bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice
Authors: Kuo Jason J. , Schonewille Martijn , Siddique Teepu , Schults Annet N. A. , Fu Ronggen , Bär Peter R. , Anelli Roberta , Heckman C. J. , Kroese Alfons B. A.
Published: January 2004

ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.
Localization of renin expressing cells in the brain, by use of a REN-eGFP transgenic model
Authors: Lavoie Julie L. , Cassell Martin D. , Gross Kenneth W. , Sigmund Curt D.
Published: January 2004

Immunoreactive renin has been reported in the hypothalamus and cerebellar cortex in the rodent brain and in neurons in all areas of the human brain. Despite these observations and the clear documentation of the expression of the other renin-angiotensin system genes in the brain, the notion that renin is endogenously expressed in the brain remains very controversial and undefined. This controversy no doubt arises because the level of renin expression in the brain is below the detection threshold of most standard assays. A transgenic mouse expressing enhanced green fluorescence protein (eGFP) under the control of the mouse renin promoter was recently reported. This model expresses eGFP in the kidney, which responds appropriately to both developmental and physiological stimuli. We therefore used eGFP as a sensitive marker to identify renin-expressing cells in the brain. We identified eGFP-containing cells in specific areas of the brain, including cerebellum, hippocampus, dorsal motor nucleus of the vagus, inferior olivary nucleus, reticular formation, rostral ventrolateral medulla, central nucleus of the amygdala, lateral parabrachial nucleus, mesencephalic trigeminal nucleus, bed nucleus of stria terminalis, and subfornical organ. By colabeling with neuron- or glia (astrocytes or oligodendrocytes)-specific antisera, we have determined the eGFP-positive cells to be mainly neuronal. These findings therefore strongly support the primary expression of renin mRNA in the brain in regions controlling cardiovascular function.
Identification of a hydrogen transfer model with dynamical boundary conditions
Authors: Zaika Yury V.
Published: January 2004

The nonlinear inverse problem of determining the hydrogen
permeability parameters of stratified materials is considered.
The model includes diffusion, invertible capture and
sorption/desorption processes on surface, which leads to
dynamical boundary conditions. For the concentration impulses
method, the equation of stationary oscillations of concentration
is obtained. Parametric identification scheme of the model is
proposed. Techniques of Fourier series and conjugate equations
are used.
On the geometry of Riemannian manifolds with a Lie structure at infinity
Authors: Ammann Bernd , Lauter Robert , Nistor Victor
Published: January 2004

We study a generalization of the geodesic spray and give conditions for noncomapct manifolds with a Lie structure at infinity to have positive injectivity radius. We also prove that the geometric operators are generated by the given Lie algebra of vector fields. This is the first one in a series of papers devoted to the study of the analysis of geometric differential operators on manifolds with Lie structure at infinity.
Comparison of Environmental and Genetic Factors for Parkinson’s Disease between Chinese and Caucasians
Authors: Chan Daniel Kam Yin , Cordato Dennis , Bui Triet , Mellick George , Woo Jean
Published: January 2004

This review paper compares the differences in prevalence, and environmental and genetic risk factors for Parkinson’s disease between Chinese and Caucasian subjects. Comparison of age-specific prevalence between Chinese people and Caucasians suggests that the prevalence is lower in the Chinese (at least in the past), although the prevalence rate in China appears to be rising. Distinctions in environmental risk factors and genetic factors are discussed. The difference in prevalence may be due to distinctions in environmental and genetic risk factors as well as the complex interaction between these environmental and genetic factors, although discrepancies in methodology for prevalence surveys can also be an explanation.
Attrition and Non-Compliance in Secondary Stroke Prevention Trials
Authors: Gencheva E. , Sloan M. , Leurgans S. , Raman R. , Harris Y. , Gorelick P.
Published: January 2004

Background: Attrition and non-compliance of subjects in secondary stroke prevention trials due to study drug-induced adverse events and loss to follow-up could lead to bias and loss of information, thus affecting the analysis of study results. Methods: We reviewed results from ten antiplatelet stroke prevention clinical trials: CAN TIA, DUTCH TIA, SWED ASA, SALT, UK TIA, CATS, TASS, ESPS, ESPS-2, and CAPRIE to tabulate the frequencies for total subject discontinuation, voluntary withdrawal, and loss to follow-up. Results: Forty thousand seven hundred and thirty (40,730) subjects participated in the aforementioned secondary stroke prevention trials. The range of outcomes was 11.8–52.0% for subjects discontinued for any reason (n = 9 trials); 3.0–20.9% for study drug-induced adverse events (n = 9 trials), and 4.2–7.8% for voluntary withdrawal (n = 10 trials). Conclusion: There is a substantial discrepancy (up to 20%) between the frequencies of total subject discontinuation for any reason and the sum of study drug-induced adverse events, voluntary withdrawal and loss to follow-up. Underestimation of these important outcomes may limit the ability of clinicians to translate results from clinical trials into medical practice.
A Meta-Analysis of Maternal Cured Meat Consumption during Pregnancy and the Risk of Childhood Brain Tumors
Authors: Huncharek Michael , Kupelnick Bruce
Published: January 2004

Objective: N-Nitroso compounds (NOCs) are recognized neural carcinogens in animal models and are suspected human carcinogens. A meta-analysis was performed examining the possible association of maternal intake of cured meat (an important source of dietary NOCs) during pregnancy and the risk of pediatric brain tumors. Methods: Data from epidemiological studies were pooled using a general variance-based meta-analytic method employing confidence intervals described by Greenland in 1986. The outcome of interest was a summary relative risk (RR) reflecting the risk of childhood brain tumor (CBT) development associated with maternal intake of cured meats during pregnancy. Sensitivity analyses were performed when necessary to explain any observed statistical heterogeneity. Results: Seven observational studies were found that met the protocol-specified inclusion criteria. Analysis for heterogeneity demonstrated a lack of statistical heterogeneity (p = 0.59), indicating that the data could be statistically combined. Pooling data from the 6 reports containing data on maternal cured meat intake of all types yielded an RR of 1.68 (1.30– 2.17), being a statistically significant result. Analyzing CBT risk by type of cured meat ingested showed that hot dog consumption increased CBT risk by 33% (1.08–1.66), with a similar increase shown by frequent ingestion of sausage, i.e. 44%. Conclusion: The data provide support for the suspected causal association between ingestion of NOCs from cured meats during pregnancy and subsequent CBT in offspring. Limitations in study design preclude definitive conclusions, but the relationship warrants exploration via additional observational and laboratory-based studies.
Association between Statin Use and Alzheimer’s Disease
Authors: Zamrini Edward , McGwin Gerald , Roseman Jeffrey M.
Published: January 2004

Context: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been associated with a decreased risk for Alzheimer’s disease (AD). Objective: To evaluate the association between statin use and AD adjusted for comorbid medical conditions. Design: A nested case-control study. Patients: Patients at the Veterans Affairs Medical Center in Birmingham, Ala., USA with a new diagnosis of AD (cases) between 1997 and 2001 (n = 309) and age-matched non-AD controls (n = 3,088). Main Outcome Measure: Odds ratio for association between AD and statin use. Results: Statin users had a 39% lower risk of AD relative to nonstatin users (odds ratio 0.61, 95% confidence interval 0.42–0.87). This association appeared to be modified by the presence of certain chronic medical conditions (i.e., hypertension, ischemic heart disease and cerebrovascular disease) in that the reduced risk was observed among those with these diseases, whereas no association was observed among those without any of these conditions. Conclusions: In this study, following adjustment for confounding factors, a statistically significant inverse association between statin use and AD was observed. The results lend support to looking at AD outcomes in trials of statins to further evaluate their possible beneficial effects.
Interaction of Androgens with Cardiotonic Drugs in Isolated Left Atrium of Rat
Authors: Secades Lorena , Cortina Rosario , Velasco Lucía , Bordallo Javier , Hidalgo Agustín , Sánchez Manuel
Published: January 2004

Pharmacological concentrations of androgens are known to elicit a rapid positive inotropism in isolated left atrium of male rats. Upon short-term exposure to androgens, an increase in intracellular cAMP levels has been observed, though delayed with respect to the time course of contraction, suggesting that other mechanisms may participate in initiating the contraction. Therefore, the interaction of positive inotropism elicited by ouabain, an inhibitor of Na+-K+-ATPase, and androgens was studied in isolated left atrium of rat. Androgens antagonized ouabain-elicited positive inotropism and increased the basal tone. Vanadate, an inhibitor of the Ca2+ pump, produced a similar effect as androgens on ouabain-elicited positive inotropism. Therefore, androgens might interact with the Ca2+ pump and this may explain the increase in basal tone. The conjugation of 5α-dihydrotestosterone with bovine serum albumin produced the same effect, suggesting an extracellular interaction of androgens inhibiting the Na+-K+-ATPase that could increase intracellular Ca2+ via the Na+-Ca2+ exchange.
7-OH-DPAT-Induced Inhibition of Norepinephrine Release in PC12 Cells
Authors: Chu Eugenia , Chu Jane , Socci Robin R. , Chu Teh-Ching
Published: January 2004

The purpose of this study was to investigate mechanisms of suppression of norepinephrine release by 7-OH-DPAT, a dopamine D2/D3 receptor agonist, in PC12 cells pretreated with nerve growth factor (NGF). 7-OH-DPAT caused inhibition of basal and K+-evoked norepinephrine release, which could be blocked by pretreatment with raclopride, a D2/D3 receptor antagonist. Moreover, dopamine D2 and D3 receptors were identified by immunocytochemistry. Expression of D2, D3, and D4 mRNAs and their proteins were detected using RT-PCR and immunoblotting. Furthermore, 7-OH-DPAT produced no change in cGMP levels; however, 7-OH-DPAT inhibited forskolin-stimulated cAMP accumulation that was antagonized by pretreatment with raclopride. In addition, 7-OH-DPAT inhibited carbachol-induced Ca2+ transient, conversely, 7-OH-DPAT had no effect on 4-aminopyridine-induced Ca2+ transient. Taken together, suppression of cAMP accumulation and calcium mobilization by 7-OH-DPAT is involved in the inhibition of norepinephrine release through activation of dopamine D2/D3 receptors.
Anti-Hypertension Effect of Vanylidilol: A Phenylaldehyde α/β-Adrenoceptor Blocker with Endothelium-Dependent and K+ Channels Opening-Associated Vasorelaxant Activities
Authors: Chiu Chaw-Chi , Wu Jiunn-Ren , Lee Chih-Hsiung , Liou Shwu-Fen , Dai Zen-Kong , Chen Ing-Jun , Yeh Jwu-Lai
Published: January 2004

The antihypertensive effect of vanylidilol, a new α/β-adrenoceptor antagonist with endothelium-dependent and K+-channel-opening activities, was investigated in normotensive and hypertensive Wistar rats. Vanylidilol competitively antagonized (–)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in isolated rat right atria, left atria, and guinea pig tracheal strips in a concentration-dependent manner. Vanylidilol’s apparent pA2 values were 6.36 ± 0.08 (right atria), 6.41 ± 0.07 (left atria), and 6.31 ± 0.06 (trachea). Vanylidilol also produced a competitive antagonism of phenylephrine-induced contraction in the isolated rat aorta with pA2 values of 6.79 ± 0.18. In the radioligand binding assay, vanylidilol inhibited [3H]CGP-12177 binding to rat ventricle and lung tissues and [3H]prazosin binding to brain membranes with Ki values of 535.17, 2,066.69, and 431.11, respectively. In isolated rat thoracic aorta, vanylidilol’s vasorelaxant effects on phenylephrine (10 µmol/l)-induced contractions were attenuated by removing endothelium and by the presence of L-NG-nitro arginine methyl ester (L-NAME; 100 µmol/l), methylene blue (10 µmol/l), 1H-[1,2,4]oxadiazolol[4,3,-a] quinoxalin-1-one (ODQ; 10 µmol/l), tetraethylammonium (10 mmol/l), glibenclamide (1 µmol/l), apamin (1 µmol/l), and charybdotoxin (0.1 µmol/l). In addition, vanylidilol, in an equally antagonistic activity, inhibited phenylephrine-induced phasic and tonic contractions. Intravenous vanylidilol further reduced mean blood pressure in pentobarbital-anesthetized normotensive Wistar rats in a dose-dependent manner. The oral administration of vanylidilol to conscious spontaneously hypertensive rats had a long-lasting hypotensive effect on the heart rate and decreased it in a dose-dependent manner. Furthermore, vanylidilol’s vasodilator effect can be attributed in part to the release of NO or NO-related substance from vascular endothelium, while the endothelium-independent mechanism involved in vanylidilol’s relaxation is probably linked to the activation of the K+ channels and the α-adrenoceptor blocking activity in these vessels.
Functional Study of the [Ca2+]i Signaling Pathway in Aortas of L-NAME-Hypertensive Rats
Authors: de Campos Grifoni Samira , Maria Bendhack Lusiane
Published: January 2004

A variety of mechanisms has been proposed to suggest that nitric oxide participates in the regulation of smooth muscle free [Ca2+]c (the primary determinant of contractile tone), including inhibition of Ca2+ influx across the plasma membrane and inhibition of intracellular Ca2+ release. In view of such considerations, the aim of this study was to investigate the possible alterations in contractile responses induced by drugs that mobilize Ca2+ from different sources in aortae from NG-nitro-L-arginine methyl ester (L-NAME) hypertensive rats (LHR). Treatment with L-NAME did not alter the contractile response induced by phenylephrine; however, indomethacin increased the contraction to phenylephrine only in LHR aortae (1.36 ± 0.08 g, n = 6, vs. 1.97 ± 0.09 g, n = 7). Both phenylephrine and caffeine evoked rapid and phasic contractions in intact or denuded aortic rings in Ca2+-free solution containing EGTA. Phenylephrine-elicited phasic contractions were lower in normotensive rats (NR; 0.41 ± 0.05 g, n = 9) than in LHR (0.57 ± 0.06 g, n = 6) and were increased by endothelium removal only in the NR group (0.64 ± 0.05 g, n = 6). Conversely, neither with treatment with L-NAME nor endothelium removal altered the phasic contractile responses induced by caffeine. The Ca2+ influx stimulated with phenylephrine was greater in NR (1.95 ± 0.08 g; pD2 6.06 ± 0.69; n = 8) than in the LHR denuded aorta (1.63 ± 0.11 g; pD2 3.52 ± 0.06; n = 6). Similarly, contractions stimulated with phorbol ester in denuded arteries were greater in NR (1.76 ± 0.08 g, n = 7) than in LHR (1.11 ± 0.11 g, n = 7). In the same manner, indomethacin failed to alter the contraction stimulated with phorbol ester in NR arteries (2.01 ± 0.21 g, n = 7), although it completely blocked the inhibitory effect of chronic treatment with L-NAME on this contractile response (1.94 ± 0.24 g; n = 9). Indomethacin did not change the contractile responses stimulated by increasing concentrations of extracellular Ca2+ in either NR aortas (1.44 ± 0.26 g; pD2 4.74 ± 0.79; n = 6) or LHR aorta (1.99 ± 0.19 g; pD2 4.10 ± 0.47; n = 8). However, in the presence of indomethacin, the Ca2+ influx was similar in NR and LHR aortae. Taken together, these results suggest that, in this model of hypertension, the increase in agonist-induced release of Ca2+ from intracellular stores may be partly compensated by inhibition of Ca2+ influx and that this effect is due to the increased production of the relaxant prostanoid in vascular smooth muscle cells.
Immunolocalization of Alk8 during Replacement Tooth Development in Zebrafish
Authors: Perrino Michael A. , Yelick Pamela C.
Published: January 2004

The novel type I transforming growth factor-β (TGF-β) family member receptor Alk8 was previously identified in a degenerate RT-PCR screen for zebrafish type I and II TGF-β family member receptors. Functional analyses revealed that Alk8 acts through Bmp signaling pathways in early embryonic dorsoventral patterning, in neural crest cell specification, and in patterning and differentiation of neural crest cell-derived pharyngeal arch cartilages. In addition, Alk8 forms active signaling complexes with TGF-β1 and the TGF-β RII receptor, suggesting that Alk8 mediates cross talk between Bmp and TGF-β subfamily members. In this study, immunohistochemical analysis was performed on zebrafish aged 2 days postfertilization to 1 year, revealing immunolocalization of Alk8 to tissues of the tooth-bearing ceratobranchial 5 (cb5) arch including dental epithelial and mesenchymal tooth tissues of developing primary and replacement teeth, mucous-producing crypt epithelium, keratinized bite plate, and developing taste buds. These results suggest roles for Alk8 in patterning tooth-bearing pharyngeal epithelium, in the initiation of tooth development, in odontoblast and ameloblast differentiation, and in osteoblast maturation. The ability for zebrafish to continuously form teeth throughout their lives allows for the comparison of Alk8 expression in both primary and replacement tooth development, revealing identical Alk8 expression profiles. This study advances our current understanding of the functions of Alk8, particularly with respect to primary and replacement tooth formation, reveals additional roles for Alk8 in dental epithelial patterning and in odontoblast, ameloblast and osteoblast differentiation, and demonstrates the utility of the zebrafish as a model for primary and replacement tooth development.
Regulation of Cranial Suture Morphogenesis
Authors: Ogle Roy C. , Tholpady Sunil S. , McGlynn Kathryn A. , Ogle Rebecca A.
Published: January 2004

The cranial sutures are the primary sites of bone formation during skull growth. Morphogenesis and phenotypic maintenance of the cranial sutures are regulated by tissue interactions, especially those with the underlying dura mater. Removal of the dura mater in fetuses causes abnormal suture development and premature suture obliteration. The dura mater interacts with overlying tissues of the cranial vault by providing: (1) intercellular signals, (2) mechanical signals and (3) cells, which undergo transformation and migrate to the suture. The intercellular signaling governing suture development employs the fibroblast growth factors (FGFs). In rats during formation of the sutures in the fetus, FGF-1 is localized mainly in the dura mater, while other FGFs are expressed in the overlying tissues. By birth, FGF-2 largely replaces FGF-1 in the dura mater. FGFs present in the calvaria bind either the IIIb or IIIc mRNA splice variants of the FGF receptors (FGFRs) 1, 2, or 3. Monoclonal antibodies to the b variant of FGFR2 were used to determine the distribution of FGFR2IIIb during suture development and its extracellular localization. FGFR2IIIb is present in association with mature osteoblasts and osteogenic precursor cells of the suture in the fetus. Ectodomains of FGFR2IIIb, the products of proteolytic cleavage of the receptors, were present throughout the extracellular matrix of sutures resisting obliteration (coronal and sagittal), but absent from the core of sutures undergoing normal fusion (posterior intrafrontal). This observation is consistent with a possible mechanism, in which truncated receptors bind FGFs, thus regulating free FGF available to nearby cells. Mechanical signaling in the calvaria results from tensional forces in the dura mater generated during rapid expansion of the neurocranium. Posterior intrafrontal sutures of rats, which fuse between days 16 and 24, were subjected to cyclical tensional forces in vitro. Significant delay in the timing of suture fusion and increases in the expression domains of FGFR1 and 2 were observed, demonstrating the sensitivity of suture patency to mechanical signals and a possible role of the FGF system in mediating such stimuli. Finally, cells of the dura mater beneath the intrafrontal and sagittal sutures were observed to undergo a morphological transformation to a dendritic morphology and migrate into the suture mesenchyme between days 10 and 16 of development. This process may participate in suture and bone morphogenesis and influence the patency of the sutures along the anterior-posterior axis.
Perlecan Functions in Chondrogenesis: Insights from in vitro and in vivo Models
Authors: Gomes Jr. Ronald R. , Farach-Carson Mary C. , Carson Daniel D.
Published: January 2004

Perlecan is a large heparan sulfate proteoglycan that is typically found in basal lamina of adult and embryonic tissues. Recent studies have demonstrated that perlecan accumulates impressively during cartilage development and is maintained as the major heparan sulfate proteoglycan of adult cartilage. In vertebrates, perlecan mutations result in skeletal defects. Moreover, in vitro studies indicate that perlecan can stimulate early stages of cartilage differentiation and cooperate with chondrogenic growth factors to promote this process. This short article will summarize these results and propose a model for perlecan function that incorporates these genetic and cell biological findings.
New Insight into Progenitor/Stem Cells in Dental Pulp Using Col1a1-GFP Transgenes
Authors: Mina Mina , Braut Alen
Published: January 2004

In recent years there has been increasing progress in identifying stem cells from adult tissues and their potential application in tissue engineering. These advances provide a promising future for tooth replacement/regeneration. Essential for this approach is the identification of donor stem cells for various components of the teeth. Our studies show that pOBCol3.6GFPtpz and pOBCol2.3GFPemd transgenic animals provide a unique model to gain insight into stem cells in the dental pulp. Our in vivo studies of the developing teeth of these transgenic lines show both Col1a1-GFP transgenes are expressed in functional and fully differentiated odontoblasts. The patterns of expression of Col1a1-GFP transgenes during odontoblast differentiation correlates with the expression of DSPP. In the developing craniofacial bones both Col1a1-GFP transgenes are also expressed in osteoblasts and osteocytes of alveolar and calvarial bones. In the alveolar bones, the expression of Col1a1-GFP in osteocytes correlates with the expression of Dmp1. Col1a1-3.6-GFP is expressed in the entire layer of the periosteum and in suture mesenchyme containing osteoprogenitor cells. On the other hand, Col1a1-2.3- GFP expression was limited to the osteoblastic layer of the periosteum and was not detected in the fibroblastic layer of the periosteum or in the suture mesenchyme. These observations indicate that Col1a1-3.6-GFP and Col1a1-2.3-GFP transgenes identify different subpopulations of cells during intramembranous ossification. By using the coronal portion of dental pulps isolated from postnatal transgenic mice our observations also provide direct evidence that the dental pulp contains progenitor/stem cells capable of giving rise to a new generation of odontoblast-like cells, as well as osteoblast-like cells.
Development of a Tissue-Engineered Human Oral Mucosa: From the Bench to the Bed Side
Authors: Izumi Kenji , Song Junhui , Feinberg Stephen E.
Published: January 2004

The main objective of this publication is to make the reader aware of the complexity and steps that are necessary to make a Food and Drug Administration (FDA)-approved laboratory produced cell-based device, for use in clinical trials for reconstructive surgery. Most tissue-engineered cell-based devices are considered as ‘human somatic cell therapy’ and fall under the auspices of the Center of Biologic Evaluation and Research (CBER) and are considered a combination product by the FDA. We have illustrated the algorithm that is necessary to follow an Independent New Drug (IND) application by using our ex vivo produced oral mucosa equivalents (EVPOME), a tissue-engineered oral mucosa, as an example of a cell-based device that needs FDA approval prior to clinical application. By illustrating the experimental approach and presenting resulting data we attempt to explain each step that we address along the way.
Interstitial Irradiation for CNS Lesions
Authors: Teixeira M.J. , Lepski G. , Correia C. , Aguiar P.H.P.
Published: January 2004

In this study, we investigated the efficacy of brachytherapy in the treatment of 138 patients with intracranial neoplasms of the CNS. Of the total number of patients, 50 presented with glioblastoma multiforme, 45 presented with low-grade glioma, 19 presented with anaplastic astrocytoma, 23 presented with metastases and 1 presented with meningioma. During the execution of this study, seeds of 125I (10–20 mCi) were inserted into the lesions to aim the irradiation at a low dose of 60 Gy in the margin of benign lesions or 1 cm beyond the radiological border of malignant lesions, which were visualized on CT scan. The results of this procedure were evaluated in terms of the survival rates, which were assessed by Kaplan-Meier curves. Significant relationships were not observed between the volume and location of the lesions, the whole-brain radiotherapy and chemotherapy, and the survival time of the patients. A low Karnofsky Index score and older age were associated with a short survival time. In light of the above, it was concluded that interstitial irradiation is a safe and effective method of treatment for brain tumors.
Bulbar Trigeminal Stereotactic Nucleotractotomy for Treatment of Facial Pain
Authors: Teixeira M.J. , Lepski G. , Aguiar P.H.P. , Cescato V.A.S. , Rogano L. , Alaminos A.B.
Published: January 2004

Many pharmacological and surgical treatments are available for the treatment of chronic facial pain. However, many of them are expensive and often very ineffective. Past publications suggested that bulbar trigeminal stereotactic nucleotractotomy is a very useful procedure for the treatment of neuropathic or oncologic facial pain. The authors describe the results of treatment with stereotactic nucleotractotomy in 58 patients with chronic facial pain. The intensity of the pain was evaluated according to the visual analogue scale, and daily life activities were also evaluated. The conclusion was that this procedure is a safe and effective method for treatment of postherpetic neuralgia, Wallenberg’s syndrome and oncologic facial pain but not of trigeminal neuralgia.
Chronic Pain after Spinal Cord Injury: Clinical Characteristics
Authors: Rogano L. , Teixeira M.J. , Lepski G.
Published: January 2004

The clinical characteristics of chronic pain in spinal cord injury patients are controversial. The authors prospectively evaluated 81 patients with chronic pain due to spinal cord lesions. The mean pain intensity according to the visual analogue scale was 9.4. The most common description of pain was a sensation of burning. The initial pain was more severe in patients presenting with myelopathy due to gunshot injuries (p < 0.001). The pain intensity was not associated with the magnitude of the spinal lesion, location of the lesion, occurrence of myofascial pain syndrome or onset of pain. Pain after spinal cord injury was severe, males were more frequently affected and it was more intense when it was the result of gunshot injury. In about 38% of the patients, pharmacological and rehabilitative procedures were effective. Dorsal root entry zone lesion was effective for the treatment of transitional pain in patients with complete section of the spinal cord, spinal cord stimulation was effective for patients with partial lesions of the spinal cord and intrathecal opioid infusion was effective for both conditions.
Spinal Cord Stimulation for the Treatment of Refractory Unilateral Limb Pain Syndromes
Authors: Kumar Abhaya , Felderhof Catriona , Eljamel M. Sam
Published: January 2004

Background: Spinal cord stimulation (SCS) is an established therapy for chronic pain. Its success depends on vigorous patient selection and good follow-up. Methods: We reviewed 75 patients who had undergone SCS to establish their outcome. 67 of these patients had refractory unilateral limb pain syndrome (RULPS). Their case notes and operative log books were critically reviewed, and when appropriate, telephone interviews were performed (58 patients). Results: 87% of patients responded initially to SCS; at 6 months, the effect waned to 79%, and by 2 years, it improved to 84%. One third of the patients had no revisions, 40% had IPG replacements and the rest had revisions because of lead-related complications (5.3%), epidural complications (mainly fibrosis; 19%) or infections (2.7%). 56% of patients reduced their analgesia, 1.5% stopped taking any painkillers and 46.8% of those who were employed returned to work. Conclusion: We feel that SCS is an effective treatment in RULPS and its results depend upon vigorous patient selection and an adequate follow-up and maintenance program.
Predictive Factors of Radiation Necrosis after Radiosurgery for Cerebral Metastases
Authors: Valéry Charles A. , Cornu Philippe , Noël Georges , Duyme Michel , Boisserie Gilbert , Sakka Laurent J. , Mazeron Jean-Jacques , van Effenterre Rémy
Published: January 2004

The aim of this study was to determine if the risk of radiation necrosis after radiosurgery is related to the presence of normal tissue included in the prescription volume. Between 1994 and 2001, 377 patients representing 760 lesions were treated by radiosurgery in our center with a 10-MV LINAC. The median age of the patients was 57 years (range 30–86 years), median tumor volume was 4.9 cm3, median peripheral dose (70%) was 15.6 Gy and median dose at the isocenter was 21.6 Gy. Karnofsky index, disease control and number of lesions were the only parameters significantly influencing survival (median 8.6 months), while disease-free survival was correlated with the number of isocenters. Seven percent of the patients presented severe complications, including nine episodes of radiation necrosis. The only parameter influencing the risk of radiation necrosis was the conformity index (p = 0.001). These findings emphasize the importance of reducing falsely irradiated normal tissue during radiosurgery to prevent radiation necrosis.
Hemorrhagic Complications of Microelectrode-Guided Deep Brain Stimulation
Authors: Binder Devin K. , Rau Geoff , Starr Philip A.
Published: January 2004

Background: The incidence of intracranial hemorrhage occurring during microelectrode-guided implantation of deep brain stimulators (DBS) for movement disorders has not been well defined. We report the incidence of hemorrhage in a large series of DBS implants into the subthalamic nucleus (STN), thalamus (VIM) and internal globus pallidus (GPi). Methods: All DBS procedures performed by a single surgeon (P.A.S.) between June 1998 and April 2003 were included in this study. Patients had postoperative imaging (MRI or CT) 4–24 h following surgery, and all hematomas >0.2 cm3 in volume were noted and scored as symptomatic (associated with any new neurologic deficit lasting >24 h) or asymptomatic. Results: The total number of lead implants was 357. There were 5 symptomatic hematomas and 6 asymptomatic hematomas. The relative risk of hematoma (any type) per lead implant was 3.1%. The incidence of hematoma by target site was 2.5% per lead for STN-DBS, 6.7% for GPi-DBS and 0% for VIM-DBS. Conclusion: The overall risk of intraoperative or early postoperative symptomatic hemorrhage with microelectrode-guided DBS, over all targets, was 1.4% per lead implant. The brain target had a significant effect on the risk of hemorrhage.
History Repeats Itself
Authors: Gildenberg Philip L.
Published: January 2004

Although many advances in stereotactic surgery appear to be of recent origin, there are precedents in the literature documenting the planting of those seeds that eventually grew into common procedures. Pallidotomy was the first stereotactic procedure in humans that used the Spiegel-Wycis apparatus in 1947. Other targets for Parkinson’s disease have their roots in the decade following that. Using stereotactic techniques to target solid or cystic lesions was introduced in the 1950’s, when either calcification or pneumoencephalography were necessary to visualize the mass. One of the first uses of computers in surgery was in stereotaxis. Infusion of a neurotransmitter was first done over 30 years ago.
Subthalamic Nucleus Deep Brain Stimulation for Parkinson’s Disease: Magnetic Resonance Imaging Targeting Using Visible Anatomical Landmarks
Authors: Pollo Claudio , Meuli Reto , Maeder Philippe , Vingerhoets François , Ghika Joseph , Villemure Jean-Guy
Published: January 2004

Background: The aim of the present study was to validate a magnetic resonance imaging (MRI) visual procedure to target the subthalamic nucleus (STN) based on surrounding anatomical landmarks. Methods: 31 consecutive bilaterally implanted parkinsonian patients were included in this study. After identification of the anterior commissure (AC), posterior commissure (PC) and midcommissural point on a three-dimensional T1-weighted sequence, inversion recovery (IR) T2-weighted coronal slices were performed orthogonal to the AC-PC line. On the slice showing the anterior pole of the red nucleus (RN), the target was placed in the inferolateral portion of the subthalamic zone, limited superiorly by the thalamus, laterally by the internal capsule, inferiorly by the substantia nigra and medially by the midline. The distribution of the targets was analyzed in the AC-PC referential. Results: The mean target coordinates were as follows: anteroposterior (AP) = –2.54 mm (±1.37 mm), lateral (LAT) = 12.03 mm (±0.91 mm) and vertical (VERT) = –6.10 mm (±1.52 mm) for the right side, and AP = –2.65 mm (±1.36 mm), LAT = –11.97 mm (±1.30 mm) and VERT = –5.89 mm (±1.52 mm) for the left side. They projected in the inferior portion of the STN on the Schaltenbrand and Wahren atlas [Stuttgart, Thieme, 1977]. Conclusion: Identification of the anterior pole of the RN and the subthalamic zone on coronal IR T2-weighted MRI performed orthogonal to the AC-PC line provides a precise visual procedure to target the STN.
Effect of Stereotactic High-Frequency Stimulation in the Anterior Lobe of the Cerebellum in Cerebral Palsy: A New Suboccipital Approach
Authors: Galanda M. , Horvath S.
Published: January 2004

The direct stereotactic suboccipital approach to the anterior lobe of the cerebellum was applied for deep high-frequency stimulation in three patients (for 29, 8 and 3 months) suffering from cerebral palsy. In agreement with our previous experience with a transtentorial approach in 30 patients, spasticity, dyskinesias and behavior were improved during chronic intermittent stimulation (frequency 185 Hz, pulse width 210 µs, voltage individually altered according to motor response at 0.5–4.0 V, 15 min on, 2–6 h off). Patients attained useful motor skill improvements. The results indicate that the method is safe, effective and reasonable.
Deep Brain Stimulation for Parkinson’s Disease: Correlation between Intraoperative Subthalamic Nucleus Neurophysiology and Most Effective Contacts
Authors: Cintas P. , Simonetta-Moreau M. , Ory F. , Brefel-Courbon C. , Fabre N. , Chaynes P. , Sabatier J. , Sol J.C. , Rascol O. , Berry I. , Lazorthes Y.
Published: January 2004

Though intraoperative neurophysiology is essential to precisely define the definitive target, little is known regarding its predictive value in defining the most effective contact for chronic deep brain stimulation. In this retrospective study, we reviewed the correlation between intraoperative neurophysiology and contacts selected for chronic stimulation. Twenty consecutive patients implanted for subthalamic nucleus (STN) stimulation were reviewed. There was no significant correlation between the electrophysiologically defined STN and the most effective contact for chronic stimulation at 3 months or at 6 months. Furthermore, there was a discrepancy between the most effective contact for rigidity versus akinesia or tremor at 3 months. Interestingly, at 3 months, the same electrode contact was maximally efficient for rigidity, akinesia and tremor in only 13 of the 39 cases. This lack of correlation did not affect the global improvement.
A Noncontacting 3-D Digitizer for Use in Image-Guided Neurosurgery
Authors: Sun Hai , Farid Hany , Roberts David W. , Rick Kyle , Hartov Alex , Paulsen Keith D.
Published: January 2004

Current neuronavigational systems face two primary challenges: (1) automatic and robust registration between preoperative images and the operating room space, and (2) compensation for brain deformations that compromise the accuracy of the initial registration. To contend with these difficulties, we firstly estimate the three-dimensional (3-D) structure of the cortical surface using a noncontacting 3-D digitizer. This 3-D structure is then used to establish the initial registration, and to update the preoperative MR volume as the brain deforms. We show that this approach improves the accuracy of registration in a phantom study, and demonstrate the ability to capture cortical motion in six clinical cases.
Stereotactic Accuracy of a 3-Tesla Magnetic Resonance Unit
Authors: Azmi Hooman , Schulder Michael
Published: January 2004

Recently, magnetic resonance imagers (MRIs) with 3-tesla magnets were approved for clinical use. The spatial accuracy of these high-resolution scanners has yet to be proven. In the present study, a computed tomography (CT)- and MRI-compatible phantom was scanned on a CT, a 1.5-tesla MRI and a 3-tesla MRI scanner. The model was registered to the images using an infrared-based surgical navigation system. The distance between the predicted position of the navigation probe tip and the actual target on the image was measured on the x, y and z axes for 13 points on each image. Error was compared across imaging modalities, peripheral versus central targets and along each axis. We found that 3-tesla MRI scans are accurate as stereotactic data sets.
Molecular Analysis of Therapy Resistance in Gastric Cancer
Authors: Lage Hermann
Published: January 2004

Therapy resistance is the main cause of therapeutic failure and death in patients suffering from gastric carcinoma. Clinical resistance against systemic chemotherapy of gastric cancer is likely to be multifactorial and heterogenous. So far, no significant resistance factor that predicts the clinical outcome of systemic treatment of gastric carcinoma has been identified. In order to gain further understanding of therapy resistance in gastric carcinoma, various in vitro model systems were established. One of these models consists of the parental, drug-sensitive and thermosensitive human gastric carcinoma cell line EPG85-257P, its classical multidrug-resistant variant EPG85-257RDB, its atypical multidrug-resistant subline EPG85-257RNOV and their thermoresistant counterparts EPG85-257P-TR, EPG85-257RDB-TR, and EPG85-257RNOV-TR. This panel of cells was analyzed using morphological, biochemical, cellular and molecular biological methods to identify potential new factors involved in therapy resistance of gastric carcinoma. Cellular alterations that could be identified in these models were evaluated by functional investigations. This review will discuss the current state of knowledge of these new therapy resistance-associated factors, e.g. glypican-3 (GPC3), as well as the impact of well-known drug resistance-associated factors, such as MDR1/P-glycoprotein, on therapy resistance of gastric carcinoma.
Clinical Implications of Alpha-Fetoprotein Expression in Gastric Adenocarcinoma
Authors: Chen Jie , Röcken Christoph , Treiber Gerhard , Jentsch-Ulrich Kathleen , Malfertheiner Peter , Ebert Matthias P.A.
Published: January 2004

Background: Alpha-fetoprotein (AFP)-producing gastric adenocarcinoma has an extremely poor prognosis. Few cases have been reported in Germany until now. Here we report on a patient with an AFP-producing gastric cancer and a subsequent analysis of AFP expression in a more extended series of gastric cancer patients. Material and Methods: A 62-year-old man was referred to our hospital with suspected gastric cancer. Gastroscopy, ultrasound, and CT scans of the abdomen showed a gastric tumour. Serological and histopathological investigations led to the diagnosis of a poorly differentiated adenocarcinoma expressing AFP. Following diagnosis, a short-term response was achieved by palliative chemotherapy. Expression of AFP and albumin was then investigated on an extended series of 25 patients with gastric cancer and four gastric cancer cell lines using immunohistochemistry and RT-PCR. No patient had suffered from hepatocellular carcinoma or germ cell tumor. Results: Using paraffin-embedded gastric cancer specimens, we found AFP immunohistochemically in 2 of 25 (8%) patients. AFP-mRNA was expressed in 3 (12%) patients and a single gastric cancer cell line (AGS). Albumin-mRNA was not found in any gastric cancer sample or gastric cancer cell line. Conclusions: Our study shows that AFP-producing gastric adenocarcinomas are an important clinical entity with a frequency that has been underestimated in the past. In the absence of a primary liver tumor, clinicians have to consider a primary gastric cancer, which has a poor prognosis, and merits a more aggressive therapy.
Comorbid Depression and Platelet Serotonin in Hemodialysis Patients
Authors: Barišić Ivan , Pivac Nela , Mück-Šeler Dorotea , Jakovljević Miro , Šagud Marina
Published: January 2004

Background/Aim: Comorbid depression often occurs in chronic renal failure patients on hemodialysis (HD). Reduced serotonin (5-HT) function is implicated in the pathophysiology of depression. Methods: Comorbid depression and different clusters of depressive symptoms were assessed in 79 male HD patients and 35 male depressed psychiatric patients. Platelet 5-HT concentration (a peripheral model for the central serotonergic neurons) was determined in all patients and 80 male healthy controls. Results: Comorbid depression occurred in 50 out of 79 HD patients. Depressed psychiatric patients and depressed HD patients had higher scores of anxiety, retardation, and cognitive symptoms than nondepressed HD patients. Platelet 5-HT concentration was lower in depressed or nondepressed HD patients than in healthy controls, or in depressed patients. Higher platelet 5-HT content was found in depressed psychiatric patients with depressive clusters than in all other patients. Among HD patients, anxious HD patients had a higher platelet 5-HT concentration than HD patients without anxiety symptoms. Conclusions: Comorbid depression occurred in 63% of HD patients. Dialyzed patients had decreased platelet 5-HT concentration, regardless of the occurrence of comorbid depression. Higher platelet 5-HT concentration was related to anxiety symptoms in HD patients. Our data suggest that platelet 5-HT concentration might be a suitable marker for anxiety symptoms in dialyzed patients.
Low Initial Vitamin B12 Levels in Helicobacter pylori-Positive Patients on Chronic Hemodialysis
Authors: Trimarchi H. , Forrester M. , Schropp J. , Pereyra H. , Freixas E.A.
Published: January 2004

Background:Helicobacter pylori has been identified as a possible cause of vitamin B12 deficiency in the general population. We assessed any potential relationship between low cyanocobalamin serum levels and Helicobacter pylori status in hemodialysis patients and subsequently correlated these results with the existence of anemia (a common complication in hemodialysis patients), and macrocytosis. Methods: In 29 chronic hemodialysis patients, active H. pylori infection was diagnosed using two different methods regardless of digestive symptoms: by searching for bacterial antigens in stools and by the detection of urea breakdown through breath testing. If these results were non-coincident, gastroscopy was performed and antral biopsies obtained. Patients were subsequently divided into group A (H. pylori-positive, n = 8, 28%) and group B (H. pylori-negative, n = 21, 72%). The corresponding initial values of erythrocytic folic acid, vitamin B12 and homocysteine prior to the first hemodialysis session of each patient were retrospectively collected. Results: Vitamin B12 levels (normal 200– 900 pg/ml) were significantly lower in group A compared to group B (225.4 ± 111.9 vs. 707.9 ± 258.3 pg/ml, p < 0.011). In group A, 5 patients (63%) had vitamin B12 deficiency (154 ± 24.6 pg/ml). Baseline hematocrits, erythrocyte folic acid and serum homocysteine levels were not different between the groups, but mean corpuscular volumes were significantly higher in group A compared to group B (109.7 ±14.1 vs. 91.8 ± 8.8 fl, p = 0.002). Conclusions:H. pylori-positive chronic hemodialysis patients may present with lower vitamin B12 blood levels and macrocytosis. H. pylori infection should be suspected in this population when low or low-normal vitamin B12 levels or macrocytosis exist.
Cytokines and Cell Adhesion Molecules in the Inflammatory Response during Acute Pyelonephritis
Authors: Webb Nicholas J.A. , Brenchley Paul E.C.
Published: January 2004

Urinary tract infection is a common bacterial infection of childhood. Renal parenchymal scarring, a recognised complication of urinary tract infection, is responsible for up to 24% of children entering end-stage renal failure. Why acute inflammation results in renal scarring in some children whilst in others complete resolution occurs without scarring is at present poorly understood. This article reviews the role of the cytokines, adhesion molecules and growth factors in the inflammatory response during acute pyelonephritis and renal parenchymal scarring. We hypothesize that inter-individual variability in cellular response may in part be responsible for this variable clinical outcome.