bluuebunny/crossref_metadata_2025 huggingface dataset:
Kidney Stones, Carbonic Anhydrase Inhibitors, and the Ketogenic Diet
Authors: Kossoff Eric H. , Pyzik Paula L. , Furth Susan L. , Hladky Heather D. , Freeman John M. , Vining Eileen P. G.
Published: March 2003

Summary: Purpose:Because carbonic anhydrase inhibitors and the ketogenic diet are each known risk factors for kidney stones, simultaneous use of these therapies has been discouraged. The objective of this study was to establish the prevalence of nephrolithiasis in children in this combination‐therapy population.

Methods:Since 1996, 301 children have been started on the ketogenic diet at our institution. A retrospective cohort study of renal calculi in ketogenic diet patients was performed to evaluate the increased risk with combined use of a carbonic anhydrase inhibitor.

Results:In 15 (6.7%) of 221 children on the ketogenic diet without the use of carbonic anhydrase inhibitors, stones developed. In five (6.3%) of the 80 children on the diet in combination with topiramate or zonisamide, stones developed. There was no difference between these two groups (p = 0.82). No child was treated with either acetazolamide or more than one carbonic anhydrase inhibitor simultaneously. Prior ketogenic diet duration was shorter (10.4 vs. 22.4 months; p = 0.03), and more children had either a family history of renal stones or significant urologic abnormalities (80 vs. 27%; p = 0.04) in the combination‐therapy group.

Conclusions:The combined use of carbonic anhydrase inhibitors and the ketogenic diet does not increase the risk of kidney stones. We recommend that all patients treated with combination therapy should be treated with increased hydration. Urine alkalinization should be considered for children with previous renal abnormalities, family histories of kidney stones, hematuria, or elevated urine calcium‐to‐creatinine ratios. If renal stones are found, we advocate discontinuation of the carbonic anhydrase inhibitor.
Risk of Extremity Fractures in Adult Outpatients with Epilepsy
Authors: Persson Hakan B. I. , Alberts K. A. , Farahmand B. Y. , Tomson T.
Published: March 2003

Summary:  Purpose: To study the incidence of extremity fractures in a group of adult patients with epilepsy attending an outpatient clinic compared with the incidence of fractures in the general population in the same geographic area.

Methods: We selected 177 consecutive adult patients with epilepsy attending the outpatient clinic at the Department of Neurology at Karolinska Hospital in Stockholm in 1995. This study population was matched with an Injury Registry to identify those epilepsy patients who during 1991 through 1995 attended the emergency department for an extremity fracture. The observed number of fractures in the epilepsy group was compared with the corresponding number of expected cases based on regional fracture rates. Relative‐risk estimates for fractures were calculated with respect to the duration of epilepsy, mono‐ or polytherapy, and history of tonic–clonic seizures.

Results: Twenty (11%) of 177 patients sustained 23 fractures that prompted a visit to the emergency department. The incidence of fractures in the epilepsy patients was 23.8/1,000 person‐years. The overall Standardized Morbidity Ratio (SMR) was 2.39 (95% CI, 1.52–3.59). A significantly higher risk for fractures was thus found in patients with epilepsy. Risk factors were age 45 years or older, male sex, and occurrence of generalized seizures. It also was found that the relative risk of fractures was higher during the first and second year compared with ≥5 years after diagnosis (RR, 3.71; 95% CI, 1.20–11.48).

Conclusions: Our results highlight the risk of fractures in outpatients with epilepsy. In this patient group, 43% of the fractures were definitely or possibly seizure related. Males 45 years or older are a particular risk group. Special attention is required for this group of patients who are at higher risk for fractures. The risk is apparently higher in the first 2 years after diagnosis, although potential bias in ascertainment of fracture incidents in our study may have underestimated the long‐term risk for fractures.
Predictive Value of Cortical Injury for the Development of Temporal Lobe Epilepsy in 21‐day‐old Rats: An MRI Approach Using the Lithium‐pilocarpine Model
Authors: Roch Catherine , Leroy Claire , Nehlig Astrid , Namer Izzie J.
Published: March 2003

Summary: Purpose:Patients with temporal lobe epilepsy (TLE) usually had an initial precipitating injury in early childhood. However, epilepsy does not develop in all children who have undergone an early insult. As in patients, the consequences of the lithium‐pilocarpine‐induced status epilepticus (SE) are age dependent, and only a subset of 21‐day‐old rats will develop epilepsy. Thus with magnetic resonance imaging (MRI), we explored the differences in the evolution of lesions in these two populations of rats.

Methods:SE was induced in 21‐day‐old rats by the injection of lithium and pilocarpine. T2‐weighted images and T2relaxation‐time measurements were used for detection of lesions from 6 h to 4 months after SE.

Results:Three populations of rats could be distinguished. The first one had neither MRI anomalies nor modification of the T2relaxation time, and these rats did not develop epilepsy. In the second one, a hypersignal appeared at the level of the piriform and entorhinal cortices 24 h after SE (increase of 49% of the T2relaxation time in the piriform cortex) that began to disappear 48–72 h after SE; epilepsy developed in all these animals. The third population of rats showed a more moderate increase of the T2relaxation time in cortices (14% in the piriform cortex) that could not be seen on T2‐weighted images. Epilepsy developed in all these rats. Only in a subpopulation of the 21‐day‐old rats with epilepsy did hippocampal sclerosis develop.

Conclusions:These results suggest that the injury of the piriform and entorhinal cortices during SE play a critical role for the installation of the epileptic networks and the development of epilepsy.
The Usefulness of Subtraction Ictal SPECT Coregistered to MRI in Single‐ and Dual‐headed SPECT Cameras in Partial Epilepsy
Authors: Kaiboriboon Kitti , Lowe Val J. , Chantarujikapong Sunanta I. , Hogan R. Edward
Published: March 2003

Summary:  Purpose: To prove the clinical usefulness of SISCOM and compare SISCOM images derived from single‐ and dual‐headed single‐photon computed tomography (SPECT) cameras for localization of partial epileptic seizures.

Methods: We retrospectively studied 38 partial epilepsy patients, using subtraction SPECT coregistered to magnetic resonance imaging (MRI; SISCOM). SPECT imaging of the first 15 patients was performed by single‐headed camera, and the next 23 patients by dual‐headed camera. Side‐by‐side ictal–interictal SPECT evaluation and SISCOM images were blindly reviewed and classified as either localizing to one of 16 sites or nonlocalizing. A third reviewer evaluated cases of disagreement between primary reviewers. Results were compared with seizure localization by any of the following three traditional techniques: surgical outcome, invasive, and noninvasive video‐EEG monitoring. The results from the single‐ and dual‐headed SPECT cameras were compared.

Results: Reviewers localized areas of hyperperfusion with SISCOM images more often than with side‐by‐side SPECT evaluation (71.0 vs. 47.4%; p = 0.01). When we compared results of SPECT evaluation with traditional techniques, SISCOM showed greater concordance than side‐by‐side SPECT evaluation (60.53 vs. 36.84%; p = 0.006). There were no differences in localization between images derived from single‐ and dual‐headed cameras. Concordance of seizure localization, compared with traditional techniques, also was not different between these groups [κ = 0.38, 95% confidence interval (CI), 0.18–0.58] vs. κ = 0.63, 95% CI (0.45–0.81)].

Conclusions: SISCOM is a worthwhile technique for preoperative evaluation in partial epilepsy patients and improves the sensitivity and specificity of seizure localization of SPECT images derived from both single‐ and dual‐headed SPECT cameras.
Early‐onset Cobalamin C/D Deficiency: Epilepsy and Electroencephalographic Features
Authors: Biancheri Roberta , Cerone Roberto , Rossi Andrea , Schiaffino Maria Cristina , Caruso Ubaldo , Minniti Giuseppe , Perrone Maria Viviana , Tortori‐Donati Paolo , Veneselli Edvige
Published: March 2003

Summary:  Purpose: To describe epilepsy and EEG findings in the early‐onset cobalamin (Cbl) C/D deficiency, an inborn error of intracellular Cbl metabolism characterized by high plasma levels of methylmalonic acid, homocystine, and homocysteine.

Methods: Type and frequency of seizures were studied in 10 patients (six boys and four girls) who underwent waking and sleep EEG.

Results: Half of patients had seizures in the first year of life (either concurrent with the other symptoms of disease or some months after the onset of disease); seizures occurred after 2 years in the other half of patients. Convulsive status epilepticus was the initial manifestation in three patients. During the follow‐up, nine patients had seizures (mainly partial) despite specific treatment for Cbl C/D deficiency and antiepileptic drugs. Focal or multifocal epileptiform abnormalities during waking EEG that increased during sleep EEG were recorded in the majority of patients. Plasma levels of homocystine and homocysteine were constantly higher than normal, despite therapy institution.

Conclusions: Epilepsy and EEG abnormalities are prominent features in the early‐onset type of combined methylmalonic aciduria and homocystinuria due to Cbl C/D deficiency, possibly related to the pathologically and persistently high levels of homocysteine, experimentally proven to induce seizures. Plasma amino acids evaluation and urinary acid organic analysis should be performed in any infant showing seizures associated with feeding difficulties and failure to thrive, at onset during the first year of life, as well as in any child with convulsive status epilepticus and a history of psychomotor developmental delay of unknown origin.
Topiramate and Phenytoin Pharmacokinetics During Repetitive Monotherapy and Combination Therapy to Epileptic Patients
Authors: Sachdeo R. C. , Sachdeo S. K. , Levy R. H. , Streeter A. J. , Bishop F. E. , Kunze K. L. , Mather G. G. , Roskos L. K. , Shen D. D. , Thummel K. E. , Trager W. F. , Curtin C. R. , Doose Dennis R. , Gisclon L. G. , Bialer Meir
Published: March 2003

Summary:  Purpose: To evaluate the potential pharmacokinetic interactions between topiramate (TPM) and phenytoin (PHT) in patients with epilepsy by studying their pharmacokinetics (PK) after monotherapy and concomitant TPM/PHT treatment.

Methods: Twelve patients with epilepsy stabilized on PHT monotherapy were enrolled in this study, with 10 and seven patients completing the phases with 400 and 800 mg TPM daily doses, respectively. TPM was added at escalating doses, and after stabilization at the highest tolerated TPM dose, PHT doses were tapered. Serial blood and urine samples were collected for PK analysis during the monotherapy phase or the lowest PHT dose after taper and the concomitant TPM/PHT phase. Potential metabolic interaction between PHT and TPM also was studied in vitro in human liver microsomal preparations.

Results: In nine of the 12 patients, PHT plasma concentrations remained stable, with a mean (±SD) area under the curve (AUC) ratio (combination therapy/monotherapy) of 1.13 ± 0.17 (range, 0.89–1.23). Three patients had AUC ratios of 1.25, 1.39, and 1.55, respectively, and with the addition of TPM (800, 400, and 400 mg daily, respectively), their peak PHT plasma concentrations increased from 15 to 21 mg/L, 28 to 36 mg/L, and 27 to 41 mg/L, respectively. Human liver microsomal studies with S‐mephenytoin showed that TPM partially inhibited CYP2C19 at very high concentrations of 300 μM (11% inhibition) and 900 μM (29% inhibition). Such high plasma concentrations would correspond to doses in humans that are 5 to 15 times higher than the recommended dose (200–400 mg). TPM clearance was approximately twofold higher during concomitant TPM/PHT therapy

Conclusions: This study provides evidence that the addition of TPM to PHT generally does not cause clinically significant PK interaction. PHT induces the metabolism of TPM, causing increased TPM clearance, which may require TPM dose adjustments when PHT therapy is added or is discontinued. TPM may affect PHT concentrations in a few patients because of inhibition by TPM of the CYP2C19‐mediated minor metabolic pathway of PHT.
Acetoacetate, Acetone, and Dibenzylamine (a Contaminant in l‐(+)‐β‐Hydroxybutyrate) Exhibit Direct Anticonvulsant Actions in Vivo
Authors: Rho Jong M. , Anderson Gail D. , Donevan Sean D. , White H. Steve
Published: March 2003

Summary:  Purpose: To investigate whether ketone bodies are directly anticonvulsant.

Methods: We tested the effects of acetoacetate (ACA), acetone, and both stereoisomers, d‐(−)‐ and l‐(+), of β‐hydroxybutyrate (BHB) on sensory‐evoked seizures in Frings audiogenic seizure‐susceptible mice.

Results: We found that these ketone bodies, with the exception of the d‐(−)‐isomer of BHB, were anticonvulsant in this model. Furthermore, with gas chromatography–mass spectrometry, we confirmed that the activity of l‐(+)‐BHB was due to dibenzylamine, a chemical contaminant.

Conclusions: Our data indicate that the anticonvulsant efficacy of the ketogenic diet may be due in part to the direct actions of ACA and acetone.
Prediction of Seizure‐onset Laterality by Using Wada Memory Asymmetries in Pediatric Epilepsy Surgery Candidates
Authors: Lee Gregory P. , Park Yong D. , Hempel Ann , Westerveld Michael , Loring David W.
Published: March 2003

Summary:  Purpose: Because the capacity of intracarotid amobarbital (Wada) memory assessment to predict seizure‐onset laterality in children has not been thoroughly investigated, three comprehensive epilepsy surgery centers pooled their data and examined Wada memory asymmetries to predict side of seizure onset in children being considered for epilepsy surgery.

Methods: One hundred fifty‐two children with intractable epilepsy underwent Wada testing. Although the type and number of memory stimuli and methods varied at each institution, all children were presented with six to 10 items soon after amobarbital injection. After return to neurologic baseline, recognition memory for the stimuli was assessed. Seizure onset was determined by simultaneous video‐EEG recordings of multiple seizures.

Results: In children with unilateral temporal lobe seizures (n = 87), Wada memory asymmetries accurately predicted seizure laterality to a statistically significant degree. Wada memory asymmetries also correctly predicted side of seizure onset in children with extra–temporal lobe seizures (n = 65). Although individual patient prediction accuracy was statistically significant in temporal lobe cases, onset laterality was incorrectly predicted in ≤52% of children with left temporal lobe seizure onset, depending on the methods and asymmetry criterion used. There also were significant differences between Wada prediction accuracy across the three epilepsy centers.

Conclusions: Results suggest that Wada memory assessment is useful in predicting side of seizure onset in many children. However, Wada memory asymmetries should be interpreted more cautiously in children than in adults.
Hippocampal Programmed Cell Death after Status Epilepticus: Evidence for NMDA‐Receptor and Ceramide‐Mediated Mechanisms
Authors: Mikati Mohamad A. , Abi‐Habib Ralph J. , El Sabban Marwan E. , Dbaibo Ghassan S. , Kurdi Rana M. , Kobeissi Mohamad , Farhat Firas , Asaad Wissal
Published: March 2003

Summary:  Purpose: Status epilepticus (SE) can result in acute neuronal injury with subsequent long‐term age‐dependent behavioral and histologic sequelae. To investigate potential mechanisms that may underlie SE‐related neuronal injury, we studied the occurrence of programmed cell death (PCD) in the hippocampus in the kainic acid (KA) model.

Methods: In adult rats, KA‐induced SE resulted in DNA fragmentation documented at 30 h after KA injection. Ceramide, a known mediator of PCD in multiple neural and nonneural tissues, increased at 2–3 h after KA intraperitoneal injection, and then decreased to control levels before increasing again from 12 to 30 h after injection. MK801 pretreatment prevented KA‐induced increases in ceramide levels and DNA fragmentation, whether there was reduction in seizure severity or not (achieved with 5 mg/kg and 1 mg/kg of MK801, respectively).

Results: Both ceramide increases and DNA fragmentation were observed after KA‐induced SE in adult and in P35 rats. Ceramide did not increase after KA‐induced SE in P7 pups, which also did not manifest any DNA fragmentation. Intrahippocampal injection of the active ceramide analogue C2‐ceramide produced widespread DNA fragmentation, whereas the inactive ceramide analogue C2‐dihydroceramide did not.

Conclusions: Our data support the hypotheses that (a) N‐methyl‐d‐aspartate–receptor activation results in ceramide increases and in DNA fragmentation; (b) ceramide is a mediator of PCD after SE; and (c) there are age‐related differences in PCD and in the ceramide response after SE. Differences in the ceramide response could, potentially, be responsible for observed age‐related differences in the response to SE.
Levetiracetam Efficacy in Refractory Partial‐onset Seizures, Especially after Failed Epilepsy Surgery
Authors: Motamedi Mahmood , Nguyen Dang K. , Zaatreh Megdad , Singh Sanjay P. , Westerveld Michael , Thompson James L. , Mattson Richard , Blumenfeld Hal , Novotny Edward , Spencer Susan S.
Published: March 2003

Summary:  Purpose: We conducted a retrospective study to evaluate the efficacy of levetiracetam as adjunctive therapy in patients with localization‐related epilepsy, and specifically in the subset of patients for whom epilepsy surgery failed.

Methods: Eighty‐two patients with uncontrolled partial‐onset seizures treated with levetiracetam were identified; epilepsy surgery had failed for 21 (25.6%; group I), and 61 (74.4%) had no prior surgery (group II). Group I and group II patients were comparable in age (mean, 40.7 vs. 41.5 years) and age at seizure onset (mean, 14.4 vs. 18.2 years). Patients who had ≥50% reduction in seizure frequency were considered responders; the remaining patients were considered nonresponders.

Results: In patients (group I) for whom surgery had failed, responder rate was 76.1% (16 of 21), including 10 (47.6%) patients who became seizure free. In nonsurgical patients (group II), responder rate was 34.3% (21 of 61), including nine (14.7%) patients who became seizure free. In group I, 11 (91.6%) of 12 temporal resection patients were responders, of whom eight were seizure free; of the remaining nine operated (extratemporal) patients, five (55.5%) were responders, and two were seizure free. In three responders, all in group I, a severe, delayed psychotic syndrome developed 4 to 9 months after levetiracetam introduction, leading to its discontinuation.

Conclusions: These findings suggest that adjunctive levetiracetam therapy should be considered early after failed epilepsy surgery, especially after temporal resection, and may have implications for its use before surgical intervention. Patients should be under close psychiatric observation in this clinical setting.
Continuous EEG Monitoring in the Intensive Care Unit
Authors: Scheuer Mark L.
Published: March 2003

Summary: Continuous EEG (CEEG) monitoring allows uninterrupted assessment of cerebral cortical activity with good spatial resolution and excellent temporal resolution. Thus, this procedure provides a means of constantly assessing brain function in critically ill obtunded and comatose patients. Recent advances in digital EEG acquisition, storage, quantitative analysis, and transmission have made CEEG monitoring in the intensive care unit (ICU) technically feasible and useful. This article summarizes the indications and methodology of CEEG monitoring in the ICU, and discusses the role of some quantitative EEG analysis techniques in near real‐time remote observation of CEEG recordings. Clinical examples of CEEG use, including monitoring of status epilepticus, assessment of ongoing therapy for treatment of seizures in critically ill pateints, and monitoring for cerebral ischemia, are presented. Areas requiring further development of CEEG monitoring techniques and indications are discussed.
Functional Role of Inflammatory Cytokines and Antiinflammatory Molecules in Seizures and Epileptogenesis
Authors: Vezzani Annamaria , Moneta Daniela , Richichi Cristina , Aliprandi Marisa , Burrows Stephanie J. , Ravizza Teresa , Perego Carlo , De Simoni M. Grazia
Published: March 2003

Summary:  Purpose: We investigated the changes in the expression of proinflammatory cytokines and related molecules in the rodent hippocampus after the induction of limbic seizures. We then studied the effects of pharmacologic intervention on the interleukin (IL)‐1 system on limbic seizures and the susceptibility to seizures of transgenic mice overexpressing the naturally occurring antagonist of IL‐1 (IL‐1Ra) in astrocytes.

Methods: Limbic seizures were induced in rodents by intrahippocampal injection of kainic acid or bicuculline methiodide or by electrical stimulation of the hippocampus causing status epilepticus (SE). Seizure activity was recorded by EEG analysis and behavioral observation according to Racine's scale. Cytokine expression in the hippocampus was studied by reverse transcriptase–polymerase chain reaction (RT‐PCR) followed by Southern blot quantification of the various messenger RNAs (mRNAs) and by immunocytochemistry.

Results: We found that limbic seizures rapidly and transiently enhanced IL‐1β, IL‐6, and tumor necrosis factor (TNF)‐α mRNA in the hippocampus with a peak effect at 6 h after SE. Immunoreactivity of the various cytokines was increased in glia. The increase of IL‐1Ra was delayed because the peak effect was observed at 24 h after SE. Moreover, IL‐1Ra was not produced in large excess, as during peripheral inflammation but in a molar ratio to IL‐1β of 1:1. Intrahippocampal injection of IL‐1β worsened seizure activity, whereas IL‐1Ra was a powerful anticonvulsant in various models of limbic seizures. Transgenic mice overexpressing IL‐1Ra in astrocytes were less sensitive to bicuculline‐induced seizures.

Conclusions: This study shows that limbic seizures in rodents rapidly and reversibly induce proinflammatory cytokines in glia and suggests that changes in the IL‐1Ra/IL‐1β ratio in brain may represent an effective physiopathologic mechanism to control seizures.
Immunohistochemical Study of Six Cases of Taylor's Type Focal Cortical Dysplasia: Correlation with Electroclinical Data
Authors: Lurton Dominique , Yacubian Elza Marcia , Sanabria Emilio Garrido , Da Silva Alexandre Valotta , Vianna Regina , Garzon Eliana , Sakamoto Americo , Spreafico Roberto , Cavalheiro Esper Abrão
Published: March 2003

Summary:  Purpose: Cortical specimens from six patients operated on for drug‐resistant epilepsy diagnosed as Taylor's type focal cortical dysplasia were submitted to neuropathological and immunohistochemical studies.

Methods: All patients were submitted to presurgical investigations including clinical and neuropsychological evaluations, EEG/video telemetry of ictal and interictal events, magnetic resonance imaging, and ictal and interictal single‐photon emission computed tomography (SPECT). Recordings from electrocorticography (ECoG) were obtained in four cases and from subdural electrode implantation in two. Postsurgical follow‐up was assessed according to Engel's score. Immunohistochemistry (IHC) was processed for parvalbumin (PV), calbindin D28‐K (CB), nonphosphorylated neurofilaments (SMI‐311), glial fibrillary acidic protein (GFAP) in all cases.

Results: We found continuous/quasi‐continuous spikes and sharp‐wave patterns in three cases and frequent repetitive bursting of polyspikes and ECoG seizures in two cases. Every patient showed cortical dyslamination, abnormal and giant neurons, and balloon cells. GFAP immunoreactivity was found in astrocytes and some balloon cells that were less intensely stained. Nonphosphorylated neurofilaments SMI‐311 immunoreactivity was found in normal and giant neurons and in some balloon cells, making visible thin neuropils. PV immunoreactivity was present in normal interneurons and in fibers in layers IV–V. PV‐negative balloon cells were surrounded by abundant PV‐positive fibers. CB immunoreactivity was found mostly in interneurons in layers II–III.

Conclusions: Our research is inconclusive. More cases should be investigated, and we must draw more accurate anatomic correlations between the ECoG recordings and surgical specimens studied with IHC.
The Treatment Gap
Authors: Kale Rajendra
Published: March 2003

Summary: A simple definition of the treatment gap is the number of people with a condition or disease who need treatment for it but who do not get it. It is an underutilised measure of health care. In epilepsy, it has been estimated by the direct method, during prevalence studies, and indirectly from the amount of antiepileptic drugs consumed in the country and the number of people with active epilepsy. The treatment gap in epilepsy is very high in the developing world. Possible causes of the treatment gap have been listed, but these have not been investigated.
Effektivität und Nebenwirkungsspektrum des ACE‐Hemmers Imidapril bei Patienten mit essentieller Hypertonie
Authors: Zweiker R. , Stoschitzky K. , Maier R. , Klein W.
Published: March 2003

Zusammenfassung: Die Wirksamkeit und Verträglichkeit des neuen ACE‐Hemmers Imidapril wurde an 2224 Patienten mit essentieller Hypertonie im Rahmen einer Feldstudie untersucht. Die durchschnittlichen Blutdruckwerte lagen bei Behandlungsbeginn bei 172 ± 19/98 ± 10 mm Hg. Durch die Behandlung mit Imidapril 5 – 20 mg einmal täglich kam es zu einer Blutdrucksenkung von 21 ± 17/11 ± 10 mm Hg (p < 0,01/0,01). Bei 71 % der Patienten wurde der systolische Ausgangsblutdruck um > 15 mm Hg gesenkt, bei 64 % der Patienten wurde der diastolische Druck um > 10 mm Hg gesenkt. Der Blutdruckzielwert von ≤ 140/90 wurde von 29 % der Patienten nach durchschnittlich 26 Tagen erreicht. Als wesentlicher die Prognose von Hypertonikern beeinflussender Parameter wird die Blutdruckamplitude angesehen, die durch die Therapie von 74 ± 17 auf 61 ± 11 mm Hg (– 18 %; p < 0,01) gesenkt werden konnte. ACE‐Hemmer‐assoziierte Nebenwirkungen wie Husten, Vertigo, Kopfschmerz, Pruritus, Tachykardie, hypotone Fehlregulation oder Übelkeit wurden bei insgesamt 38 Patienten (= 2 %) festgestellt. In einem Fragebogen‐Score wurde die Effektivität der Behandlung durch den betreuenden Arzt klassifiziert und bei 2088 Patienten (96 %) mit sehr gut bis gut, bei 3 % mit mäßig und bei < 1 % mit schlecht beurteilt. Die blutdrucksenkende Wirkung von Imidapril war ähnlich jener von anderen ACE‐Hemmern, die Nebenwirkungsrate war jedoch deutlich geringer und damit vergleichbar mit jener von Angiotensin‐II‐Antagonisten.
Pathogenese der Osteoporose bei chronischer Polyarthritis
Authors: Brosch Susanne , Redlich K. , Pietschmann P.
Published: March 2003

Zusammenfassung: Bei Patienten mit chronischer Polyarthritis finden sich nicht nur eine gelenksnahe Osteopenie und Knochenerosionen, sondern auch eine generalisierte axiale und periphere Osteoporose, den entzündeten Gelenken weit entfernten Stellen. Die Pathogenese der Knochendichteverminderung bei chronischer Polyarthritis ist multifaktoriell begründet; die Krankheitsaktivität ist sicherlich ein bestimmender Faktor für den Knochenverlust. Weitere pathogenetisch relevante Faktoren sind die entzündungshemmende Therapie (insbesondere Glukokortikoide), die reduzierte Mobilität und ein Östrogen‐ und/oder Androgenmangel. In den letzten Jahren wurden die Gegenspieler Receptor activator of nuclear factor κB‐ligand und Osteoprotegerin als zentrale Regulatoren der Osteoklastenentstehung‐ und aktivierung identifiziert. Die Produktion von Receptor activator of nuclear factor κB‐ligand und Osteoprotegerin wird von verschiedensten Zytokinen, Wachstumsfaktoren und Hormonen beeinflußt. Im Synovium von Patienten mit chronischer Polyarthritis fördern Fibroblasten und aktivierte T‐Zellen durch vermehrte Expression von Receptor activator of nuclear factor κB‐ligand die Entstehung und Aktivierung von Osteoklasten. Infolgedessen stellen Osteoprotegerin und Receptor activator of nuclear factor κB‐ligand wichtige molekulare Bindeglieder zwischen dem Immunsystem und dem Knochenmetabolismus bei chronischer Polyarthritis dar.
Intracellular trafficking of micronutrients: from gene regulation to nutrient requirements
Authors: Hesketh John E. , Villette Stéphane
Published: March 2003

Résumé

La distribution intracellulaire des micronutriments ainsi que leur absorption sont importantes pour les fonctions cellulaires. Dans certains cas la distribution des micronutriments ou des protéines associées est déterminée par des mécanismes liés à l'expression des gènes. La région 3' non traduite (3'UTR) de l'ARNm de la métallothioneine-1 détermine la localisation de ce message et, par conséquent, la localisation intracellulaire de la protéine qu'il code. En utilisant des cellules transfectées nous avons montré que la métallothioneine-1 est transportée vers le noyau ou elle exerce un rôle dans la protection contre le stress oxydant et les dommages causés à l'ADN. Quand l'apport nutritionnel en Se est limité, l'expression des sélénoproteines est altérée. Toutefois celle-ci n'est pas affectée de fac¸on identique pour toutes les sélénoproteines; le Se disponible étant utilisé de fac¸on prioritaire pour la synthèse de certaines d'entre elles. Cet ordre de priorité met en jeu des différences dans la traduction et la stabilité de leur ARNm qui sont sous le controle de séquences dans la région 3' non traduite. Potentiellement, des variations génétiques affectant ces mécanismes régulateurs peuvent moduler les besoins en nutriments. Des polymorphismes génétiques ont été décrits dans le 3'UTR des ARNm de deux sélénoproteines; l'un d'entre eux affectant la synthèse de la sélénoproteine correspondante. Ces exemples illustrent comment des approches moléculaires peuvent contribuer à accroître notre compréhension du métabolisme et des besoins en nutriments à différents niveaux. Premièrement, elles permettent d'étudier les effets régulateurs des gènes et de leurs produits. Ensuite, la compréhension de ces effets peut fournir un modèle pour étudier le métabolisme des nutriments au niveau cellulaire. Ainsi, lorsque des effets essentiels sont identifiés, la connaissance du génome humain et les bases de données sur les polymorphismes génétiques constituent des outils complémentaires pour définir l'étendue de la variation génétique des gènes revêtant une importance nutritionnelle. Enfin, la fonctionnalité de ces variations peut être définie et des sous-groupes de la population, possédant des besoins nutritionnels différents, peuvent etre identifiés.
Coronary heart disease: a disorder of growth
Authors: Robinson S. M. , Barker D. J. P.
Published: March 2003

The search for the causes of CHD has been guided by a `destructive' model, which proposes that influences acting in adult life, such as smoking, obesity or high saturated fat intakes, lead to an acceleration of age-related destructive processes, including a rise in blood pressure and the formation of atheroma. One explanation for the failure of the model to account for, or indeed to prevent rising epidemics of CHD, is that individuals are heterogeneous in their responses to such influences. This heterogeneity in response is linked to different paths of early growth. The recent discovery that individuals who develop CHD grew differently from other individuals during fetal life and in childhood has led to a new `developmental' model for the disease. Reduced fetal growth followed by poor growth in infancy leads to an increased risk of development of CHD, and its associated conditions, stroke, hypertension and impaired glucose tolerance. These effects are compounded by accelerated weight gain, which may represent 'compensatory growth' in childhood.
Food policies: a threat to health?
Authors: Lobstein Tim
Published: March 2003

Food policies deliver large quantities of food relatively safely, but they are failing to deliver healthy diets. Policies fall into three broad categories: the supply of sufficient amounts of food (food security); the provision of food free from contamination (food safety); the provision of a healthy diet available to all (nutritional quality). These three aspects are dealt with by institutions that rarely engage with each other, let alone coordinate their strategies. Greater financial support has been given to agricultural policy than to any other joint EU endeavour. In the last decade food safety has dominated headlines and has influenced recent changes to EU food policies. New food authorities and agencies have been established and ministerial responsibilities have been redefined. Yet, it is nutrition, or rather `mis-nutrition', that is the largest single cause of death and disease within the region, and indeed worldwide. This need not be the case. Nutrition and dietary policies may find themselves in close alliance with policies for sustainable agriculture. However, the change in thinking that will be required will mean reconsidering the role of commercial food production. Successful nutrition policies may yet prove to be the next major step in the improvement of public health.
Healthy diet and lifestyle clustering and glucose intolerance
Authors: Perry I. J.
Published: March 2003

Glucose intolerance represents a spectrum of abnormalities, including impaired fasting glucose, impaired glucose tolerance and type 2 diabetes. It is a major public health challenge worldwide, with rapidly increasing prevalence rates in both developed and developing countries. This global epidemic of diabetes is largely driven by the globalisation of Western culture and lifestyles. Specifically, there is now evidence from large-scale observational studies, and from intervention studies, of powerful synergistic interactions between diet, obesity, exercise, smoking and alcohol in the development of glucose intolerance. It is estimated that > 90 % of cases of type 2 diabetes in the population could be prevented with the adoption of a prudent diet (high in cereal fibre and polyunsaturated fatty acids and low intrans-fatty acids and glycaemic load), avoidance of overweight and obesity (BMI < 25 kg/m2), engagement in moderate to vigorous physical activity for at least 05 h/d, non-smoking and moderate alcohol consumption. These findings are biologically plausible and have major public health implications. They form the basis for a clear, simple and coherent message for health promotion and public policy. However, to make progress on these issues health will need to be placed at the centre of public policy and relevant vested interests tackled, notably in the food, entertainment, tobacco and automobile industries.
Integrin α2β1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCγ2
Authors: Inoue Osamu , Suzuki-Inoue Katsue , Dean William L. , Frampton Jon , Watson Steve P.
Published: March 2003

Collagen plays a critical role in hemostasis by promoting adhesion and activation of platelets at sites of vessel injury. In the present model of platelet–collagen interaction, adhesion is mediated via the inside-out regulation of integrin α2β1 and activation through the glycoprotein VI (GPVI)–Fc receptor (FcR) γ-chain complex. The present study extends this model by demonstrating that engagement of α2β1 by an integrin-specific sequence from within collagen or by collagen itself generates tyrosine kinase–based intracellular signals that lead to formation of filopodia and lamellipodia in the absence of the GPVI–FcR γ-chain complex. The same events do not occur in platelet suspensions. α2β1 activation of adherent platelets stimulates tyrosine phosphorylation of many of the proteins in the GPVI–FcR γ-chain cascade, including Src, Syk, SLP-76, and PLCγ2 as well as plasma membrane calcium ATPase and focal adhesion kinase. α2β1-mediated spreading is dramatically inhibited in the presence of the Src kinase inhibitor PP2 and in PLCγ2-deficient platelets. Spreading is abolished by chelation of intracellular Ca2+. Demonstration that adhesion of platelets to collagen via α2β1 generates intracellular signals provides a new insight into the mechanisms that control thrombus formation and may explain the unstable nature of β1-deficient thrombi and why loss of the GPVI–FcR γ-chain complex has a relatively minor effect on bleeding.
Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins
Authors: Czekay Ralf-Peter , Aertgeerts Kathleen , Curriden Scott A. , Loskutoff David J.
Published: March 2003

The binding of urokinase plaminogen activator (uPA) to its cell surface receptor (uPAR; CD87) promotes cell adhesion by increasing the affinity of the receptor for both vitronectin (VN) and integrins. We provide evidence that plasminogen activator inhibitor (PAI)-1 can detach cells by disrupting uPAR–VN and integrin–VN interactions and that it does so by binding to the uPA present in uPA–uPAR–integrin complexes on the cell surface. The detached cells cannot reattach to VN unless their surface integrins are first activated by treatment with MnCl2. Immunoprecipitation and subcellular fractionation experiments reveal that PAI-1 treatment triggers deactivation and disengagement of uPA–uPAR–integrin complexes and their endocytic clearance by the low density lipoprotein receptor–related protein. Transfection experiments demonstrate that efficient cell detachment by PAI-1 requires an excess of matrix-engaged uPA–uPAR–integrin complexes over free engaged integrins and that changes in this ratio alter the efficacy of PAI-1. Together, these results suggest a VN-independent, uPA–uPAR-dependent mechanism by which PAI-1 induces cell detachment. This pathway may represent a general mechanism, since PAI-1 also can detach cells from fibronectin and type-1 collagen. This novel “deadhesive” activity of PAI-1 toward a variety of cells growing on different extracellular matrices may begin to explain why high PAI-1 levels often are associated with a poor prognosis in human metastatic disease.
Regulation of cytochrome c oxidase activity by c-Src in osteoclasts
Authors: Miyazaki Tsuyoshi , Neff Lynn , Tanaka Sakae , Horne William C. , Baron Roland
Published: March 2003

The function of the nonreceptor tyrosine kinase c-Src as a plasma membrane–associated molecular effector of a variety of extracellular stimuli is well known. Here, we show that c-Src is also present within mitochondria, where it phosphorylates cytochrome c oxidase (Cox). Deleting the c-src gene reduces Cox activity, and this inhibitory effect is restored by expressing exogenous c-Src. Furthermore, reducing endogenous Src kinase activity down-regulates Cox activity, whereas activating Src has the opposite effect. Src-induced Cox activity is required for normal function of cells that require high levels of ATP, such as mitochondria-rich osteoclasts. The peptide hormone calcitonin, which inhibits osteoclast function, also down-regulates Cox activity. Increasing Src kinase activity prevented the inhibitory effect of calcitonin on Cox activity and osteoclast function. These results suggest that c-Src plays a previously unrecognized role in maintaining cellular energy stores by activating Cox in mitochondria.
Fluorescence resonance energy transfer (FRET) microscopy imaging of live cell protein localizations
Authors: Sekar Rajesh Babu , Periasamy Ammasi
Published: March 2003

The current advances in fluorescence microscopy, coupled with the development of new fluorescent probes, make fluorescence resonance energy transfer (FRET) a powerful technique for studying molecular interactions inside living cells with improved spatial (angstrom) and temporal (nanosecond) resolution, distance range, and sensitivity and a broader range of biological applications.
Meiotic cohesin REC8 marks the axial elements of rat synaptonemal complexes before cohesins SMC1β and SMC3
Authors: Eijpe Maureen , Offenberg Hildo , Jessberger Rolf , Revenkova Ekaterina , Heyting Christa
Published: March 2003

In meiotic prophase, the sister chromatids of each chromosome develop a common axial element (AE) that is integrated into the synaptonemal complex (SC). We analyzed the incorporation of sister chromatid cohesion proteins (cohesins) and other AE components into AEs. Meiotic cohesin REC8 appeared shortly before premeiotic S phase in the nucleus and formed AE-like structures (REC8-AEs) from premeiotic S phase on. Subsequently, meiotic cohesin SMC1β, cohesin SMC3, and AE proteins SCP2 and SCP3 formed dots along REC8-AEs, which extended and fused until they lined REC8-AEs along their length. In metaphase I, SMC1β, SMC3, SCP2, and SCP3 disappeared from the chromosome arms and accumulated around the centromeres, where they stayed until anaphase II. In striking contrast, REC8 persisted along the chromosome arms until anaphase I and near the centromeres until anaphase II. We propose that REC8 provides a basis for AE formation and that the first steps in AE assembly do not require SMC1β, SMC3, SCP2, and SCP3. Furthermore, SMC1β, SMC3, SCP2, and SCP3 cannot provide arm cohesion during metaphase I. We propose that REC8 then provides cohesion. RAD51 and/or DMC1 coimmunoprecipitates with REC8, suggesting that REC8 may also provide a basis for assembly of recombination complexes.
Differential regulation of cell motility and invasion by FAK
Authors: Hsia Datsun A. , Mitra Satyajit K. , Hauck Christof R. , Streblow Daniel N. , Nelson Jay A. , Ilic Dusko , Huang Shuang , Li Erguang , Nemerow Glen R. , Leng Jay , Spencer Kathryn S.R. , Cheresh David A. , Schlaepfer David D.
Published: March 2003

Cell migration and invasion are fundamental components of tumor cell metastasis. Increased focal adhesion kinase (FAK) expression and tyrosine phosphorylation are connected with elevated tumorigenesis. Null mutation of FAK results in embryonic lethality, and FAK−/− fibroblasts exhibit cell migration defects in culture. Here we show that viral Src (v-Src) transformation of FAK−/− cells promotes integrin-stimulated motility equal to stable FAK reexpression. However, FAK−/− v-Src cells were not invasive, and FAK reexpression, Tyr-397 phosphorylation, and FAK kinase activity were required for the generation of an invasive cell phenotype. Cell invasion was linked to transient FAK accumulation at lamellipodia, formation of a FAK–Src-p130Cas–Dock180 signaling complex, elevated Rac and c-Jun NH2-terminal kinase activation, and increased matrix metalloproteinase expression and activity. Our studies support a dual role for FAK in promoting cell motility and invasion through the activation of distinct signaling pathways.
Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination
Authors: Suzuki Akira , Kaisho Tsuneyasu , Ohishi Minako , Tsukio-Yamaguchi Manae , Tsubata Takeshi , Koni Pandelakis A. , Sasaki Takehiko , Mak Tak Wah , Nakano Toru
Published: March 2003

Pten is a tumor suppressor gene mutated in human cancers. We used the Cre-loxP system to generate a B cell–specific mutation of Pten in mice (bPtenflox/floxmice). bPtenflox/flox mice showed elevated numbers of B1a cells and increased serum autoantibodies. Among B2 cells in bPtenflox/flox spleens, numbers of marginal zone B (MZB) cells were significantly increased while those of follicular B (FOB) cells were correspondingly decreased. Pten-deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and showed enhanced migration. The survival kinase PKB/Akt was highly activated in Pten-deficient splenic B cells. In addition, immunoglobulin class switch recombination was defective and induction of activation-induced cytidine deaminase (AID) was impaired. Thus, Pten plays a role in developmental fate determination of B cells and is an indispensable regulator of B cell homeostasis.
Presentation of Antigen by Endothelial Cells and Chemoattraction Are Required for Homing of Insulin-specific CD8+ T Cells
Authors: Savinov Alexei Y. , Wong F. Susan , Stonebraker Austin C. , Chervonsky Alexander V.
Published: March 2003

Activated insulin-specific CD8+ T cells (IS-CD8+ cells) home to the pancreas, destroy β cells, and cause rapid diabetes upon transfer into diabetes-prone NOD mice. Surprisingly, they also cause diabetes in mouse strains that are free of preexistent inflammation. Thus, we hypothesized that islet-specific homing may be in part dependent on IS-CD8+ cells' recognition of the cognate major histocompatibility complex (MHC)/peptide complexes presented by pancreatic endothelial cells, which acquire the antigen (insulin) from β cells. In fact, islet-specific homing was abrogated in mice that lack MHC class I expression, or presentation of the specific peptide, or have impaired insulin secretion. Moreover, we found that IS-CD8+ cells directly recognized pancreatic endothelial cells in islet organ cultures. Triggering of IS-CD8+ cells' T cell receptor (TCR) led to activation of integrins expressed by these cells. In addition, chemokines, particularly SLC (CCL21), were also required for IS-CD8+ cells' adhesion to endothelial monolayers and for successful homing in vivo. Thus, signaling through TCR and chemokine receptors work in concert to assure firm adhesion of T cells to the pancreatic endothelium. The antigen cross-presentation ability of endothelia may therefore contribute to the specificity of homing of activated T lymphocytes to the tissues where antigens are generated by other cell types.
Myeloperoxidase and Plasminogen Activator Inhibitor 1 Play a Central Role in Ventricular Remodeling after Myocardial Infarction
Authors: Askari Arman T. , Brennan Marie-Luise , Zhou Xiaorong , Drinko Jeanne , Morehead Annitta , Thomas James D. , Topol Eric J. , Hazen Stanley L. , Penn Marc S.
Published: March 2003

Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to myocardial rupture and LV dilation. Myeloperoxidase (MPO), which accumulates in the infarct zone, is released from neutrophils and monocytes leading to the formation of reactive chlorinating species capable of oxidizing proteins and altering biological function. We studied acute myocardial infarction (AMI) in a chronic coronary artery ligation model in MPO null mice (MPO−/−). MPO−/− demonstrated decreased leukocyte infiltration, significant reduction in LV dilation, and marked preservation of LV function. The mechanism appears to be due to decreased oxidative inactivation of plasminogen activator inhibitor 1 (PAI-1) in the MPO−/−, leading to decreased tissue plasmin activity. MPO and PAI-1 are shown to have a critical role in the LV response immediately after MI, as demonstrated by markedly delayed myocardial rupture in the MPO−/− and accelerated rupture in the PAI-1−/−. These data offer a mechanistic link between inflammation and LV remodeling by demonstrating a heretofore unrecognized role for MPO and PAI-1 in orchestrating the myocardial response to AMI.