Novel design of (PEG-ylated)PAMAM-based nanoparticles for sustained delivery of BDNF to neurotoxin-injured differentiated neuroblastoma cells.

Brain-derived neurotrophic factor (BDNF) is essential for the development and function of human neurons, therefore it is a promising target for neurodegenerative disorders treatment. Here, we studied BDNF-based electrostatic complex with dendrimer nanoparticles encapsulated in polyethylene glycol (PEG) in neurotoxin-treated, differentiated neuroblastoma SH-SY5Y cells, a model of neurodegenerative mechanisms. PEG layer was adsorbed at dendrimer-protein core nanoparticles to decrease their cellular uptake and to reduce BDNF-other proteins interactions for a prolonged time. Cytotoxicity and confocal microscopy analysis revealed PEG-ylated BDNF-dendrimer nanoparticles can be used for continuous neurotrophic factor delivery to the neurotoxin-treated cells over 24 h without toxic effect. We offer a reliable electrostatic route for efficient encapsulation and controlled transport of fragile therapeutic proteins without any covalent cross-linker; this could be considered as a safe drug delivery system. Understanding the polyvalent BDNF interactions with dendrimer core nanoparticles offers new possibilities for design of well-ordered protein drug delivery systems.

Patient safety in procedural dermatology: Part II. Safety related to cosmetic procedures.

Cosmetic procedures are growing in popularity and are associated with unique risks. Considering potential complications and prioritizing patient safety will help practitioners improve outcomes of elective procedures. In part II of this continuing medical education article, we provide a comprehensive review of patient safety in cosmetic procedures, including medical and legal issues surrounding the supervision and training of physician extenders.

Facial filler and neurotoxin complications.

Botulinum neuromodulators and injectable dermal fillers have become part of the armamentarium in the treatment of facial aging. Their successful use requires a fundamental knowledge of anatomy and physiology and a sound understanding of their risks and complications. Although neuromodulators and fillers continue to demonstrate a strong record of safety, several notable risks exist.

Complications of injectable fillers and neurotoxins.

All cosmetic injectable products are associated with the risk of both early and delayed complications. Early and expected side effects include swelling, bruising, and erythema at the injection. It is of utmost importance that patients are educated on the treatment they are consenting to receive and the potential risk of these therapies. Side effects of the various cosmetic injectable products, including both injectable neurotoxins and soft tissue fillers, are often technique associated, such as placing the filler too superficial or unintentional paralysis of facial muscles. Other complications, such as necrosis, intravascular injections, and infection may not be entirely technique-dependent, and must be managed swiftly and effectively. Finally, immunologic phenomena, such as delayed-type hypersensitivity reactions and foreign body granulomas, are complications that have no relationship to technique, and thus proper counseling and knowledge of management is required.

[Fetal and perinatal exposure to mercury and selenium: baseline evaluation of a cohort of children in Friuli Venezia Giulia, Italy]. / Esposizione fetale e perinatale a mercurio e selenio: valutazione alla baseline di una coorte di bambini del Friuli Venezia Giulia.

OBJECTIVE: neurotoxicity of prenatal exposure to high concentrations of mercury (Hg) is well known; however, the doseresponse relationship at low exposure levels has not been quantified yet. This article illustrates the measurement of prenatal exposure to Hg and the pathway of exposure through the diet in Friuli Venezia Giulia, Italy. DESIGN: description of a prospective cohort at the baseline. SETTING AND PARTICIPANTS: 242 mother- infant pairs living in Friuli Venezia Giulia were enrolled between 1999 and 2001. MAIN OUTCOME MEASURES: We measured the concentrations of Hg in the hair of mothers and children and of Hg and selenium (Se) in breast milk. The diet during pregnancy was estimated through a food frequency questionnaire (FFQ) with a detailed section regarding fish. We calculated the correlations between Hg and Se in the biological samples and estimated the association between Hg concentrations and fish consumption. RESULTS: in general, Hg levels in hair and milk were positively associated with the consumption of fish from the lagoon of Grado and Marano. However, they were low in comparison with those of other fish-eating populations and below theWHO alert limits, likely because of the small consumption of fish among pregnant women, estimated from the FFQ. The concentration of Se in milk was also smaller than that reported in other international studies. CONCLUSION: in Friuli Venezia Giulia, fetal and perinatal Hg exposure is low. The children of the cohort will be followed- up at school age to measure possible neurodevelopmental effects of such low exposures to Hg.

Botulinum toxin assessment, intervention and aftercare for paediatric and adult drooling: international consensus statement.

Many individuals with neurological problems or anatomical abnormalities of the jaw, lips or oral cavity may drool, which can impact on health and quality of life. A thorough evaluation of the patient's history, examination of the oral region by a speech pathologist and, in individuals over 3 years, a dental examination is warranted. Questionnaires with established validity such as the Drooling Impact Scale are useful assessment tools. A hierarchical approach to treatment is taken from least invasive therapies, such as speech pathology, to more invasive, such as injection of botulinum neurotoxin type-A (BoNT-A) into the salivary glands (parotid and submandibular). The wishes of the individual and their carer are crucial considerations in determining the suitability of the intervention for the patient. In the presence of dysphagia and cerebral palsy (CP), careful assessment is required prior to the injection of BoNT-A. Favourable responses to intervention include a reduction in the secretion of saliva and in drooling, as well as psychosocial improvements. BoNT-A is usually well tolerated, although potential side effects should be discussed with the patient and carer.

Morphologic and bony structural changes in the mandible after a unilateral injection of botulinum neurotoxin in adult rats.

PURPOSE: Previous animal experiments showed how reduced masticatory function plays an important role in the craniofacial and mandibular regions in the growing period. However, articles focusing on the effects of reduced masticatory function in adult animals are quite scarce. The purpose of this study was to evaluate the effects of reduced masticatory muscle activity on the jaw bones of adult rats. MATERIALS AND METHODS: Botulinum neurotoxin type A (BTX-A) was injected into the left masseter muscle to reduce masticatory muscle function, and sequential changes in the jaw bones were investigated. Ten male 60-day-old Sprague-Dawley rats with a mean body weight of about 300 g were used. The following procedures were performed on each sample: 25 U/mL (0.3 mL) of BTX-A was injected into the left masseter muscle, whereas the right masseter muscle received an equal amount of sterilized saline solution. Ninety days after the procedure, the rats were sacrificed, and the weights of the masseter muscles were recorded. Meanwhile, direct anthropometric measurements were taken, and the cortical thickness, trabecular thickness, and bone mineral content of the skull and mandible were measured. All measurements were evaluated with statistical software. RESULTS: There were significant differences in all measurements on the BTX-A side compared with those on the control side. The differences included a decreased ramus height, increased gonial angle, and increased crown height of the posterior teeth on the injection side. Significant decreases in the muscle weight, bone mineral content, cortical thickness, and trabecular thickness were also seen on the paralyzed side compared with the non-injection side. CONCLUSIONS: We found that reduced masticatory function in adult rats affected the weight of the masseter muscle and the bony structure and dentition.

Effects of crude venom, tityustoxin and toxin Ts-gamma from Tityus serrulatus scorpion on secretion and structure of the rat submandibular gland.

Changes in the rat submandibular glands after intravenous injections of Tityus serrulatus scorpion venom, tityustoxin or toxin Ts-gamma were studied histologically and morphometrically. The acini and the granular convoluted tubules presented the most prominent changes. The following variables were measured: (a) relative volume occupied by the glandular structures; (b) diameter of the granular convoluted tubules and thickness of their epithelium; (c) diameter of the acini. The cytoplasm of the acinar cells was extensively occupied by large confluent vacuoles and had a reduced number of secretory granules after intravenous injections of venom or toxins. The morphological changes caused by toxin Ts-gamma were greater than those evoked by tityustoxin or crude venom injections. In spite of the changes in acinar cells, acinar diameter showed no significant alterations after venom or toxin injections. Reduction of diameter and depletion of the cytoplasmic secretory granules were observed in the granular convoluted tubules 2 h after intravenous injections of crude venom, or after 1 h with tityustoxin or toxin Ts-gamma. The intravenous injection of crude venom did not induce any visible change in the granular convoluted tubules after 1 h. These structural changes could explain the concomitant intense sialagogue effect elicited by crude venom, tityustoxin and toxin Ts-gamma. The sialagogue effect induced by toxin Ts-gamma was larger than those induced by crude venom or tityustoXin.

Epidemiologia e fatores de riscos relacionados à intoxicação alimentar causada por Clostridium Botulinum: uma revisão narrativa / Epidemiology and risk factors related to food intoxication caused by Clostridium Botulinum: a narrative review

O botulismo é uma doença resultante da ação de uma toxina produzida pelo Clostridium botulinum. Devido à sua gravidade e alta mortalidade é considerado um problema de saúde pública. Nesta revisão apresentamos os principais fatores de riscos associados à intoxicação alimentar provocada pelo Clostridium botulinum, bem como realizamos um levantamento epidemiológico sobre o botulismo alimentar e infantil. A busca bibliográfica considerou as bases de dados Scielo, Medline, Lilacs e PubMed. Foram selecionados artigos originais e relatos de caso publicados em inglês, espanhol e português, incluindo publicações dos últimos dez anos. A partir das análises dos títulos, resumos e artigos, um total de 26 artigos foram incluídos nesta revisão. Verificou-se predomínio de 54% dos casos referentes ao botulismo alimentar, dos quais aproximadamente 58% confirmaram a ocorrência da toxina tipo A; e 35% referente ao botulismo infantil. Na literatura consultada os principais sintomas, relacionados ao botulismo alimentar, identificados foram: visão turva, vômito, paralisia flácida, náuseas, tontura, diplopia, dificuldade respiratória, disatria, disfagia, fraqueza muscular, boca seca, ptose e cefaleia. Dentre as principais fontes de contaminação, 65% das publicações selecionadas identificaram as conservas como principal causa do botulismo alimentar. Embora o mel (42%) seja a única fonte registrada de alimento veiculador do agente causador do botulismo infantil, alguns relatos na literatura (25%) associaram à doença com a inalação de poeira contendo esporos do Clostridium botulinum, bem como o uso de plantas medicinais (25%). Os sintomas mais comuns observados na literatura foram: constipação dificuldade respiratória e dificuldade de sucção. Apesar de vários relatos na literatura acerca das duas doenças, o botulismo ainda é muito subnotificado dado ao diagnóstico muitas vezes equivocado, ressaltando-se a importância do diagnóstico precoce no tratamento da doença pelos profissionais de saúde, bem como a disponibilidade de informações relevantes para a investigação epidemiológica de doenças de notificação compulsória. Os dados apresentados também demonstram a importância de sensibilizar a população dos principais riscos e medidas de prevenção, já que a maioria dos casos relatados está relacionada a práticas inadequadas de preparo dos alimentos. (AU)

Botulism is a disease resulting from the action of a toxin produced by Clostridium botulinum. Because of its severity and high mortality, it is considered a public health problem. In this review, we present the main risk factors associated with food poisoning caused by Clostridium botulinum, as well as an epidemiological survey on foodborne and infant botulism. A bibliographic search was conducted in SciELO, MEDLINE, LILACS and PubMed databases. Original articles and case reports published in English, Spanish and Portuguese in the past ten years were selected. After analyzing titles, abstracts and articles, 26 articles were used in this review. In total, 54% of the cases were related to foodborne botulism, of which approximately 58% had confirmed type A botulism, and 35% were related to infant botulism. In the literature consulted, the main symptoms related to foodborne botulism were blurred vision, vomiting, flaccid paralysis, nausea, dizziness, diplopia, respiratory distress, dysarthria, dysphagia, muscle weakness, dry mouth, ptosis and headache. Among the sources of contamination, 65% of the published studies reported home-canned foods as the main cause of foodborne botulism. Although honey (42%) is the only reported food source for the agent causing infant botulism, some reports in the literature (25%) associated the disease with inhalation of dust containing Clostridium botulinum spores, as well as use of medicinal plants (25%). The most common symptoms observed in the literature were constipation, difficulty breathing and difficulty suckling. Although several reports on the two forms of the disease exist, botulism remains under-reported because of often incorrect diagnosis. Thus, early diagnosis is important for an adequate treatment provided by health professionals, as well as availability of relevant information for the epidemiological investigation of notifiable diseases. The data presented in this study also demonstrate the importance of raising people's awareness to main risks and prevention measures, as most reported cases were related to inadequate food preparation practices. (AU)

Lasers, fillers, and neurotoxins: avoiding complications in the cosmetic facial practice.

Lasers, injectable fillers, and neurotoxins are widely used in facial restoration and rejuvenation by a variety of practitioners. Although they are less invasive than traditional surgical modalities, they still carry risks for both transient as well as permanent complications. It is paramount for the practitioner to understand these complications, optimize their prevention, and initiate appropriate treatment when they are encountered. This article reviews early, often transient, complications as well as delayed, often prolonged or permanent, complications, with particular focus on prevention and management.

Complications from toxins and fillers in the dermatology clinic: recognition, prevention, and treatment.

Adverse reactions and unintended effects can occasionally occur with toxins for cosmetic use, even although they generally have an outstanding safety profile. As the use of fillers becomes increasingly more common, adverse events can be expected to increase as well. This article discusses complication avoidance, addressing appropriate training and proper injection techniques, along with patient selection and patient considerations. In addition to complications, avoidance or amelioration of common adverse events is discussed.

Botulinum toxin type A on oral health in treating sialorrhea in children with cerebral palsy: a randomized, double-blind, placebo-controlled study.

Intrasalivary gland injection of botulinum toxin type A is known to treat sialorrhea effectively in children with cerebral palsy. However, oral health may be compromised with escalating dose. In this randomized, double-blind, and placebo-controlled pilot trial, the authors aim to determine the therapeutic effect of low-dose, ultrasonography-controlled botulinum toxin type A injection to bilateral parotid and submandibular glands on oral health in the management of sialorrhea. Twenty children diagnosed with cerebral palsy were randomly assigned to 2 groups. The treatment group received botulinum toxin type A injections, whereas the control received normal saline in the same locations. The authors evaluated subjective drooling scales, salivary flow rate, and oral health (salivary compositions and cariogenic bacterial counts). A significant decrease was found in salivary flow rate at the 1- and 3-month follow-up in the botulinum toxin-treated group. The authors suggest that current protocol can effectively manage sialorrhea while maintaining oral health.

Injectable neurotoxins and fillers: there is no free lunch.

Injection of neurotoxins and filling agents for the treatment of facial aesthetics has increased dramatically during the past few decades due to an increased interest in noninvasive aesthetic improvements. An aging but still youth-oriented population expects effective treatments with minimal recovery time and limited risk of complications. Injectable neurotoxins and soft tissue stimulators and fillers have filled this niche of "lunch-time" procedures. As demand for these procedures has increased, supply has followed with more noncore cosmetic specialty physicians, as well as unsupervised ancillary staff, becoming providers and advertising them as easy fixes. Despite an excellent record of safety and efficacy demonstrated in scores of published studies, injectable agents do carry risks of complications. These procedures require a physician with in-depth knowledge of facial anatomy and injection techniques to ensure patient safety and satisfaction. In general, adverse events are preventable and technique-dependent. Although most adverse events are minor and temporary, more serious complications can occur. The recognition, management, and treatment of poor outcomes are as important as obtaining the best aesthetic results. This review addresses important considerations regarding the complications of injectable neurotoxins and fillers used for "lunch-time" injectable procedures.

The pathology of amiodarone neurotoxicity. I. Experimental studies with reference to changes in other tissues.

Rats and mice were given amiodarone by mouth at doses of 50 mg/kg/day. The drug induced accumulations of lipids within lysosomes, leading to the formation of cytoplasmic bodies. These were found in many tissues, both nervous and nonnervous, but were excluded from regions with blood-brain or blood-nerve barriers. Of nervous system regions lying outside a vascular barrier, autonomic ganglia were the most affected, with large accumulations of lysosomal bodies in nerve cells and processes, and evidence of degenerative changes. the myenteric plexus was also involved. No significant changes were seen in peripheral nerves. A limited period of increased permeability caused by nerve crush, or due to immaturity of the blood-nerve barrier resulted in the short-lived appearance of drug-induced inclusions. The rate of regeneration of axons following nerve crush was not affected, although there were small defects in myelination.

[Multiple chemical sensitivity disorder in patients with neurotoxic illnesses]. / Vielfache Chemikalienunverträglichkeit (Multiple Chemical Sensitivity Disorder) bei Patienten mit neurotoxischen Gesundheitsstörungen.

The data of 466 subjects suffering from neurologic disorders which are suggested to be caused by neurotoxic agents in their environment retrospectively was evaluated and documented. Among these cases there were 151 subjects with symptoms of Multiple Chemical Sensitivity Disorder (MCSD). The relationship between the neurological health impairments and neurotoxic agents in the environment of these patients was characterised using five different categories (probable = A, possible = B, uncertain = C, unclarified = D, not probable = E). From the 466 patients 320 subjects (69%) could be assigned to the categories A and B, respectively. Within theses 320 cases with chronic neurotoxic health impairments 136 subjects (79 females and 57 males) showed signs of MCSD. Age and gender of cases as well as duration and character of exposure to neurotoxic substances retrospectively were assessed from the explicit files of the patients, which had been made anonymous for this purpose. Frequency of characteristic symptoms of neurotoxicity were analysed. Results are given for patients with neurotoxic health impairments with MCSD (n = 136) and without MCSD (n = 184). Neurotoxic substances which were used as indoor wood preservatives (mainly Pentachlorophenol and/or Lindane) were found to be the causative agents in 63% of the cases with neurotoxic health impairments and MCSD. Other important neurotoxic substances to which the patients were mainly exposed were organic solvents (25%), formaldehyde (15%), dental materials (15%), pyrethroides (13%), and other biocides (19%) (multiple exposures were possible). The time of exposure was calculated as being > or = 10 years for 55% of the patients with MCSD and for 50% of the group with neurotoxic health impairments but without MCSD. Out of the 184 cases with neurotoxic health impairments but without MCSD there were 22%, and out of the 136 cases with MCSD there were 39% who showed all symptoms of chronic fatigue syndrome. 53% of the cases with MCSD had an allergic disposition compared to only 20% of the cases without MCSD. This work is not a controlled epidemiological study but a retrospective documentation and evaluation of data related to environmental medicine. With the present documentation in this purely descriptive manner the proof of a causal relationship was not possible or intended. But because corresponding epidemiological studies are lacking, this documentation can give important information on characteristic features of Multiple Chemical Sensitivity Disorder and chronic neurotoxic health impairments. Such information is essential for planning and carrying out epidemiological studies urgently needed in this field.

Myelotoxic, neurotoxic and reproductive adverse effects of nitrous oxide.

N2O is a relatively safe general anaesthetic under normal medical and dental anaesthetic use. It is more likely to produce megaloblastosis or neuropathy when used repetitively or for periods longer than 3 hours or in individuals with vitamin B12 deficiencies. The mechanism responsible for its myelotoxicity, neurotoxicity and most likely its reproductive toxicity, involves its inhibition of MetSyn and the resulting reduction in SAM and THF levels. Administration of folinic acid or methionine have been shown to protect against megaloblastosis and neurotoxicity occurring following N2O administration. Occupational N2O exposure of medical and dental personnel during its use as an analgesic is not likely to produce adverse reproductive outcomes except in B12-deficient individuals or in those routinely exposed to high N2O levels.