bluuebunny/crossref_metadata_2025 huggingface dataset:
Secretion of ATP from Schwann cells in response to uridine triphosphate
Authors: Liu Guo Jun , Werry Eryn L. , Bennett Max R.
Published: January 2005

The mechanisms by which uridine triphosphate (UTP) stimulates ATP release from Schwann cells cultured from the sciatic nerve were investigated using online bioluminescence techniques. UTP, a P2Y2 and P2Y4 receptor agonist, stimulated ATP release from Schwann cells in a dose‐dependent manner with an ED50 of 0.24 µm. UTP‐stimulated ATP release occurs through P2Y2 receptors as it was blocked by suramin which inhibits P2Y2 but not P2Y4 receptors. Furthermore, positive immunostaining of P2Y2 receptors on Schwann cells was revealed and GTP, an equipotent agonist with UTP at rat P2Y4 receptors, did not significantly stimulate ATP release. UTP‐stimulated ATP release involved second messenger pathways as it was attenuated by the phospholipase C inhibitor U73122, the protein kinase C inhibitor chelerytherine chloride, the IP3 formation inhibitor lithium chloride, the cell membrane‐permeable Ca2+ chelator BAPTA‐AM and the endoplasmic reticulum Ca2+‐dependent ATPase inhibitor thapsigargin. Evidence that ATP may be stored in vesicles that must be transported to the cell membrane for exocytosis was found as release was significantly reduced by the Golgi‐complex inhibitor brefeldin A, microtubule disruption with nocodazole, F‐actin disruption with cytochalasin D and the specific exocytosis inhibitor botulinum toxin A. ATP release from Schwann cells also involves anion transport as it was significantly reduced by cystic fibrosis transmembrane conductance regulator inhibitor glibencamide and anion transporter inhibitor furosemide. We suggest that UTP‐stimulated ATP release is mediated by activation of P2Y2 receptors that initiate an IP3–Ca2+ cascade and protein kinase C which promote exocytosis of ATP from vesicles as well as anion transport of ATP across the cell membrane.
Presynaptic NMDA autoreceptors facilitate axon excitability: a new molecular target for the anticonvulsant gabapentin
Authors: Suárez Luz M. , Suárez Francisco , Del Olmo Nuria , Ruiz Manuel , González‐Escalada José R. , Solís José M.
Published: January 2005

Gabapentin is a drug with anticonvulsant and analgesic properties causing the reduction of neurotransmitter release. We show that one of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of rat hippocampal slices. Interestingly, we found that gabapentin‐induced depression of FV is mimicked and occluded by NMDA receptor (NMDA‐R) antagonists, indicating that these receptors are located presynaptically and are activated by ambient levels of glutamate. Conversely, NMDA application (20 µm, 10 min) elicits a reversible FV potentiation which is reduced by gabapentin. Both NMDA‐ and gabapentin‐induced FV changes are partially explained by modifications in the firing threshold of individual fibres. Increasing [K+]o does not mimic or occlude (at a concentration of 6.5 mm) the effect of NMDA on FV amplitude, which makes it unlikely that a rise in [K+]o induced by NMDA receptor activation could indirectly participate in the potentiation of the FV. The NMDA‐induced FV potentiation is independent of extracellular calcium presence but is completely inhibited in a low‐Na+ solution (50% reduction) or under NMDA channel block (high Mg2+ or MK 801). These findings suggest that sodium entry through presynaptic NMDA‐R channels facilitates axon excitability. The interaction of gabapentin with this newly described mechanism might contribute to its therapeutic benefits.
A rat model of slow Wallerian degeneration (WldS) with improved preservation of neuromuscular synapses
Authors: Adalbert Robert , Gillingwater Thomas H. , Haley Jane E. , Bridge Katherine , Beirowski Bogdan , Berek Livia , Wagner Diana , Grumme Daniela , Thomson Derek , Celik Arzu , Addicks Klaus , Ribchester Richard R. , Coleman Michael P.
Published: January 2005

The slow Wallerian degeneration phenotype, WldS, which delays Wallerian degeneration and axon pathology for several weeks, has so far been studied only in mice. A rat model would have several advantages. First, rats model some human disorders better than mice. Second, the larger body size of rats facilitates more complex surgical manipulations. Third, rats provide a greater yield of tissue for primary culture and biochemical investigations. We generated transgenic WldS rats expressing the Ube4b/Nmnat1 chimeric gene in the central and peripheral nervous system. As in WldS mice, their axons survive up to 3 weeks after transection and remain functional for at least 1 week. Protection of axotomized nerve terminals is stronger than in mice, particularly in one line, where 95–100% of neuromuscular junctions remained intact and functional after 5 days. Furthermore, the loss of synaptic phenotype with age was much less in rats than in mice. Thus, the slow Wallerian degeneration phenotype can be transferred to another mammalian species and synapses may be more effectively preserved after axotomy in species with longer axons.
The astrocytic barrier to axonal regeneration at the dorsal root entry zone is induced by rhizotomy
Authors: McPhail Lowell T. , Plunet Ward T. , Das Partha , Ramer Matt S.
Published: January 2005

After dorsal rhizotomy, sensory axons fail to regenerate beyond the astrocytic glia limitans at the dorsal root entry zone (DREZ) but this inhibition can be overcome with the delivery of exogenous neurotrophin‐3. We investigated whether axonal inhibition at the DREZ is constitutive or induced after dorsal rhizotomy. Primary afferent neurones from enhanced green fluorescent protein‐expressing mice were transplanted into adult rat dorsal root ganglia in the presence or absence of dorsal rhizotomy. In the absence of dorsal rhizotomy mouse axons freely extended into the rat central nervous system. After host dorsal rhizotomy, mouse axons were unable to cross the DREZ. However, in rats that received a dorsal rhizotomy concomitant with intrathecal neurotrophin‐3, the mouse axons were able to cross the DREZ. These results indicate that, under normal circumstances, the adult DREZ is permissive to the regeneration of adult sensory axons and that it only becomes inhibitory once dorsal root axons have been injured and astrocytes at the DREZ have become reactive.
Deafferentation and neurotrophin‐mediated intraspinal sprouting: a central role for the p75 neurotrophin receptor
Authors: Scott Angela L. M. , Borisoff Jaimie F. , Ramer Matt S.
Published: January 2005

Axonal plasticity in the adult spinal cord is governed by intrinsic neuronal growth potential and by extracellular cues. The p75 receptor (p75NTR) binds growth‐promoting neurotrophins (NTs) as well as the common receptor for growth‐inhibiting myelin‐derived proteins (the Nogo receptor) and so is well situated to gauge the balance of positive and negative influences on axonal plasticity. Using transgenic mice lacking the extracellular NT‐binding domain of p75NTR (p75–/– mice), we have examined the influence of p75NTR on changes in the density of primary afferent (calcitonin gene‐related peptide‐expressing) and descending monoaminergic (serotonin‐ and tyrosine hydroxylase‐expressing) projections to the dorsal horn after dorsal rhizotomy, with and without concomitant application of exogenous nerve growth factor and NT‐3. We found that, in intact p75–/– mice, the axon density of all populations was equal to or less than that in wild‐type mice but that rhizotomy‐induced intraspinal sprouting was significantly augmented. Monoaminergic axon sprouting was enhanced in both nerve growth factor‐ and NT‐3‐treated p75–/– mice compared with similarly treated wild‐type mice. Primary afferent sprouting was particularly robust in NT‐3‐treated p75–/– mice. These in vivo results illustrate the interactions of p75NTR with NTs, with their respective tropomyosin‐related kinase receptors and with inhibitory myelin‐derived molecules. Our findings illustrate the pivotal role of p75NTR in spinal axonal plasticity and identify it as a potential therapeutic target for spinal cord injury.
Dopaminergic control of local interneuron activity in the thalamus
Authors: Munsch Thomas , Yanagawa Yuchio , Obata Kunihiko , Pape Hans‐Christian
Published: January 2005

The dorsal lateral geniculate nucleus (dLGN), the major thalamic station of the visual pathway, contains a fairly large number of dopaminergic terminals, and dopamine was found to reduce spontaneous and visually evoked activity in the dLGN in vivo. The cellular basis of this influence remained unknown. Here we have used whole cell patch‐clamp techniques to analyse the effects of dopamine (DA) on GABAergic transmission in dLGN slices of juvenile postnatal day (P) 12–P24 Long–Evans rats or juvenile (P12–P22) GAD67‐GFP (Δneo) mice. Spontaneous inhibitory postsynaptic currents (sIPSCs) were increased in frequency by the D2‐like agonist quinpirole (QUIN) in rat (n = 6), as well as in mouse (n = 5) thalamic slices. This effect was blocked in the presence of the D2‐like antagonist sulpiride (SULP, n = 5) and was absent in the ventrobasal complex (VB) of rat (n = 7) and mouse (n = 4) thalamus, which is devoid of GABAergic interneurons. Direct recordings from labelled GABAergic neurons in the dLGN of GAD67‐GFP mice revealed a QUIN‐mediated membrane depolarization (n = 12), which was attenuated by SULP (n = 6). These data demonstrate that DA through activation of D2‐like receptors in GABAergic interneurons induces an increase in inhibitory interactions most likely at F2 dendrodendritic terminals, thereby providing a cellular correlate of the observation made in vivo that DA predominantly acts through inhibition of relay cell activity in the dLGN.
GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress
Authors: Verkuyl J. Martin , Karst Henk , Joëls Marian
Published: January 2005

Parvocellular neurons in the hypothalamic paraventricular nucleus receive hormonal inputs mediated by corticosterone as well as neuronal inputs, prominent among which is a GABAergic inhibitory projection. In the present study we examined the functional properties of this GABAergic innervation when corticosteroid levels fluctuate. Frequency, amplitude and kinetic properties of miniature inhibitory postsynaptic potentials (mIPSCs), mediated by γ amino butyric acid (GABA) were studied with whole cell recording in parvocellular neurons. Injection of a high dose of corticosterone in vivo suppressed the frequency but did not change the amplitude and kinetic properties of mIPSCs recorded 1–5 h later in vitro. Similar effects were observed after restraint stress. The corticosteroid actions do not require involvement of extrahypothalamic brain regions, because in vitro administration of 100 nm corticosterone (20 min) directly to a hypothalamic slice also suppressed the frequency of mIPSCs recorded several hours later. Corticosterone administration to hypothalamic slices from restraint rats did not result in stronger reduction of mIPSC frequency than either treatment alone, pointing to a common underlying mechanism. Paired pulse response inhibition was reduced by corticosterone, suggesting that the hormone decreases the release probability of GABA‐containing vesicles. Unlike neurosteroids, corticosterone induced no rapid effects on mIPSC properties. These results indicate that increases in glucocorticoid level due to stress can slowly but persistently inhibit the GABAergic tone on parvocellular hypothalamic neurons via a hitherto unknown local mechanism independent of limbic projections.
Excitotoxic death induced by released glutamate in depolarized primary cultures of mouse cerebellar granule cells is dependent on GABAA receptors and niflumic acid‐sensitive chloride channels
Authors: Babot Zoila , Cristòfol Rosa , Suñol Cristina
Published: January 2005

Excitotoxic neuronal death has been linked to neurological and neurodegenerative diseases. Several studies have sought to clarify the involvement of Cl– channels in neuronal excitotoxicity using either N‐methyl‐d‐aspartic acid (NMDA) or α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate/kainic acid agonists. In this work we induced excitotoxic death in primary cultures of cerebellar granule cells by means of endogenously released glutamate. Excitotoxicity was provoked by exposure to high extracellular K+ concentrations ([K+]o) for 5 min. Under these conditions, a Ca2+‐dependent release of glutamate was evoked. When extracellular glutamate concentration rose to between 2 and 4 µm, cell viability was significantly reduced by 30–40%. The NMDA receptor antagonists (MK‐801 and d‐2‐amino‐5‐phosphonopentanoic acid) prevented cell death. Exposure to high [K+]o produced a 36Cl– influx which was significantly reduced by picrotoxinin. In addition, the GABAA receptor antagonists (bicuculline, picrotoxinin and SR 95531) protected cells from high [K+]o‐triggered excitotoxicity and reduced extracellular glutamate concentration. The Cl– channel blockers niflumic acid and 5‐nitro‐2‐(3‐phenylpropylamino)benzoic acid also exerted a neuroprotective effect and reduced extracellular glutamate concentration, even though they did not reduce high [K+]o‐induced 36Cl– influx. Primary cultures of cerebellar granule cells also contain a population of GABAergic neurons that released GABA in response to high [K+]o. Chronic treatment of primary cultures with kainic acid abolished GABA release and rendered granule cells insensitive to high [K+]o exposure, even though NMDA receptors were functional. Altogether, these results demonstrate that, under conditions of membrane depolarization, low micromolar concentrations of extracellular glutamate might induce an excitotoxic process through both NMDA and GABAA receptors and niflumic acid‐sensitive Cl– channels.
Inflammation alters somatostatin mRNA expression in sensory neurons in the rat
Authors: El‐Aleem Seham A. Abd , Morales‐Aza Begonia M. , McQueen Daniel S. , Donaldson Lucy F.
Published: January 2005

Proinflammatory neuropeptides, such as substance P and calcitonin gene‐related peptide, are up‐regulated in primary afferent neurons in acute and chronic inflammation. While these neuropeptides have been intensively studied, potentially anti‐inflammatory and/or anti‐nociceptive neuropeptides such as somatostatin (SS) have been less widely investigated. Endogenous somatostatin is thought to exert a tonic antinociceptive effect. Exogenous SS is anti‐inflammatory and antinociceptive and is thought to exert these actions through inhibition of proinflammatory neuropeptide release. In this study we have compared the expression of somatostatin in two inflammatory models: arthritis, a condition associated with increased nociception, and periodontitis, in which there is little evidence of altered nociceptive thresholds. In acute arthritis (< 24 h) SS mRNA was down‐regulated in ipsilateral dorsal root ganglia (DRG; 52 ± 7% of control, P < 0.05), and up‐regulated in contralateral DRG (134 ± 10% of control; P < 0.05). In chronic arthritis (14 days) this pattern of mRNA regulation was reversed, with SS being up‐regulated ipsilaterally and down‐regulated contralaterally. In chronic mandibular periodontitis (7–10 days), SS mRNA was up‐regulated in only the mandibular division of the ipsilateral trigeminal ganglion (TG) (day 7, 219 ± 9% and day 10, 217 ± 12% of control; P < 0.02) but showed no change in other divisions of the trigeminal ganglion or in the mesencephalic nucleus. These data show that antinociceptive and anti‐inflammatory neuropeptides are also regulated in inflammation. It is possible that the degree of inflammation and nociception seen may depend on the balance of pro‐ and anti‐inflammatory and nociceptive peptide expression in a particular condition.
Metabolic engineering of the mevalonate and non‐mevalonate isopentenyl diphosphate‐forming pathways for the production of health‐promoting isoprenoids in tomato
Authors: Enfissi Eugenia M. A. , Fraser Paul D. , Lois Luisa‐Maria , Boronat Albert , Schuch Wolfgang , Bramley Peter M.
Published: January 2005

The genetic manipulation of both the mevalonic acid (MVA) and methylerythritol‐4‐phosphate (MEP) pathways, leading to the formation of isopentenyl diphosphate (IPP), has been achieved in tomato using 3‐hydroxymethylglutaryl CoA (hmgr‐1) and 1‐deoxy‐d‐xylulose‐5‐phosphate synthase (dxs) genes, respectively. Transgenic plants containing an additional hmgr‐1 from Arabidopsis thaliana, under the control of the cauliflower mosaic virus (CaMV) 35S constitutive promoter, contained elevated phytosterols (up to 2.4‐fold), but IPP‐derived isoprenoids in the plastid were unaltered. Transgenic lines containing a bacterial dxs targeted to the plastid with the tomato dxs transit sequence resulted in an increased carotenoid content (1.6‐fold), which was inherited in the next generation. Phytoene and β‐carotene exhibited the greatest increases (2.4‐ and 2.2‐fold, respectively). Extra‐plastidic isoprenoids were unaffected in these lines. These data are discussed with respect to the regulation, compartmentalization and manipulation of isoprenoid biosynthetic pathways and their relevance to plant biotechnology.
Initial evaluation of sugarcane as a production platform for p‐hydroxybenzoic acid
Authors: McQualter Richard B. , Chong Barrie Fong , Meyer Knut , Van Dyk Drew E. , O'Shea Michael G. , Walton Nicholas J. , Viitanen Paul V. , Brumbley Stevens M.
Published: January 2005

Sugarcane (Saccharum hybrids) was evaluated as a production platform for p‐hydroxybenzoic acid using two different bacterial proteins (a chloroplast‐targeted version of Escherichia coli chorismate pyruvate‐lyase and 4‐hydroxycinnamoyl‐CoA hydratase/lyase from Pseudomonas fluorescens) that both provide a one‐enzyme pathway from a naturally occurring plant intermediate. The substrates for these enzymes are chorismate (a shikimate pathway intermediate that is synthesized in plastids) and 4‐hydroxycinnamoyl‐CoA (a cytosolic phenylpropanoid intermediate). Although both proteins have previously been shown to elevate p‐hydroxybenzoic acid levels in plants, they have never been evaluated concurrently in the same laboratory. Nor are there any reports on their efficacy in stem tissue. After surveying two large populations of transgenic plants, it was concluded that the hydratase/lyase is the superior catalyst for leaf and stem tissue, and further studies focused on this pathway. p‐Hydroxybenzoic acid was quantitatively converted to glucose conjugates by endogenous uridine diphosphate (UDP)‐glucosyltransferases and presumably stored in the vacuole. The largest amounts detected in leaf and stem tissue were 7.3% and 1.5% dry weight (DW), respectively, yet there were no discernible phenotypic abnormalities. However, as a result of diverting carbon away from the phenylpropanoid pathway, there was a severe reduction in leaf chlorogenic acid, subtle changes in lignin composition, as revealed by phloroglucinol staining, and an apparent compensatory up‐regulation of phenylalanine ammonia‐lyase. Although product accumulation in the leaves at the highest level of gene expression obtained in the present study was clearly substrate‐limited, additional experiments are necessary before this conclusion can be extended to the stalk.
High‐level production of yeast (Schwanniomyces occidentalis) phytase in transgenic rice plants by a combination of signal sequence and codon modification of the phytase gene
Authors: Hamada Akira , Yamaguchi Ken‐ichi , Ohnishi Naoto , Harada Michiko , Nikumaru Seiya , Honda Hideo
Published: January 2005

This study was designed to produce yeast (Schwanniomyces occidentalis) phytase in rice with a view to future applications in the animal feed industry. To achieve high‐level production, chimeric genes with the secretory signal sequence of the rice chitinase‐3 gene were constructed using either the original full‐length or N‐truncated yeast phytase gene, or a modified gene whose codon usage was changed to be more similar to that of rice, and then introduced into rice (Oryza sativa L.). When the original phytase genes were used, the phytase activity in the leaves of transgenic rice was of the same level as in wild‐type plants, whose mean value was 0.039 U/g fresh weight (g‐FW) (1 U of activity was defined as 1 µmol P released per min at 37 °C). In contrast, the enzyme activity was increased markedly when codon‐modified phytase genes were introduced: up to 4.6 U/g‐FW of leaves for full‐length codon‐modified phytase, and 10.6 U/g‐FW for truncated codon‐modified phytase. A decrease in the optimum temperature and thermal stability was observed in the truncated heterologous enzyme, suggesting that the N‐terminal region plays an important role in enzymatic properties. In contrast, the optimum temperature and pH of full‐length heterologous phytase were indistinguishable from those of the benchmark yeast phytase, although the heterologous enzyme was less glycosylated. Full‐length heterologous phytase in leaf extract showed extreme stability. These results indicate that codon modification, combined with the use of a secretory signal sequence, can be used to produce substantial amounts of yeast phytase, and possibly any phytases from various organisms, in an active and stable form.
Enhanced levels of methionine and cysteine in transgenic alfalfa (Medicago sativaL.) plants over‐expressing theArabidopsiscystathionine γ‐synthase gene
Authors: Avraham Tal , Badani Hanna , Galili Shmuel , Amir Rachel
Published: January 2005

With the aim of increasing the methionine level in alfalfa (Medicago sativaL.) and thus improving its nutritional quality, we produced transgenic alfalfa plants that expressed theArabidopsiscystathionine γ‐synthase (AtCGS), the enzyme that controls the synthesis of the first intermediate metabolite in the methionine pathway. The AtCGScDNA was driven by theArabidopsisrubisco small subunit promoter to obtain expression in leaves. Thirty transgenic plants were examined for the transgene protein expression, and four lines with a high expression level were selected for further work. In these lines, the contents of methionine,S‐methylmethionine (SMM), and methionine incorporated into the water‐soluble protein fraction increased up to 32‐fold, 19‐fold, and 2.2‐fold, respectively, compared with that in wild‐type plants. Notably, in these four transgenic lines, the levels of free cysteine (the sulphur donor for methionine synthesis), glutathione (the cysteine storage and transport form), and protein‐bound cysteine increased up to 2.6‐fold, 5.5‐fold, and 2.3‐fold, respectively, relative to that in wild‐type plants. As the transgenic alfalfa plants over‐expressing AtCGS had significantly higher levels of both soluble and protein‐bound methionine and cysteine, they may represent a model and target system for improving the nutritional quality of forage crops.
Expression of a fungal phytase gene in Nicotiana tabacum improves phosphorus nutrition of plants grown in amended soils
Authors: George Timothy S. , Simpson Richard J. , Hadobas Paul A. , Richardson Alan E.
Published: January 2005

Transgenic Nicotiana tabacum plants expressing a chimeric phytase gene (ex::phyA) from the soil fungus Aspergillus niger were generated. Three independently transformed lines showed increased extracellular phytase activity compared with a vector control and wild‐type plants, both of which had no detectable extracellular phytase. Transgenic N. tabacum plants grown in sterile agar supplied with phosphorus (P) as phytate accumulated 3.7‐fold more P than vector control plants. Despite this, the expression of ex::phyA in plants did not lead to an improved accumulation of P from two unamended P‐deficient soils. However, when soils were amended with either phytate or phosphate and lime, transgenic plants accumulated up to 52% more P than controls. Positive responses by transgenic plants were, in some instances, coincident with a putative increase in soil phytate. We conclude that the development of plants that exude phytase to the soil may not ensure improved plant P nutrition, as the availability of phytate in the soil also appears to be critical. Nevertheless, if plants that express ex::phyA are combined with soil amendments that promote the availability of phytate, there is the potential to enhance the P nutrition of crop plants and to improve the efficiency of P fertilizer use in agricultural systems.
Attention and memory biases in the offspring of parents with bipolar disorder: indications from a pilot study
Authors: Gotlib Ian H. , Traill Saskia K. , Montoya Rebecca L. , Joormann Jutta , Chang Kiki
Published: January 2005

Background Although children of bipolar parents are at heightened risk for developing emotional disorders, the processes underlying this vulnerability are not well understood. This study examined biases in the processing of emotional stimuli as a potential vulnerability marker of bipolar disorder.

Methods: Sixteen children of bipolar parents who did not show any indication of having an emotional disorder at the time of testing and ten children of never‐disordered control parents underwent a negative mood induction designed to activate cognitive schemas and were then administered an emotion Stroop task and a self‐referent encoding task.

Results: Children of bipolar parents were found to exhibit an attentional bias towards social‐threat and manic‐irritable words. Furthermore, although high‐ and low‐risk children did not differ in their endorsement of positive and negative words as self‐descriptive, the high‐risk children demonstrated better recall of negative words than did the low‐risk children.

Conclusions: Thus, children without a mood disorder who are at high risk for developing a mood disorder were found to exhibit biases in attention and memory that are similar to those found for bipolar and unipolar depressed adults, suggesting that children at increased risk for affective disorder are characterized by potentially pathogenic cognitive structures that can be activated by sad mood. These findings offer insights into mechanisms of cognitive vulnerability for bipolar disorders.
Psychiatric disorders in parents of children with autism: a meta‐analysis
Authors: Yirmiya Nurit , Shaked Michal
Published: January 2005

Background:  The genetic basis of autism has received great attention during the last few years. The psychiatric status of parents of persons with autism has been studied as part of the broad phenotype of autism.

Methods:  In the current study we examined all studies in which psychiatric difficulties of parents of children with autism were compared to those of parents of other children, as part of the broad phenotype of autism.

Results:  Overall, when parents of children with autism were compared to all other parents taken together, i.e., parents of typically developing children grouped together with parents of children with diagnoses other than autism, they were found to have more psychiatric difficulties, but this finding was inconsistent. Once type of comparison group (e.g., Down Syndrome, learning disabilities) and method of assessing psychiatric difficulties (e.g., self‐report, clinical measures) were taken into account, different findings were yielded for the various comparison groups and methods of assessing psychiatric difficulties in parents, suggesting that parents of children with autism present more psychiatric difficulties, mostly in comparisons involving samples of parents of children with no known genetic risk (e.g., Down Syndrome).

Conclusions:  These findings suggest that in future studies, researchers should carefully consider the advantages and disadvantages of various comparison groups and other characteristics, such as method of assessment, gender, and level of functioning, in attempting to delineate the specificity and universality of the broad phenotype of autism.
Larger deficits in brain networks for response inhibition than for visual selective attention in attention deficit hyperactivity disorder (ADHD)
Authors: Booth James R. , Burman Douglas D. , Meyer Joel R. , Lei Zhang , Trommer Barbara L. , Davenport Nicholas D. , Li Wei , Parrish Todd B. , Gitelman Darren R. , Marsel Mesulam M.
Published: January 2005

Background:  Brain activation differences between 12 control and 12 attention deficit hyperactivity disorder (ADHD) children (9‐ to 12‐year‐olds) were examined on two cognitive tasks during functional magnetic resonance imaging (fMRI).

Method:  Visual selective attention was measured with the visual search of a conjunction target (red triangle) in a field of distracters and response inhibition was measured with a go/no‐go task.

Results:  There were limited group differences in the selective attention task, with control children showing significantly greater intensity of activation in a small area of the superior parietal lobule region of interest. There were large group differences in the response inhibition task, with control children showing significantly greater intensity of activation in fronto‐striatal regions of interest including the inferior, middle, superior and medial frontal gyri as well as the caudate nucleus and globus pallidus.

Conclusion:  The widespread hypoactivity for the ADHD children on the go/no‐go task is consistent with the hypothesis that response inhibition is a specific deficit in attention deficit hyperactivity disorder.
Pharmacologic adjuvants to epoetin in the treatment of anemia in patients on hemodialysis
Authors: Berns Jeffrey S. , Mosenkis Ari
Published: January 2005

Anemia is a common complication of chronic kidney disease, particularly in patients who are on dialysis. The use of recombinant human erythropoietin has led to the eradication of severe anemia in the dialysis population. Correction of anemia in these patients has been associated with better quality of life and clinical outcomes. Some hemodialysis patients have anemia that either is relatively refractory to epoetin therapy or requires very high doses of epoetin (i.e., hyporesponsiveness), despite having adequate iron stores, and are thus unable to achieve or maintain target hemoglobin levels. Several pharmacologic agents have been studied for effects on improving response to epoetin, either to counter hyporesponsiveness or simply to reduce epoetin use for purely economic reasons. This review examines the available literature regarding the efficacy of these potential pharmacologic adjuvants to epoetin in the treatment of anemia in patients on maintenance hemodialysis, with special emphasis on androgens, vitamin C (ascorbic acid), and l‐carnitine. A review of published guidelines and recommendations for use of these agents in hemodialysis patients is provided.
Overproduction of reactive oxygen species in end‐stage renal disease patients: A potential component of hemodialysis‐associated inflammation
Authors: Morena Marion , Delbosc Sandrine , Dupuy Anne‐Marie , Canaud Bernard , Cristol Jean‐Paul
Published: January 2005

During the past decade, hemodialysis (HD)‐induced inflammation has been linked to the development of long‐term morbidity in end‐stage renal disease (ESRD) patients on regular renal replacement therapy. Because interleukins and anaphylatoxins produced during HD sessions are potent activators for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, an example of an enzyme that is responsible for overproduction of reactive oxygen species (ROS), this may constitute a link between leukocyte activation and cell or organ toxicity. Oxidative stress, which results from an imbalance between oxidant production and antioxidant defense mechanisms, has been documented in ESRD patients using lipid and/or protein oxidative markers.

Characterization of HD‐induced oxidative stress has included identification of potential activators for NADPH oxidase. Uremia per se could prime phagocyte oxidative burst. HD, far from improving the oxidative status, results in an enhancement of ROS owing to hemoincompatibility of the dialysis system, hemoreactivity of the membrane, and trace amounts of endotoxins in the dialysate. In addition, the HD process is associated with an impairment in antioxidant mechanisms. The resulting oxidative stress has been implicated in long‐term complications including anemia, amyloidosis, accelerated atherosclerosis, and malnutrition. Prevention of oxidative stress in HD might focus on improving the hemocompatibility of the dialysis system, supplementation of deficient patients with antioxidants, and modulation of NADPH oxidase by pharmacologic approaches.
Development of a new method for monitoring blood purification: The blood flow analysis of the head and foot by laser Doppler blood flowmeter during hemodialysis
Authors: Niwayama Jun , Sanaka Tsutomu
Published: January 2005

The management of blood pressure in hemodialysis patients greatly affects not only their quality of life, but also the duration of dialysis (dialysis life). Approximately 25% of dialysis patients suffer from continuous low blood pressure; however, the relationship between blood pressure and blood flow during dialysis has not been established. We hypothesized that with complete extracorporeal circulation, blood purification methods might affect blood flow, resulting in a change in blood pressure. The purpose of this study was to develop a noninvasive continuous monitoring method (NICOMM) as a microcirculation monitor by devising a laser‐Doppler flowmeter (LDF) system with a wavelength of 780 nm. The aim was to use this system to simultaneously measure blood flow rate in both the head and the foot during dialysis and to determine the effectiveness of NICOMM by measuring blood flow and arterial distensibility. When exhibiting a significant decline in blood pressure at 240 min after the initiation of hemodialysis, a drop in blood flow in parallel with the blood pressure fall was recorded by the LDF. However, no changes were observed, in the readings by a continuous hematocrit monitor (Crit‐Line monitor, CLM). Furthermore, a significant correlation was registered between mean arterial blood pressure and blood flow rate in the earlobe tissue from 180 min after the initiation of hemodialysis to the completion of hemodialysis (p < 0.001, r = 0.78). Comparisons were made by measuring vascular dehydration using the CLM. NICOMM showed more stable readings than the CLM in monitoring blood flow in response to changes in blood pressure.
High frequency of occult HCV infection in HD patients
Authors: Barril G. , Castillo I , Arenas D. , Rodriguez‐Inigo E. , Espinosa M. , Garcia Valdecases J. , Selgas R. , Carreno V.
Published: January 2005

Occult HCV infection in liver and peripheral blood mononuclear cells (PBMC) of patients with cryptogenic chronic hepatitis (anti‐HCV, serum HCV RNA negative) and no renal diseases, has been reported (1). In this work we studied the existence of occult HCV infection in PBMC of HD patients. Inclusion criteria: high ALT (>28 IU/l) and/or gamma‐GPT levels, negative serological HCV and HBV markers (anti‐HCV, serum HCV‐RNA and HBsAg negative), and exclusion of other causes of liver damage. Four Spanish HD units participated in the study and 40 patients were enrolled; 40 (25 males) fulfilled the inclusion criteria. HCV‐RNA in PBMC was tested by RT‐PCR and by in situ hybridization. Occult HCV infection was found in 24/40 (60%) patients by RT‐PCR and all cases were confirmed by in situ hybridization. No differences were found regarding gender, etiology of renal disease, or fluctuant or persistent abnormal liver enzymes values. Among patients with occult HCV infection, 4/24 (16.7%) had only increased ALT levels; 7/24 (29.2.%) GGTP values; and both enzymes were elevated in 13/24 (54.2%).

In our population, 60% HD patients with persistent or fluctuant ALT and/or GGTP values of unknown etiology and negative for serological viral markers (including serum HCV‐RNA) have an occult HCV infection in PBMC and these patients could be potentially infectious.

(1)J Infect Dis 2004;189: 7–14.
Intermittent and short daily hemodialysis increase HGF plasma levels and diminish HCV viral load
Authors: Barril G. , Bartolome J. , Sanz P. , Buoncristiani E. , Traver J.A. , Selgas R. , Carreno V. , Buoncristiani U.
Published: January 2005

Decrease of HCV viral load and HGF plasma levels increase have been related to HD sessions. Beneficial effects of HGF stimulation in HD on the outcome of HCV liver disease have been described. Aim was to analyze potential differences between intermittent (3 × week) and short daily (6 × week) HD, examining differences between HCV+ and – pts. We studied 41 pts from 2 HD centres, 26 on intermittent HD (6 on line HF), 8 HCV+, and 15 on short‐daily HD with 4 HCV+ 40 pts used synthetic HD membranes (low‐flux and high‐flux). Among HCV + we determined viral load by Amplicor (Roche) pre‐ and post‐ HD. All pts were studied for HGF levels (ELISA) baseline, 15 min, end, and at start of the following session viral load is significantly higher preHD and decreases over session. High‐flux membranes were more efficient in reducing viremia (67% vs 45%), which level was higher pre‐ and post‐HD principally in patients using low‐flux membranes. Viremia in DHD is lower than in intermittent (470067.3 ± 663974.5 vs 1015695.5 ± 1202679.0).

HCV+
HCV−
p

HGF baseline
3261.3 ± 1904.5
2186.5 ± 815.7
0.01

HGF 15 min
8000.0 ± 0.0
7774.0 ± 1129.8
ns

HGF end
6142.5 ± 2262.3
4443.7 ± 2515.7
0.03

HGF start
3391.0 ± 1680.6
2311.7 ± 633.6
0.007

HGF at baseline, at the end of the session, and starting the following one was significantly higher in HCV + patients. Maximum increase appears always at 15 min. HGF levels were significantly higher in daily HD than intermittent. Of the 14 patients who showed HGF after session higher than 8000, 8 were HCV+(3 in DHD, 5 high flux), 6 were HCV−(5 DHD and 3 high flux), 14 pts finished HD session with HGF>8000, 8HCV+(3 DHD, 5 high flux) and 6HCV−(5 DHD, 4 high‐flux). HGF stimulation appears in daily and intermittent HD, with higher level in the latter; HCV+ showed higher HGF vs negative, independently from the HD frequency; HCV viral load diminishes in all HD sessions, more in those with high‐flux membranes. Short‐daily HD with high‐flux synthetic membranes seems the best option for HCV+ patients, and when performed in home precludes nosocomial transmission.
Hypertension and left ventricular mass index (L.VMI) in patients on regular hemodialysis (RDT)
Authors: Papadimitriou M. , Pashalidis K. , Vakianis P. , Diamantopoulou D. , Interbalkan Chr. Raidis.
Published: January 2005

It has already been established that the most frequent cause of death in patients (pts) on RDT is cardiovascular. In fact, more than half of the deaths are related to cardiovascular disease. The purpose of the study was to investigate in pts with end‐stage renal disease the impact of hypertension on LVMI, a parameter which has already been found increased in early renal disease. Two hundred ninety seven pts (174 male) were included in this study with a mean follow‐up of 3 years. Sixty‐ six percent of these pts (first group) were on antihypertensive agents with one or more (in combination up to 4) drugs. Analytically, as monotherapy or in combination, 29.7% of the pts were taking a β‐blocker, 25.7% an a MEA, 8.9% an angiotensin receptor antagonist, 51.5% a calcium channel blocker, 11.9% a centrally active agent and 1% an α‐blocker. Forty‐four percent of the pts (secound group) were not on antihypertensive therapy at any time. Left atrial dimension (LAD) less than 3 cm, left venticular volume (LVV) less than 150 ml, and left ventricular mass index (LVMI) less than 130 gm/m2 for male and less than 100 gm/m2 for female pts were considered as normal values. The above parameters were measured using 3D Gen. Electric echocardiograph (Model VIVIO 3). There was no difference between the 2 groups in sex, age, EPO administration, high or low flux filter dialysis, and remaining urine volume. On the other hand, there was a statistically significant correlation between the systolic blood pressure (BP) and the blood urea before dialysis (p = 0.015) and the increase of body weight in between dialysis (p = 0.03). Finally, there was no statistical difference between the 2 groups in LAD and LVV, but 37.8% of the hypertensives had higher LVMI as compared with 23.2% of the normotensives (x2 = 3.028, p < 0.05). In conclusion, mainly the pts who had no compliance with their diet needed antihypertensive treatment. On the other hand, despite the clinically efficient antihypertensive therapy, the LVMI remained high in this group, and possibly this is one of the reasons of higher morbidity and mortality in this category of patients as it has already been shown in pts before starting haemodialysis.
Quality of life, self‐care and sense of coherence in patients on hemodialysis:  A comparative study
Authors: Ageborg M. , Allenius B.‐L. , Cederfjäall C
Published: January 2005

The number of patients treated for end‐stage renal disease increases in Sweden like the rest of the world. During the last six years more than 1000 persons a year started renal replacement therapy. Today hemodialysis patients have the opportunity to choose different treatment modalities—home hemodialysis, self‐care dialysis, or conventional dialysis. Purpose: The aim of the study was to investigate differences in patient on home hemodialysis, self‐care dialysis, and conventional dialysis regarding quality of life, self‐care, and sense of coherence. Methods: Questionnaires were used: Short Form (SF‐36), Appraisal of Self‐Care Agency (ASA‐scale), and Sense of Coherence scale (SOC). 19 patients were included in the study (five patients on home hemodialysis, six self‐care patients, and eight patients on conventional dialysis). Results: The results showed a tendency of higher scores in quality of life, self‐care, and sense of coherence for the home hemodialysis patients. Conclusion: Since the number of participants in this study was low, it is necessary to include more patients in a future study in order to verify the results.
Survival to discharge among patients treated with CRRT
Authors: Wald R. , Deshpande R. , Bell C.M. , Bargman J.M.
Published: January 2005

Continuous renal replacement therapy (CRRT) is widely used in critically ill patients with acute renal failure (ARF). The survival of patients who require CRRT and the factors predicting their outcomes are not well defined. We sought to identify clinical features to predict survival in patients treated with CRRT. We reviewed the charts of all patients who received CRRT at the Toronto General Hospital during the year 2002. Our cohort (n = 85) represented 97% of patients treated with this modality in 3 critical care units. We identified demographic variables, underlying diagnoses, transplantation status, location (medical‐surgical, coronary or cardiovascular surgery intensive care units), CRRT duration, baseline creatinine clearance (CrCl), and presence of oliguria (<400 ml/d) on the day of CRRT initiation. The principal outcome was survival to hospital discharge. Among those alive at discharge, we assessed whether there was an ongoing need for renal replacement therapy. Greater than one‐third (38%, 32/85) of patients survived to hospital discharge. Three (9%) of the survivors remained dialysis‐dependent at the time of discharge. Survivors were younger than non‐survivors (mean age 56 vs 60 y.), were on CRRT for a shorter duration (7 vs 13 d.), and had a higher baseline CrCl (79 vs 68 ml/min). Patient survival varied among different critical care units (medical surgical 33%, coronary 38%, and cardiovascular surgery 45%). Multivariable logistic regression revealed that shorter duration of CRRT, non‐oliguria, and baseline CrCl > 60 ml/min were independently associated with survival to hospital discharge (p < 0.05). Critically ill patients with ARF who require CRRT continue to have high in‐hospital mortality. A shorter period of CRRT dependence, non‐oliguria, and higher baseline renal function may predict a more favorable prognosis. The majority of CRRT patients who survive their critical illness are independent from dialysis at the time of hospital discharge.
Association between serum bicarbonate and death in hemodialysis patients: Is it better to be acidotic or alkalotic?
Authors: Wu D.Y.J. , Kilpatrick R.D. , Dadres S. , McAllister C.J. , Kopple J.D. , Kalantar‐Zadeh K.
Published: January 2005

The optimal acid base status for survival in maintenance hemo‐dialysis (MHD) patients (pts) remains controversial. According to some reports acidosis is associated with improved survival in MHD pts, i.e., reverse epidemiology. We examined associations between baseline (first 3‐month averaged) serum bicarbonate (HCO3), divided into 12 categories, and 2‐yr mortality in 56,376 MHD pts across the US after controlling for confounding effects of malnutrition‐inflammation complex syndrome (MICS). Three sets of Cox regression models were evaluated to estimate hazard ratios (HR) of death and 95% confidence intervals (CI): (1) Unadjusted; (2) Multivariate adjusted for case‐mix (age, gender, diabetes, race, insurance, marital status, vintage, standardized mortality ratio, residual renal function, dialysate HCO3, and Kt/V); and (3) Additional adjustments for 8 markers of MICS (body mass index, serum albumin, creatinine, ferritin, TIBC, dietary protein intake, WBC and lymphocyte counts). See Figure for HR and 95% CI:

We conclude that, although high HCO3 levels appear to be associated with increased mortality in MHD pts, this paradoxical effect is almost entirely due to the overwhelming impact of MICS on survival.
Dose of paricalcitol inversely associates with risk of hospitalization
Authors: Melnick J.Z.
Published: January 2005

Background: 
Among patients receiving chronic HD, therapy with paricalcitol (Z) was associated with reduced mortality and morbidity compared to treatment with calcitriol (C). Furthermore, patients who did not receive any vitamin D therapy experienced highest mortality and morbidity. This study examined the hypothesis of a relationship between the dose of Z and subsequent hospitalization, more specifically, that patients receiving lower doses of Z would have a higher risk of being hospitalized. Methods: We performed a retrospective cohort study of patients new to HD who received treatment with Z or C between Jan 1999 and Dec 2001 using Poisson regression models. The primary exposure variable was the average dose/day, examined as categorical data by quintiles, during a 3‐month and then 12‐month follow‐up period excluding the days in hospitals. This latter exclusion was made due to uncertainty of the treatment during the period of hospitalization. Additional covariates included vitamin‐D group (Z vs. C), age, gender, race, and diabetes status, serum albumin, alkaline phosphatase, calcium, phosphorus, and iPTH. Results: We first examined dose of Z and C over a 3‐month period and then hospitalizations over the ensuing year. We did not find a dose‐response relationship in these analyses – i.e., dose over the first three months of dialysis is not associated with increased or reduced risk of hospitalizations during the ensuing 12 months. We then examined average dose of Z or C over the entire year and risk for hospitalization during the same year. Compared to total doses, average doses (total dose over the entire year divided by number of dialysis sessions during the same year) are less prone to bias. Risk of hospitalizations according to dose (lowest dose, Quintile 1) of injectable vitamin D is shown in the table below:

Quintile
HR
95% CI

1
1.093
1.025–1.165

2
1.073
1.007–1.143

3
1.055
0.990–1.124

4
1.050
0.978–1.116

5
1.0
REF

Compared to those who received the highest doses of injectable vitamin D, those receiving the lowest had a 9% increased risk for a hospitalization. At each level, the risk for hospitalizations was 4% lower with Z compared to C. Conclusion: This pilot study indicates that higher average doses of Z are associated with a lower risk of hospitalization and suggests additional beneficial effects of vitamin D beyond mineral metabolism and PTH control.