bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anticonvulsant Efficacy of the Low‐affinity Partial Benzodiazepine Receptor Agonist ELB 138 in a Dog Seizure Model and in Epileptic Dogs with Spontaneously Recurrent Seizures
Authors: Löscher Wolfgang , Potschka Heidrun , Rieck Susanne , Tipold Andrea , Rundfeldt Chris 
Published: September 2004

Summary:  Purpose:Ataxia, sedation, amnesia, ethanol and barbiturate potentiation, loss of efficacy (tolerance), development of dependence, and the potential for drug abuse limit the clinical use of benzodiazepines (BZDs) for long‐term treatment of epilepsy or anxiety. BZD ligands that are in current use act as full allosteric modulators of γ‐aminobutyric acid (GABA)‐gated chloride channels and, on long‐term administration, trigger a functional uncoupling between the GABAA and BZD recognition sites. Partial allosteric modulators, which have a low intrinsic activity at the BZD recognition site of the GABAA receptor, might eventually overcome the limitations of full agonists such as diazepam (DZP). Methods: In the present study, the new low‐affinity partial BZD‐receptor agonist ELB 138 [former name AWD 131‐138; 1‐(4‐chlorophenyl)‐4‐morpholino‐imidazolin‐2‐one] was evaluated in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Results: ELB 138 was shown to increase potently the pentylenetetrazole (PTZ) seizure threshold in dogs. Prolonged oral administration with twice‐daily dosing of ELB 138 with either 5 or 40 mg/kg over a 5‐week period was not associated with loss of anticonvulsant efficacy in the PTZ dog model. To study whether physical dependence developed during long‐term treatment, the BZD antagonist flumazenil was injected after 5 weeks of treatment with ELB 138. Compared with prolonged treatment with DZP, only relatively mild abstinence symptoms were precipitated in dogs treated with ELB 138, particularly at the lower dosage (5 mg/kg, b.i.d.). In a prospective trial in dogs with newly diagnosed epilepsy, ELB 138 markedly reduced seizure frequency and severity without significant difference to standard treatments (phenobarbital or primidone) but was much better tolerated than the standard drugs. In dogs with chronic epilepsy, most dogs exhibited a reduction in seizure frequency and severity during add‐on treatment with ELB 138. Conclusions: The data demonstrate that the partial BZD receptor agonist ELB 138 exerts significant anticonvulsant efficacy without tolerance in a dog seizure model as well as in epileptic dogs with spontaneously recurrent seizures. These data thus substantiate that partial agonism at the BZD site of GABAA receptors offers advantages versus full agonism and constitutes a valuable approach for treatment of seizures.
The Prevalence of Epilepsy in Patients with Celiac Disease
Authors: Tengah Dayangku S. N. A. Pengiran , Holmes Geoff K. T. , Wills Adrian J. 
Published: September 2004

Summary:  Purpose: The relation between celiac disease and epilepsy is uncertain. Previous studies have suggested an association, whereas others have not. Methods: We ascertained the prevalence of active epilepsy in a cohort of 801 celiac patients by patient interviews and retrospective case note review. All the celiac patients had diagnostic confirmation by small bowel biopsy. Results: Twenty‐one patients had a history of epileptic seizures, but only nine (1.1%) had active epilepsy. No specific epileptic syndrome was identified. Conclusions: This study suggests that a causal relation between gluten sensitivity and active epilepsy is unlikely.
Psychopathology and Pediatric Complex Partial Seizures: Seizure‐related, Cognitive, and Linguistic Variables
Authors: Caplan Rochelle , Siddarth Prabha , Gurbani Suresh , Ott Derek , Sankar Raman , Shields W. Donald 
Published: September 2004

Summary: Purpose:This study examined the role of cognition, language, seizure‐related, and demographic variables in the psychopathology of children with complex partial seizure disorder (CPS) of average intelligence.Methods:One‐hundred one CPS and 102 normal children, aged 5.1 to 16.9 years, had a structured psychiatric interview and cognitive and language testing. Parents provided demographic, perinatal, and seizure‐related information, as well as behavioral information through the Child Behavior Checklist (CBCL) and a structured psychiatric interview about the child.Results:Significantly more CPS patients had psychopathology, cognitive deficits, and linguistic deficits than did those in the normal group. Among the patients, Verbal IQ predicted the presence of a psychiatric diagnosis, as well as CBCL scores in the borderline/clinical range. Seizure, linguistic, and demographic variables were unrelated to psychopathology. The cognitive and linguistic deficits of the CPS group, however, were predicted by seizure factors (e.g., prolonged seizures/febrile convulsions; seizure frequency/number of antiepileptic drugs) and demographic factors (e.g., minority status).Conclusions:Because subtle verbal cognitive deficits predict behavioral disturbances in pediatric CPSs, the study's findings highlight the importance of assessing behavior, cognition, and language in these children. They also underscore the negative impact of prolonged seizures, febrile convulsions, seizure frequency, and antiepileptic drug polytherapy on cognition and language in pediatric CPSs.
Metabolic Acidosis and Malnutrition in Dialysis Patients
Authors: Szeto Cheuk‐Chun , Chow Kai‐Ming 
Published: September 2004

ABSTRACTAcidosis is a classic uremic toxin that causes protein catabolism, mainly by selective breakdown of skeletal muscle protein. However, the importance of acidosis is often overlooked in dialysis patients. In the presence of acidosis, there is activation of the ubiquitin‐proteasome machinery as well as the branched‐chain keto acid dehydrogenase, resulting in catabolism of muscle protein. Acidosis acts synergistically with other catabolic factors, such as inflammatory cytokines and insulin resistance, in inducing protein catabolism. There is ample laboratory evidence showing that correction of acidosis prevents the up‐regulation of the ubiquitin‐proteasome machinery and reduces protein degradation. Randomized control trials further show that acidosis in dialysis patients can be treated successfully by a higher dialysate bicarbonate or lactate concentration, or by oral bicarbonate supplement. Correction of mild acidosis in dialysis patients is effective in improving nutritional status and reducing the duration of hospitalization.
Measuring Quality of Dying in End‐Stage Renal Disease
Authors: Spital Aaron , Cohen Lewis M. , Germain Michael J. 
Published: September 2004

ABSTRACTPalliative medicine operates under the presumption that it is possible to improve the quality of a patient's death. Nephrology has justifiably taken pride in its reliance on internal benchmarking and the use of quality targets to shape clinical practice innovations, and this article discusses the efforts that are being made to measure end‐of‐life care of dialysis patients. A tool called the Dialysis Quality of Dying Apgar is described that examines five domains (pain, nonpain symptoms, advance care planning, peacefulness, and time) which are scored and then summed. A recent interdisciplinary workgroup of renal professionals has commissioned a series of focus groups that have attempted to ascertain patient and family values and preferences for the management of terminal situations. The results are summarized, and they should hopefully form a basis for the development of additional research and clinical measurement tools.
Special Article: Improving Outcomes in CKD and ESRD Patients: Carrying the Torch from Training to Practice
Authors: Nissenson Allen R. , Agarwal Rajiv , Allon Michael , Cheung Alfred K. , Clark William , Depner Tom , Diaz‐Buxo Jose A. , Kjellstrand Carl , Kliger Alan , Martin Kevin J. , Norris Keith , Ward Richard , Wish Jay 
Published: September 2004

ABSTRACTPracticing nephrologists are spending more time caring for end‐stage renal disease (ESRD) and chronic kidney disease (CKD) patients. Despite this focus, and considerable advances in the understanding of those aspects of care that impact on clinical outcomes, morbidity, mortality, and quality of life for these patients has not improved substantially over the past decade. One of the possible explanations for this lack of progress is the structure of current nephrology training programs, where ESRD and CKD patient care is not emphasized. To address this issue, we developed a short preceptorship for second‐year nephrology fellows, including didactic lectures and workshops. Of 67 participating fellows, 50% were from programs offering 3 or fewer months of exposure to outpatient hemodialysis, and 25% reported no exposure to peritoneal dialysis. Of more concern, 25% reported no “official rounds” with an attending nephrologist on dialysis patients. If nephrologists are to take their appropriate place as leaders of the care delivery team, nephrology fellowships must be restructured with appropriate emphasis placed on the comprehensive care of ESRD and CKD patients.
Use of Low Molecular Weight Heparins and Glycoprotein IIb/IIIa Inhibitors in Patients with Chronic Kidney Disease
Authors: Perazella Mark A. , Mosenkis Ari , Berns Jeffrey S. 
Published: September 2004

ABSTRACTDespite aggressive intervention, cardiac causes of death, including acute coronary syndrome (ACS), continue to be a major source of mortality in patients with chronic kidney disease (CKD), including end‐stage renal disease (ESRD). Multiple large prospective trials have demonstrated the clinical benefits of both low molecular weight heparin (LMWH) and glycoprotein (Gp) IIb/IIIa inhibitors in treating patients with ACS. Unfortunately patients with significant impairment of kidney function have generally been excluded from these major clinical trials. Consequently relatively little is known about the pharmacokinetics, appropriate dosing, efficacy, and safety of these medications in patients with CKD of various stages. This article examines the available literature regarding the pharmacokinetics, dosing, efficacy, and safety of LMWH and Gp IIb/IIIa inhibitors in patients with CKD.
American Society of Diagnostic and Interventional Nephrology Section Editor: Stephen Ash: Peritoneal Dialysis Access‐Related Procedures by Nephrologists
Authors: Asif Arif 
Published: September 2004

ABSTRACTTraditionally the placement of a peritoneal dialysis (PD) catheter in a patient with end‐stage renal disease (ESRD) has been accomplished by a surgeon and using general anesthesia. This approach often introduces delays in starting PD, incurs additional costs in utilizing an operating room as well as anesthesia services, and introduces the mortality risk associated with general anesthesia. Recent data have emphasized that interventional nephrologists can safely and successfully perform PD access procedures. In this context, operating room facilities and staff and anesthesia services are not required and catheter insertion can be performed in a procedure room using local anesthesia, thereby reducing costs and completely bypassing the mortality risk associated with general anesthesia. When performed by a nephrologist, the catheter insertion can be accomplished swiftly and dialysis therapy initiated in a timely manner. Once begun, the success of PD hinges on reliable and long‐term access to the peritoneal cavity. Prospective randomized and nonrandomized studies have shown that PD catheters peritoneoscopically placed by nephrologists have fewer complications (infection, exit site leak) and longer catheter survival rates than those inserted surgically. Although PD offers a variety of advantages, it remains an underutilized form of renal replacement therapy. To counteract PD underutilization, at least two separate centers have demonstrated a positive impact on the growth of the PD population when catheter insertion is performed by nephrologists. This article presents PD access‐related procedures currently performed by interventional nephrologists. Furthermore, some of the complicating issues (bowel perforation, catheter migration, prior abdominal surgery) related to PD catheter insertion and management are also discussed.
Review article: anti‐reflux surgery and endoluminal therapies
Authors: Sonnenberg A. 
Published: September 2004

SummaryIn the short term, fundoplication and antisecretory medication are equally effective in the management of gastro‐oesophageal reflux disease. However, over the long term, the fundoplication wrap tends to become loose, and many surgical patients continue to take antisecretory medication after surgery. The operation is technically complex and takes a long time to learn. Inexperience of the individual surgeon is a major factor contributing to the occurrence of postsurgical complications. Fundoplication does not prevent the occurrence of Barrett's oesophagus nor its progression to oesophageal adenocarcinoma. There is no evidence to suggest that the procedure is less costly or more cost‐effective than long‐term maintenance therapy with antisecretory medications, especially if surgical failures and postsurgical complications are taken into account. Fundoplication represents an alternative to medical therapy in patients with gastro‐oesophageal reflux disease who cannot or do not want to be on long‐term maintenance therapy with antisecretory medication. Endoluminal procedures, such as radiofrequency ablation, endoscopic suturing and injection at the gastro‐oesophageal junction, work only in mild forms of reflux disease. They fail to provide complete relief of reflux symptoms and do not heal erosive oesophagitis. All endoluminal procedures would have to undergo major technological improvements before they could become comparable with fundoplication or antisecretory therapy.
Practical examples: trials and conclusions — an interactive segment
Authors: Talley N. J. 
Published: September 2004

SummaryThere is a requirement for a critical review of the literature published in the field of reflux disease management, particularly when the literature is used as a basis for the adoption of specific interventions into everyday practice. Numerous published studies are valid and robust, but many are not. Particularly common is the over‐interpretation of positive studies based on small patient numbers, which may be subject to publication bias. Claims of equivalence are invalid without a pre‐specified level of equivalence and adequate power to measure this. More generally, a lack of pre‐defined primary end‐points, clinically relevant and measured appropriately, is a common feature of reflux trial methodology.
Review article: gastric pH — the most relevant predictor of benefit in reflux disease?
Authors: Armstrong D. 
Published: September 2004

SummaryIn patients with gastro‐oesophageal reflux disease, the pH of refluxed gastric contents has a direct bearing on disease severity and oesophageal damage. A pH of 4 has been defined as a threshold below which refluxed gastric contents become injurious to the oesophagus. Studies in patients with erosive oesophagitis have shown that the 8‐week healing rates produced by acid suppressive therapy are related to the duration of time over a 24‐h period that the intragastric pH > 4. The most effective agents, providing more hours with gastric pH > 4 and higher healing rates in erosive oesophagitis patients, are the proton pump inhibitors. The intragastric pH is often used to gauge the efficacy of acid suppressive therapies. There are several factors, however, that may affect the clinical relevance of such data, and these should be taken into account when comparing the effectiveness of different therapies. Firstly, because of inter‐individual variation, studies comparing therapies should be of a crossover design, so that responses to therapy are measured in the same individuals. Secondly, the Helicobacter pylori status of the individual should be known, as H. pylori infection has been shown to increase intragastric pH readings when examining the effect of acid suppressive therapy. Other factors, such as positioning of the pH electrode and the duration of previous therapy, also need to be standardized when using intragastric pH to assess the efficacy of different therapies. Crossover studies comparing standard doses of different proton pump inhibitors have shown that esomeprazole 40 mg produces a significantly greater amount of time at intragastric pH > 4 on day 5 of treatment than standard doses of other proton pump inhibitors. The correlation between greater efficacy in acid suppression and clinical benefit is supported by the findings that esomeprazole 40 mg is the only proton pump inhibitor to provide greater 8‐week healing rates in patients with erosive oesophagitis than both omeprazole and lansoprazole. These data all suggest strongly that intragastric pH monitoring is an effective surrogate marker and a relevant predictor of outcome in gastro‐oesophageal reflux disease.
Review article: towards the optimization of symptom evaluation in reflux disease
Authors: Dent J. 
Published: September 2004

SummaryA recent workshop has taken stock of the processes used for the evaluation of reflux disease symptoms. Such evaluations are vital both for routine clinical practice and for the critical assessment and comparison of therapeutic options. The workshop endorsed the importance of the assessment of symptom patterns for the diagnosis of reflux disease. Patient self‐report symptom questionnaires were considered to be potentially valuable instruments, but have been researched relatively little in reflux disease. On the basis of a survey of the literature and data from generic methodological research, the workshop concluded that virtually all trials of the therapy of reflux disease have used too few response options for a sensitive definition of symptom status, and recommended that six to seven response options be used. Modified Likert scales with defined individual response options and structured patient self‐report, rather than physician assessment, were considered to be the best approaches. These views on symptom status assessment are not reflected fully in the current practice of reflux disease clinical trials. Furthermore, the terminology used to describe symptom status is frequently ambiguous or tautological. Quality of life measures were acknowledged as valid and useful secondary measures of therapeutic benefit. By contrast, evaluation of the state of the art of assessment of patient satisfaction with therapy led to the conclusion that the methodology for this particular assessment was still in its infancy. The outputs of the workshop revealed many aspects of the assessment of reflux disease that would benefit from further research and development. A report on the detailed outputs of the workshop has been published recently.
Positive supercoiling is generated in the presence of Escherichia coli SeqA protein
Authors: Klungsøyr Hege Kjellesvik , Skarstad Kirsten 
Published: September 2004

SummaryIn Escherichia coli, the SeqA protein is known as a negative regulator of chromosome replication. This protein is also suggested to have a role in chromosome organization. SeqA preferentially binds to hemi‐methylated DNA and is by immunofluorescence microscopy seen as foci situated at the replication factories. Loss of SeqA leads to increased negative supercoiling of the DNA. We show that purified SeqA protein bound to fully methylated, covalently closed or nicked circular DNA generates positive supercoils in vitro in the presence of topoisomerase I or ligase respectively. This means that binding of SeqA changes either the twist or the writhe of the DNA. The ability to affect the topology of DNA suggests that SeqA may take part in the organization of the chromosome in vivo. The topology change performed by SeqA occurred also on unmethylated plasmids. It is, however, reasonable to suppose that in vivo the major part of such activity is performed on hemi‐methylated DNA at the replication factories and presumably forms the basis for the characteristic SeqA foci observed by fluorescence microscopy.
Identification of ComW as a new component in the regulation of genetic transformation in Streptococcus pneumoniae
Authors: Luo Ping , Li Haiying , Morrison Donald A. 
Published: September 2004

SummaryRegulation of competence for genetic transformation in Streptococcus pneumoniae depends on a quorum‐sensing system, genes involved in DNA uptake and recombination and a link between these two gene sets. The alternative sigma factor ComX provides this link. ComE, the response regulator of the quorum‐sensing system, is required for expression of ComX and other early genes. However, an unknown ComE‐dependent regulator is also required for competence when comX is expressed under control of the raffinose‐responsive promoter of the aga operon. The gene comW (SP0018) is required for a high level of competence and is regulated by the quorum‐sensing system, but its function is unknown. To explore its role further, comW was cloned into the multicopy plasmid pMSP3535, under the control of a nisin‐inducible promoter (PN), and transformed into pneumococcal strains containing a raffinose‐inducible comX gene (PR::comX). Further introduction of a comE deletion blocked the endogenous CSP signal transduction pathway. In the resulting strain, competence was independent of CSP but depended on treatment with both nisin and raffinose, showing that coexpression of comW and comX complemented the comE deficiency. ComX protein accumulation and expression of a late competence gene in the above strain support the conclusion that ComW is a new positive factor involved in competence regulation.
RNase HI overproduction is required for efficient full‐length RNA synthesis in the absence of topoisomerase I in Escherichia coli
Authors: Baaklini Imad , Hraiky Chadi , Rallu Fabien , Tse‐Dinh Yuk‐Ching , Drolet Marc 
Published: September 2004

SummaryIt has long been known that Escherichia coli cells deprived of topoisomerase I (topA null mutants) do not grow. Because mutations reducing DNA gyrase activity and, as a consequence, negative supercoiling, occur to compensate for the loss of topA function, it has been assumed that excessive negative supercoiling is somehow involved in the growth inhibition of topA null mutants. However, how excess negative supercoiling inhibits growth is still unknown. We have previously shown that the overproduction of RNase HI, an enzyme that degrades the RNA portion of an R‐loop, can partially compensate for the growth defects because of the absence of topoisomerase I. In this article, we have studied the effects of gyrase reactivation on the physiology of actively growing topA null cells. We found that growth immediately and almost completely ceases upon gyrase reactivation, unless RNase HI is overproduced. Northern blot analysis shows that the cells have a significantly reduced ability to accumulate full‐length mRNAs when RNase HI is not overproduced. Interestingly, similar phenotypes, although less severe, are also seen when bacterial cells lacking RNase HI activity are grown and treated in the same way. All together, our results suggest that excess negative supercoiling promotes the formation of R‐loops, which, in turn, inhibit RNA synthesis.