bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacology and Therapeutic Aspects of Antiepileptic Drugs in Pediatrics
Authors: Dodson W. Edwin , Bourgeois Blaise F.D.
Published: September 2009

In the past year, several new antiepileptic drugs have emerged that have potential benefits for children with epilepsy. The spectrum of adverse effects is the principal feature that differentiates among the older drugs used to treat partial and related seizures, including simple partial, complex partial, and partial secondarily generalized seizures. Based on studies in adults with refractory seizures, the new or investigational compounds felbamate, gabapentin, lamotrigine, and vigabatrin should be active against these types of seizures in children, but none of them have been subjected to pediatric randomized controlled trials, and no studies have been done that compare new and old drugs in this category. Thus, the new drugs hold promise in children with these types of seizures, but their role relative to old drugs has not been elucidated. Several of the new drugs are active against myoclonic and generalized tonic-clonic seizures, but thus far, none have been proven to possess antiabsence activity in children. Open-label investigations suggest that lamotrigine may be helpful in Lennox-Gastaut syndrome, and vigabatrin in infantile spasms. Only felbamate has been evaluated in a randomized controlled study in children, in which it has proven beneficial against astatic and generalized tonic-clonic seizures in children with Lennox-Gastaut syndrome. Whereas investigations of these and other novel drugs are ongoing, this is an active and exciting period in pediatric antiepileptic drug development. (J Child Neurol 1994;9(Suppl):2S1-2S7).
The Contributions of Epidemiology to the Understanding of Childhood Seizures and Epilepsy
Authors: Berg Anne T. , Shinnar Shlomo
Published: September 2009

Up through the 1960s, studies of epilepsy were based on patients seen in tertiary referral centers, many of whom had refractory epilepsy. Based on these early studies, epilepsy was believed to be a chronic, progressive, and incurable disorder. Seizures were thought to cause damage and result in further seizures. Clinical management of children with seizures reflected these beliefs. Over the last 25 to 30 years, epidemiologic studies have demonstrated that, contrary to these earlier beliefs, the prognosis of most childhood seizures and epilepsy is excellent. Prognosis is largely determined by the underlying etiology and not the seizures themselves. The differences in the assessment of the prognosis of seizures derived from the earlier studies versus the later epidemiologic studies are largely due to several biases that occurred in the earlier studies. These biases are explained. Several examples are provided of how the epidemiologic studies have greatly altered the prevailing views regarding the prognosis of seizures, and, by doing so, the management of seizures. (J Child Neurol 1994;9(Suppl):2S19-2S26).
Early Surgery for Epilepsy: Redefining Candidacy
Authors: Resnick Trevor J. , Duchowny Michael , Jayakar Prasanna
Published: September 2009

Surgical resection for localization-related epilepsy has recently become a generally accepted treatment in children. Evidence of the poor outcome in natural history studies of temporal lobe epilepsy in childhood initiated consideration of surgical intervention. Subsequent favorable outcome following surgery was encouraging. A number of variables differentiate adults with focal seizures from children. Evolving biologic factors modify the clinical and electroencephalographic expression of seizures in childhood. The pathologic substrate is different, and there is a higher incidence of extratemporal epilepsy. Chronic seizures beginning under age 2 years rarely remit, especially when associated with a demonstrable structural lesion. Behavioral consequences of chronic seizures are significant and become a major problem by adolescence if seizures are not controlled. Early surgery results in superior functional outcome, although subtle deficits persist postoperatively. Surgical outcome is as favorable as in adults with improvements in behavioral status and socialization. Abundant data exist to more adequately assess the benefits and risks of surgery in children so that intervention is not deferred longer than it needs to be. (J Child Neurol 1994;9(Suppl):2S36-2S41)
Commissurotomies in Children
Authors: Carmant Lionel , Holmes Gregory L.
Published: September 2009

Although corpus callosotomy has been used since 1940 to treat severe, medically intractable seizure disorders, controversy remains as to when, or even if, the surgery should be performed. Unlike other types of surgical therapy of epilepsy where the epileptic focus is identified and removed, corpus callosotomy is used to interrupt the propagation of epileptic discharges. The procedure is primarily used in patients with secondarily generalized seizures in whom focal resections are not possible. Long-term follow-up studies of post-callosotomy patients are few and flawed by lack of accurate seizure counts and quality-of-life measures. Although it remains difficult to predict those patients who will benefit from the surgery, it appears that patients with "drop" attacks benefit the most from the procedure. (J Child Neurol 1994;9(Suppl):2S50-2S60).
Subdural Monitoring in the Evaluation of Children for Epilepsy Surgery
Authors: Jayakar Prasarma , Duchowny Michael , Resnick Trevor J.
Published: September 2009

Noninvasive assessment of children with chronic epilepsy is often imprecise and localization of seizure foci requires intracranial electroencephalographic monitoring. Subdural electrodes provide coverage of large areas of neocortex and are ideally suited for evaluating children with intractable epilepsy and to functionally map critical cortex. This report discusses the role of subdural electroencephalography in the evaluation of childhood epilepsy. (J Child Neurol 1994; 9(Suppl):2S61-2S66).
A Review of Cognitive Outcome After Unilateral Lesions Sustained During Childhood
Authors: Vargha-Khadem Faraneh , Isaacs Elizabeth , Muter Valerie
Published: September 2009

Views on human brain organization early in development have swung back and forth between the extreme notions of complete equipotentiality and adult-like specialization. Recent research on the cognitive effects of early brain damage supports an intermediate position and suggests that many claims on the older literature must be re-examined in the light of new evidence that cognitive impairments are sometimes attributable to previously ignored factors, such as a history of seizures, time since injury, and unsuspected lesions that are now detectable with neuroimaging techniques. (J Child Neurol 1994;9(Suppl):2S67-2S73).
Adult Experience With Lamotrigine
Authors: Willmore L. James , Messenheimer John A.
Published: September 2009

Lamotrigine is a phenyltriazine derivative with anticonvulsant properties that initially was tested in adults with partial seizures. Pharmacokinetics in adults includes a volume of distribution of 1.0 to 1.3 L/kg. Plasma protein binding is 55% and none of the metabolites are active as anticonvulsants. The placebo-controlled studies evaluated the responder rate as the percent of patients with 50% or greater seizure reduction when compared to baseline assessment. The responder rate for 300 mg per day was 20% and 36% for 500 mg per day dosages. Adverse events were infrequent but the occurrence of rash appeared to correlate with rapid ascension dosing and comedication with valproic acid. Slow titration is required when initiating treatment with lamotrigine. Accumulating experience in adults suggests that lamotrigine has a broad spectrum of effect; data from further controlled trials should suggest other clinically important forms of epilepsy that respond to lamotrigine. (J Child Neurol 1997;12(Suppl 1):S16-S18).
Lamotrigine in Absence and Primary Generalized Epilepsies
Authors: Mikati Mohamad A. , Holmes Gregory L.
Published: September 2009

Although lamotrigine has been approved in the United States as adjunctive therapy for partial seizures in patients older than 12 years, there is increasing evidence that it is just as effective, if not more effective, in the treatment of generalized seizures. A large number of open-label studies and some single-blind data, all using lamotrigine as add-on therapy in patients with previously refractory generalized seizures, are available. Controlled studies, some on newly diagnosed, previously untreated patients with generalized seizures are ongoing. Investigations have demonstrated that patients with the following generalized seizure types improve with lamotrigine add-on therapy: Typical and atypical absence, atonic, generalized tonic-clonic, myoclonic, and clonic seizures. Response rates, defined as the percentage of patients with better than 50% reduction in seizure frequency, have been, depending on seizure type, in the range of 30% to 56%, with 0 to 33% of the patients becoming seizure free. The best responses have been noted in typical and atypical absences, and atonic seizures. Children and adults appear to have comparable responses. In addition, add-on studies in patients with specific, previously refractory, epilepsy syndromes have demonstrated that the best improvement in seizure control occurs in patients with petit mal epilepsy, "other symptomatic" generalized epilepsies, and in Lennox-Gastaut syndrome, followed by patients with other myoclonic epilepsies, myoclonic absence and West syndrome. Many previously refractory patients are able to achieve lamotrigine monotherapy. However, patients with nonprogressive myoclonic epilepsy have little, if any, response. Early data from ambulatory encephalographic (EEG) recordings in patients with previously refractory absence seizures, and from controlled studies on patients with newly diagnosed typical absence seizures, appear to confirm the efficacy of lamotrigine in those patients. Controlled studies are ongoing in patients with absence seizures, in patients with generalized tonic-clonic seizures, and in patients with Lennox-Gastaut syndrome. Dosing in generalized seizures is similar to that for partial seizures. Because of the shorter half-life of lamotrigine in children, as compared to adults, higher (mg/kg) doses are often needed in young patients. We conclude that lamotrigine is a promising drug for absence and primary generalized seizures in both children and adults. (J Child Neurol 1997;12(Suppl 1):S29-S37).
Behavioral and Cognitive Effects of Lamotrigine
Authors: Meador Kimford J. , Baker Gus A.
Published: September 2009

Lamotrigine is a new antiepileptic drug that may possess unique cognitive and behavioral characteristics. Although lamotrigine can produce neurobehavioral toxicity, it is generally well tolerated. In one study directly comparing lamotrigine to placebo as add-on therapy in patients with intractable epilepsy, no objective cognitive effects were observed in a limited neuropsychological battery. Several studies have demonstrated favorable effects of lamotrigine on psychological well-being that were not explained by simple effects on seizure frequency and severity. In direct comparisons with carbamazepine and phenytoin, lamotrigine has been reported to produce positive effects on quality of life scales of patient perception. In addition, positive behavioral effects have also been observed in two blinded studies and several open trials for patients with severe mental disability and refractory epilepsy. Future studies with more extensive neuropsychological assessments are needed to delineate the differential cognitive and behavioral effects of lamotrigine in epilepsy and psychiatric disorders. (J Child Neurol 1997;12(Suppl 1):S44-S47).
Clinical Experience With Fosphenytoin in Adults: Pharmacokinetics, Safety, and Efficacy
Authors: Knapp Lloyd E. , Kugler Alan R.
Published: September 2009

Fosphenytoin, a prodrug of phenytoin, is rapidly and completely converted to phenytoin in adults after intravenous or intramuscular administration and is significantly better tolerated than parenteral phenytoin. Fosphenytoin is highly plasma-protein bound and, when present in sufficient concentration, will displace phenytoin from plasma proteins. The clinical utility is that fosphenytoin may be used to achieve therapeutic phenytoin concentrations more rapidly than intravenous phenytoin infused at its maximum recommended rate. In a clinical study of generalized convulsive status epilepticus, fosphenytoin, with or without benzodiazepine pretreatment, controlled seizures in 76 (93.8%) of 81 patients. In other studies, fosphenytoin maintained seizure control when substituted for oral phenytoin and for seizure prophylaxis in neurosurgery and trauma patients. Adverse events associated with fosphenytoin generally were related to the central nervous system and were similar to those associated with phenytoin, except for a higher incidence of transient pruritus with fosphenytoin. Intravenous fosphenytoin has significant advantages over intravenous phenytoin: It requires a shorter infusion time and fewer intravenous disruptions, causes less pain and burning at the infusion site and minimal consequences in case of intravenous infiltration, allows longer maintenance of intravenous sites, and has better intravenous fluid compatibility and stability. In contrast to intramuscular phenytoin, intramuscular fosphenytoin is well tolerated in both large loading doses and maintenance doses. (J Child Neurol 1998;13(Suppl 1):S15-S18).
Knowledge of Motivational Interviewing
Authors: Goodwin Amy C. , Bar Bonnie B. , Reid Gail G. , Ashford Susan A.
Published: September 2009

Purpose: The overall goal of this pilot study was to determine the effects of a motivational interviewing (MI) educational program on MI knowledge. Design: Pretest/posttest intervention study. Method: Eleven participants completed a 20-item test prior to a 6-hour course on motivational interviewing. Six of those participants completed a second 2-hour educational session and a posttest. Findings: On average, participants increased their score from the pretest (mean [ M] = 12.7, range 8-16; standard error [ SE] = 1.256) to the posttest ( M = 15.5, range 14-17; SE = 0.428). Although, this difference was not significant, t(5) = −2.49; p = .055; r = .55, given a standard level of significance of .5, the effect size was large, representing a substantive change. Conclusions: The motivational interviewing intervention was deemed clinically successful by the multidisciplinary committee based on the large effect size.
Guidance for handling and use of nanomaterials at the workplace
Authors: Heinemann M. , Schäfer HG
Published: September 2009

Chances and risks of nanomaterials is a most fascinating challenge of future technologies. This new technology and their related materials are beneficial, for example, for energy reduction, lower emissions to the environment, and safe resources. However, there are concerns about health effects related to the very small dimensions of such materials. Because of our commitment to the principles of “Sustainable Chemistry” and “Responsible Care®,” the chemical industry actively cooperates with all relevant stakeholders to assure a safe handling and use of nanomaterials. In this manner, the German chemical industry is committed to establish and disseminate best practices for a responsible production and use of nanomaterials. Protection of human life and the environment is a fundamental principle for our industry. Even though in the European Union the existing legal framework for risk assessment for chemical substances applies for nanomaterials, specific properties of nanomaterials may require amendments. The German Chemical Industry Association (Verband der Chemischen Industrie, VCI) has, therefore, issued guidance documents and recommendation papers to support companies in the sustainable and responsible development of nanotechnology-based applications. One of these guidance documents focused on ensuring the workplace safety of our employees. Background for this document was a joint survey on occupational health and safety in the handling and use of nanomaterials, which was conducted in spring 2006 from the German Federal Institute for Occupational Safety and Health (Bundesanstalt für Arbeitsschutz und Arbeitsmedizin, BAuA) and VCI. The purpose of the survey was to obtain an overview of occupational health and safety methods currently applied in the chemical industry in activities involving nanomaterials. The questionnaire survey was evaluated by BAuA; the "Guidance for Handling and Use of Nanomaterials at the Workplace" was elaborated predominantly by VCI. This Guidance provides some orientation regarding measures in the production and use of nanomaterials at the workplace. The recommendations given there reflect the current state of science and technology.
Preparation of nanoparticle dispersions for in-vitro toxicity testing
Authors: Vippola M. , Falck GCM , Lindberg HK , Suhonen S. , Vanhala E. , Norppa H. , Savolainen K. , Tossavainen A. , Tuomi T.
Published: September 2009

Studies on potential toxicity of engineered nanoparticle (ENP) in biological systems require a proper and accurate particle characterization to ensure the reproducibility of the results and to understand biological effects of ENP. A full characterization of ENP should include various measurements such as particle size and size distribution, shape and morphology, crystallinity, composition, surface chemistry, and surface area of ENP. It is also important to characterize the state of ENP dispersions. In this study, four different ENPs, rutile and anatase titanium dioxides and short single- and multi-walled carbon nanotubes, were characterized in two dispersion media: bronchial epithelial growth medium, used for bronchial epithelial BEAS cells, and RPMI-1640 culture media with 10% of fetal calf serum (FCS) for human mesothelial (MeT-5A) cells. The purpose of this study was to determine the characteristics of ENPs and their dispersions as well as to compare dispersion additives suitable for toxicity tests and thus establish an appropriate way to prepare dispersions that performs well with the selected ENP. Dispersion additives studied in the media were bovine serum albumin (BSA) as a protein resource, dipalmitoyl phosphatidylcholine (DPPC) as a model lung surfactant, and combination of BSA and DPPC. Dispersions were characterized using optical microscopy and transmission electron microscopy. Our results showed that protein addition, BSA or FCS, in cell culture media generated small agglomerates of primary particles with narrow size variations and improved the stability of the dispersions and thus also the relevance of the in-vitro genotoxicity tests to be done.
Cross-sectional study on respiratory effect of toner exposure
Authors: Terunuma Niina , Kurosaki Shizuka , Kitamura Hiroko , Hata Koichi , Ide Reiko , Kuga Hiroaki , Kakiuchi Noriaki , Masuda Masashi , Totsuzaki Takafumi , Osato Atsushi , Uchino Bungo , Kitahara Kayo , Iwasaki Akio , Yoshizumi Koji , Morimoto Yasuo , Kasai Hiroshi , Murase Tadashi , Higashi Toshiaki
Published: September 2009

In this baseline study, part of a cohort study to clarify the effect of toner exposure on the respiratory system, we surveyed 803 male toner workers and 802 referents with regard to their subjective respiratory symptoms and chest X-ray results. We also examined individual exposure history, current working conditions, and personal exposure levels to toner. There was a significantly higher prevalence of “coughing and sputum” related complaints among toner-exposed workers in the 30 and 40-year age groups. The group with toner-exposure history showed a higher odds ratio, by logistic regression, in relation to all questions regarding coughing. Mild fibrotic changes were observed in the chest X-rays of four workers who had engaged in toner-exposure work for at least a decade or more, and all four had reported allergic disease. Although we observed a tendency of higher prevalence of “coughing and sputum” in toner-exposed workers, the possibility of information bias cannot be eliminated. It should also be noted that this tendency did not exceed that of the general public. Further analysis is required in this ongoing 10-year cohort study to clarify the effect of toner exposure on the respiratory system.
Occupational safety and health’s role in sustainable, responsible nanotechnology: gaps and needs
Authors: Iavicoli S. , Rondinone BM , Boccuni F.
Published: September 2009

The newly fledged nanotechnologies offer opportunities for social development, but uncertainties prevail about their impact on human and environmental health. There is still a huge gap between technological progress and research into the health and safety aspects of nanomaterials. This is clear from the quantity of nanoproducts already on the market — more than 600 — and the public and private funds dedicated to the development of nanotechnologies, which are almost a hundred times those available for research into their effects on health and safety. Estimates have it that by 2014, nanotechnologies will be widely used in our society and ten million new jobs will be created. Therefore, it becomes essential to plan an integrated approach to specific risk analysis at work. The following gaps and needs come to light: limited information, difficulties in relating nanotechnologies and production of nanomaterials to specific areas of application, efforts required to assess the hazards posed by nanomaterials in realistic exposure conditions, ethical issues about nanotechnology in the workplace likely to arise from today’s knowledge about the hazards of nanomaterials and the risks they may pose to workers. An integrated approach to research, cooperation, and communication strategies is essential if we are to direct our efforts toward responsible and sustainable growth of nanotechnologies.
Safety assessment of azelaic acid and its derivatives entrapped in nanovesicles
Authors: Panyosak A. , Manosroi J. , Rojanasakul Y. , Manosroi A.
Published: September 2009

The aim of this study was to determine the safety of azelaic acid (AA) and its derivatives in nanovesicles for pharmaceutical and cosmetic uses. The hydrophilic property of AA was modified by complexing AA with hydroxypropyl-β-cyclodextrin (AACD). The lipophilic property of AA was improved to diethyl azelate (DA) by esterification with Fischer reaction. AA, AACD and DA were entrapped in liposomes and niosomes with the compositions of L-α-dipalmitoyl phosphatidylcholine/cholesterol = 7:3 and Tween 61/cholesterol = 1:1, respectively, by chloroform film method with sonication. The size of the vesicles ranged from 50 to 200 nm, indicating nanosize characteristics. The cytotoxicity of AA, AACD and DA entrapped nanovesicular formulations on mouse epidermal cell lines (JB6, normal cell lines) by the sulforhodamine B assay was modest when compared with cisplatin. Blank liposomes and niosomes gave no growth inhibitory effect. The irritation of AA, AACD and DA entrapped and not entrapped in nanovesicles on rabbit skin was examined according to the Environmental Protection Agency health effect test guidelines. The results showed no signs of erythema or edema within 72 h. AA and its derivatives were safe for topical use when entrapped in nanovesicles because of no toxicity to normal cell lines and no allergy on rabbit skin.
Vanquishing the Enemy or Civilizing the Neighbour? Controlling the Risks from Hazardous Industries
Authors: Haines Fiona
Published: September 2009

Inclusion of the local community in a continuous dialogue aimed at reducing the risks posed by hazardous industries such as chemical plants and oil refineries is an increasingly common feature of some regulatory regimes. This article explores the implications of this regulatory shift for the reduction of risk through research undertaken in a major Australian city. The study found that local communities, when given a formal voice in regulatory regimes, did push industry to consider an extended range of risks. These risks included the risk of explosion or major chemical spill threatening health and the environment (termed here actuarial risks) but also concerns about the orderliness within the local neighbourhood and proper relationships between industry and community (risks of a more socio-cultural nature). Further, the escalation of political risk was critical in determining which actuarial and socio-cultural concerns of the community were listened to. Regulatory innovations involving increased accountability of hazardous industry to the local community may increase pressure on targeted industry to reduce risk, but the ensuing risk management is likely to involve political and socio-cultural as well as actuarial risks.
‘To Check . . . the Very Worst and Meanest of Our Passions’: Common Sense, ‘Cobbon Sense’, and the Socialization of Cadets at Antebellum West Point
Authors: Rafuse Ethan S.
Published: September 2009

This essay adds to a growing body of scholarship that challenges the image of the United States Military Academy at West Point and US Army officer corps as institutions that were isolated in the nineteenth century from developments in civilian society. It does so by calling attention to parallels between the ideas that shaped the antebellum military academy‘s approach to cadet education and socialization and those of the Scottish-American ‘common sense’ school of moral philosophy that was popular among members of America’s emerging middle class before the Civil War. It describes these parallels, how they reflected a common cultural milieu that shaped the outlook of the common sense philosophers, their adherents and education theorists in antebellum America, and the authorities at West Point, and identifies traits that distinguished how many West Point graduates conducted themselves during the American Civil War that are suggestive of these parallels.
Britain and the Resale of Argentine Cruisers to Japan before the Russo-Japanese War
Authors: Yabuki Hiraku
Published: September 2009

In late 1903 Britain bought Chilean battleships, whereas Japan bought Argentine cruisers in the face of Russian counter-bidding. Previous scholarship has considered this arms trade as a case in which Britain showed its sympathy, or rather gave assistance, to Japan. However, this paper, based on multi-archival research in both Japan and Britain, argues that there was no sign of any such sympathy. The resale and transfer of the Argentine cruisers also shed light on the strategic views of the British government and the actual state of Anglo-Japanese relations just before the Russo-Japanese War.
Atrocities, Conscience, and Unrestricted Warfare
Authors: Sturma Michael
Published: September 2009

This article explores the meanings of ‘unrestricted warfare’ as practised by US submarines in the Pacific during the Second World War. The submarine war in the Pacific is typically represented as a series of torpedo attacks that devastated Japanese warships, freighters, and tankers. There was also, however, a less familiar submarine war fought on the surface with deck guns. Particularly in the later stages of the war, submarines attacked hundreds of small craft of questionable military value. Drawing on comparisons with Allied aerial bombing campaigns, it is argued that, while the submarine war involved a similar blurring of combat and atrocity, submariners frequently acted on their consciences in encounters with the enemy and civilians.
Amended Final Report On the Safety Assessment of Pyrocatechol
Authors: Andersen F. Alan
Published: September 2009

Pyrocatechol is a phenol used primarily in hair dyes but has one reported use in skin care preparations. When this ingredient was first reviewed it was concluded that Pyrocatechol was safe for use in formulations designed for discontinuous, brief use followed by rinsing from the skin and hair at concentrations of up to 1.0%. This amendment to that report was prepared in order to incorporate the results from several studies, including those reporting immunologic, carcinogenic, and cocarcinogenic effects of Pyrocatechol. In vitro, Pyrocatechol has been shown to affect several immunologic and other properties of murine bone marrow cells, both alone and when combined with hydroquinone. Pyrocatechol, when produced as an hepatic metabolite of benzene, has been reported to concentrate in the bone marrow and to adversely affect hematopoietic precursor cells. These effects are somewhat species specific. In vivo, dermal exposure of mice to Pyrocatechol affects the number and distribution of Langerhans cells at the site of exposure but is not associated with a change in contact sensitivity. Oral exposure of pregnant rats to Pyrocatechol did result in an increase in teratogenic effects. The results of a micromass teratogen test in vitro were also positive. Pyrocatechol was tested in a number of bacterial and mammalian mutagenesis systems. Both negative and positive results were observed. Carcinogenicity studies were conducted in rats and mice. Pyrocatechol was provided in the feed. While adenomatous hyperplasia was noted in both species, adenocarcinomas were seen in male and female rats only. In cocarcinogenesis studies there is a similar pattern of hyperplasia and adenomas of the glandular stomach in the groups exposed to Pyrocatechol alone. When administered with several other carcinogens, Pyrocatechol had a cocarcinogenic effects. Pyrocatechol was not a tumor promoter in dermal studies. Based on these data and the significant potential for skin absorption of Pyrocatechol in leave-on preparations, it was concluded that Pyrocatechol is unsafe for use in leave-on cosmetic formulations. Pyrocatechol used in a rinse-off application such as hair dyes may not present a similar concern if Pyrocatechol is completely and rapidly oxidized. Because no data were available, it was concluded that there are insufficient data to support the safety of this ingredient. The data needed to complete the safety assessment include the extent and rate of oxidation when used in hair dyeing. If not rapidly and completely oxidized, then further chemical characterization of cosmetic grade Pyrocatechol is needed, along with cutaneous absorption data in aqueous and alcohol vehicles and ultraviolet absorption data (if positive, photosensitization studies may be needed).
Final Report On the Safety Assessment of Cetyl Esters1
Authors: Andersen F. Alan
Published: September 2009

Cetyl Esters is a synthetic wax composed of a mixture of esters ofsaturated fatty acids and fatty alcohols with carbon chain lengths between 14 and 18. Cetyl Esters is currently used as a skin conditioning agent-emollient in over 200 cosmetic formulations at concentrations of up to 7%. The esters that are found in Cetyl Esters include Cetyl Palmitate, Cetyl Stearate, Myristyl Myristate, Myristyl Stearate, Cetyl Myristate, and Stearyl Stearate. Safety data on four of these (Cetyl Palmitate, Cetyl Stearate, Myristyl Myristate, and Myristyl Stearate) have previously been reviewed and are summarized in this report; overall, the data show no systemic toxicity, no sensitization or photosensitization, and little irritation. Because of the structural similarity of Cetyl Myristate and Stearyl Stearate to these four ingredients, it is expected that they would behave in a similarly nontoxic manner. Therefore, it was concluded that Cetyl Esters (as a mixture of all six ingredients) is safe as used in cosmetics.
Effects of Diet and Overfeeding On Body Weight and Survival in the Rodent Bioassay: the Impact On Pharmaceutical Safety Assessment
Authors: Keenan Kevin P
Published: September 2009

Uncontrolled body weight due to ad libitum (AL) overfeeding is the most significant variable affecting the rodent bioassay. The correlation between AL food consumption, the resultant excessive adult body weight, and the low 2-yr survival in Sprague-Dawley (SD) rats was highly significant. However, initial body weight does not correlate with adult body weight or survival. AL feeding of diets that varied in protein, fiber, and energy content did not improve low 2-yr survival. Only moderate dietary restriction (DR) of all diets tested significantly improved survival and delayed the onset or severity of spontaneous degenerative diseases and tumors. Moderate DR-fed rats had a similar incidence of tumors as AL-fed rats by 2 yr; however, the tumors were more likely to be incidental and not fatal. There was a decreased age-adjusted incidence of pituitary and mammary-gland tumors, but tumor volume and growth time were similar between AL and moderate DR groups. These data indicate a similar tumor progression, but only a delay in tumor onset. Moderate DR did not significantly alter drug-metabolizing enzyme activities nor the toxicologic response to five pharmaceuticals tested at maximum tolerated doses (MTDs). However, moderate DR did require higher doses of compounds to be given before classical MTDs were produced with four drug candidates. Toxicokinetic studies of two of these compounds demonstrated steady-state systemic exposures that were equal or higher in moderate DR-fed rats. Biochemical markers of oxidative stress (lipid peroxidation, protein oxidation) were decreased and cytoprotective markers were increased by moderate DR. These and other data indicate that moderate DR is the most appropriate method of body weight control when used to assess pharmaceuticals for human safety.
Final Report On the Safety Assessment of Hc Yellow No. 4
Authors: Andersen F.A.
Published: September 2009

HC Yellow No. 4 is a colorant for use mostly in hair dyes and colors, but also in a few hair tints. Concentrations at which the ingredient is used range from 0.1 % to 1.0%. Confusion has existed regarding the proper structure for this ingredient, but was resolved through additional analysis; the correct CAS number is 59820-43-8. Commercially available HC Yellow No. 4 may contain a nitroaniline impurity. Percutaneous absorption studies using commercial products containing 1% HC Yellow No. 4 found little absorption. Body weight decreases were noted in short-term oral toxicity studies and in a subchronic oral toxicity study. HC Yellow No. 4 did not produce irritation, sensitization, or photosensitization in animal tests (primarily using guinea pigs). In some feeding studies, fetal toxicity was observed, but no such effect was found in other feeding studies. HC Yellow No. 4 was mutagenic in several assays, but no evidence of carcinogenesis was found in oral or dermal studies. Two repeated insult patch tests, totalling over 200 human volunteers, found no sensitization reactions. While there was concern expressed over the reproduction and developmental toxicity found in feeding studies, such adverse responses would not be expected from the use of this ingredient in hair coloring products because so little HC Yellow No. 4 is absorbed. The presence of a low level of nitroaniline derivative impurity (0.3 to 7%) is not considered to present a human health risk because the products containing HC Yellow No. 4 are used in a brief and discontinuous manner, followed by rinsing. On the basis of the available data, therefore, it is concluded that HC Yellow No. 4 is safe as a hair colorant in the present practices of use.
Final Report On the Safety Assessment of Polyvinylpyrrolidone (PVP)
Authors: Nair Bindu
Published: September 2009

Polyvinylpyrrolidone (PVP) is a linear polymer of 1-vinyl-2-pyrrolidone monomers used as a binder, emulsion stabilizer, film former, hair fixative, and suspending agent-nonsurfactant. The molecular weight of the polymer ranges from 10,000 to 700,000. PVP K-30, with an average molecular weight of 40,000, is typically used in cosmetic formulations. The highest concentration reported to be used is 35%. There was no significant absorption of PVP K-30 given orally to rats, and the acute oral LD50 was >100 g/kg for rats and guinea pigs. Neither toxic effects nor gross lesions were found in rats maintained for two years on a diet containing 10% PVP K-30. Short-term PVP inhalation studies produced mild lymphoid hyperplasia and fibroplasia in rats, but no inflammatory response. In animal studies, no evidence of significant ocular irritation, skin irritation, or skin sensitization was found at PVP-iodine solution concentrations of 10%. While PVP-iodine is not a cosmetic ingredient, these negative findings were considered to support the safety of the PVP component. Undiluted PVP K-30 was not a dermal irritant or sensitizer in clinical tests. No developmental toxicity was seen in vehicle controls where PVP was used as a vehicle for another agent. In certain assay systems, PVP was genotoxic, but was negative in the majority of studies. Orally administered PVP significantly decreased the rate of bladder tumors in mice exposed to bracken fern. Several studies tested the carcinogenicity of subcutaneous implants of particulate PVP in rats, mice, and rabbits. Although the majority of these studies conducted in rats were positive, tumors (sarcomas) were localized to the site of implantation. Based on the available data, it was concluded that PVP is safe as used in cosmetics.
Final Report on the Safety Assessment of Bisabolol
Authors: Andersen F. Alan
Published: September 2009

Bisabolol is a naturally occuring unsaturated monocyclic terpene alcohol, the alpha form of which is used in a wide range of cosmetic formulations as a skin conditioning agent at low concentrations ranging from 0.001% in lipstick to 1% in underarm deodorants. Animal studies demonstrate that Bisabolol is well absorbed following dermal exposure and one study using cadaver skin demonstrated that Bisabolol can enhance the penetration of 5-fluorouracil. Bisabolol was relatively nontoxic in acute oral studies in rats, dogs, and monkeys. Short-term oral exposure using rats did produce inflammatory changes in several organs, and reduced body weight and increased liver weights relative to body weight in dogs. The no-observable-adverse-effect level in a 28-day dermal toxicity study using rats was 200 mdkg/day. No evidence of sensitization or photosensitization was found. Bisabolol was negative in bacterial and mammalian genotoxicity tests, and it did not produce reproductive or developmental toxicity in rats. The results of oral and dermal toxicity, genotoxicity, reproductive/developmental toxicity, sensitization, and photosensitization studies show little toxicity at levels expected in cosmetic formulafions. Formulators should be alert to the possibility that use of Bisabolol may increase the penetration of other components of a cosmetic formulation. Based on the available data it was concluded that Bisabolol is safe as used in cosmetic formulafions.
Final Report on the Safety Assessment of Ceteareth-2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18,-20,-22,-23,-24,-25,-27, -28, -29, -30, -33, -34, -40, -50, -55, -60, -80, and -100
Authors: Andersen F. Alan
Published: September 2009

Ceteareths, used in a large number of cosmetics as surfactants, are the polyethylene glycol (PEG) ethers of Cetearyl Alcohol (q,v.). To supplement the limited available data on Ceteareths, previous findings from the safety assessment of Polyethylene Glycol (PEG), several fatty alcohols (Cetearyl Alcohol, Cetyl Alcohol, and Stearyl Alcohol), and Steareths were considered. These data indicate little evidence of toxicity. Although various metabolites of monoalkyl ethers of ethylene glycol are reproductive and developmental toxins, given the methods of manufacture of Ceteareth compounds, there is no likelihood of such compounds being present as impurities. Further, there would be only limited ethylene glycol monomer linked by an ether group to the Ceteareth moiety for the PEG-5 compounds, little for the PEG-10 compounds, and virtually none for the PEG-20 and higher compounds. Even if linked to ethylene glycol monomer, it was considered unlikely that the Ceteareth moieties would be metabolized (e,g., via β-oxidation) to simple methyl, ethyl, propyl, or butyl alkyl groups. As the current data indicate, such short alkyl chains are needed in order for the production of toxic alcohol or aldehyde dehydrogenase metabolites. For longer alkyl chains there is evidence of diminishing toxicity, and extrapolation to much longer chains such as expected in the Ceteareth moieties suggests that there is no reproductive or developmental hazard posed by these Ceteareth compounds. The principal clinical finding related to PEGs is based on data in bum patients— PEGs were mild irritants/sensitizers and there was evidence of nephrotoxicity. No such effects were seen in animal studies on intact skin. Cosmetic manufacturers should adjust product formulations containing Polyethylene Glycol to minimize any untoward effects when products are used on damaged skin. In the absence of specific impurities data, the possible presence of 1,4-dioxane and ethylene oxide impurities was of concern. The importance of using the necessary purification procedures to remove these impurities was stressed. Creams containing Ceteareth-20 enhanced drug absorption. Ceteareth-15 (10% in formulation) was minimally irritating to rabbits after a single dermal exposure. In ocular studies, ethoxylated Cetearyl Alcohol solution was a severe irritant to unrinsed rabbit eyes and moderately irritating to rinsed eyes. In clinical studies, Ceteareth-15 (1.5 % in formulation) produced minimal irritation when tested in both a 4- and 21-day patch test, and was not a sensitizer when tested (1.35% in formulation) in a repeat-insult patch test. Based on the limited data on Ceteareths and the extensive data on chemically related ingredients, it was concluded that these ingredients are safe as used in cosmetic formulations. These ingredients, however, should not be used on damaged skin.
Using practice development methodology to develop children’s centre teams: Ideas for the future
Authors: Hemingway Ann , Cowdell Fiona
Published: September 2009

The Children’s Centre Programme is a recent development in the UK and brings together multi-agency teams to work with disadvantaged families. Practice development methods enable teams to work together in new ways. Although the term practice development remains relatively poorly defined, its key properties suggest that it embraces engagement, empowerment, evaluation and evolution. This paper introduces the Children’s Centre Programme and practice development methods and aims to discuss the relevance of using this method to develop teams in children’s centres through considering the findings from an evaluation of a two-year project to develop inter-agency public health teams. The evaluation showed that practice development methods can enable successful team development and showed that through effective facilitation, teams can change their practice to focus on areas of local need. The team came up with their own process to develop a strategy for their locality.
Review: Systemic therapy for advanced renal cell carcinoma
Authors: Larkin James M.G. , Kipps Emma L.S. , Powell Ceri J. , Swanton Charles
Published: September 2009

Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy - immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors - sorafenib sunitinib, temsirolimus and everolimus - are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease.
A pre-S gene chip to detect pre-S deletions in hepatitis B virus large surface antigen as a predictive marker for hepatoma risk in chronic hepatitis B virus carriers
Authors: Shen Fan-Ching , Su Ih-Jen , Wu Han-Chieh , Hsieh Yi-Hsuan , Yao Wei-Jen , Young Kung-Chia , Chang Tsung-Chuan , Hsieh Hui-Chuan , Tsai Han-Ni , Huang Wenya
Published: September 2009

Background

Chronic hepatitis B virus (HBV) infection is an important cause of hepatocellular carcinoma (HCC) worldwide. The pre-S1 and -S2 mutant large HBV surface antigen (LHBS), in which the pre-S1 and -S2 regions of the LHBS gene are partially deleted, are highly associated with HBV-related HCC.

Methods

The pre-S region of the LHBS gene in two hundred and one HBV-positive serum samples was PCR-amplified and sequenced. A pre-S oligonucleotide gene chip was developed to efficiently detect pre-S deletions in chronic HBV carriers. Twenty serum samples from chronic HBV carriers were analyzed using the chip.

Results

The pre-S deletion rates were relatively low (7%) in the sera of patients with acute HBV infection. They gradually increased in periods of persistent HBV infection: pre-S mutation rates were 37% in chronic HBV carriers, and as high as 60% in HCC patients. The Pre-S Gene Chip offers a highly sensitive and specific method for pre-S deletion detection and is less expensive and more efficient (turnaround time 3 days) than DNA sequencing analysis.

Conclusion

The pre-S1/2 mutants may emerge during the long-term persistence of the HBV genome in carriers and facilitate HCC development. Combined detection of pre-S mutations, other markers of HBV replication, and viral titers, offers a reliable predictive method for HCC risks in chronic HBV carriers.
Exploratory and inferential analysis of gene cluster neighborhood graphs
Authors: Scharl Theresa , Voglhuber Ingo , Leisch Friedrich
Published: September 2009

Background

Many different cluster methods are frequently used in gene expression data analysis to find groups of co-expressed genes. However, cluster algorithms with the ability to visualize the resulting clusters are usually preferred. The visualization of gene clusters gives practitioners an understanding of the cluster structure of their data and makes it easier to interpret the cluster results.

Results

In this paper recent extensions of package gcExplorer are presented. gcExplorer is an interactive visualization toolbox for the investigation of the overall cluster structure as well as single clusters. The different visualization options including arbitrary node and panel functions are described in detail. Finally the toolbox can be used to investigate the quality of a given clustering graphically as well as theoretically by testing the association between a partition and a functional group under study.

Conclusion

It is shown that gcExplorer is a very helpful tool for a general exploration of microarray experiments. The identification of potentially interesting gene candidates or functional groups is substantially accelerated and eased. Inferential analysis on a cluster solution is used to judge its ability to provide insight into the underlying mechanistic biology of the experiment.