bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular Effects of Deep Brain Stimulation: Model-Based Analysis of Activation and Inhibition
Authors: McIntyre Cameron C. , Grill Warren M. , Sherman David L. , Thakor Nitish V.
Published: March 2004

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.
Haptic Synthesis of Shapes and Sequences
Authors: Henriques Denise Y. P. , Flanders Martha , Soechting John F.
Published: March 2004

Haptic perception of shape is based on kinesthetic and tactile information synthesized across space and time. We studied this process by having subjects move along the edges of multisided shapes and then remember and reproduce the shapes. With eyes closed, subjects moved a robot manipulandum whose force field was programmed to simulate a quadrilateral boundary in a horizontal plane. When subjects then reproduced the quadrilateral using the same manipulandum, with eyes still closed but now with the force field set to zero, they made consistent errors, overestimating the lengths of short segments and underestimating long ones, as well as overestimating acute angles and underestimating obtuse ones. Consequently their reproductions were more regular than the shapes they had experienced. When subjects felt the same quadrilaterals with the same manipulandum but drew them on a vertical screen with visual feedback, they made similar errors, indicating that their distortions reflected mainly perceptual rather than motor processes. In a third experiment, subjects explored the 3 sides of an open shape in a fixed order. The results revealed a temporal pattern of interactions, where the lengths and angles of previously explored segments influenced the drawing of later segments. In all tasks, our subjects were as accurate as subjects in earlier studies who haptically explored only single lines or angles, suggesting that the mental processes that synthesize haptic data from multiple segments into complete shapes do not introduce any net error.
Distinct Intracellular Calcium Profiles Following Influx Through N- Versus L-Type Calcium Channels: Role of Ca2+-Induced Ca2+Release
Authors: Tully Keith , Treistman Steven N.
Published: March 2004

Selective activation of neuronal functions by Ca2+is determined by the kinetic profile of the intracellular calcium ([Ca2+]i) signal in addition to its amplitude. Concurrent electrophysiology and ratiometric calcium imaging were used to measure transmembrane Ca2+current and the resulting rise and decay of [Ca2+]iin differentiated pheochromocytoma (PC12) cells. We show that equal amounts of Ca2+entering through N-type and L-type voltage-gated Ca2+channels result in significantly different [Ca2+]itemporal profiles. When the contribution of N-type channels was reduced by ω-conotoxin MVIIA treatment, a faster [Ca2+]idecay was observed. Conversely, when the contribution of L-type channels was reduced by nifedipine treatment, [Ca2+]idecay was slower. Potentiating L-type current with BayK8644, or inactivating N-type channels by shifting the holding potential to −40 mV, both resulted in a more rapid decay of [Ca2+]i. Channel-specific differences in [Ca2+]idecay rates were abolished by depleting intracellular Ca2+stores with thapsigargin or by blocking ryanodine receptors with ryanodine, suggesting the involvement of Ca2+-induced Ca2+release (CICR). Further support for involvement of CICR is provided by the demonstration that caffeine slowed [Ca2+]idecay while ryanodine at high concentrations increased the rate of [Ca2+]idecay. We conclude that Ca2+entering through N-type channels is amplified by ryanodine receptor mediated CICR. Channel-specific activation of CICR provides a mechanism whereby the kinetics of intracellular Ca2+leaves a fingerprint of the route of entry, potentially encoding the selective activation of a subset of Ca2+-sensitive processes within the neuron.
Changes in the Readily Releasable Pool of Transmitter and in Efficacy of Release Induced by High-Frequency Firing at Aplysia Sensorimotor Synapses in Culture
Authors: Zhao Yali , Klein Marc
Published: March 2004

Synaptic transmission at the sensory neuron-motor neuron synapses of Aplysia, like transmission at many synapses of both vertebrates and invertebrates, is increased after a short burst of high-frequency stimulation (HFS), a phenomenon known as posttetanic potentiation (PTP). PTP is generally attributable to an increase in transmitter release from presynaptic neurons. We investigated whether changes in the readily releasable pool of transmitter (RRP) contribute to the potentiation that follows HFS. We compared the changes in excitatory postsynaptic potentials (EPSPs) evoked with action potentials to changes in the RRP as estimated from the asynchronous transmitter release elicited by a hypertonic solution. The changes in the EPSP were correlated with changes in the RRP, but the changes matched quantitatively only at connections whose initial synaptic strength was greater than the median for all experiments. At weaker connections, the increase in the RRP was insufficient to account for PTP. Weaker connections initially released a smaller fraction of the RRP with each EPSP than stronger ones, and this fraction increased at weaker connections after HFS. Moreover, the initial transmitter release in response to the hypertonic solution was accelerated after HFS, indicating that the increase in the efficacy of release was not restricted to excitation-secretion coupling. Modulation of the RRP and of the efficacy of release thus both contribute to the enhancement of transmitter release by HFS.
Tone-Evoked Excitatory and Inhibitory Synaptic Conductances of Primary Auditory Cortex Neurons
Authors: Tan Andrew Y. Y. , Zhang Li I. , Merzenich Michael M. , Schreiner Christoph E.
Published: March 2004

In primary auditory cortex (AI) neurons, tones typically evoke a brief depolarization, which can lead to spiking, followed by a long-lasting hyperpolarization. The extent to which the hyperpolarization is due to synaptic inhibition has remained unclear. Here we report in vivo whole cell voltage-clamp measurements of tone-evoked excitatory and inhibitory synaptic conductances of AI neurons of the pentobarbital-anesthetized rat. Tones evoke an increase of excitatory synaptic conductance, followed by an increase of inhibitory synaptic conductance. The synaptic conductances can account for the gross time course of the typical membrane potential response. Synaptic excitation and inhibition have the same frequency tuning. As tone intensity increases, the amplitudes of synaptic excitation and inhibition increase, and the latency of synaptic excitation decreases. Our data indicate that the interaction of synaptic excitation and inhibition shapes the time course and frequency tuning of the spike responses of AI neurons.
Developmental Changes in Pedunculopontine Nucleus (PPN) Neurons
Authors: Kobayashi T. , Good C. , Biedermann J. , Barnes C. , Skinner R. D. , Garcia-Rill E.
Published: March 2004

The developmental decrease in rapid-eye-movement (REM) sleep in man occurs between birth and after puberty. We hypothesize that if this decrease in REM sleep does not occur, lifelong increases in REM sleep drive may ensue. Such disorders are characterized by hypervigilance and sensory-gating deficits, such as are present in postpubertal onset disorders like schizophrenia, panic attacks (a form of anxiety disorder), and depression. The decrease in REM sleep in the rat occurs between 10 and 30 days of age. We studied changes in size and physiological properties of pedunculopontine nucleus (PPN) cells involved in the control of arousal, i.e., waking and REM sleep. During the largest decrease in REM sleep (12–21 days), cholinergic PPN neurons doubled in cell area, the hypertrophy peaking at 15–16 days, then decreasing in area by 20–21 days. Noncholinergic PPN cells did not change in area during this period. We confirmed the presence of two populations of PPN neurons based on action potential (AP) duration, with the proportion of short-AP-duration cells increasing and long AP duration decreasing between 12 and 21 days. Most cholinergic and noncholinergic cells had short AP durations. Afterhyperpolarization (AHP) duration became segregated into long and short AHP duration after 15 days. Cells with short AP duration also had short AHP duration. The proportion of PPN cells with Ih current increased gradually, peaking at 15 days, then decreased by 21 days. These changes in morphological and physiological properties are discussed in relation to the developmental decrease in REM sleep.
Photolysis of Postsynaptic Caged Ca2+Can Potentiate and Depress Mossy Fiber Synaptic Responses in Rat Hippocampal CA3 Pyramidal Neurons
Authors: Wang Jun , Yeckel Mark F. , Johnston Daniel , Zucker Robert S.
Published: March 2004

The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+([Ca2+]i). Ca2+is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+compounds to test whether a postsynaptic rise in [Ca2+]iis sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]ito approximately 1 μm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+buffer capacity than CA1 neurons, limiting the rise in [Ca2+]iachievable by photolysis. This [Ca2+]irise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.
Presynaptic Inactivation of Action Potentials and Postsynaptic Inhibition of GABAA Currents Contribute to KA-Induced Disinhibition in CA1 Pyramidal Neurons
Authors: Kang Ning , Jiang Li , He Wei , Xu Jun , Nedergaard Maiken , Kang Jian
Published: March 2004

Kainate-type glutamate ionotropic receptors (KAR) mediate either depression or potentiation of inhibitory transmission. The mechanisms underlying the depressant effect of KAR agonists have been controversial. Under dual patch-clamp recording techniques in synaptically coupled pairs of CA1 interneurons and pyramidal neurons in hippocampal slices, micromolar concentrations of KAR agonists, kainic acid (KA, 10 μM) and ATPA (10 μM), induced inactivation of action potentials (APs) in 58 and 50% of presynaptic interneurons, respectively. Inactivation of interneuronal APs might have significantly contributed to KA-induced decreases in evoked inhibitory postsynaptic currents (eIPSCs) that are obtained by stimulating the stratum radiatum. With controlled interneuronal APs, KAR agonists induced a decrease in the potency (mean amplitude of successful events) and mean amplitude (including failures) of unitary inhibitory postsynaptic currents (uIPSCs) without significantly changing the success rate (Ps) at perisomatic high-Ps synapses. In contrast, KAR agonists induced a decrease in both the Ps and potency of uIPSCs at dendritic high-Ps synapses. KAR agonists induced an inhibition of GABAA currents by activating postsynaptic KARs in pyramidal neurons; this was more prominent at dendrites than at soma. Both the exogenous GABA-induced current and the amplitude of miniature IPSCs (mIPSCs) were attenuated by KAR agonists. Thus the postsynaptic KAR-mediated inhibition of GABAA currents may contribute to the KAR agonist-induced decrease in the potency of uIPSCs and KA-induced disinhibition.
Signals From Load Sensors Underlie Interjoint Coordination During Stepping Movements of the Stick Insect Leg
Authors: Akay Turgay , Haehn Sebastian , Schmitz Josef , Büschges Ansgar
Published: March 2004

During stance and swing phase of a walking stick insect, the retractor coxae (RetCx) and protractor coxae (ProCx) motoneurons and muscles supplying the thorax-coxa (TC)-joint generate backward and forward movements of the leg. Their activity is tightly coupled to the movement of the more distal leg segments, i.e., femur, tibia, and tarsus. We used the single middle leg preparation to study how this coupling is generated. With only the distal leg segments of the middle leg being free to move, motoneuronal activity of the de-afferented and -efferented TC-joint is similarly coupled to leg stepping. RetCx motoneurons are active during stance and ProCx motoneurons during swing. We studied whether sensory signals are involved in this coordination of TC-joint motoneuronal activity. Ablation of the load measuring campaniform sensilla (CS) revealed that they substantially contribute to the coupling of TC-joint motoneuronal activity to leg stepping. Individually ablating trochanteral and femoral CS revealed the trochanteral CS to be necessary for establishing the coupling between leg stepping and coxal motoneuron activity. When the locomotor system was active and generated alternating bursts of activity in ProCx and RetCx motoneurons, stimulation of the CS by rearward bending of the femur in otherwise de-afferented mesothoracic ganglion terminated ongoing ProCx motoneuronal activity and initiated RetCx motoneuronal activity. We show that cuticular strain signals from the trochanteral CS play a major role in shaping TC-joint motoneuronal activity during walking and contribute to their coordination with the stepping pattern of the distal leg joints. We present a model for the sensory control of timing of motoneuronal activity in walking movements of the single middle leg.
DNA microarray analysis of vitamin D-induced gene expression in a human colon carcinoma cell line
Authors: Wood Richard J. , Tchack Laurie , Angelo Giana , Pratt Richard E. , Sonna Larry A.
Published: March 2004

The full extent to which 1,25-dihydroxyvitamin D3 affects gene expression in human intestinal epithelial cells is unknown. We used oligonucleotide arrays to catalog vitamin D-induced changes in gene expression in Caco-2 cells, a human colon carcinoma cell line. Five paired sets of Caco-2 cell cultures were subjected to either control conditions or 1,25-dihydroxyvitamin D (10−7 mol/l × 24 h), and RNA was analyzed on an Affymetrix cDNA array containing 12,625 human sequences. Only 13 sequences representing 12 distinct genes exhibited statistically significant changes in expression of twofold or greater and were also called as “present” or “marginal” by the array-reading software in all five experiments. Genes regulated by 1,25-dihydroxyvitamin D included two previously known genes (25-hydroxyvitamin D-24-hydroxylase and amphiregulin) and 10 genes (sorcin, Gem, adaptin-γ, TIG1, CEACAM6, carbonic anhydrase XII, junB, ceruloplasmin, and two unidentified sequences) that were novel. We tested and independently confirmed the effect of 1,25-dihydroxyvitamin D on 11 of these genes by RT-PCR. Increased protein expression was tested and confirmed in two of the novel 1,25-dihydroxyvitamin D-regulated genes, ceruloplasmin and sorcin. The known function of these genes suggests that many of them could be involved in the antiproliferative effects of 1,25-dihydroxyvitamin D3.
Genetic analysis of blood pressure in C3H/HeJ and SWR/J mice
Authors: DiPetrillo Keith , Tsaih Shirng-Wern , Sheehan Susan , Johns Conrado , Kelmenson Peter , Gavras Haralambos , Churchill Gary A. , Paigen Beverly
Published: March 2004

Hypertension is a complex phenotype induced by multiple environmental and genetic factors. Quantitative trait locus (QTL) analysis is a powerful method for identifying genomic regions underlying complex diseases. We conducted a QTL analysis of blood pressure in mice using 217 F2progeny (males and females) from a cross between the normotensive C3H/HeJ and hypertensive SWR/J inbred strains. Our analysis identified significant QTL controlling blood pressure on chromosome 1 [Chr 1; Bpq8; peak 78 cM; 95% confidence interval 64–106 cM; logarithm of the odds ratio (LOD) 3.5; peak marker D1Mit105] and on Chr 16 ( Bpq9; peak 56 cM; 95% confidence interval 46–58 cM; LOD 3.6; peak marker D16Mit158). Bpq8 was previously identified in a cross between C57BL/6J and A/J mice, and we narrowed this QTL from 42 to 18 cM (95% confidence interval 68–86 cM) by combining the data from these crosses. By examining Bpq8 for regions where ancestral alleles were conserved among the high allele strains (C57BL/6J, SWR/J) and different from the low allele strains (A/J, C3H/HeJ), we identified a 2.3-cM region where the high allele strains shared a common haplotype. Bpq8 is concordant with known QTL in both rat and human, suggesting that the causal gene underlying Bpq8 may be conserved as a disease gene in human hypertension.
Concentration of Carbon Dioxide in Exhaled Air in Fluent and Non-Fluent Speech
Authors: Raczek Barbara , Adamczyk Bogdan
Published: March 2004

The results of dynamic measurements of carbon dioxide (CO2, in %) in exhaled air during speech are presented. Fourteen stuttering persons and 14 persons with fluent speech took part in a test that involved independent speaking and echo-assisted speaking (delayed auditory feedback). A statistical comparative analysis of average levels of CO2 concentration registered during speech and resting respiration immediately before speaking indicated significant differences in non-fluent speech and insignificant differences in fluent speech. It was determined that the average concentration of CO2 in exhaled air while stuttering was 1/5 lower than the concentration of CO2 registered during fluent speaking.
Voice and Resonance Disorders in Genetic Syndromes: A Meta-Analysis
Authors: van Borsel John
Published: March 2004

It is well known that many genetic syndromes are associated with communication disorders and especially with disorders of voice and resonance. This paper reports the results of a meta-analysis with the aim of documenting the occurrence of voice and resonance disorders in genetic syndromes. The analysis studied the occurrence of voice and resonance disorders in general, the occurrence in different etiological subtypes of syndromes and the association with other disorders, in particular clefting, a cognitive impairment and hearing problems. The database for the analysis was a list by Sphrintzen of 299 different syndromes all of which have been reported to entail communication disorders. Major findings are that disorders of voice and resonance in genetic syndromes are only rarely isolated problems, that causal mechanisms are not a major factor in determining the presence of voice and resonance disorders and, foremost, that voice and resonance disorders in genetic syndromes constitute an underresearched area.
Acoustic Investigation of Vocal Quality following Treatment for Childhood Cerebellar Tumour
Authors: Cornwell Petrea L. , Murdoch Bruce E. , Ward Elizabeth C. , Kellie Stewart
Published: March 2004

The aim of the study was firstly to document the acoustic parameters of voice using the Multidimensional Voice Program (MDVP, Kay Elemetrics) in a group of children with dysarthria subsequent to treatment for cerebellar tumour (CT). Then, secondly, compare the acoustic findings to perceptual voice characteristics as described by the GIRBAS (grade, instability, roughness, breathiness, asthenicity, strain). The assessments were performed on 29 voice samples; 9 cerebellar tumour participants with dysarthria, and 20 control participants. None of the control voices were rated as exhibiting any of the six parameters described by the GIRBAS, while 7 of the CT participants were noted to have at least a mild voice disorder. Roughness, instability, breathiness and asthenicity were all identified as voice characteristics in the CT voice samples. Acoustically, the CT voice samples differed significantly from the controls’ voices on frequency and amplitude perturbation measures. Our findings confirmed voice dysfunction as a component of dysarthria in children treated for cerebellar tumour, and discussed the links between acoustic and perceptual descriptions.
Language Development in Very Low Birth Weight Preterm Children: A Follow-Up Study
Authors: Jansson-Verkasalo E. , Valkama M. , Vainionpää L. , Pääkkö E. , Ilkko E. , Lehtihalmes M.
Published: March 2004

The language development of 17 very low birth weight (VLBW) preterm children was compared with that of matched controls at the ages of 2 and 4 years. At the age of 2 years, the VLBW preterm children achieved significantly lower scores in the language comprehension test than their matched controls. In addition, they used shorter and more immature sentences. At the age of 4 years, difficulties in the VLBW preterm children manifested as deficiencies in language comprehension, naming and auditory discrimination. The language test results at the age of 2 years significantly correlated with those at the age of 4 years, but mainly in the preterm group. The highest and most frequent correlations were found between the language test scores at 2 years and the auditory discrimination test scores at 4 years. The only significant correlation to be found in the control group was between the vocabulary test score at 2 years and the consonant discrimination test score at 4 years. Therefore, language development of the VLBW preterm children should be measured and monitored from toddler age onwards. Special attention should be paid to measurements of auditory processing. While the results of the present study, however, represent mainly the outcome in a group of VLBW preterm children with changes in the neonatal MRI, the results should not be generalized to all VLBW preterm children.
Training Outcome in Future Professional Voice Users after 18 Months of Voice Training
Authors: Timmermans Bernadette , De Bodt Marc S. , Wuyts Floris L. , Van de Heyning Paul H.
Published: March 2004

The goal of this study is to define the long-term influence of vocal hygiene education and the effectiveness of voice training in 46 students. Half of the subjects, called the trained group (n = 23), received vocal hygiene education during 1 school year and voice training during 2 school years (18 months). The other half, also 23 subjects, received neither vocal hygiene education nor voice training as such (called the untrained group). The voice training is made up of technical workshops (30 h a year in groups of 5–8 subjects) and vocal coaching in the radio and drama projects (30 h whole class). In the lectures (30 h) a theoretical background on breathing, articulation, voicing and vocal hygiene was discussed. A multidimensional test battery containing the GRBAS scale, videolaryngostroboscopy, maximum phonation time, jitter, lowest intensity, highest frequency, Dysphonia Severity Index (DSI) and Voice Handicap Index (VHI) was applied before and after 18 months to evaluate the effect of voice training over time. A questionnaire on daily habits was presented before the lectures, and after 18 months to detect the long-term effect of the lectures. The objectively measured voice quality (DSI) of the trained group improved significantly over time (p < 0.001) due to training (p = 0.008), which was not the case in the untrained group. The self-assessed VHI, on the other hand, changed over time (p < 0.001) in both groups. For the trained group the VHI changed from 18.4 to 14.4 and in the untrained group from 20.1 to 15.3. It is important to note that the VHI scores of both groups remained high. The interpretation of the results of the daily habit questionnaire is disturbing: the initial high degree of smoking, vocal abuse, stress and late meals was not influenced by the lectures or training and remained high. This study proves the positive outcome and emphasizes the need for a well-organized voice training program in future professional voice users. However, the lectures and training on vocal hygiene failed to improve voice-conserving habits.
Bursting Oscillations in Two Coupled FitzHugh-Nagumo Systems
Authors: Doss-Bachelet Catherine , Françoise Jean-Pierre , Piquet Claude
Published: March 2004

The purpose of this short article is to show that bursting oscillations occur naturally in two coupled FitzHugh-Nagumo systems. As far as we know, this has not been observed previously. We gradually came to this conclusion after a discussion (reproduced herein) of known examples where these oscillations have been described in biological systems. Bursting activity typically is the result of the interaction of a fast excitatory subsystem and a slow subsystem. We consider here three different time scales. The fast excitatory subsystem is itself a ‘fast-slow dynamics. The special pattern of the bursting oscillations obtained (appearance of a transitory bump between the spiking phase and the silent phases) is discussed in the framework of qualitative plane analysis and geometric singular perturbation theory.
Episodic Learning: Towards the Emergences of Partial Cooperation
Authors: Bergman Aviv , Tennenholtz Moshe
Published: March 2004

We introduce and apply a new learning mechanism, episodic learning. This learning paradigm is shown to be tightly linked to a natural form of reinforcement learning. Surprisingly, though the defect action in the ‘Prisoners Dilemma setting is a dominant strategy (and the only evolutionary stable strategy), when using episodic learning partial cooperation is obtained, which is stable against invasion of individuals with defection as their most frequent action. We further show the emergence of partial cooperation (‘altruism), in the context of the ‘Centipede game. Our results are consistent with the experimental data about partial cooperation obtained by cognitive psychologists.
Toward a Systemic Approach to Disease
Authors: Thurler G. , Bréant C. , Lehner B. , Bunge M. , Samii K. , Hochstrasser D. , Nendaz M. , Gaspoz J.-M. , Tahintzi P. , Borst F.
Published: March 2004

The categorization of biological states into healthy and sick, normal and abnormal, is central to medicine. It is therefore of fundamental consequence to know on what this dichotomy is based. A way of approaching this question is to adopt the systemic approach which would make it possible to clear up the concept of disease. The introduced notions are illustrated with a very simple example. Considering the blood system, we have defined an ‘ideal pattern characterizing the iron deficiency anemia. This pattern was tested on a collective of patients composed of all the female patients hospitalized in two medical clinics during the year 2000 at the University Hospital of Geneva.
Graphic Requirements for Multistationarity
Authors: Soulé Christophe
Published: March 2004

We discuss properties which must be satisfied by a genetic network in order for it to allow differentiation. These conditions are expressed as follows in mathematical terms. Let F be a differentiable mapping from a finite dimensional real vector space to itself. The signs of the entries of the Jacobian matrix of F at a given point a define an interaction graph, i.e. a finite oriented finite graph G(a) where each edge is equipped with a sign. René Thomas conjectured 20 years ago that if F has at least two nondegenerate zeroes, there exists a such that G(a) contains a positive circuit. Different authors proved this in special cases, and we give here a general proof of the conjecture. In particular, in this way we get a necessary condition for genetic networks to lead to multistationarity, and therefore to differentiation. We use for our proof the mathematical literature on global univalence, and we show how to derive from it several variants of Thomas rule, some of which had been anticipated by Kaufman and Thomas.
Telomeres and Telomerase Activity Are Regulated as a Complex System in Cultured Hepatoma Cells
Authors: Deschatrette J. , Lauga J. , Maigné J. , Wolfrom C.
Published: March 2004

Non-linear dynamics, often chaotic, are now accepted as the normal way in which major physiological functions proceed, allowing adaptation. The length of telomeres, the chromosome endings, is critical in limiting cell lifespan and in controlling subsets of downstream genes. Telomere length dynamics in tumoral cells is the net result of mitotic erosion of telomeric DNA and telomere repair by the enzyme telomerase. We observed telomere length oscillations in the long-lived hepatoma Fao cell line, for forty three 6-day passages in culture. Telomerase activity oscillated with similar frequency and opposite amplitude. We mapped the combined data of telomere erosion and telomerase activity. There was reverse symmetry between consecutive periods of 10 passages. Thus, telomere length and telomerase activity can be considered to be a single complex system with strong reciprocal regulation.
Resilience of Cholesterol Concentration to a Wide Range of Mutations in the Cell
Authors: Ratushny A.V. , Likhoshvai V.A. , Ignatieva E.V. , Goryanin I.I. , Kolchanov N.A.
Published: March 2004

The study of normal and pathological states of the gene network regulating cholesterol biosynthesis in the cell is a topical problem. Impairments of this system play a key role in the development of hypercholesterolemia and atherosclerosis of humans and various animals. Knowledge of the behavior of this system under various conditions is necessary to develop optimal strategies for correcting various pathologies while taking into account the genotype-specific distinctions of individuals and the targets for pharmacological regulation. The model simulating cholesterol biosynthesis in the cell and its exchange with blood plasma cholesterol developed earlier using a generalized chemical kinetic approach was used for the analysis of a mutational portrait of this system. The sensitivity of the stationary content of free cholesterol to mutational changes in the rates of molecular processes running within the gene network was analyzed. The resilience of the free cholesterol concentration to a wide range of mutations in the gene network was demonstrated. In addition, it was shown that the mutations hitting regulatory processes changed the stationary content of free cholesterol to the largest degree.
The Zebrafish as a Model Organism for Eye Development
Authors: Glass Anne S. , Dahm Ralf
Published: March 2004

In recent years, the zebrafish has become a favourite model organism for biologists studying developmental processes in vertebrates. Its rapid embryonic development, the transparency of its embryos, the large number of offspring together with several other advantages make it ideal for discovering and understanding the genes that regulate embryonic development as well as the physiology of the adult organism. Zebrafish are very visually orientated, and their retina and lens show much the same morphology as other vertebrates including humans. For this reason, they are well suited for examining ocular development, function and disease. This review describes the advantages of the zebrafish as a model organism as well as giving an overview of eye development in this species. It has a particular focus on morphological as well as molecular aspects of the development of the lens.
A New Model for Assessing Proteolysis in the Intact Mouse Lens in Organ Culture
Authors: Petersen A. , Zetterberg M. , Sjöstrand J. , Karlsson J.-O.
Published: March 2004

Purpose: To develop a new method to investigate proteolysis in the intact lens in organ culture. Methods: Intact mouse lenses were assayed at regular intervals for proteolytic activity using fluorogenic peptide substrates ± addition of ionomycin. Specific inhibitors were used to determine the activity of calpains, the proteasome and acid lysosomal enzymes. Results: Significant levels of proteolytic activity were present in the intact lens. Proteolysis was stimulated by ionomycin. Preincubation with an inhibitor to the proteasome significantly decreased proteolysis whereas inhibitors of calpain and acid lysosomal enzymes did not. Conclusion: This study indicates that in the intact mouse lens in culture, the proteasome is an important protease. Its activity is at least partially regulated by calcium.
Survival of Subretinal Pancreatic Islet Cell Allografts and Apoptosis in Infiltrating Lymphocytes in Rats
Authors: Inoue Makoto , Maeno Takatoshi , Miki Daijiro , Embabi Sherif , Hatchell Diane L.
Published: March 2004

Survival of pancreatic islet cells transplanted into the subretinal space in rat eyes was studied in relation with apoptosis of infiltrating lymphocytes. Islets isolated from inbred DA rats were transplanted into the subretinal space of fully MHC-mismatched Lewis rats. Syngeneic subretinal transplants and allogeneic subretinal transplants from Sprague-Dawley (SD) rats were performed as controls. From 7 to 60 days after transplantation, immunoperoxidase staining for insulin, glucagon, CD4, CD8, and interleukin (IL)-2, and evaluation of apoptosis using nick-end labeling (TUNEL) were performed. Fully MHC-mismatched grafts were rejected by day 14, showing massive infiltration by CD4+, CD8+, and IL-2+ lymphocytes. Syngeneic transplants and allografts in SD rats survived up to 60 days without appreciable lymphocytic infiltration. Endocrine cells were the major component of surviving transplanted tissue. No difference in distribution of TUNEL+ cells was seen between syngeneic transplants and subretinal allografts in SD rats on day 60. A few TUNEL+ CD8+ lymphocytes were found in rejected MHC-mismatched transplants, but apoptotic lymphocytes were not seen in surviving or syngeneic grafts. Pancreatic islet survival in the subretinal space is MHC dependent. Accumulation of infiltrating lymphocytes may be suppressed by a modified immune response.
Ascorbic Acid as a Free Radical Scavenger in Porcine and Bovine Aqueous Humour
Authors: Erb Carl , Nau-Staudt Kerstin , Flammer Josef , Nau Werner
Published: March 2004

Aim: To study the antioxidant activity, UV absorption, concentration and stability of ascorbic acid (AA) in porcine and bovine aqueous humour (AH). Methods: Porcine and bovine AH was taken within 5 min after death and frozen at –70°C. The characteristic UV absorption band of AA and the concentration of AA in AH was determined by UV spectrophotometry. The antioxidant activity of AA to serve as a free radical scavenger in AH has been determined by using a novel fluorescent probe for antioxidants, the azoalkane 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO). The fluorescence lifetime and intensity of this probe reflect the concentration of dissolved antioxidants. The time-resolved fluorescence of DBO (laser excitation at 351 nm) in AH and in a neutral phosphate-buffered saline (PBS) solution containing only the natural amount of AA as an additive were measured. Results: The characteristic UV absorption band of AA has its maximum at 266 nm in AH. The concentration of AA in porcine and bovine AH was found to be 0.547 ± 0.044 and 1.09 ± 0.16 mM, respectively, by spectrophotometry. The fluorescence lifetime of the probe DBO was reduced from 320 ± 5 ns in pure aerated PBS to 205 ± 5 ns in porcine AH and 165 ± 3 ns in bovine AH. A detailed kinetic analysis of the lifetime shortening suggests that AA contributes approximately 75 and 85% to the antioxidant activity of porcine and bovine AH, respectively. Conclusions: Our experiments suggest that AA is the major contributor to the antioxidant activity of porcine and bovine AH. The role of AA to serve as an antioxidant in AH is discussed. In addition, UV spectrophotometry is established as an alternative method to determine the concentration of AA in AH.
A Novel Homozygous Gly107Arg Mutation in the RDH5 Gene in a Japanese Patient with Fundus albipunctatus with Sectorial Retinitis pigmentosa
Authors: Sato Masaki , Oshika Tetsuro , Kaji Yuuichi , Nose Harumi
Published: March 2004

We examined the RDH5 gene for mutations in two unrelated Japanese families with fundus albipunctatus. Each proband with fundus albipunctatus in two families (family A’s case was atypical with sectorial retinitis pigmentosa, while family B’s case was typical), and 2 obligate carriers underwent molecular analysis of their RDH5 gene. DNA was amplified for all coding exons of the RDH5 gene with established primer pairs, and sequenced directly. Each family had a different mutation in the RDH5 gene. Family A had a homozygous mutation (Gly107Arg) while family B had a compound heterozygous mutation (Arg280His and Leu310GluVal). The obligate carriers were heterozygous with the wild-type and mutant-type alleles. The homozygous Gly107Arg mutation in the RDH5 gene described in this paper has not previously been described, though compound heterozygous mutations (Gly107Arg and Leu310GluVal) in the RDH5 gene have previously been reported.
Eye Lens Crystallins: A Component of Intraocular Pseudoexfoliative Material
Authors: Veromann Siiri , Sünter Alar , Juronen Erkki , Tasa Gunnar , Panov Aleksei
Published: March 2004

Feeding experimental animals (19 pigs) with surplus sucrose and salt (NaCl) caused cataractous changes in lens tissue and triggered the formation of pseudoexfoliative material on the lens capsule. In the control animals (15 pigs) pseudoexfoliative material was absent. The avidin-biotin complex immunohistochemical method was applied to the pseudoexfoliative material obtained from 15 porcine experimental precataractous lenses and 1 spontaneously cataractous eye and revealed crystallins as a component of the intraocular pseudoexfoliative material. To prevent the development of both intraocular pseudoexfoliative material and crystallin-dependent glaucomatous changes in the trabecular meshwork of the eye, it is important to avoid any cataractogenic insult, including surplus sucrose and salt consumption, causing crystallin leakage from the lens.
Modified High-Performance Liquid Chromatography Technique for Detection of Vancomycin in Human Vitreous
Authors: Raju Biju , Thiagarajan Geetha , Das Taraprasad
Published: March 2004

Purpose: To standardize the technique and methodology for estimating the level of vancomycin in human vitreous using a modified high-performance liquid chromatographic method. Methods: Sample preparation involved spiking the vitreous with known quantities of the drug followed by a brief treatment with 30% trichloroacetic acid. Samples were analyzed on a C18 reverse-phase column using a mobile phase of 50 mM phosphate buffer (pH 4.0) and 10% acetonitrile. Results: Vancomycin was detected at 198 nm. It showed a retention time of 2.2 min in the vitreous. A linear increase in the area under the peak corresponding to the drug was observed with increase in concentration of vancomycin in the vitreous. The method was applied to detect the vancomycin levels in vitreous of 5 patients with exogenous endophthalmitis, 24–48 h after intravitreal injection of vancomycin 1 mg/0.1 ml. The mean concentration of vancomycin in these samples was 120.022 ± 59.87 µg/ml (43.859–179.09 µg/ml). The present technique allowed a quantification limit of 1 µg/ml. Conclusion: This technique is suitable to estimate vancomycin levels in human vitreous in a variety of clinical and experimental studies. It has the added advantages of being less expensive, simple and rapid.
Quantitative Determination of Histamine in Tears during Conjunctivitis by a Novel HPLC Method
Authors: Venza Isabella , Visalli Maria , Ceci Guglielmo , Teti Diana
Published: March 2004

The histamine content of tears of healthy sex- and age-matched subjects and patients affected by allergic or nonallergic inflammatory ocular diseases was determined through a new competitive reverse-phase high-performance liquid chromatography (HPLC) method. Tear samples from 50 healthy subjects, 30 patients affected by seasonal allergic conjunctivitis, 12 patients with bacterial conjunctivitis associated with Haemophilus influenzae and 8 patients with bacterial conjunctivitis associated with Streptococcus pneumoniae were analyzed for histamine concentration by o-phthaldialdehyde precolumn derivatization-based HPLC. In physiological conditions, the tear histamine content was low (2.26 ng/ml) and did not vary in relation to age and sex. Histamine levels were significantly higher in all the patients studied, to a greater extent in those affected by allergic (23.61 ng/ml) or Haemophilus influenzae-associated (21.53 ng/ml) conjunctivitis.
Criminality in Drug Addicts: A Follow-Up Study over 25 Years
Authors: Rogne Gjeruldsen Susanne , Myrvang Bjørn , Opjordsmoen Stein
Published: March 2004

Background/Aims/Method: 214 drug addicts were included in a 25-year study on criminality using data from the National Register of Convictions, and 84% of those still living in Oslo attended a follow-up examination. Results: 89% of the 214 had committed offences, compared to 25% in a control group without drug use. 83% had been imprisoned. Males showed more criminal behavior than females and committed the most serious crimes. Male gender and more than two convictions were risk factors for reduced survival. At the follow-up examination 65% had abandoned illegal drugs and the majority had simultaneously stopped their criminal activities. There were significantly less drug offenders, thieves and people committing fraud or violations of traffic laws among the former drug addicts, but not less violent criminals. Criminality diminished with increasing age. Conclusions: Drug addicts were heavily involved in criminal affairs. Abandonment of illegal drugs and increasing age were associated with discontinuation of criminality.
Self-Reported Substance Misuse in Greek Male Prisoners
Authors: Fotiadou Maria , Livaditis Miltos , Manou Ioanna , Kaniotou Eleni , Samakouri Maria , Tzavaras Nicolaos , Xenitidis Kiriakos
Published: March 2004

The aim of this survey was to determine levels and severity of self-reported alcohol and drug misuse and associated physical and mental health problems in Greek male prisoners. The sample consisted of 80 randomly selected convicted and remanded male prisoners in a prison in northern Greece. The Mini International Neuropsychiatric Interview (MINI) was used to assess psychiatric disorders including substance abuse and dependence. All prisoners who participated completed the Alcohol Use Disorders Identification Test (AUDIT). Those who reported daily use of opiates and stimulants completed the Severity of Dependence Scale (SDS). Information was obtained from medical notes about the prisoners’ hepatitis B and HIV status. The MINI identified 27.5% of the prisoners as dependent on opiates, 26.3% on alcohol and 73.8% as cannabis users, while 13.8% were misusing both alcohol and illicit drugs. Severity of dependence was rated, using SDS, as serious for all opiate and stimulant users. In terms of physical health examination of medical records indicated that no prisoner was HIV-positive but 26.5% were hepatitis-B-positive. Of those who had a previous history of substance misuse, 31.2% fulfilled the criteria for depression and 37.5% for antisocial personality disorder. Similarly, 15% of those misusing substances had a previous history of deliberate self-harm and 16% were assessed to have moderate to high suicide risk.
Changes in Prevalence of Problem Opiate Use in Germany between 1990 and 2000
Authors: Augustin Rita , Kraus Ludwig
Published: March 2004

Objectives: Estimates of opiate use are calculated for the years 1990/1991, 1995 and 2000 in order to explore the development of problem opiate use in Germany in the preceding decade. Methods: The estimates stem from multiplier methods which extrapolate from a sample (benchmark) of known drug users to the total population by multiplying the benchmark by an appropriate factor that accounts for the unknown population. Data came from the German treatment monitoring system, police and mortality statistics. Results: The population estimates for 2000 resulted in 166,300–197,500 problem opiate users based on treatment data, 153,000–190,000 heroin users from police data, and 126,900–169,200 (current) injectors from mortality data. Recalculated estimates for 1990/1991 and 1995 derived from the same data sources were found to be somewhat lower. Discussion: The reported estimates between 1990 and 2000 point at a moderate increase of problem opiate users in the 1990s. The population estimates based on the multiplier method using three different data sources may be considered consistent for the highly overlapping target groups of (current) injectors, problem heroin and problem opiate users. Nevertheless, some of the applied multipliers are based on small-scale studies, raising the question of representativeness. National prevalence estimates may be improved by using other techniques such as multivariate indicator, capture-recapture, or dynamic models.
Children Attending Addiction Treatment Services in Dublin, 1990–1999
Authors: Smyth Bobby P. , O’Brien Mary
Published: March 2004

In Europe, adolescent substance misuse increased during the 1990s. Ireland has among the highest rates of substance misuse among schoolchildren in Europe. We sought to describe the socio-demographic and drug misuse profile of children presenting to addiction treatment services in Dublin during the 1990s. Of the 9,874 individuals who sought addiction treatment, 1,953 (20%) were aged less than 18 years. There was a sharp increase in the number of children after 1993. The main drug of abuse was an opiate in 48% of cases. Compared to adults, the children were more likely to be female and less likely to inject. As the decade progressed the proportion of girls increased, injecting was reported more frequently and there was a dramatic rise in heroin misuse. Child heroin users were more likely to be female and to be homeless compared to their adult counterparts. This study highlights the need for a dedicated service for child drug users in Dublin.