bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological interventions that directly stimulate or modulate insulin secretion from pancreatic β‐cell: implications for the treatment of type 2 diabetes
Authors: Farret Anne , Lugo‐Garcia Laura , Galtier Florence , Gross René , Petit Pierre
Published: November 2005

Blood glucose concentration is controlled by a number of hormone and neurotransmitter signals, either increasing or reducing glucose levels in the case of hypoglycemia or hyperglycemia, respectively. The pancreatic β‐cell responds to an increase in circulating glucose levels by a cascade of metabolic and electrophysiological events leading to the secretion of insulin. Type 2 diabetes is a metabolic disorder characterized by chronic hyperglycemia; the progressive pancreatic β‐cell dysfunction, with altered insulin production and secretion, is a major pathophysiological determinant of the disease together with the resistance of insulin‐sensitive tissues to the action of the hormone. Hence, drugs which stimulate or enhance insulin secretion will reduce plasma glucose concentrations; this lowering of hyperglycemia will, in turn, reduce the occurrence of long‐term complications. KATP channels play a critical role in insulin secretion and can be considered as transducers of glucose‐induced metabolic changes into biophysical events leading to the exocytosis of insulin granules. All currently marketed insulin secretagogues, sulfonylureas and glinides, target the β‐cell KATP channels and reduce their opening probability. They induce insulin release regardless of the plasma glucose concentration, thus favoring the occurrence of hypoglycemia in the fasting state. Despite the intensive use of current drugs, many patients suffering from type 2 diabetes still exhibit poor glycemic control, others fail to respond to the treatment, and some develop serious complications. Therefore, there is a real need for innovative compounds, either enhancing insulin secretion from the pancreas or improving insulin action on the hormone‐sensitive tissues. Here, we overview the existing and novel approaches targeting the β‐cell to enhance the release of insulin, with special emphasis on new ways of amplifying insulin secretion in a glucose‐dependent manner.
An overview of the pharmacology and clinical efficacy of indapamide sustained release
Authors: Sassard J. , Bataillard A. , McIntyre H.
Published: November 2005

The relationship between blood pressure (BP) and cardiovascular risk is clearly established; hypertension increases the rate of cardiovascular. High systolic blood pressure (SBP) may be the main parameter involved in cardiovascular morbidity and mortality. The benefit of lowering BP, particularly with diuretics has been proven in many outcome studies. Indapamide, a thiazide‐type diuretic, was available for many years at a dosage of 2.5 mg in an immediate release formulation. A new sustained release (SR) formulation has been developed in order to allow the same antihypertensive efficacy with a better acceptability profile. This paper reviews the pharmacology of indapamide 1.5 mg SR from the bench to the bedside. Indapamide has a dual mechanism of action: diuretic effect at the level of the distal tubule in the kidney and a direct vascular effect, both of which contribute to the antihypertensive efficacy of the drug. The SR formulation contains a hydrophilic matrix, which delivers a smoother pharmacokinetic profile. This avoids unnecessary plasma peak concentrations, which may be associated with side effects. Indapamide SR has now been extensively used in hypertensive patients, including those at increased risk, for example elderly or diabetic patients. It has been shown to decrease BP, particularly SBP, with 24‐h efficacy, allowing a once‐daily dosage. Studies have demonstrated BP lowering to be at least as effective as all major therapeutic classes including the more recent antihypertensive drugs. Beyond BP decrease, indapamide SR has also been shown to protect against hypertensive target‐organ damage in the heart and the kidney and to have a favorable metabolic profile. A broad evidence‐base has accumulated to support the benefit of indapamide 1.5 mg SR in hypertensive patients, alone or as part of combination therapy, as recommended by the majority of guidelines.
High expression of eosinophil chemoattractant ecalectin/galectin‐9 in drug‐induced liver injury
Authors: Takahashi Yoshihisa , Fukusato Toshio , Kobayashi Yuko , Akiyama Shuichi , Tamatani Takuya , Shiga Junji , Mori Shigeo
Published: November 2005

Abstract: Backgound: Ecalectin/galectin‐9 (ECL/GL9) is an eosinophil chemoattractant isolated from T lymphocytes. Drug‐induced liver injury (DILI), often caused by an allergic mechanism, is occasionally accompanied by eosinophilic infiltration. In this study, we intended to determine whether DILI can induce augmentation of ECL/GL9 expression. Further, we investigated whether this augmentation is associated with tissue eosinophilia.

Methods: We examined the expression of ECL/GL9 in biopsy specimens of DILI using the immunohistochemical technique. A rabbit anti‐ECL/GL9 antibody was produced by immunizing rabbits with synthetic peptide corresponding to a molecular epitope of ECL/GL9. Thereafter, immunohistochemical staining with the use of this antibody was performed on 16 DILI needle biopsy specimens, and on biopsy specimens of chronic viral hepatitis, liver cirrhosis, and normal liver tissues as controls.

Results: In all cases of DILI specimens, but not in control liver specimens, a clear positive staining for ECL/GL9 was observed. Such positive staining was noted on Kupffer cells, fibroblasts, and histiocytes, but not on lymphocytes or hepatocytes. However, the intensity of immunolabeling did not correlate with the extent of eosinophile leukocyte infiltration.

Conclusion: High expression of ECL/GL9 is suggested to be a specific finding of DILI. However, tissue eosinophilia in DILI cannot be explained by the augmentation of ECL/GL9 expression.
A randomized trial of 24‐ vs. 48‐week courses of PEG interferon α‐2b plus ribavirin for genotype‐1b‐infected chronic hepatitis C patients: a pilot study in Taiwan
Authors: Yu Ming‐Lung , Dai Chia‐Yen , Lin Zu‐Yau , Lee Li‐Po , Hou Nei‐Jen , Hsieh Ming‐Yen , Chen Shinn‐Cherng , Hsieh Ming‐Yuh , Wang Liang‐Yen , Chang Wen‐Yu , Chuang Wan‐Long
Published: November 2005

Abstract: Background: To assess the efficacy of 24‐ or 48‐week peginterferon/ribavirin treatment of Taiwanese patients with chronic hepatitis C virus genotype‐1b (HCV‐1b) infection, and to identify subgroups of patients in whom the 48‐week treatment has benefits. Methods: We assigned 60 patients receiving peginterferon‐α‐2b (80–100 mcg/week) plus ribavirin (1000–1200 mg/day), depending on body weight, for 24 or 48 weeks, with a 3:1 randomization ratio. Results: The sustained virological response (SVR) rate was significantly higher in the 48‐week (80.0%, 12/15) than in the 24‐week group (48.9%, 22/45, P<0.05). The 60 patients were classified into two subgroups according to the presence of unfavorable baseline predictors: viral loads ≥400 000 IU/ml or a hepatic fibrosis score of 3–4. In 19 patients without an unfavorable predictor, the SVR rate was comparable in the 24‐week (78.6%) and 48‐week (75.0%) groups; in patients with either unfavorable predictors, the SVR rate was significantly higher in the 48‐week (81.1%, 9/11) than in the 24‐week group (36.7%, 11/30, P=0.015). The discontinuation rate was significantly higher in the 48‐week (20.0%, 3/15) than in the 24‐week group (2.2%, 1/45, P<0.05). Conclusion: A 48‐week course of peginterferon‐α‐2b/ribavirin was more effective than a 24‐week course in Taiwanese HCV‐1b patients, mainly in those with high viral loads and/or advanced hepatic fibrosis.
Laparoscopic findings in patients with nonalcoholic steatohepatitis
Authors: Tanaka Naoki , Ichijo Tetsuya , Okiyama Wataru , Mutou Hidetomo , Misawa Noriko , Matsumoto Akihiro , Yoshizawa Kaname , Tanaka Eiji , Kiyosawa Kendo
Published: November 2005

Abstract: Background/Aims: Laparoscopic observation of the liver is important to diagnose liver conditions accurately. However, the laparoscopic findings of nonalcoholic steatohepatitis (NASH) have not been characterized. The aim of this study was to clarify the laparoscopic characteristics of NASH.

Methods: Twenty‐four patients were enrolled. The degrees of hepatomegaly, color and irregularity of the liver surface, and the presence of depressions, patches, and vesicles were investigated. These laparoscopic findings were compared among NASH, alcoholic liver disease (ALD), and autoimmune hepatitis (AIH).

Results: Mild hepatomegaly, dullness of the liver edge, increased fat accumulation of the round ligament, and whitish markings were found in most of the patients with NASH. Small depressions were observed in approximately 70% of the patients. As fibrosis developed, the liver surface became whiter and more uneven. Compared with patients with ALD and AIH, increased fat accumulation of the round ligament and dullness of the liver edge were observed more frequently in those with NASH. However, coarse and groove‐like depressions were rare in NASH patients.

Conclusions: Several findings, including mild hepatomegaly, increased fat accumulation of the round ligament, rounded liver edge, whitish markings, and small depressions were common in patients with NASH. However, coarse and groove‐like depressions were rare. These findings may be helpful for confirming a diagnosis of NASH.
Prognostic analysis in chronic hepatitis B patients: a retrospective study of 216 cases about Scheuer scores, in situ expression of viral antigens and tissue hepatitis B virus DNA levels
Authors: Zhu Rong , Huang Hai , Zhang Huiping , Wang Zhen , Hu Xiqi , Zhai Weirong , Lin Yuqin , Wang Jiyao , Zhu Hongguang
Published: November 2005

Abstract: Background: Most of the previous studies of patients with chronic hepatitis B virus (HBV) infection concentrated on serum samples. Liver biopsy specimens for HBV have not been systematically analyzed. This study was performed to analyze some histopathological indicators (Scheuer scores, the expression of HBV antigens in situ, HBV DNA quantification) in the biopsy samples and showed the relationship among them and the prognosis of chronic hepatitis.

Methods: A total of 216 consecutive chronic HBV‐infected patients were followed up by clinical and laboratory data and classified into two groups at first: carcinogenesis and non‐carcinogenesis. The non‐carcinogenesis also included two groups: cirrhosis and non‐cirrhosis. The non‐cirrhosis was still divided into fluctuation and normalization at last. Histological activity index was described by Scheuer scores. Two‐step immunohistochemical staining showed the expression of viral antigens in situ. Tissue HBV DNA levels were determined by fluorescence quantitative real‐time PCR.

Results: Regression analysis revealed significant positive correlations between the expression of hepatitis B e antigen (HBeAg) and grading, as well as between hepatitis Bx (HBx) protein and grading or staging of Scheuer scores. Positive correlations between grading or staging and prognosis were statistically significant. The expressions of HBeAg and HBx protein were higher in patients with cirrhosis than those without cirrhosis. Scheuer score was the most important indicator of prognosis.

Conclusions: HBeAg and HBx protein can be used as indicators of hepatitis activity and their positive expressions increase the risk for cirrhosis remarkably. In addition to be a marker of liver damage, Scheuer score is the most reliable indicator of the prognosis.
Design‐based stereological estimation of hepatocyte number, by combining the smooth optical fractionator and immunocytochemistry with anti‐carcinoembryonic antigen polyclonal antibodies
Authors: Marcos Ricardo , Monteiro Rogério A. F. , Rocha Eduardo
Published: November 2005

Abstract: Background/Aims: Hepatocytes (HEP) have been the major target for structural quantification in the liver, but an estimation of their total number (N), their percentage in relation to the global number of liver cells and the evaluation of the percentage of binucleated hepatocytes (BnHEPs) have never been performed with modern design‐based stereological techniques. The establishment of sound technical guidelines and baseline quantitative data in non‐pathological conditions are relevant to properly evaluate HEP hyperplasia and BnHEP responses.

Methods: In this study, we combined immunocytochemistry with sound design‐based stereology for estimating the N of HEP and the N of non‐hepatocytic cells (NHCs). For obtaining systematic uniform random sections (30 μm thick), a smooth fractionator sampling scheme was applied to the liver of five male Wistar rats (3 month old). Those sections were immunostained with polyclonal antibodies against carcinoembryonic antigen. Because biliary canaliculi were then marked, an unequivocal counting of mononucleated hepatocytes (MnHEP) and BnHEP was allowed.

Results: The N of HEP was estimated to be 1.93 × 109, with a coefficient of error (CE) of 0.02, corresponding to 129 × 106 HEP/g of liver. BnHEP represented 26% of total HEP number. The N of NHC was estimated as 1.31 × 109 (CE=0.02).

Conclusion: The strategy here presented provides a reliable method for accessing the N of HEP (distinguishing MnHEP from BnHEP) in situations in which these parameters are relevant, namely for evaluating the magnitude of an hyperplastic liver response from its very early onset.
DLPC and SAMe combined prevent leptin‐stimulated TIMP‐1 production in LX‐2 human hepatic stellate cells by inhibiting H2O2‐mediated signal transduction
Authors: Cao Qi , Mak Ki M. , Lieber Charles S.
Published: November 2005

Abstract: Background/Aims: Both dilinoleoylphosphatidylcholine (DLPC) and S‐adenosylmethionine (SAMe) have antioxidant properties and antifibrogenic actions. Because H2O2 mediates signal transduction‐stimulating liver fibrogenesis, we investigated whether DLPC and SAMe attenuate the production of tissue inhibitor of metalloproteinase (TIMP)‐1 by inhibiting H2O2 formation.

Methods: LX‐2 human hepatic stellate cells were treated with leptin with or without DLPC, SAMe or various inhibitors.

Results: Leptin‐stimulated TIMP‐1 mRNA and its protein were diminished by DLPC or SAMe alone, and the response was fully prevented by the combination of DLPC and SAMe. H2O2 was increased while glutathione was decreased; these changes were prevented by AG490, suggesting a Janus kinases (JAK)‐mediated process. Up‐regulation of leptin receptor and activation of JAK1 and 2 were not affected by DLPC+SAMe, whereas phosphorylation of ERK1/2 and p38 was blocked by DLPC+SAMe or catalase, suggesting an H2O2‐dependent mechanism. These treatments also suppressed leptin‐stimulated TIMP‐1 promoter activity and decreased TIMP‐1 mRNA stability, contributing to TIMP‐1 mRNA down‐regulation. PD098059, an ERK1/2 inhibitor, suppressed TIMP‐1 promoter activity, whereas SB203580, a p38 inhibitor, decreased TIMP‐1 message stability; both resulted in a partial reduction of TIMP‐1 mRNA.

Conclusion: As decreased TIMP‐1 production may enhance collagen deposition, the combined administration of DLPC+SAMe should be considered for the prevention of H2O2‐mediated signaling and the resulting fibrosis.
Epidemiology of Idiopathic Generalized Epilepsies
Authors: Jallon Pierre , Latour Patrick
Published: November 2005

Summary:  Idiopathic generalized epilepsies (IGEs) are a relatively new category of disorders defined by strict clinical and electroencephalogram (EEG) features proposed by the International League Against Epilepsy (ILAE) classification of epileptic syndromes. IGEs are usually easy to diagnose when clinical and EEG data are collected, but epilepsy is not synonymous with epileptic syndrome. So far, IGEs are studied in the large group of epilepsies of undetermined or unknown etiology although the genetic origin is now largely accepted. ILAE‐proposed criteria are helpful in the clinical and therapeutic management of IGEs, but many epidemiologic studies still confuse the cryptogenic and idiopathic groups. Some syndromes in childhood, which are completely described by strict electroclinical criteria such as the absence epilepsies, juvenile myoclonic epilepsies, are usually included and analyzed in epidemiologic studies; however, other epileptic syndromes observed in infancy, such as benign familial neonatal seizures and benign myoclonic epilepsy in infancy, are quite rare and are usually excluded from epidemiologic surveys because they are difficult to describe completely in electro‐clinical terms. Another strong limitation in the study of epidemiology of IGEs is the lack of EEG data, either because EEG is not available or the routine EEG is normal. This is particularly relevant in the inclusion of patients with only tonic–clonic seizures. IGEs encompass several different syndromes, and a few patients shift from one phenotype to another. The overlapping of some syndromes during infancy and adolescence increased the difficulty to individualize strictly the correct syndrome. Many discrepancies can be observed in the distribution of the different syndromes included in the group of IGEs, because the strict criteria for classifying these syndromes proposed by the ILAE are often not respected. With this understanding, the general frequency of IGEs can be assessed at 15–20% of all epilepsies. The frequency and the distribution of incidence and prevalence of the different syndromes are tentatively reported and discussed. When the term idiopathic is used following the restrictive ILAE criteria, the mortality data concerning patients with idiopathic epilepsies do not show an increased standardized mortality ratio.
Genetics of Idiopathic Generalized Epilepsies
Authors: Gardiner Mark
Published: November 2005

Summary:  The idiopathic generalized epilepsies (IGEs) are considered to be primarily genetic in origin. They encompass a number of rare mendelian or monogenic epilepsies and more common forms which are familial but manifest as complex, non‐mendelian traits. Recent advances have demonstrated that many monogenic IGEs are ion channelopathies. These include benign familial neonatal convulsions due to mutations in KCNQ2 or KCNQ3, generalized epilepsy with febrile seizures plus due to mutations in SCN1A, SCN2A, SCN1B, and GABRG2, autosomal‐dominant juvenile myoclonic epilepsy (JME) due to a mutation in GABRA1 and mutations in CLCN2 associated with several IGE sub‐types. There has also been progress in understanding the non‐mendelian IGEs. A haplotype in the Malic Enzyme 2 gene, ME2, increases the risk for IGE in the homozygous state. Five missense mutations have been identified in EFHC1 in 6 of 44 families with JME. Rare sequence variants have been identified in CACNA1H in sporadic patients with childhood absence epilepsy in the Chinese Han population. These advances should lead to new approaches to diagnosis and treatment.
Idiopathic Generalized Epilepsies Recognized by the International League Against Epilepsy
Authors: Nordli Douglas R.
Published: November 2005

Summary:  There are eight syndromes currently recognized by the International League Against Epilepsy (ILAE) that would fit the original operational definition of idiopathic generalized epilepsy (IGE) syndromes, including benign myoclonic epilepsy in infancy; generalized epilepsy with febrile seizures plus, an entity in evolution; epilepsy with myoclonic absences; epilepsy with myoclonic‐astatic seizures; childhood absence epilepsy; juvenile absence epilepsy; juvenile myoclonic epilepsy; and epilepsy with generalized tonic–clonic seizures only. All of these syndromes can be easily diagnosed when distinctive features are present. In some cases, such features are not present or only appear later in the course of the disease, making it challenging to distinguish the various syndromes. Electroencephalogram (EEG) is the most helpful laboratory test and often will strongly support the diagnosis of IGE, but may not be very helpful in discriminating between several of the syndromes with overlapping features. The same applies for genetic testing, although it is expected that further research exploring the genotype‐phenotype relationships will enhance our abilities to make definitive diagnoses. At the current time, clinical features are still the cornerstone of accurate classification, and accurate classification, in turn, is the best predictor of outcome.
Syndromes of Idiopathic Generalized Epilepsies Not Recognized by the International League Against Epilepsy
Authors: Panayiotopoulos Chrysostomos P.
Published: November 2005

Summary: This chapter assesses probable epileptic syndromes within the idiopathic generalized epilepsies (IGE) that have not yet been recognized by the International League Against Epilepsy (ILAE). Jeavons syndrome, a purely reflex IGE that predominantly manifests with eyelid myoclonia and electroencephalogram (EEG) abnormalities on eye closure, is the most distinct and undisputed of the syndromes. Another is autosomal‐dominant cortical tremor, myoclonus, and epilepsy, a purely monogenic disorder that has been documented in numerous reports, mainly from Japan and Italy. Perioral myclonia with absences is certainly a seizure type that may constitute an IGE syndrome when it is associated with a number of other clinical and EEG manifestations. Similarly, many patients suffer for years from phantom absences, a type of mild absence, before a first generalized tonic‐clonic seizure that usually occurs in adulthood. Both perioral myoclonia with absences and phantom absences are clinically significant because they are probably lifelong and are associated with a very high incidence (around 50%) of absence status epilepticus that may escape diagnosis and appropriate treatment. The position of early childhood IGE, which manifests mainly with typical absence seizures that are distinctly different from childhood absence epilepsy and other recognized IGE syndromes, is less clear. The prevalence of these syndromes is significant. Their identification allows better clinical management and is important for genetic research and counselling. In addition, their recognition permits application of exclusion criteria for a more purified definition and a better understanding of the true boundaries of the other IGE syndromes already accepted by the ILAE.
Photosensitivity in Idiopathic Generalized Epilepsies
Authors: Covanis Athanasios
Published: November 2005

Summary:  Photosensitivity is an abnormal visual sensitivity of the brain in reaction to flickering light sources or patterns and is expressed in the electroencephalogram as generalized spike‐and‐wave discharge and in more susceptible individuals as clinical seizures. The most common types of seizures are generalized tonic‐clonic, followed by myoclonic and absence. The photosensitive epilepsies are classified as pure photosensitive, where seizures occur only with the flickering light source/pattern or during intermittent photic stimulation (IPS) in the laboratory, and epilepsy with photosensitivity, where spontaneous seizures also occur. Positive response to IPS in idiopathic epilepsy syndromes, which are included in the International Classification or are in development, is reported to range from 7.5% in juvenile absence epilepsy to 100% in pure photosensitive epilepsy.

The treatment of photosensitivity and pure photosensitive epilepsy with rare seizures includes general and specific protective measures. For most patients, however, combination treatment with antiepileptic drugs is necessary. Valproic acid monotherapy has a success rate of 73–86%. Levetiracetam appears to be a new alternative therapeutic option. Clobazam, lamotrigine, ethosuximide, and topiramate also have been recommended as second‐choice therapies.
Brain Imaging in Idiopathic Generalized Epilepsies
Authors: Duncan John S.
Published: November 2005

Summary:  While it is generally accepted that there is no neuroimaging abnormality in idiopathic generalized epilepsy (IGE), image processing and quantitative magnetic resonance imaging (MRI) studies suggest that there may be subtle structural abnormalities. Magnetic resonance spectroscopy indicates neuronal dysfunction with differing abnormalities in the IGE subsyndromes, and high concentrations of glutamate and glutamine have been inferred in the frontal lobes, and low gamma‐aminobutyric acid levels in the occipital lobe. Studies of cerebral blood distribution at the time of absences have given complex results. The general consensus is of an increase in the thalamus and broad decreases in the neocortex, reflecting a suppression of neuronal activity, but with some increases, that may indicate focal areas of activation. Positron emission tomography (PET) ligand studies with an opioid tracer have inferred neocortical release of endogenous opioids at the time of serial absences. In combination with neurophysiological methods, PET studies with specific ligands have the potential to clarify the functional anatomy and neurochemical circuits that underlie IGE.
Seizure Aggravation in Idiopathic Generalized Epilepsies
Authors: Chaves J. , Sander J.W.
Published: November 2005

Summary:  Seizures in the idiopathic generalized epilepsies (IGEs) usually remit completely with antiepileptic drugs (AEDs). Occasionally, however, they may be aggravated by AEDs. Before attributing exacerbation of seizures to an AED, alternative explanations need to be excluded. These include natural fluctuation of seizures, irregular compliance, maladjustment to the disease, comorbid illness, and development of tolerance. Aggravation may be due to a paradoxical reaction or drug‐induced encephalopathy, sedative effects, or inappropriate use of a drug; and this need to be established, as it will guide management. An important caveat is that most data on aggravation of generalized seizures are based on anecdotal case reports or case series. Whether considering efficacy or aggravation, the interpretation of data from uncontrolled studies and case reports must be treated with caution. In practice, despite the fact that clear evidence is lacking, the possibility of seizure aggravation must be considered when treating people with IGEs. Predictive factors for seizure aggravation in a particular patient with a specific drug are yet to be fully defined. It is paramount to classify seizure type correctly in all patients. If this is not possible, a broad‐spectrum AED should be used. Drugs that modulate Na+‐channels and GABAergic drugs seem to be more prone to aggravating seizures, and therefore are best avoided in the initial management of IGE. Further studies are required to elucidate this phenomenon in full. It is interesting to speculate that paradoxical responses to AEDs may have pharmacogenetic value, serving as tools for a more precise and useful characterization of the epilepsies.
Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies
Authors: Patsalos Philip N.
Published: November 2005

Summary:  Although valproate is considered to be the drug of first choice for the treatment of idiopathic generalized epilepsies (IGEs), other antiepileptic drugs (AEDs), both old (ethosuximide, clobazam, and clonazepam) and new (lamotrigine, levetiracetam, topiramate, and zonisamide) are also available. These AEDs do not appear to have a common mechanism of action in that both inhibitory gamma‐aminobutyric acid (GABA; e.g., clobazam, clonazepam, and valproate) and excitatory glutamate (e.g., lamotrigine and topiramate) mechanisms are involved. Ethosuximide primarily acts by blocking T‐type voltage‐gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action. In contrast, levetiracetam is unique in that it may act via a specific binding site in the brain.

In terms of their pharmacokinetic characteristics, all eight AEDs are rapidly absorbed after oral ingestion with peak blood concentration being achieved within 1–4 hours. Bioavailability is 100% with the exception clonazepam (90%) and topiramate (81–95%). Plasma protein binding is variable with valproate (90%), clobazam (85%) and clonazepam (86%) showing substantial binding, lamotrigine (55%) and zonisamide (50%) intermediate binding, and levetiracetam (0%), ethosuximide (0%) and topiramate (10%) being minimally bound. However, the binding by zonisamide is complicated by its binding to erythrocytes as well as albumin. All AEDs, with the exception of lamotrigine and levetiracetam, undergo elimination as a result of extensive metabolism by hepatic cytochrome P450 enzymes, which are highly amenable to induction and inhibition by other drugs and therefore susceptible to pharmacokinetic interactions. Lamotrigine metabolism is via hepatic glucuronidation, a process that is also susceptible to induction and inhibition by concurrent drugs. Levetiracetam is minimally metabolized (by hydrolysis in blood), is excreted predominantly unchanged in urine, and to date has not been associated with any clinically significant pharmacokinetic interactions. Using a semiquantitative pharmacokinetic rating system, based on 16 pharmacokinetic characteristics, a direct comparison between AEDs is possible. Thus valproic acid, regarded as the drug of first choice in the treatment of IGEs, rates lowest with respect to favorable pharmacokinetic characteristics, mostly because of its nonlinear pharmacokinetics, extensive hepatic metabolism, and its high propensity to interact both with other AEDs and non‐AEDs. Levetiracetam rates highest with topiramate in second place.
Evidence‐based Treatment of Idiopathic Generalized Epilepsies with Older Antiepileptic Drugs
Authors: Hitiris Nikolas , Brodie Martin J.
Published: November 2005

Summary: Older antiepileptic drugs continue to play a major role in the treatment of the idiopathic generalized epilepsies. Comparative studies of ethosuximide and valproate have demonstrated equivalence in the treatment of childhood absence epilepsy. Valproate can be regarded as the recommended first‐line treatment for juvenile myoclonic epilepsy based on case series reports. Studies in patients with generalized tonic‐clonic seizures have not separated out idiopathic from secondary generalized events. Treatment for the other idiopathic generalized epilepsy syndromes lacks evidence other than a few case reports and diverse expert opinion. Further randomized controlled trials of older antiepileptic drugs are recommended to solidify the evidence‐based treatment of the idiopathic generalized epilepsies.
TEMPORAL PATTERNS IN POPULATION GENETIC DIVERSITY OF PROROCENTRUM MICANS (DINOPHYCEAE)1
Authors: Shankle Amy M. , Mayali Xavier , Franks Peter J. S.
Published: November 2005

We describe temporal changes in the genetic structure of populations of the dinoflagellate Prorocentrum micans Ehrenberg over a period of 2 years at Scripps Pier (La Jolla, CA, USA). We collected 12 water samples over the course of two blooms and analyzed 166 single‐cell isolates using randomly amplified polymorphic DNA analysis. Six PCR primers uncovered 27 polymorphic markers, allowing the identification of 40 unique haplotypes. Analysis of molecular variance demonstrated that >92% of the genetic variance was partitioned within water samples, providing evidence of high levels of genetic diversity and possibly sexual reproduction. Although the level of genetic diversity remained fairly stable over the sampled time interval, several populations (sampled in June 1998 and March 1999) exhibited significantly different genetic composition, demonstrating differences among bloom and nonbloom periods. About 40% of the isolates in each sample were identified as one haplotype, suggesting that a genetically distinct subgroup was a common member of the populations during the sampled periods. The composition of the remaining isolates was genetically diverse and changed over time, indicating rapid responses (days) to changing environmental conditions or extensive genetic spatial patchiness (kilometers). Within the limitations of our sampling, these two genetically distinct groups appear to exhibit different population dynamics (one stable and the other variable), suggesting that genetic diversity may be closely linked to the change in abundance of phytoplankton on ecological time scales.
ENVIRONMENTAL EFFECTS ON EXOPOLYMER PRODUCTION BY MARINE BENTHIC DIATOMS: DYNAMICS, CHANGES IN COMPOSITION, AND PATHWAYS OF PRODUCTION1
Authors: Underwood Graham J. C. , Boulcott Matthew , Raines Christine A. , Waldron Keith
Published: November 2005

Marine benthic diatoms excrete large quantities of extracellular polymeric substances (EPS), both as a function of their motility system and as a response to environmental conditions. Diatom EPS consists predominantly of carbohydrate‐rich polymers and is important in the ecology of cells living on marine sediments. Production rates, production pathways, and monosaccharide composition of water‐soluble (colloidal) carbohydrates, EPS, and intracellular storage carbohydrate (glucans) were investigated in the epipelic (mud‐inhabiting) diatoms Cylindrotheca closterium (Ehrenburg), Navicula perminta (Grün.) in Van Heurck, and Amphora exigua Greg. under a range of experimental conditions simulating aspects of the natural environment. Cellular rates of colloidal carbohydrate, EPS, and glucan production were significantly higher during nutrient‐replete compared with nutrient‐limited growth for all three species. The proportion of EPS in the extracellular carbohydrate pool increased significantly (to 44%–69%) as cells became nutrient limited. Cylindrotheca closterium produced two types of EPS differing in sugar composition and production patterns. Nutrient‐replete cells produced a complex EPS containing rhamnose, fucose, xylose, mannose, galactose, glucose, and uronic acids. Nutrient‐limited cells produced an additional EPS containing mannose, galactose, glucose, and uronic acids. Both EPS types were produced under illuminated and darkened conditions. 14C‐labeling revealed immediate production of 14C‐glucan and significant increases in 14C‐EPS between 3 and 4 h after addition of label. The glucan synthesis inhibitor 2,6‐dichlorobenzonitrile significantly reduced 14C‐colloidal carbohydrate and 14C‐EPS. The glucanase inhibitor P‐nitrophenyl β‐d‐glucopyranoside resulted in accumulation of glucan within cells and lowered rates of 14C‐colloidal and 14C‐EPS production. Cycloheximide prevented glucan catabolism, but glucan production and EPS synthesis were unaffected.
A UNIQUELY CALCIFIED BROWN ALGA FROM HAWAII:NEWHOUSIA IMBRICATAGEN. ET SP. NOV. (DICTYOTALES, PHAEOPHYCEAE)1
Authors: Kraft Gerald T. , Saunders Gary W. , Abbott Isabella A. , Haroun Ricardo J.
Published: November 2005

An encrusting brown alga from subtidal habitats around the island of Oahu (Hawaiian Islands) represents only the second genus of the class Phaeophyceae to form calcium carbonate, which it deposits primarily as both extracellular and intracellular aragonite, admixed with small (3.3%) amounts of calcite. Plants form expanses 15–100+ cm in extent consisting of horizontally aligned imbricating tiers of distromatic blades 1–4 mm in diameter that are separated from one another by cementing layers of extracellular aragonite, the tiers forming stacks of dozens of laminae and anchored to coral substrata by a basement layer that adheres tightly without haptera or rhizoids. The hypodermal layer of each blade consists of lightly pigmented rectilinear cells bearing either one or two smaller deeply pigmented epidermal cells in cross‐sectional profiles and three or four in long‐sectional profiles, the cells of both layers becoming encased in rigid carbonate skeletons laid down in their outer wall matrices. The successive tiers become stacked by either overgrowing marginal proliferations or new blade primordia that arise from the hypodermal layer of surface laminae and initially spread centrifugally by means of continuous marginal meristems. Neither plurilocular nor unilocular reproductive structures are known. The alga is described as the new genus and speciesNewhousia imbricataKraft, G.W. Saunders, Abbott et Haroun and is assigned on the basis of small subunit rDNA gene sequence analyses to the order Dictyotales, family Dictyotaceae, within a strongly supported monophyletic clade that includesDistromium,Lobophora, andZonaria.
Comorbidity Profile of Dementia Patients in Primary Care: Are They Sicker?
Authors: Schubert Cathy C. , Boustani Malaz , Callahan Christopher M. , Perkins Anthony J. , Carney Caroline P. , Fox Christopher , Unverzagt Frederick , Hui Siu , Hendrie Hugh C.
Published: November 2005

OBJECTIVES: To compare the medical comorbidity of older patients with and without dementia in primary care.

DESIGN: Cross‐sectional study.

SETTING: Wishard Health Services, which includes a university‐affiliated, urban public hospital and seven community‐based primary care practice centers in Indianapolis.

PARTICIPANTS: Three thousand thirteen patients aged 65 and older attending seven primary care centers in Indianapolis, Indiana.

MEASUREMENTS: An expert panel diagnosed dementia using International Classification of Diseases, 10th Revision, criteria. Comorbidity was assessed using 10 physician‐diagnosed chronic comorbid conditions and the Chronic Disease Score (CDS).

RESULTS: Patients with dementia attending primary care have on average 2.4 chronic conditions and receive 5.1 medications. Approximately 50% of dementia patients in this setting are exposed to at least one anticholinergic medication, and 20% are prescribed at least one psychotropic medication. After adjusting for patients' age, race, and sex, patients with and without dementia have a similar level of comorbidity (mean number of chronic medical conditions, 2.4 vs 2.3, P=.66; average CDS, 5.8 vs 6.2, P=.83).

CONCLUSION: Multiple medical comorbid conditions are common in older adults with and without dementia in primary care. Despite their cholinergic deficit, a substantial proportion of patients with dementia are exposed to anticholinergic medications. Models of care that incorporate this medical complexity are needed to improve the treatment of dementia in primary care.
Outcome of Critically Ill Oldest‐Old Patients (Aged 90 and Older) Admitted to the Intensive Care Unit
Authors: Rellos Konstantinos , Falagas Matthew E. , Vardakas Konstantinos Z. , Sermaides George , Michalopoulos Argyris
Published: November 2005

OBJECTIVES: To compare the outcomes of critically ill oldest‐old patients (≥90) with those of younger patients.

DESIGN: Prospective cohort study.

SETTING: General intensive care unit (ICU) of a tertiary care hospital in Athens, Greece.

PARTICIPANTS: The oldest‐old and younger patients.

MEASUREMENTS: In‐hospital and ICU mortality and stay, demographics, comorbidity, and complications.

RESULTS: Of 5,505 consecutive patients admitted to the ICU, 60 (1.1%) were in the oldest‐old group (aged 90–98). Their mean length of ICU and hospital stay±standard deviation was 5.3±6.8 and 23.3±35.7 days, respectively. ICU mortality was 20%. Total in‐hospital mortality was 40%, compared with 8.9% (P=.001) in younger patients. Acute Physiology and Chronic Health Evaluation II score was independently associated with in‐hospital mortality (odds ratio=1.18, 95% confidence interval=1.05–1.33). Of 24 oldest‐old patients who died, 22 (91.7%) died in the ICU or in the ward within 30 days after ICU discharge.

CONCLUSION: All‐cause in‐hospital mortality was higher in the oldest‐old group than in younger patients, but the mortality of this cohort of patients did not seem to reach a figure that would make physicians, relatives, and healthcare administrators decide against ICU care in this population.
In the Name of Equal Rights: “Special” Rights and the Politics of Resentment in Post–Civil Rights America
Authors: Dudas Jeffrey R.
Published: November 2005

This article explores the character of conservative legal activism in post–civil rights America, arguing that this activism is motivated by two related factors: (1) resentment over the increased political participation of historically marginalized Americans and (2) principled allegations that these historically marginalized Americans are making illegitimate claims for “special,” not equal, rights. I argue that the allegation of special rights is tied to the activists' resentment in multiple and complex ways. On the one hand, the allegation that the rights claims of the historically marginalized are illegitimate claims for special rights is itself an expression of resentment. Like arguments that oppose redistributive social change by relying upon discourses of color blindness, states' rights, evangelical Christianity, and community harmony, special rights talk channels resentment into recognizable and intelligible forms. But, on the other hand, the use of special rights talk is not simply cover for an underlying, fully formed resentment. Instead, the allegation of special rights propels and amplifies activists' resentment, transforming it from one that is based primarily upon competing self-interests into one that is concerned with values, morality, and national identity. Special rights talk thus partially constitutes resentment; it hardens the resolve of opponents of redistributive social change, encouraging them to understand themselves as defenders not only of their own self-interests but also, primarily even, as defenders of the core American values and ideals that are promoted by equal rights and assaulted by special rights. Thus convinced that their opposition is authorized by American tradition, conservative legal activists redouble their counter-mobilization efforts, leading to an exacerbation of already tense conflicts. A case study of the nationwide anti-treaty-rights movement grounds this analysis.
(Un)anticipated Effects of Sentencing Reform on the Disparate Treatment of Defendants
Authors: Wooldredge John , Griffin Timothy , Rauschenberg Fritz
Published: November 2005

Despite concerns over racial disparities in imprisonment across the United States, little empirical attention has been paid to how changing the structure of sentencing might affect levels of disparity. This article examines whether Ohio's shift to determinate sentencing corresponded with significant changes in legal and extralegal effects on case outcomes, both generally and differentially for African American and white defendants. Bilevel analyses of felony defendants from 24 jurisdictions reveal relatively few substantive changes in these effects over time. Some changes involved reductions in race-related disparities (e.g., in the severity of charges convicted on), with others reflectingincreaseddisparity (e.g., higher imprisonment likelihoods for African Americans). Findings underscore a modest link between restructured sentencing and actual case outcomesoverall, with some relatively mixed effects on levels of disparity.
Procedural Justice and the Assessment of Civil Justice in Japan
Authors: Ohbuchi Ken-ichi , Teshigahara Kazuhiko , Sugawara Ikuo , Imazai Kei-ichiro
Published: November 2005

In analyzing the data from a structured interview survey with Japanese litigants of civil trials, we examined the relationships between their perceptions of outcomes and process of the trials, responses to the trials, and evaluation of the judicial system. The results showed that both favorability of trial outcomes and procedural fairness of trials increased satisfaction with the trial outcomes and evaluation of the judicial system. Satisfaction was largely determined by perceived favorability, while the evaluation of the judicial system was largely determined by perceived procedural fairness, suggesting a justice bond effect that justice fortifies people's societal commitment. Consistent with procedural justice theories, the perception of procedural fairness was increased by the sense of control and the appraisal of relational factors, though both were affected by favorability.
The Reconstitution of Law in Local Settings: Agency Discretion, Ambiguity, and a Surplus of Law in the Policing of Hate Crime
Authors: Grattet Ryken , Jenness Valerie
Published: November 2005

An important yet poorly understood function of law enforcement organizations is the role they play in distilling and transmitting the meaning of legal rules to frontline law enforcement officers and their local communities. In this study, we examine how police and sheriff's agencies in California collectively make sense of state hate crime laws. To do so, we gathered formal policy documents called “hate crime general orders” from all 397 police and sheriff's departments in the state and conducted interviews with law enforcement officials to determine the aggregate patterns of local agencies' responses to higher law. We also construct a “genealogy of law” to locate the sources of the definitions of hate crime used in agency policies. Despite a common set of state criminal laws, we find significant variation in how hate crime is defined in these documents, which we attribute to the discretion local law enforcement agencies possess, the ambiguity of law, and the surplus of legal definitions of hate crime available in the larger environment to which law enforcement must respond. Some law enforcement agencies take their cue from other agencies, some follow statewide guidelines, and others are oriented toward gaining legitimacy from national professional bodies or groups within their own community. The social mechanisms that produce the observed clustering patterns in terms of approach to hate crime law are mimetic (copying another department), normative (driven by professional standards about training and community social movement pressure), and actuarial (affected by the demands of the crime data collection system). Together these findings paint a picture of policing organizations as mediators between law-on-the-books and law-in-action that are embedded in interorganizational networks with other departments, state and federal agencies, professional bodies, national social movement organizations, and local community groups. The implications of an interorganizational field perspective on law enforcement and implementation are discussed in relation to existing sociolegal research on policing, regulation, and recent neo-institutional scholarship on law.
Intraspecific Genetic Variation in Paramecium Revealed by Mitochondrial Cytochrome c Oxidase I Sequences
Authors: BARTH DANA , KRENEK SASCHA , FOKIN SERGEI I. , BERENDONK THOMAS U.
Published: November 2005

ABSTRACT. Studies of intraspecific genetic diversity of ciliates, such as population genetics and biogeography, are particularly hampered by the lack of suitable DNA markers. For example, sequences of the non‐coding ribosomal internal transcribed spacer (ITS) regions are often too conserved for intraspecific analyses. We have therefore identified primers for the mitochondrial cytochrome c oxidase I (COI) gene and applied them for intraspecific investigations in Paramecium caudatum and Paramecium multimicronucleatum. Furthermore, we obtained sequences of the ITS regions from the same strains and carried out comparative sequence analyses of both data sets. The mitochondrial sequences revealed substantially higher variation in both Paramecium species, with intraspecific divergences up to 7% in P. caudatum and 9.5% in P. multimicronucleatum. Moreover, an initial survey of the population structure discovered different mitochondrial haplotypes of P. caudatum in one pond, thereby demonstrating the potential of this genetic marker for population genetic analyses. Our primers successfully amplified the COI gene of other Paramecium. This is the first report of intraspecific variation in free‐living protozoans based on mitochondrial sequence data. Our results show that the high variation in mitochondrial DNA makes it a suitable marker for intraspecific and population genetic studies.