via unknown transcriptional mechanisms. Various FETUA promoter/cat constructs transiently transfected in the Hep3B hepatoma cell line allowed us to identify four NF-1 and C/EBP binding sites (N, C) arranged in a 5'-N2-C2-N1-C1-3' order and required for basal promoter activity. Mutant constructs demonstrated that C1 and C2 but not N1 nor N2 are required for the cytokine-driven down-regulation of the promoter. A variable spacing between C2 and N1 showed that the alignment of the (C1+N1) and (C2+N2) areas is critical for the promoter activity in quiescent but not cytokine-stimulated cells. Co-transfection of a plasmid only producing either a long or short C/EBPbeta isoform prevented FETUA regulation by cytokines. Electromobility shift assays with liver nuclear extracts showed that during the acute phase the complexes formed over N1 and N2 are not modified whereas short C/EBPalpha and -beta isoforms replace the long isoforms bound to C1 and C2 in the quiescent liver. Therefore the basal promoter activity requires an interaction between the long C/EBP isoforms bound to C1 and C2 whereas the inflammation-induced down-regulation results from the loss of interaction between the cytokine-induced, short C/EBP isoforms.

Animals↗

PubMed1999

Canonical phase-space approach to the noisy Burgers equation: probability distributions.

We present a canonical phase-space approach to stochastic systems described by Langevin equations driven by white noise. Mapping the associated Fokker-Planck equation to a Hamilton-Jacobi equation in the nonperturbative weak noise limit we invoke a principle of least action for the determination of the probability distributions. We apply the scheme to the noisy Burgers and Kardar-Parisi-Zhang equations and discuss the time-dependent and stationary probability distributions. In one dimension we derive the long-time skew distribution approaching the symmetric stationary Gaussian distribution. In the short-time region we discuss heuristically the nonlinear soliton contributions and derive an expression for the distribution in accordance with the directed polymer-replica and asymmetric exclusion model results. We also comment on the distribution in higher dimensions.

Journal Article↗

PubMed1997

Excitability changes in human cutaneous afferents induced by prolonged repetitive axonal activity.

1. The present study was undertaken to document the excitability changes produced by prolonged high-frequency trains of impulses in cutaneous afferents of six human subjects. 2. Trains of supramaximal stimuli at 200 Hz for 2 min or less produced a prolonged depression in excitability, consistent with activation of the electrogenic Na+-K+ pump. Trains of longer duration resulted in an initial period of hyperexcitability which, with 10 min trains, was associated with the sensation of paraesthesiae in all subjects. This transient hyperexcitability gradually gave way to a long-lasting period of hypoexcitability. 3. The excitability changes were reproducible, and were accompanied by corresponding changes in supernormality, refractoriness, strength-duration time constant and rheobase current, suggesting that the changes in axonal excitability reflected a change in membrane potential. 4. The transient increase in excitability that follows tetanic trains of 10 min had qualitatively similar effects on cutaneous axons as ischaemia or application of a depolarizing current. The post-tetanic changes in the supernormal period of sensory axons were those expected from the changes in excitability, without evidence of a gross distortion in its time course, as has been previously demonstrated in a hyperstimulated human motor axon. 5. It is concluded that the post-tetanic hyperexcitability of human sensory axons is probably driven by increased K+ accumulation in the restricted diffusion space under the myelin sheath, much as in motor axons, the differences in behaviour of sensory and motor axons being explicable by greater inward rectification in sensory axons.

Adult↗

PubMed1992

Pulmonary edema associated with salt water near-drowning: new insights.

In this case report we describe the clinical and laboratory findings of a man who nearly drowned after aspirating a large quantity of seawater. The aspiration of salt water, which is strongly hypertonic with respect to plasma, resulted in severe pulmonary edema, both from the quantity of aspirated seawater and the osmotically driven ultrafiltrate of plasma that accumulated in the air spaces. The initial concentration of protein in the edema fluid sample was very low, 0.7 g/dl, consistent with only a minimal increase in epithelial permeability. Approximately 4 h later, there was a marked increase in the concentration of protein in the residual alveolar fluid associated with improvement in several clinical indices, indicating that the excess alveolar fluid was reabsorbed very rapidly. In addition, the magnesium concentration was markedly elevated because of the aspiration of magnesium-containing seawater, which may have diagnostic importance for near-drowning in salt water. The data from this case provide evidence for well-preserved alveolar epithelial barrier function after aspiration of large quantities of hypertonic salt water.

Animals↗

PubMed2005

The interstellar conundrum: a survey of concepts and proposed solutions.

Once considered intractable, the problem of interstellar flight is slowly yielding to analysis. Although manned missions to the stars are exceedingly improbable in this century, the possibility of interstellar robotic probes should not be ruled out. Recent laboratory work and theoretical analysis suggest several near-term technologies that could, given the development of an adequate space-based infrastructure, provide the needed propulsion. Laser-driven lightsails offer the key advantage of leaving the fuel behind, with the laser beam focused by a large Fresnel lens in the outer Solar System. Perhaps more efficient is the use of a particle beam to boost a spacecraft by interacting with its magnetic sail, the latter a system already under intense scrutiny. Variations on "pellet" propulsion using macroscopic objects continue to surface, their mass converted to energy as they arrive at the departing starship. Interstellar flight will be both difficult and expensive, although it can no longer be considered an impossibility. This paper examines the above concepts and relates them to older ideas, such as the Bussard ramjet, that are currently out of favor. The vibrancy of interstellar flight studies is its syncretism-it was through analysis of the drag problem in fusion ramjet designs that a practical means of decelerating an interstellar probe by deployment of a magnetic sail emerged. The intermingling of such ideas offers the hope of robust hybrid concepts that may make interstellar flight a reality.

Journal Article↗

PubMedDate not supplied

Clinical and technical aspects of implant-supported restorations in the edentulous maxilla: the fixed partial denture design.

PURPOSE: The aim of the present article was to describe the treatment planning for an implant-supported maxillary fixed prosthesis and the clinical procedure involved, including the laboratory fabrication sequence. MATERIALS AND METHODS: If patients request a fixed prosthesis to restore the edentulous maxilla, it is essential to decide as soon as possible whether this prosthesis design can satisfy the requirements of esthetics, phonetics, comfort, and function. Thus, the crucial clinical factors need to be checked during examination. Furthermore, the relationships between ideal implant angulation, available bone, and intended crown should be assessed using reformatted computed tomography. RESULTS: In patients with minimal bone resorption and limited intermaxillary space, implants can usually be placed in the prosthetically driven implant position for a fixed prosthesis. To evaluate and optimize esthetics, biology, and function, a fixed provisional restoration should be inserted for a 6-month diagnostic period. The ideal provisional then serves as a guide for the final restoration. CONCLUSION: If clinical and radiologic diagnostics indicate that an implant-supported fixed complete denture is feasible, meticulous presurgical planning, precise execution of implant positioning, and a progressive prosthetic treatment sequence are required. The ceramometal fixed implant-supported restoration can then be established in an ideally prepared and matured oral environment.

Dental Prosthesis, Implant-Supported↗

PubMed1995

[Patient-controlled analgesia in treatment of postoperative pain].

Patient-controlled analgesia (PCA) is a newer technique for pain management. Patients are allowed to self-administer small analgesic bolus doses, which have been preprogrammed by the physician, into a running intravenous infusion, intramuscularly, subcutaneously or even into the epidural space. Patients' demands are mostly controlled by computer-driven infusion pumps, but can also be delivered by simple disposable devices. Lockout times, concomitant infusions and hourly maximum doses can be set in most PCA pumps. Clinical experience with PCA demonstrates that individual variability in pain sensitivity and analgesic needs are of utmost importance. In contrast to earlier expectations, PCA opiate consumption is usually higher than with restrictive conventional dosing regimes, but without an increase of serious side effects. Such results let assume that many patients under conventional i.m. techniques must be considered to be underdosed. Patients acceptance is generally enthusiastic for self-control. It is suggested that PCA results should be used for the improvement of conventional techniques. PCA has also been found valuable for scientific pain studies, e.g. to determine predictors of postoperative pain, drug interactions and pharmacokinetic experiments. This review concentrates on intravenous PCA during the early postoperative period.

Analgesia, Patient-Controlled↗

PubMed1999

Effect of circumferential plasma-spray porous coating on the rate of femoral osteolysis after total hip arthroplasty.

BACKGROUND: Osteolysis of the femur has been a serious problem associated with some designs of total hip-replacement implants; it frequently leads to failure of the femoral component. We evaluated the effect of a circumferential plasma-spray porous coating on the rate of osteolysis in a study that included two groups of hips, each of which received an implant with the same design except for the extent of the porous coating. Our goal was to determine the possible role of circumferential porous coating in protecting the bone-implant interface from osteolysis. METHODS: A series of consecutive primary total hip replacements performed with insertion of the Mallory-Head implant without cement was divided into two study groups. The first 126 hips (Group 1) were treated with a femoral stem that had a noncircumferential plasma-spray porous titanium coating. The next ninety hips (Group 2) were treated with a circumferentially coated stem of the same design. The average duration of radiographic follow-up was 7.8 years in Group 1 and 7.5 years in Group 2. RESULTS: The average rate of polyethylene wear was similar for the two groups (0.187 millimeter per year in Group 1 and 0.189 millimeter per year in Group 2). The prevalence of osteolysis in Group 1 (40 percent; fifty of 126 hips) was significantly higher than that in Group 2 (10 percent; nine of ninety hips) (p < 0.001). Osteolysis remote from the joint space (distal to zones 1 and 7) was found in 11 percent (fourteen) of the hips in Group 1 but in none of those in Group 2 (p = 0.0004). The average total area of osteolysis in Group 1 (5.0 square centimeters) was significantly larger than that in Group 2 (2.9 square centimeters) (p < 0.05). CONCLUSIONS: A circumferential plasma-spray titanium porous coating on the femoral component of a total hip-replacement prosthesis inserted without cement appears to provide an effective barrier preventing wear debris from gaining access to the endosteal surface of the femur and the greater trochanter. This finding supports the hypothesis of the so-called effective joint space, which predicts that wear debris from the joint bearing can migrate, driven by intracapsular pressures, to all areas to which joint fluid has access and thus can result in osteolysis. The reduction of the prevalence of osteolysis and the elimination of osteolysis from the zones remote from the joint space by the use of a circumferential plasma-spray porous coating indicates that the femur was effectively sealed off from the joint space. We believe that the durability and longevity of the femoral component should be enhanced by the use of such a coating.

Coated Materials, Biocompatible↗

PubMed2006

Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice.

The deposition of the amyloid beta-protein (Abeta) is a hallmark of Alzheimer's disease (AD). One reason for Abeta-accumulation and deposition in the brain may be an altered drainage along perivascular channels. Extracellular fluid is drained from the brain towards the cervical lymph nodes via perivascular channels. The perivascular space around cerebral arteries is the morphological correlative of these drainage channels. Here, we show that Abeta is immunohistochemically detectable within the perivascular space of 25 months old wild-type and amyloid precursor protein (APP)-transgenic mice harboring the Swedish double mutation driven by a neuron specific promoter. Only small amounts of Abeta can be detected immunohistochemically in the perivascular space of wild-type mice. Cerebrovascular and parenchymal Abeta-deposits were absent. In APP-transgenic mice, large amounts of Abeta were found in the perivascular drainage channels accompanied with cerebrovascular and parenchymal Abeta-deposition. The apolipoprotein E (apoE) immunostaining within the perivascular channels did not vary between wild-type and APP-transgenic mice. Almost 100% of the area that represents the perivascular space was stained with an antibody directed against apoE. Here, Abeta co-localized with apoE indicating an involvement of apoE in the perivascular clearance of Abeta. Fibrillar congophilic amyloid was not seen in wild-type mice. In APP-transgenic animals, congophilic fibrillar amyloid material was seen in the wall of cerebral blood vessels but not in the perivascular space. In conclusion, our results suggest that non-fibrillar forms of Abeta are drained along perivascular channels and that apoE is presumably involved in this clearance mechanism. Overloading such a clearance mechanism in APP-transgenic mice appears to result in insufficient Abeta-clearance, increased Abeta-levels in the brain and the perivascular drainage channels, and finally in Abeta-deposition. In so doing, our results strengthen the hypothesis that an alteration of perivascular drainage supports Abeta-deposition and the development of AD.

Aging↗

PubMed1995

Stimulus-driven or autonomous shift or attention?

Hsieh and Allport studied shifts of attention in semantic space, using a semantic monitoring task based on rapid, serial, visually presented sequences of words. They reported that following a shift of criterion, accuracy of semantic monitoring dropped abruptly to a low level, then gradually recovered to reach the preshift level over successive stimuli in the sequence. They further examined the nature of the recovery of accuracy following a shift of criterion. Despite the striking results they obtained, some problems of their design remained. Hence, the current research replicated Hsieh and Allport's experiments with some modifications and showed that a shift of semantic criterion in a rapidly presented sequence indeed appears to be stimulus-driven rather than an autonomous process.

Adult↗

PubMed1992

Conformational analysis of beta-D-fructofuranosyl-(2-->6)-beta-D-glucopyranoside by molecular mechanics (MM2) calculations.

Conformational energies for models of the disaccharide beta-D-fructofuranosyl-(2-->6)-beta-D-glucopyranoside were computed by molecular mechanics using MM2(87). An initial investigation of staggered forms examined the linkage bonds characterized by the torsion angles phi, psi, and omega, and subsequently the fructose hydroxymethyl side groups, characterized by the torsion angles chi-1 and chi-6. Then, in our major search of conformational space, the torsion angles of two linkage bonds, phi and omega, were driven through 360 degrees in 20 degree increments at all staggered side group combinations. From these results, the low-energy forms were minimized without the driver restrictions to generate the global minimum structure found and herein reported. This conformer was then used to map the conformational space of phi and omega by driving only those torsion angles through 360 degrees. Both the 4(3)T (northern) conformer (Cremer-Pople puckering phase angle of phi 2 = 265 degrees) and the 3(4)T, (southern) conformer (phi 2 = 80 degrees) of the fructofuranose ring were tested for comparison, and both were shown to be significant contributors of populated forms. As these two conformers had different minima for a number of important torsion angles, experimental studies may reveal different properties than those expected solely from the preferred northern conformer.

Carbohydrate Conformation↗

PubMed2003

Role of aquaporin and sodium channel in pleural water movement.

The role of the ENaC sodium channel and aquaporin-1 (AQP1) water channel on pleural fluid dynamics in mice was investigated. 0.25 ml of hypertonic or isosmolar fluid was infused into the pleural space in anesthetized wildtype and AQP1 null mice. Pleural fluid was sampled at specified times to quantify the osmolality and volume. The sodium channel activator terbutaline increased isosmolar fluid clearance by 90% while the sodium channel inhibitor amiloride decreased it by 15%, but had no effect on osmotically driven water transport. AQP1 deletion significantly decreased osmotic water transport in pleural space by twofold, but it had no effect on isosmolar fluid clearance. Pretreatment with dexamethasone increased pleural osmotic fluid entry by 25%, while intravenous injection of HgCl2 decreased osmotic pleural water movement by 43%. These results provided evidence for a role of a sodium channel in pleural fluid absorption; AQP1 plays a major role in osmotic liquid transport but it does not affect isosmolar fluid clearance.

Amiloride↗