bluuebunny/crossref_metadata_2025 huggingface dataset:
Microglial apolipoprotein E and astroglial apolipoprotein J expression in vitro: opposite effects of lipopolysaccharide
Authors: Saura Josep , Petegnief Valerie , Wu Xin , Liang Yanbin , Paul Steven M.
Published: June 2003

Apolipoprotein E (apoE) and apoJ are lipid carriers produced in the brain primarily by glial cells. A variety of glial‐activating stimuli induce a parallel upregulation of both apolipoproteins expression in vivo and in vitro. To further characterize the cell type and mechanisms by which apoE and apoJ expression are upregulated in activated glia, mixed glial cultures from neonatal rat cortex were treated with the endotoxin lipopolysaccharide (LPS). LPS induced dose‐dependent increases in apoJ and decreases in apoE expression and secretion with maximum effects at 1–10 ng/mL and 0.1–1 µg/mL, respectively. Experiments with enriched astroglial and microglial cultures demonstrated that apoE and apoJ expression are predominantly microglial and astroglial, respectively. Given the pivotal role that nuclear factor‐κB (NF‐κB) plays in glial activation, we assessed its possible role in mediating apoE and apoJ expression by activated glia. LPS robustly increased NF‐κB activation in mixed glial cultures. Two NF‐κB inhibitors, aspirin (10 mm) and MG‐132 (0.1 µm), blocked basal apoE and apoJ secretion as well as LPS‐induced apoJ secretion. These data demonstrate that glial apoE and apoJ expression are independently regulated by LPS in microglia and astroglia, respectively, and that activated microglia are the predominant source of apoE in mixed glial cultures. The transcription factor NF‐κB appears to be a critical mediator of LPS‐stimulated apoJ expression from astroglia.
c‐Fos is essential for the response of the tyrosine hydroxylase gene to depolarization or phorbol ester
Authors: Sun Baoyong , Tank A. William
Published: June 2003

Tyrosine hydroxylase (TH) gene transcription rate increases in response to numerous pharmacological and physiological stimuli. The AP1 site within the TH gene proximal promoter is thought to play an important role in mediating many of these responses; however, it is unclear which AP1 factors are required. To investigate whether c‐Fos is essential for the response of the TH gene to different stimuli, c‐Fos‐deficient PC12 cell lines were produced utilizing an antisense RNA strategy. In these cell lines, stimulus‐induced increases in c‐Fos protein levels were dramatically attenuated, while c‐Jun and CREB levels remained unchanged. TH gene transcription rate increased from four‐ to eight‐fold in control cells after treatment with either 50 mm KCl or TPA. These responses were dramatically decreased in the c‐Fos‐deficient cell lines. In contrast, c‐Fos down‐regulation had little effect on the response of the TH gene to forskolin. Stimulation of TH gene promoter activity, which was observed in control cell lines treated with either 50 mm KCl or TPA was also dramatically inhibited in the c‐Fos‐deficient cells. These results suggest that c‐Fos induction is essential for maximal stimulation of the TH gene in response to either depolarization or PKC activation in PC12 cells.
α‐Synuclein up‐regulates expression of caveolin‐1 and down‐regulates extracellular signal‐regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson's disease
Authors: Hashimoto Makoto , Takenouchi Takato , Rockenstein Edward , Masliah Eliezer
Published: June 2003

α‐Synuclein accumulation plays an important role in the pathogenesis of Lewy body disease (LBD) and Parkinson's disease (PD). Although the mechanisms are not yet clear, it is possible that dysregulation of the extracellular signal‐regulated kinase (ERK) might play a role. As caveolins form scaffolds onto which signaling molecules such as ERK can assemble, we propose that signaling alterations associated with α‐synuclein accumulation and neurodegeneration, might be mediated via caveolae. Therefore, the objective of the present study was to investigate the potential contribution of alterations in the caveolar system in mediating α‐synuclein effects on the ERK signaling pathway. For this, synuclein‐transfected B103 neuroblastoma cells were used as a model system. In this cell line, caveolin‐1 expression was up‐regulated, whereas, ERK was down‐regulated. ERK was weakly but consistently co‐immunoprecipitated with α‐synuclein but caveolin‐1 did not co‐immunoprecipitate with α‐synuclein. Moreover, treatment of α‐synuclein‐ overexpressing cells with caveolin‐1 antisense oligonucleotides resulted in stimulation of ERK activity, with amelioration of the neuritic alterations. Transduction of α‐synuclein‐overexpressing cells, with an adenoviral vector directing the expression of ERK, resulted in suppression of caveolin‐1 expression and re‐establishment of the normal patterns of neurite outgrowth. These results suggest that α‐synuclein may also interfere with ERK signaling by dysregulating caveolin‐1 expression. Thus, the caveolin‐1/ERK pathway could be a therapeutic target for the α‐synuclein‐related neurodegenerative disorders.
Role of protein phosphatase 2C from bovine adrenal chromaffin cells in the dephosphorylation of phospho‐serine 40 tyrosine hydroxylase
Authors: Bevilaqua Lia R. M. , Cammarota Martín , Dickson Phillip W. , Sim Alistair T. R. , Dunkley Peter R.
Published: June 2003

Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in the synthesis of catecholamines. It is dephosphorylated by protein phosphatase (PP) 2A and PP2C. In this study we used a fixed amount of bacterially expressed rat TH (5 µm), phosphorylated only at serine 40 (pSer40TH), to determine the PP activities against this site that are present in extracts from the bovine adrenal cortex, adrenal medulla, adrenal chromaffin cells and rat striatum. We found that PP2C was the main TH phosphatase activity in extracts from the adrenal medulla and adrenal chromaffin cells. In adrenal cortex extracts PP2C and PP2A activities toward pSer40TH did not differ significantly. PP2A was the main TH phosphatase activity in extracts from rat striatum. Kinetic studies with extracts from adrenal chromaffin cells showed that when higher concentrations of pSer40TH (> 5 µm) were used the activity of PP2C increased more than the activity of PP2A. PP2C was maximally activated by 1.25 mm Mn2+ and by 5 mm Mg2+ but was inhibited by calcium. Our data suggest a more important role for PP2C than was previously suggested in the dephosphorylation of serine 40 on TH.
Cyclosporin A prevents calpain activation despite increased intracellular calcium concentrations, as well as translocation of apoptosis‐inducing factor, cytochrome c and caspase‐3 activation in neurons exposed to transient hypoglycemia
Authors: Ferrand‐Drake Michel , Zhu Changlian , Gidö Gunilla , Hansen Anker J. , Karlsson Jan‐Olof , A. Bahr Ben , Zamzami Naoufal , Kroemer Guido , Chan Pak H. , Wieloch Tadeusz , Blomgren Klas
Published: June 2003

Blockade of mitochondrial permeability transition protects against hypoglycemic brain damage. To study the mechanisms downstream from mitochondria that may cause neuronal death, we investigated the effects of cyclosporin A on subcellular localization of apoptosis‐inducing factor and cytochrome c, activation of the cysteine proteases calpain and caspase‐3, as well as its effect on brain extracellular calcium concentrations. Redistribution of cytochrome c occurred at 30 min of iso‐electricity, whereas translocation of apoptosis‐inducing factor to nuclei occurred at 30 min of recovery following 30 min of iso‐electricity. Active caspase‐3 and calpain‐induced fodrin breakdown products were barely detectable in the dentate gyrus and CA1 region of the hippocampus of rat brain exposed to 30 or 60 min of insulin‐induced hypoglycemia. However, 30 min or 3 h after recovery of blood glucose levels, fodrin breakdown products and active caspase‐3 markedly increased, concomitant with a twofold increase in caspase‐3‐like enzymatic activity. When rats were treated with neuroprotective doses of cyclosporin A, but not with FK 506, the redistribution of apoptosis‐inducing factor and cytochrome c was reduced and fodrin breakdown products and active caspase‐3 immuno‐reactivity was diminished whereas the extracellular calcium concentration was unaffected. We conclude that hypoglycemia leads to mitochondrial permeability transition which, upon recovery of energy metabolism, mediates the activation of caspase‐3 and calpains, promoting cell death.
Bcl‐2‐related protein family gene expression during oligodendroglial differentiation
Authors: Itoh Takayuki , Itoh Aki , Pleasure David
Published: June 2003

Oligodendroglial lineage cells (OLC) vary in susceptibility to both necrosis and apoptosis depending on their developmental stages, which might be regulated by differential expression of Bcl‐2‐related genes. As an initial step to test this hypothesis, we examined the expression of 19 Bcl‐2‐related genes in purified cultures of rat oligodendroglial progenitors, immature and mature oligodendrocytes. All ‘multidomain’ anti‐apoptotic members (Bcl‐x, Bcl‐2, Mcl‐1, Bcl‐w and Bcl2l10/Diva/Boo) except Bcl2a1/A1 are expressed in OLC. Semiquantitative and real‐time RT‐PCR revealed that Bcl‐xL and Mcl‐1 mRNAs are the dominant anti‐apoptotic members and increase four‐ and twofold, respectively, with maturation. Bcl‐2 mRNA is less abundant than Bcl‐xL mRNA in progenitors and falls an additional 10‐fold during differentiation. Bcl‐w mRNA also increases, with significant changes in its splicing pattern, as OLC mature. Transfection studies demonstrated that Bcl‐xL overexpression protects against kainate‐induced excitotoxicity, whereas Bcl‐2 overexpression does not. As for ‘multidomain’ pro‐apoptotic members (Bax, Bad and Bok/Mtd), Bax and Bak are highly expressed throughout differentiation. Among ‘BH3 domain‐only’ members examined (Bim, Biklk, DP5/Hrk, Bad, Bid, Noxa, Puma/Bbc3, Bmf, BNip3 and BNip3L), BNip3 and Bmf mRNAs increase markedly during differentiation. These results provide basic information to guide further studies on the roles for Bcl‐2‐related family proteins in OLC death.
Presenilin endoproteolysis mediated by an aspartyl protease activity pharmacologically distinct from γ‐secretase
Authors: Campbell William A. , Reed Megan L. O. , Strahle Jennifer , Wolfe Michael S. , Xia Weiming
Published: June 2003

Presenilin (PS)‐dependent γ‐secretase cleavage is the final proteolytic step in generating amyloid β protein (Aβ), a key peptide involved in the pathogenesis of Alzheimer's disease. PS undergoes endoproteolysis by an unidentified ‘presenilinase’ to generate the functional N‐terminal and C‐terminal fragment heterodimers (NTF/CTF) that may harbor the γ‐secretase active site. To better understand the relationship between presenilinase and γ‐secretase, we characterized the biochemical properties of presenilinase and compared them with those of γ‐secretase. Similar to γ‐secretase, presenilinase was most active at acidic pH 6.3. Aspartyl protease inhibitor pepstatin A blocked presenilinase activity with an IC50 of ∼ 1 µm. Difluoroketone aspartyl protease transition state analogue MW167 was relatively selective for presenilinase (IC50 < 1 µm) over γ‐secretase (IC50−16 µm). Importantly, removing the transition state mimicking moiety simultaneously abolished both presenilinase and γ‐secretase inhibition, suggesting that presenilinase, like γ‐secretase, is an aspartyl protease. Interestingly, several of the most potent γ‐secretase inhibitors (IC50 = 0.3 or 20 nm) failed to block presenilinase activity. Although de novo generation of PS1 fragments coincided with production of Aβin vitro, blocking presenilinase activity without reducing pre‐existing fragment levels permitted normal de novo generation of Aβ and amyloid intracellular domain. Therefore, presenilinase has characteristics of an aspartyl protease, but this activity is distinct from γ‐secretase.
Co‐expression of non‐selective cation channels of the transient receptor potential canonical family in central aminergic neurones
Authors: Sergeeva Olga A. , Korotkova Tatiana M. , Scherer Annette , Brown Ritchie E. , Haas Helmut L.
Published: June 2003

The mammalian transient receptor potential canonical (TRPC) group of channels is a family of Ca2+‐permeable cation channels that are activated following receptor‐mediated stimulation of different isoforms of phospholipase C. In vitro TRPC proteins can form hetero‐ or homo‐oligomeric channels. We performed single‐cell RT–PCR analysis to reveal the co‐expression of seven TRPC channels in identified rat aminergic neurones. All serotonergic neurones of the dorsal raphe (DR), the majority of histaminergic (tuberomamillary nucleus; TMN) and dopaminergic cells of the ventral tegmental area (VTA), as well as some GABAergic neurones from the VTA, expressed at least one variant of TRPC channels. No TRPC channel expression was found in the locus coeruleus. In raphe neurones TRPC6 and TRPC5 mRNAs occurred most frequently. In VTA and TMN co‐expression of TRPC4 with TRPC5 and TRPC6 with TRPC7 was not found in individual neurones (in contrast to the whole‐brain regions). Their co‐expression in non‐neuronal cells could not be excluded. The neonatal TRPC3 subunit was rarely seen. In DR, but not in the other nuclei studied, the expression of orexin receptors correlated with the expression of TRPC channels. We conclude that several TRPC channel populations exist in individual neurones and that their subunit co‐expression pattern is region and cell‐type specific.
Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats
Authors: Basselin Mireille , Chang Lisa , Seemann Ruth , Bell Jane M. , Rapoport Stanley I.
Published: June 2003

Studies were performed to determine if the reported ‘proconvulsant’ action of lithium in rats given cholinergic drugs is related to receptor‐initiated phospholipase A2 signaling via arachidonic acid. Regional brain incorporation coefficients k* of intravenously injected [1‐14C]arachidonic acid, which represent this signaling, were measured by quantitative autoradiography in unanesthetized rats at baseline and following administration of subconvulsant doses of the cholinergic muscarinic agonist, arecoline. In rats fed LiCl for 6 weeks to produce a therapeutically relevant brain lithium concentration, the mean baseline values of k* in brain auditory and visual areas were significantly greater than in rats fed control diet. Arecoline at doses of 2 and 5 mg/kg intraperitoneally increased k* in widespread brain areas in rats fed the control diet as well as the LiCl diet. However, the arecoline‐induced increments often were significantly greater in the LiCl‐fed than in the control diet‐fed rats. Lithium's elevation of baseline k* in auditory and visual regions may correspond to its ability in humans to increase auditory and visual evoked responses. Additionally, its augmentation of the k* responses to arecoline may underlie its reported ‘proconvulsant’ action with cholinergic drugs, as arachidonic acid and its eicosanoid metabolites can increase neuronal excitability and seizure propagation.
Truncated beta‐amyloid peptide species in pre‐clinical Alzheimer's disease as new targets for the vaccination approach
Authors: Sergeant Nicolas , Bombois Stepanie , Ghestem Antoine , Drobecq Hervé , Kostanjevecki Vesna , Missiaen Carla , Wattez Annick , David Jean‐Phillipe , Vanmechelen Eugeen , Sergheraert Christian , Delacourte André
Published: June 2003

Vaccination against human beta‐amyloid peptide (Aβ) has been shown to remove the amyloid burden produced in transgenic mice overexpressing the mutated human amyloid precursor protein (APP) gene. For human beings, the efficiency of this therapeutic strategy has to take into account the specificities of human amyloid, especially at the early stages of ‘sporadic’ Alzheimer's disease (AD). Aβ 40/42 were previously quantified in tissues from our well‐established brain bank, including non‐demented individuals with both mild amyloid and tau pathologies, hence corresponding to the earliest stages of Alzheimer pathology. Herein, we have adapted a proteomic method combined with western blotting and mass spectrometry for the characterization of insoluble Aβ extracted in pure‐formic acid. We demonstrated that amino‐truncated Aβ species represented more than 60% of all Aβ species, not only in full blown AD, but also, and more interestingly, at the earliest stage of Alzheimer pathology. At this stage, Aβ oligomers were exclusively made of Aβ‐42 species, most of them being amino‐truncated. Thus, our results strongly suggest that amino‐truncated Aβ‐42 species are instrumental in the amyloidosis process. In conclusion, a vaccine specifically targeting these pathological amino‐truncated species of Aβ‐42 are likely to be doubly beneficial, by inducing the production of specific antibodies against pathological Aβ products that are, in addition, involved in the early and basic mechanisms of amyloidosis in humans.
Gastrointestinal effects of nonsteroidal anti‐inflammatory drugs
Authors: Whittle Brendan J. R.
Published: June 2003

Non‐steroidal anti‐inflammatory drugs (NSAIDs) causes extensive damage to the gastrointestinal (GI) tract. The underlying mechanisms of gastric injury include topical irritant actions that disrupt the epithelial barrier, as well as the inhibition of cyclo‐oxygenase (COX), which is predominantly the COX‐1 isoform in the mucosa. This damage can be attenuated by antisecretory agents or by mucosal protective agents such as the synthetic prostanoids or nitric oxide (NO) donors. Compounds designed to attenuate topical irritancy, or have protective agents incorporated, such as NO‐containing NSAIDs, the CINODs (cyclo‐oxygenase‐inhibiting NO‐donating drugs) show reduced mucosal injury. NSAIDs also cause injury in the small intestine, which appears to result from initial COX inhibition, with subsequent translocation of indigenous bacteria, induction of NO synthase and production of the cytotoxic moiety, peroxynitrite. The COX‐2 selective agents, the coxibs, which inhibit prostanoid biosynthesis at inflammatory sites, but not the endogenous protective prostanoids in the gut formed by COX‐1, have proved so far to be a successful therapeutic approach to reducing NSAIDs GI damage. The clinical outcome of the use of the second generation of coxibs, and the newer NO NSAIDs is now awaited.
Different vascular responsiveness to angiotensin II in two normotensive rat strains
Authors: Herin Laetitia , Blanc Jocelyne , Basset Alexandra , Laude Dominique , Laurent Stéphane , Elghozi Jean‐Luc
Published: June 2003

Rats of the Fischer 344 (F344) and Wistar Kyoto (WKY) strains are known to present differences in stimuli responses involving the renin–angiotensin system and in cardiovascular responses to an acoustic startle stimulus. Here we compared the vascular reactivity to angiotensin II (ANG II) of these normotensive, inbred rat strains.  Blood pressure (BP) and heart rate (HR) were recorded in conscious rats, before and after a neurohumoral blockade obtained by successive administration of chlorisondamine, enalapril, a V1‐vasopressinergic receptor antagonist (Manning compound) and atropine methyl nitrate. BP was restored by a constant infusion of noradrenaline. Boluses of ANG II ranging from 0.001 to 1280 ng/kg were injected randomly. Average dose–response curves were established. After neurohumoral blockade, the minimum mean BP (MBP) produced by hydralazine (3 mg/kg, i.v.) and the maximum MBP produced by noradrenaline (60 μg/mL and 800 μL/min, i.v.) were used to reflect arterial wall structure.

 The maximal systolic blood pressure (SBP) and pulse pressure (PP) responses to ANG II were higher in F344 compared with WKY (+86 ± 3 mmHg vs. +71 ± 3 mmHg, P < 0.01 for SBP, +31 ± 2 mmHg vs. +18 ± 1 mmHg, P < 0.001 for PP). After the ANG II type 1 (AT1) receptor blocker valsartan, ANG II had no significant effect on BP. F344 and WKY exhibited the same maximum MBP in response to noradrenaline. However, MBP level following hydralazine was higher in F344 (F344: 48 ± 2 mmHg vs. WKY: 37 ± 3 mmHg, P < 0.01).

 The amplification in F344 of the vasoconstrictive response to ANG II mediated by AT1 receptors is compatible with a high number of AT1 receptors in this strain. In F344, the exaggerated systolic and PP responses to ANG II and the higher MBP level after hydralazine most likely reflect a structural modification of the arterial wall such as hypertrophic remodelling in F344.
Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations
Authors: Yang Jue Quin , Morin Sandrine , Verstuyft Céline , Fan Li An. , Zhang Yong , Xu Chun Di , Barbu Véronique , Jaillon Patrice , Becquemont Laurent
Published: June 2003

Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme responsible for the metabolism of different drugs with low therapeutic index such as oral anticoagulants. CYP2C9*2 and CYP2C9*3 are two single nucleotide polymorphic allelic variants. The frequency of these alleles in different ethnic populations is extremely variable. In this study, we compared the frequencies of CYP2C9 allelic variants among 394 Chinese living in Shanghai to 151 French Caucasians living in Paris. The allelic frequencies of CYP2C9 variants of the Chinese and the French subjects were 0.963, 0.001, 0.036 and 0.77, 0.15, 0.08 for CYP2C9*1, CYP2C9*2, CYP2C9*3, respectively. Chinese CYP2C9*3 allelic frequency was twice as lower as the French subjects, but three times higher than Korean (0.036 vs. 0.011). The CYP2C9*2 allele could be detected in only one Chinese subject, whereas it represented the major allelic variant in French Caucasians. The low frequency of the CYP2C9*2 and CYP2C9*3 allelic variants in Chinese subjects does not justify their detection in clinical practice, unlike French Caucasians.
Effect of drugs on cholesterol crystallization in an artificial bile model and relation of this effect to drug binding to albumin
Authors: Šmídková Markéta , Špundová Marcela , Mareček Zdeněk , Entlicher Gustav
Published: June 2003

Substances that can affect the crystallization of cholesterol from human bile and consequently the gallstone formation have been given considerable attention. We improved the model system for testing cholesterol crystallization‐affecting activity (promoting or inhibiting) of substances and used it for some drugs that are excreted into bile. Besides other factors natural lipid–protein complexes isolated from the native human bile have been shown to be responsible for nucleation and fast crystal growth in cholesterol supersaturated model bile. Artificial lipid–protein complex of taurolithocholate, human serum albumin and Ca2+ (TLTC–HSA–Ca2+) exhibited a lower crystallization activity than both the artificial lipid–protein complexes of taurodeoxycholate, human serum albumin and Ca2+ and the lipid–protein complex isolated from native human bile. The model bile supplemented with this artificial lipid–protein complex (TLTC–HSA–Ca2+) formed a convenient system for testing of various substances (drugs) for their crystallization‐affecting activity. From the 20 tested drugs, which could occur at least in small amounts in human bile, the highest crystallization‐promoting activity was found for complexes with ampicillin, butorphanol and colchicine. Complexes with tetracycline, thioridazine and doxycycline were the strongest inhibitors.

The drugs, which had some effect on cholesterol crystallization, affected somehow the artificial lipid–albumin complex by displacing its components. Interactions of different drugs with HSA and its artificial complexes with the conjugated bile salt and Ca2+ ions were followed by absorption spectroscopy to observe displacement interactions. On the basis of these experiments we could classify drugs into four groups which differ by their effects on spectral characteristics of complexes.
Twelve‐hour shift on ITU: a nursing evaluation
Authors: Richardson Annette , Dabner Nichola , Curtis Sarah
Published: June 2003

This paper describes the introduction and subsequent evaluation of a 12‐h shift system in a large ITU in the northeast of UK

To date, only a small number of studies has evaluated nurses working the 12‐h shifts in critical care areas

To evaluate the level of staff satisfaction, data were collected by means of a questionnaire involving 41 nurses, at 3 months following the introduction of the 12‐h shifts

The responses from the evaluation advocated the continuation of 12‐h shifts with alternative shift patterns for nurses who felt dissatisfied with the current system

Twelve‐hour shifts can be seen as a flexible system for nurses working in intensive care and may assist with staff satisfaction and improving nurse recruitment and retention
Nursing care of the acute head injury: a review of the evidence
Authors: Price Ann M , Collins Timothy J , Gallagher Alison
Published: June 2003

This article aims to review the current evidence in relation to acute head injury care

Head injuries are a frequent cause of death and disability in western society with the first 72 h being an important period for prevention of further brain damage

The underlying physiology behind head injury and intracranial pressure will be discussed

The monitoring of intracranial pressure and implications for practice will be addressed

The specialized nursing care and drug therapy management that is necessary for acute head injury patients will be highlighted

Recommendations for practice will be given
Catecholaminergic Innervation of the Human Dura Mater Involved in Headache
Authors: Cavallotti Daniela , Artico Marco , De Santis Stefano , Iannetti Giandomenico , Cavallotti Carlo
Published: June 2003

The catecholaminergic innervation of cranial dura mater in humans was studied by examining several dural zones (vascular, perivascular, intervascular) in different regions (basal, calvarial, occipital, frontal, tentorial, parietal, temporal).

The results demonstrate that catecholaminergic nerve fibers are present in human cranial dura mater and that these fibers, after exposure to formaldehyde vapors, show the specific fluorescence of catecholamines.

There are more dural catecholaminergic nerve fibers in the basal region than in the calvarial region. Moreover, these nerve fibers are more abundant in the perivascular dural zone than in the intervascular zone.

We hypothesize that these catecholaminergic nerve fibers may be involved in headache.
SUNCT Syndrome. Two Cases in Argentina
Authors: Raimondi Elsa , Gardella Lorenzo
Published: June 2003

Two patients suffering from SUNCT syndrome are presented. Some features are remarkable. The first patient was a 69‐year‐old man whose first crisis was located in the right supraorbital region. After a 4‐month spontaneous remission, the pain returned to the upper part of the cheek, radiating to the supraciliary region on the same side, with lacrimation and conjunctival injection. Rhinorrhea was absent The painful attacks were triggered by head movements. Clinical improvement occurred with carbamazepine treatment

The second patient was a 48‐year‐old woman whose painful attacks lasted from 30 to 45 seconds followed by a burning sensation lasting 2 hours. Autonomic signs such as conjunctival injection, lacrimation, and edema and ipsilateral ptosis of the upper lid were rather marked. There was never any rhinorrhea. Her attacks were triggered by head and eye movements. She responded to the administration of corticosteroids and carbamazepine.

According to these features, the two patients had SUNCT syndrome, and the positive carbamazepine response suggests a relationship with trigeminal neuralgia.
Acute glucose deprivation leads to apoptosis in a cell model of acute diabetic neuropathy
Authors: Honma Hiroyuki , Podratz Jewel L. , Windebank And Anthony J.
Published: June 2003

Abstract Objective:  Our aims were to better understand the mechanisms underlying peripheral neuropathy with diabetes mellitus and to test the hypothesis that acute lowering of glucose levels induces apoptosis in hypoxic neurons.

Methods:  We used rat dissociated dorsal root ganglion (DRG) neurons incubated in a medium high in glucose concentration (700 mg%) and room air (PO2 150 torr). After 5 days, DRG neurons were placed in hypoxic conditions (PO2 7.6 torr) with a normal‐glucose (100 mg%) or high‐glucose (700 mg%) medium containing 3 or 100 ng/mL of nerve growth factor. Acute lowering of glucose levels under hypoxic conditions led to apoptosis of DRG neurons. Apoptosis was demonstrated by bis‐benzimide staining for nuclear fragmentation, electron microscopy, DNA laddering, and TUNEL staining. Caspase 3 immunocytochemistry and inhibition of neuronal death by the caspase inhibitor z‐VAD‐fmk (100 μM) confirmed that death was apoptotic.

Results:  Hypoxia‐induced death was decreased when DRG neurons were maintained in high‐glucose medium, suggesting that high levels of substrate protected against hypoxia. Apoptosis was completely prevented by increasing the concentration of nerve growth factor from 3 to 100 ng/mL and was partially prevented by the addition of the antioxidant α‐lipoic acid (500 μM).

Conclusions:  This model provides a novel means for studying the pathogenesis and treatment of early stages of diabetic neuropathy.
The relation of clinical symptoms and anti‐ganglioside antibodies to MEPPs frequency increase in 8 cases of variant type Guillain‐Barré syndrome
Authors: Kishi Masahiko , Fujioka Toshiki , Miura Hiroko , Sekine Akiko , Iguchi Hiroaki , Nakazora Hiroshi , Kiyozuka Tetuhito , Igarashi Osamu , Ichikawa Yasumitu , Sugimoto Hideki , Kurihara Teruyuki , Irie Sachiko , Saito Toyokazu
Published: June 2003

Abstract Many patients with variant forms of Guillain‐Barré syndrome (vGBS) associated with anti‐ganglioside antibodies, including Miller Fisher syndrome (MFS), sometimes exhibit miniature endplate potential (MEPP) frequency increases (MFI, described as α‐latrotoxin‐like effects in a previous report) and the factor to produce this effect is present in their sera. MFI‐positive sera increase the frequency of MEPPs, then block neuromuscular transmission at the mouse neuromuscular junction. A connection between this effect at the neuromuscular junction and some vGBS symptoms is suspected. We measured MFI directly at several points during the clinical course of 8 vGBS patients who had various symptoms and courses. Six patients had confirmed MFI and this activity decreased with convalescence. In 3 clinically mild cases, we were able to elicit MFI using normal serum to supply complement after exposure to the patient's serum. The anti‐GQ1b/GT1a IgG titer, the extent of ophthalmoplegia and the extent of MFI were significantly correlated. They did not correlate with the severity of limb weakness or the occurrence of respiratory failure. These results support the hypothesis that MFI caused by anti‐ganglioside antibodies is the pathogenic mechanism responsible for ophthalmoplegia in vGBS; different mechanisms or antibodies may explain limb weakness and respiratory failure. Furthermore, MFI may be an important indicator of how serum injures the nerve terminals. The symptoms of vGBS may result from multiple pathogenic factors.
Nerve compound action current (NCAC) measurements and morphometric analysis in the proximal segment after nerve transection and repair in a rabbit model
Authors: Walbeehm Erik T. , Michiel Dudok van Heel E. B. , Kuypers Paul D. L. , Terenghi Giorgio , Hovius Steven E. R.
Published: June 2003

Abstract  In the evaluation of nerve regeneration using magneto‐neurography (MNG), the proximal segment showed a reproducible decrease in peak–peak amplitude of the nerve compound action current's (NCAC) of 60%. To explain these changes, morphometry of myelinated axons in the proximal segment is compared to the MNG signals. A standardised nerve transection and reconstruction was performed in rabbits. NCACs were measured approximately 5 cm proximal to the lesion from operated and control nerves after 12 weeks. Histological samples were taken from the same area of the nerve where the NCACs were obtained. Results showed a decrease of the peak–peak amplitude of the NCAC of 57% compared to the control. Conduction velocity decreased 15%(not significant). Morphometry elicited a decrease in larger (10–15 μm) axons (284 ± 134 vs 82 ± 55) and an increase in smaller (2–5 μm) axons (1445 ± 360 vs 1921 ± 393). A strong correlation existed between the decrease in amplitude and the decrease in larger axons (0.85). Peak–peak amplitude varies approximately with the square of the diameter axon. Therefore, because peak–peak amplitude is mainly dependent on the larger‐diameter axons, the decrease in peak–peak amplitude of the NCACs may be explained by a decrease in numbers of 10–15‐μm axons.
Interactions of Copper with Glycated Proteins: Possible Involvement in the Etiology of Diabetic Neuropathy
Authors: Eaton JW , Qian MW
Published: June 2003

Humans and animals with diabetes frequently develop peripheral vascular dysfunction and peripheral neuropathies. There is accumulating evidence that impaired peripheral nerve function may derive from diminished endoneural blood flow. The decrements in nerve blood flow may, in turn, be due to diminished endothelium‐dependent vasodilation. Although a number of possible causes of this defective vasodilation have been suggested, none has been definitely proven. Regardless of the precise cause, the impaired vasodilatory activity may reflect diminished availability of endothelium‐derived relaxing factor (EDRF), variously thought to be nitric oxide or thiol adducts of nitric oxide. Other investigators have reported that administration of transition metal chelators to diabetic rats corrects EDRF‐mediated arterial relaxation and restores both neural blood flow and nerve conduction velocity, suggesting the involvement of transition metals. Our investigations center about the hypothesis that glycated proteins bind transition metals such as copper and iron, and that such ‘glycochelates’ accumulate within the vasculature in diabetes and catalytically inactivate EDRF. In partial support of this hypothesis: (1) Glycated albumin binds 3‐fold greater amounts of both copper and iron. (2) Copper bound to glycated albumin remains redox active (e.g. capable of supporting the oxidation of ascorbic acid). (3) Copper and copper‐containing glycochelates cause the rapid decomposition of one putative form of EDRF, nitrosocysteine. (4) The amount of exchangeable (i.e. chelatable) copper in the plasma of diabetic rats is approximately twice that in normal rat plasma. (5) Similarly, tail tendons of diabetic animals have about twice as much bound copper as do tendons of normal rats. (6) Implants bearing adsorbed glycated albumin placed in the peritonea of normal mice for 48 h accumulate 5 times as much bound copper as do implants coated with control albumin. Overall, these observations support—but do not conclusively prove—the hypothesis that transition metals such as copper, bound to glycated proteins, may blunt normal EDRF‐dependent relaxation of diabetic arteries and provide a rationale for the use of transition metal chelators in the therapy of diabetic vasculopathy and neuropathy.
Effects of the Protein Kinase C Beta Inhibitor LY333531 on Neural and Vascular Function in Rats with Streptozotocin‐induced Diabetes
Authors: Cotter MA , Jack AM , Cameron NE
Published: June 2003

Elevated protein kinase C activity has been linked to the vascular and neural complications of diabetes. The aim of the present study was to examine the involvement of the beta‐isoform of protein kinase C in abnormalities of neuronal function, neural tissue perfusion and endothelium‐dependent vasodilation in diabetes, by treatment with the selective inhibitor LY333531 (10 mg · kg−1 · day−1). Diabetes was induced in rats by streptozotocin; the duration of diabetes was 8 weeks. Nerve conduction velocity was monitored, and responses to noxious mechanical and thermal stimuli were estimated by the Randall‐Sellito and Hargreaves tests respectively. Sciatic nerve and superior cervical ganglion blood flow were measured by microelectrode polarography and hydrogen clearance. Vascular responses were examined using the in vitro mesenteric bed preparation. An 8‐week period of diabetes caused deficits in sciatic motor (20%) and saphenous nerve sensory (16%) conduction velocity, which were reversed by LY333531. Diabetic rats had mechanical and thermal hyperalgesia. LY333531 treatment did not affect mechanical thresholds, but corrected thermal hyperalgesia. Sciatic nerve and superior cervical ganglion blood flow were both reduced by 50% by diabetes; this was almost completely corrected by 2 weeks of LY333531 treatment. Diabetes caused a 32% reduction in vasodilation of the mesenteric vascular bed in response to acetylcholine, mediated by nitric oxide and endothelium‐derived hyperpolarizing factor. When the former was abolished during nitric oxide synthase inhibition, an 80% diabetic deficit in the remaining relaxation was noted. LY333531 treatment attenuated the development of these defects by 64% and 53% respectively. Thus protein kinase Cbeta contributes to the neural and vascular complications of experimental diabetes; LY333531 is a candidate for further study in clinical trials of diabetic neuropathy and vasculopathy.
Peripheral Neuropathy in Acrodermatitis Chronica Atrophicans – Effect of Treatment
Authors: Kindstrand E , Nilsson BY , Hovmark A , Pirskanen R , Asbrink E
Published: June 2003

Forty‐seven patients with the late borrelial manifestation acrodermatitis chronica atrophicans (ACA) and with objective neurological and/or neurophysiological findings were followed up after antibiotic treatment with dermatological, serological, neurological and neurophysiological controls. Despite a good therapeutic effect on ACA lesions, specific antibody values and symptoms of irritative nerve lesions, the objective neurological and neurophysiological findings of nerve deficit remained unchanged. There was no progress of neuropathy findings during the follow‐up time. Our interpretation of the results is that the remaining neuropathy signs after treatment of ACA are neurological sequelae and not manifestations of persisting Borrelia infection.
Loss of Phosphatase Activity in Myotubularin‐related Protein 2 is Associated with Charcot‐marie‐tooth Disease Type 4B1
Authors: Berger P , Bonneick S , Willi S , Wymann M , Suter U
Published: June 2003

Mutations in the gene encoding myotubularin‐related protein 2 (MTMR2) are responsible for autosomal recessive Charcot‐Marie‐Tooth disease type 4B1 (CMT4B1), a severe hereditary motor and sensory neuropathy characterized by focally folded myelin sheaths and demyelination. MTMR2 belongs to the myotubularin family, which is characterized by the presence of a phosphatase domain. Myotubularin (MTM), the archetype member of this family, is mutated in X‐linked myotubular myopathy. Although MTMR2 and MTM are closely related, they are likely to have different functions. Recent studies revealed that MTM dephosphorylates specifically phosphatidylinositol 3‐phosphate. Here we analyze the biochemical properties of the mouse MTMR2 protein, which shares 97% amino acid identity with human MTMR2. We show that phosphatidylinositol‐3‐phosphate is also a substrate for MTMR2, but, unlike myotubularin, MTMR2 dephosphorylates phosphatidylinositol 3,5‐bisphosphate with high efficiency and peak activity at neutral pH. We demonstrate that the known disease‐associated MTMR2 mutations lead to dramatically reduced phosphatase activity, suggesting that the MTMR2 phosphatase activity is crucial for the proper function of peripheral nerves in CMT4B1. Expression analysis of MTMR2 suggests particularly high levels in neurons. Thus, the demyelinating neuropathy CMT4B1 might be triggered by the malfunction of neural membrane recycling, membrane trafficking, and/or endocytic or exocytotic processes, combined with altered axon‐Schwann cell interactions. Furthermore, the different biochemical properties of MTM and MTMR2 offer a potential explanation for the different human diseases caused by mutations in their respective genes.
Acrylamide Neuropathy – I. Spatiotemporal Characteristics of Nerve Cell Damage in Rat Cerebellum
Authors: Lehning EJ , Balaban CD , Ross JF , Reid MA , LoPachin RM
Published: June 2003

Based on evidence from morphometric studies of PNS, we suggested that acrylamide (ACR)‐induced distal axon degeneration was a secondary effect related to duration of exposure (Toxicol Appl Pharmacol 151 [1998] 211). To test this hypothesis in CNS, the cupric‐silver stain method of de Olmos was used to define spatiotemporal characteristics of nerve somal, dendritic, axonal and terminal degeneration in rat cerebellum. Rats were exposed to ACR at either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.) and at selected times (i.p. = 5, 8 and 11 days; p.o. = 7, 14, 21, 28 and 38 days) brains were removed and processed for silver staining. Results demonstrate that intoxication at the higher ACR dose‐rate produced early (day 5) and progressive degeneration of Purkinje cell dendrites in cerebellar cortex. Nerve terminal degeneration occurred concurrently with somatodendritic argyrophilia in cerebellar and brainstent nuclei that receive afferent input from Purkinje neurons. Relatively delayed (day 8), abundant axon degeneration was present in cerebellar white matter but not in cortical layers or in tracts carrying afferent fibers (cerebellar peduncles) from other brain nuclei. Axon argyrophilia coincided with the appearance of perikaryal degeneration, which was selective for Purkinje cells since silver impregnation of other cerebellar neurons was not evident in the different cortical layers or cerebellar nuclei. Intoxication at the lower ACR dose‐rate produced simultaneous (day 14) dendrite, axon and nerve terminal argyrophilia and no somatic Purkinje cell degeneration. The spatiotemporal pattern of dendrite, axon and nerve terminal loss induced by both ACR dose‐rates is consistent with Purkinje cell injury. Injured neurons are likely to be incapable of maintaining, distal processes and, therefore, axon degeneration in the cerebellum is a component of a “dying‐back” process of neuronal injury. Because cerebellar coordination of somatomotor activity is mediated solely through efferent projections of the Purkinje cell, injury to this neuron might contribute significantly to gait abnormalities that characterize ACR neurotoxicity.
Acrylamide Neuropathy – II. Spatiotemporal Characteristics of Nerve Cell Damage in Brainstem and Spinal Cord
Authors: Lehning EJ , Balaban CD , Ross JF , LoPachin RM
Published: June 2003

Previous studies of acrylamide (ACR) neuropathy in rat PNS (Toxicol Appl Pharmacol 151 [1998] 211) and cerebellum (Neurotoxicology, 2002a) have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To continue morphological examination of ACR neurotoxicity in CNS, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal degeneration in brainstem and spinal cord. Rats were exposed to ACR at a dose‐rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.), and at selected times brains and spinal cord were removed and processed for silver staining. Results show that intoxication at the higher ACR dose‐rate produced a nearly pure terminalopathy in brainstem and spinal cord regions, i.e. widespread nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the lower ACR dose‐rate caused initial nerve terminal argyrophilia in selected brainstem and spinal cord regions. As intoxication continued, axon degeneration developed in white matter of these CNS areas. At both dose‐rates, argyrophilic changes in brainstem nerve terminals developed prior to the onset of significant gait abnormalities. In contrast, during exposure to the lower ACR dose‐rate the appearance of axon degeneration in either brainstem or spinal cord was relatively delayed with respect to changes in gait. Thus, regardless of dose‐rate, ACR intoxication produced early, progressive nerve terminal degeneration. Axon degeneration occurred primarily during exposure to the lower ACR dose‐rate and developed after the appearance of terminal degeneration and neurotoxicity. Spatiotemporal analysis suggested that degeneration began at the nerve terminal and then moved as a function of time in a somal direction along the corresponding axon. These data suggest that nerve terminals are a primary site of ACR action and that expression of axonopathy is restricted to subchronic dosing‐rates.
Favorable Impact of a Vegan Diet with Exercise on Hemorheology: Implications for Control of Diabetic Neuropathy
Authors: McCarty MF
Published: June 2003

A little‐noticed clinical report indicates that a low‐fat, whole‐food vegan diet, coupled with daily walking exercise, leads to rapid remission of neuropathic pain in the majority of type 2 diabetics expressing this complication. Concurrent marked improvements in glycemic control presumably contribute to this benefit, but are unlikely to be solely responsible. Consideration should be given to the possibility that improved blood rheology – decreased blood viscosity and increased blood filterability – plays a prominent role in mediating this effect. There is considerable evidence that neural hypoxia, secondary to impaired endoneurial microcirculatory perfusion, is a crucial etiologic factor in diabetic neuropathy; the unfavorable impact of diabetes on hemorheology would be expected to exacerbate endoneurial ischemia. Conversely, measures which improve blood fluidity would likely have a beneficial impact on diabetic neuropathy. There is indeed evidence that vegan diets, as well as exercise training, tend to decrease the viscosity of both whole blood and plasma; reductions in hematocrit and in fibrinogen may contribute to this effect. The fact that vegan diets decrease the white cell count is suggestive of an improvement in blood filterability as well; filterability improves with exercise training owing to an increase in erythrocyte deformability. Whether these measures influence the activation of leukocytes in diabetics – an important determinant of blood filterability – remains to be determined. There are various reasons for suspecting that a vegan diet can reduce risk for other major complications of diabetes – retinopathy, nephropathy, and macrovascular disease – independent of its tendency to improve glycemic control in type 2 patients. The vegan diet/exercise strategy represents a safe, ‘low‐tech’ approach to managing diabetes that deserves far greater attention from medical researchers and practitioners.
Phrenic Nerve Paralysis, Vegetative Symptoms and Restrictive Cardiomyopathy in a Case of Poems Syndrome
Authors: Delalande S , Stojkovic T , Rose C , Millaire A , Hurtevent JF , Vermersch P
Published: June 2003

We report a case of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M protein and Skin changes) with unusual clinical features. A 62‐year‐old woman presented a severe polyneuropathy with dysphonia and vegetative symptoms, including bradycardia and sphincterial disorders. The clinical examination showed facial hyperpigmentation, cachexia, anasarca and splenomegaly. She also presented restrictive cardiomyopathy and endocrine disturbances. Nerve conduction studies revealed a severe demyelinating sensorimotor neuropathy. Cerebrospinal fluid analysis showed an elevated protein level. We detected a biclonal gammapathy (Ig G and Ig A with lambda light chain) and lytic pelvic bone lesions. Later, she developed a severe ventilatory failure due to a bilateral phrenic nerve paralysis leading to a mechanical ventilation. Steroids followed by localized radiotherapy partially improved the respiratory status and stabilized the neuropathy. Phrenic nerve paralysis, restrictive cardiomyopathy, vegetative symptoms and cranial nerve palsy are exceptional in POEMS syndrome. Moreover, this case emphasizes the importance of radiological investigations since the discover of plasmocytoma may improve the prognosis of POEMS syndrome.