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OBJECTIVE To describe the fifth-year medical students' self-evaluation based on the reflexive discourse of the Activities Diaries (portfolio) from the Pediatric Internship I and Child Care Rotations. METHODS Cross sectional, qualitative and descriptive study using the collective subject discourse of the diaries used during the internship of the Medical School, in Catanduva, São Paulo, from January to November, 2011. The registered students' testimonials in the portfolio sections called self-assessment and students' impression were assessed according to their central ideas (discipline organization, breastfeeding outpatient clinic, number of admissions in the pediatric hospital ward and satisfaction with the Child Health training ), related to the teaching of Pediatrics and Child Care. The portfolios with incomplete registers were excluded. RESULTS The testimonials of 47 interns (75% of the students) were analyzed, and 21.3% of them expressed satisfaction with the discipline organization and 27.7% praised the inclusion of the breastfeeding outpatient clinics in the course. For 25.5% of the academics, the number of admissions in the pediatric wards was insufficient for an ideal learning; however, 70.2% were satisfied with the Child Health training. CONCLUSIONS This critical analysis allowed a summary of the reflections, suggestions and critics registered by the interns and can be used as a tool for improvement of the professional cycle.

The term access is understood from the perspective of admission or entry into the system, related to the use of the system. This research seeks to analyze access to primary health care from the perspective of professionals in family health teams of three municipalities in the State of Minas Gerais: Ipatinga, Coronel Fabriciano and Santana do Paraíso. This work is a qualitative case study into the understanding of access on the part of professionals in family health teams. Twelve health professionals from different professional categories participated in the study. The data was collected through taped and subsequently transcribed interviews and analyzed using Bardin's content analysis technique. As a result the professionals showed that they believe that it is possible to improve working conditions and consequently the supply of services. The type of care and the inherent complexity make a difference in waiting time and the ability of the system to respond thereby impacting the quality of access. Professionals in the municipalities of Coronel Fabriciano and Santana do Paraíso consider the service to be organized and decisive. However, in the municipality of Jaipur, there is high management turnover that hampers the organization of the service and the smooth operation of flows and routines.

Science has a critical role to play in guiding more sustainable development trajectories. Here, we present the Sustainable Amazon Network (Rede Amazônia Sustentável, RAS): a multidisciplinary research initiative involving more than 30 partner organizations working to assess both social and ecological dimensions of land-use sustainability in eastern Brazilian Amazonia. The research approach adopted by RAS offers three advantages for addressing land-use sustainability problems: (i) the collection of synchronized and co-located ecological and socioeconomic data across broad gradients of past and present human use; (ii) a nested sampling design to aid comparison of ecological and socioeconomic conditions associated with different land uses across local, landscape and regional scales; and (iii) a strong engagement with a wide variety of actors and non-research institutions. Here, we elaborate on these key features, and identify the ways in which RAS can help in highlighting those problems in most urgent need of attention, and in guiding improvements in land-use sustainability in Amazonia and elsewhere in the tropics. We also discuss some of the practical lessons, limitations and realities faced during the development of the RAS initiative so far.

Myasthenia gravis is an autoimmune disease, manifested by progressive muscular weakness and fatigue. There are frequent ocular and bulbar symptoms, among them, dysphonia. This article reports a case of dysphonia that contributed to the diagnosis of myasthenia gravis through a speech evaluation. The patient sought speech therapy with the ENT diagnosis of presbyphonia. The perceptual voice assessment and acoustic analysis pointed out respiration, glottal voice source and resonance affections. Considering that some of the data obtained from anamnesis and vocal assessments were not directly related to presbyphonia, the speech therapist discussed the case with the physician and they both concluded it was necessary to refer the patient to a neurological evaluation. The neurologist then raised the diagnostic hypotheses of myasthenia gravis and requested further examinations. The patient underwent speech therapy and drug treatment. A vocal reassessment, which occurred two months after the initial treatment, showed improvement in voice quality, with great impact on quality of life. This article shows the importance of detailed clinical speech evaluation and participation of a speech therapist in an interdisciplinary team.

Dengue is a serious disease transmitted by the mosquito Aedes aegypti during blood meal feeding. It is estimated that the dengue virus is transmitted to millions of individuals each year in tropical and subtropical areas. Dengue control strategies have been based on controlling the vector, Ae. aegypti, using insecticide, but the emergence of resistance poses new challenges. The aim of this study was the identification of specific protease inhibitors of the digestive enzymes from Ae. aegypti larvae, which may serve as a prospective alternative biocontrol method. High affinity protein inhibitors were selected by all of the digestive serine proteases of the 4th instar larval midgut, and the specificity of these inhibitors was characterized. These inhibitors were obtained from a phage library displaying variants of HiTI, a trypsin inhibitor from Haematobia irritans, that are mutated in the reactive loop (P1-P4'). Based on the selected amino acid sequence pattern, seven HiTI inhibitor variants were cloned, expressed and purified. The results indicate that the HiTI variants named T6 (RGGAV) and T128 (WNEGL) were selected by larval trypsin-like (IC(50) of 1.1 nM) and chymotrypsin-like enzymes (IC(50) of 11.6 nM), respectively. The variants T23 (LLGGL) and T149 (GGVWR) inhibited both larval chymotrypsin-like (IC(50) of 4.2 nM and 29.0 nM, respectively) and elastase-like enzymes (IC(50) of 1.2 nM for both). Specific inhibitors were successfully obtained for the digestive enzymes of Ae. aegypti larvae by phage display. Our data also strongly suggest the presence of elastase-like enzymes in Ae. aegypti larvae. The HiTI variants T6 and T23 are good candidates for the development as a larvicide to control the vector., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Rhipicephalus (Boophilus) microplus is an ectoparasite responsible for an important decrease in meat, milk and leather production, caused both by cattle blood loss and by the transmission of anaplasmosis and babesiosis. R. microplus is a rich source of serine protease inhibitors, including the trypsin inhibitors BmTI-A and BmTI-6, the subtilisin inhibitor BmSI, and the recently described thrombin inhibitor, boophilin. Boophilin is a double Kunitz-type thrombin inhibitor, with the unusual ability to form a ternary complex with a second (non-thrombin) serine proteinase molecule. The large-scale expression and purification of boophilin and of its isolated N-terminal (D1) domain in Pichia pastoris, its expression profile, and the effect of RNAi-mediated gene silencing in tick egg production are reported. Full-length boophilin and D1 were expressed at 21 and 37.5mg/L of culture, respectively. Purified boophilin inhibited trypsin (K(i) 0.65 nM), neutrophil elastase (K(i) 21 nM) and bovine thrombin (K(i) 57 pM), while D1 inhibited trypsin and neutrophil elastase (K(i) of 2.0 and 129 nM, respectively), but not thrombin. Boophilin gene silencing using RNAi resulted in 20% reduction in egg weight production, suggesting that the expression of boophilin in this life stage would be important but not vital, probably due to functional overlap with other serine proteinase inhibitors in the midgut of R. microplus. Considering our data, Boophilin could be combining with other antigen in a vaccine production for tick control., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The venom of social wasps has been poorly studied so far, despite the high number of accidents in humans and assessment of the use of these wasps as a biological control of pests. The study of the pharmacological effects of the venom is of great importance since the poisoning is dangerous causing serious systemic effects, including death in the case of multiple attacks. In this study, the pharmacological activities of venom from the social wasp Synoeca cyanea were evaluated by the following assays: LD50 in mice, the behavioural effects and the hemorrhagic activity induced by the venom in mice, the oedematogenic activity in rat, the haemolysis in human blood, the stimulating effect on guinea-pig smooth muscle, and the antimicrobial activity. The aim was to determine the toxic effects of venom and to perform a comparative study with earlier work conducted with venom from other wasp species. Results showed that S. cyanea venom produced a potent dose-dependent oedema, as well as antibacterial and haemolytic activities, suggesting the presence of histamine, serotonin, kinins and other molecules related to increased vascular permeability and cytolytic activity in this venom. Despite previous studies with wasp venoms, S. cyanea venom presented a slight hemorrhagic effect. Data obtained in the smooth muscle assay also suggest the presence of BK or analogues in S. cyanea whole venom. The knowledge of symptoms and effects produced by S. cyanea venom is critical for health organizations, in order to improve clinical treatment in accidents caused by wasp stings., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Migraine and nocturnal enuresis are highly prevalent disorders with striking similarities. Both have unknown pathophysiology and are considered multifactorial, with neurobiological, genetic, and behavioral aspects involved. Interestingly, the same neurological structures thought to be involved in the pathogenesis of migraine are also thought to be involved in nocturnal enuresis. Few studies, however, have addressed these conditions as related. The aim of this study was to evaluate the antecedent of nocturnal enuresis in a large consecutive series of adolescents with migraine as compared to controls., Methods: A total of 151 subjects were evaluated; 50 had episodic migraine, 50 had chronic migraine, and 51 were control subjects. All patients were submitted to a detailed questionnaire addressing epidemiological and clinical aspects., Results: There was a strong correlation between the clinical history of nocturnal enuresis and the diagnosis of migraine., Conclusion: Our study showed that nocturnal enuresis is a precursor of migraine and a migraine comorbid condition. These results support a pathophysiological linkage between the two conditions., (Copyright © 2012 S. Karger AG, Basel.)

Trypsin-like enzymes play an important role in the Aedes aegypti digestive process. The trypsin-like enzymes present in adults were characterized previously, but little is known about trypsins in larvae. In the present work, we identified one of the trypsin enzymes from Ae. aegypti larval midgut using a library of trypsin gene fragments, which was the sequence known as AAEL005607 from the Ae. aegypti genome. Quantitative PCR analysis showed that AAEL005607 was transcribed in all larval instars, but it was not present in adult midgut. In order to confirm transcription data, the trypsin-like enzymes from 4th instar larvae of Ae. aegypti midgut were purified and sequenced. Purified trypsin showed identity with the amino-terminal sequence of AAEL005607, AAEL005609 and AAEL005614. These three trypsins have high amino acids identity, and could all be used as a template for the design of inhibitors. In conclusion, for the first time, digestive enzymes of 4th larval instar of Ae. aegypti were purified and characterized. The knowledge of digestive enzymes present in Ae. aegypti larvae may be helpful in the development of a larvicide., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The tick Rhipicephalus (Boophilus) microplus is one of the most important bovine ectoparasites, a disease vector responsible for losses in meat and milk productions. A cysteine protease similar to cathepsin L, named BmCL1, was previously identified in R. microplus gut, suggesting a role of the enzyme in meal digestion. In this work, BmCL1 was successfully expressed in Pichia pastoris system, yielding 54.8 mg/L of culture and its activity was analyzed by synthetic substrates and against a R. microplus cysteine protease inhibitor, Bmcystatin. After rBmCl1 biochemical characterization it was used in a selection of a peptide phage library to determine rBmCL1 substrate preference. Obtained sequenced clones showed that rBmCL1 has preference for Leu or Arg at P(1) position. The preference for Leu at position P(1) and the activation of BmCL1 after a Leu amino acid residue suggest possible self activation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Purpose: To analyze the scientific literature about the physiology and effects of exercises used in the treatment of oral myofunctional disorders., Research Strategy: The methodology used followed the concepts of the Cochrane Handbook and involved question formulation related to the topic of investigation, identification and selection of the studies, and a critical evaluation of the selected articles., Selection Criteria: Papers were selected on PubMed database using the following keyword combinations: "physiology exercise AND speech, language and hearing science", "exercise physiology AND speech therapy", "exercise physiology AND myofunctional therapy", and "physiology exercise AND swallowing therapy". Only papers written in English and published between the years of 2000 and 2010 were included in the analysis., Data Analysis: Manuscripts were analyzed according to their objectives, research design, participants, inclusion of a control group, assessment criteria, therapeutic proposal, results and existence about physiology of the chosen exercises., Results: One hundred and eight studies were identified, out of which 38 had access to the full text and were directly related to the investigated topic. The articles were classified as clinical trials and experimental research, case studies, literature reviews and theoretical articles, letters to the editor and critical analyses., Conclusion: This review concluded that there is a lack of knowledge about the effects of the myofunctional exercises used by clinicians. Also there is a lack of scientific evidence to determine the frequency at which they should be performed. Generally, the articles investigate the efficacy of treatment programs without inquiring whether the included exercises are individually effective.

The kappa-KTx family of peptides, which is the newest K⁺-channel blocker family from scorpion venom, is present in scorpions from the families Scorpionidae and Liochelidae. Differently from the other scorpion KTx families, the three-dimensional structure of the known kappa-KTxs toxins is formed by two parallel α-helices linked by two disulfide bridges. Here, the characterization of a new kappa-KTx peptide, designated kappa-KTx 2.5, derived from the Liochelidae scorpion Opisthacanthus cayaporum, is described. This peptide was purified by HPLC and found to be identical to OcyC8, a predicted mature sequence precursor (UniProtKB C5J89) previously described by our group. The peptide was chemically synthesized and the circular dichroism (CD) spectra of both, native and synthetic, conducted at different temperatures in water and water/trifluoroethanol (TFE), showed a predominance of α-helices. The kappa-KTx 2.5 is heat stable and was shown to be a blocker of K⁺-currents on hKv1.1, and hKv1.4, with higher affinity for Kv1.4 channels (IC₅₀= 71 μM). Similarly to the other kappa-KTxs, the blockade of K⁺-channels occurred at micromolar concentrations, leading to uncertainness about their proper molecular target, and consequently their pharmacologic effect. In order to test other targets, kappa-KTx2.5 was tested on other K⁺-channels, on Na⁺-channels, on bacterial growth and on smooth muscle tissue, a known assay to identify possible bradykinin-potentiating peptides, due to the presence of two contiguous prolines at the C-terminal sequence. It has no effect on the targets used except on hKv1.1, and hKv1.4 expressed in Chinese hamster ovary cells. Since the only plausible function found for kappa-KTx2.5 seems to be the blockade of K⁺-channels, a discussion regarding the analysis of structure-function relationships is included in this communication, based on sequence alignments of members of the kappa-KTx toxin family, and on computational simulation of a structural model of the kappa-KTx2.5-Kv1.2 complex., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To analyze the changes in local health care governance resulting from the decentralization process associated with the Unified Health System (SUS) in Brazil between 1996 and 2006., Methods: A questionnaire was answered in 1996 and again in 2006 by all city officials involved in health care management in Brazil. Information was collected on the innovative characteristics of administrative practices in terms of three dimensions: social, management, and care. The present article analyzes the results relating to the social dimension (relationship between municipal officials and the various community actors) according to four attributes: preparing the budget (degree of influence of various actors), establishing priorities, accountability, and flow of information to the community., Results: The influence of municipal secretaries of health and health councils on budget preparation has increased, with a decrease of local politician influence. In prioritizing health issues, local politicians and spontaneous demands have also become less influential, with strengthening of the influence of technical opinions and proposals by health councils and conferences. Public disclosure of results has become institutionalized as a result of the diversification of stakeholders (especially municipal secretaries and health councils) and of the methods available for disclosure, even though balance sheets are still the most common type of information disclosed (which imply technical knowledge for interpretation of results). Finally, the information conveyed to the community still mainly refers to health actions and campaigns and functioning of health services, even though a larger amount of innovative information is being communicated. This was observed in all regions and in cities of all sizes, with a more progressive trend in the South of Brazil., Conclusions: The relationship between government and society has changed toward a more democratic standard of local governance, despite the maintenance of centralized government decision-making practices. The process of decentralization still faces important obstacles to the establishment of a more participative model, with enhanced social control, accountability and interaction between government and society.

Background: Detection of hypertensive retinopathy (HR) with direct ophthalmoscopy is part of the assessment of hypertensive patients. Its use has been questioned because of its subjectivity and high interobserver variability., Objective: To determine the prevalence of HR in hypertensive patients under outpatient monitoring, the correlation between diagnosis and ophthalmoscopy and angiography, and to correlate it with other target organ damages., Methods: An observational, analytical and cross-sectional evaluation of 99 patients. Direct ophthalmoscopy and angiography performed by two investigators independently. Classification of RH, as described by Keith, Wagener and Barker., Results: The prevalence of HR of any grade was higher than 90.0% by both methods. On ophthalmoscopy, we observed grade I abnormalities in 51.0%, grade II in 43.0%, with one patient with grade III HR. On angiography, we observed grade I abnormalities in 42.0% and grade II in 52.0%. We detected three patients with grade III HR, two of which were not detected by ophthalmoscopy. Observers' agreement for the presence and severity of HR was poor with direct ophthalmoscopy and good with angiography. Renal dysfunction, ECG abnormalities (ventricular hypertrophy, pathological Q wave, repolarization abnormalities), and history of stroke were observed in 70.0%, 27.0% and 10.0% of patients, respectively. There was no relationship between the severity of HR and other target organ damages., Conclusion: We observed a high prevalence of HR using both methods. Observers' agreement for the diagnosis and determination of the severity of HR was better with angiography. In our sample, there was no association of the severity of HR with other target organ damages.

Kazal-type inhibitors play several important roles in invertebrates, such as anticoagulant, vasodilator and antimicrobial activities. Putative Kazal-type inhibitors were described in several insect transcriptomes. In this paper we characterized for the first time a Kazal unique domain trypsin inhibitor from the Aedes aegypti mosquito. Previously, analyses of sialotranscriptome of A. aegypti showed the potential presence of a Kazal-type serine protease inhibitor, in female salivary glands, carcass and also in whole male, which we named AaTI (A. aegypti trypsin inhibitor). AaTI sequence showed amino acid sequence similarity with insect thrombin inhibitors, serine protease inhibitor from Litopenaeus vannamei hemocytes and tryptase inhibitor from leech Hirudo medicinalis (LDTI). In this work we expressed, purified and characterized the recombinant AaTI (rAaTI). Molecular weight of purified rAaTI was 7 kDa rAaTI presented dissociation constant (K(i)) of 0.15 and 3.8 nM toward trypsin and plasmin, respectively, and it weakly inhibited thrombin amidolytic activity. The rAaTI was also able to prolong prothrombin time, activated partial thromboplastin time and thrombin time. AaTI transcription was confirmed in A. aegypti female salivary gland and gut 3 h and 24 h after blood feeding, suggesting that this molecule can act as anticoagulant during the feeding and digestive processes. Its transcription in larvae and pupae suggested that AaTI may also play other functions during the mosquito's development., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

Objective: To analyze the spatial and seasonal distribution of leptospirosis and identify possible ecological and social components of its transmission., Methods: A total of 2,490 cases registered in each district of the municipality of São Paulo, Southeastern Brazil, between 1998 and 2006, were georeferenced. The data were obtained from the Notifiable Diseases Information System. Thematic maps were made, showing the variables of incidence rate, lethality rate, literacy rate, average monthly income, number of residents per household, water supply and sewage system. To identify spatial patterns (dispersed, clustered or random), these variables were analyzed using the global and local Moran indices. Spearman's correlation coefficient was used to test associations between variables with clustered spatial patterns., Results: Clustered spatial patterns were observed for the variables of leptospirosis incidence, literacy rate, average monthly income, number of residents per household, water supply and sewage system. There were 773 notified cases in the dry season and 1,717 cases in the rainy season. The incidence and lethality rates correlated with the population's socioeconomic conditions, independently of the period., Conclusions: Leptospirosis is spread throughout the municipality of São Paulo, and its incidence increases during the rainy season. In the dry season, the localities where cases appear coincide with the areas of poorest housing conditions. In the rainy season, it also increases in other districts, probably due to the proximity of rivers and streams.

In our study we investigated the possible role of MBL2 functional single nucleotide polymorphisms (SNPs) in the augmented susceptibility to develop other autoimmune diseases in presence of type 1 diabetes (T1D) in a group of Brazilian patients. Patients were stratified for the presence of autoimmune diseases known to be associated with T1D, such as autoimmune thyroid disease (AITD) and celiac disease (CD), and compared with healthy controls (HC). Our findings suggest that MBL2 functional SNPs are more closely related to AITD than to T1D, being MBL2 SNPs frequencies in T1D patients not affected by AITD comparable to the HC ones, while significantly different between AITD patients and patients not affected by the disease. Thus, the association between MBL2 polymorphisms and T1D that we previously reported, seems to result from the stronger association of MBL2 SNPs with another autoimmune disease, the AITD, frequently associated with T1D.

To evaluate differences in growth and adaptability of maritime pine (Pinus pinaster Ait.), we studied growth, polycyclism, needle tissue carbon isotope composition (delta(13)C) as an estimate of water-use efficiency (WUE) and survival of seven populations at 10 years of age growing in a performance trial at a provenance test site in Escaroupim, Portugal. Six populations were from relatively high rainfall sites in Portugal and southwestern France (Atlantic group), and one population was from a more arid Mediterranean site in Spain. There were significant differences between some populations in total height, diameter at breast height, delta(13)C of bulk needle tissue, polycyclism and survival. A population from central Portugal (Leiria, on the Atlantic coast) was the tallest and had the lowest delta(13)C. Overall, the variation in delta(13)C was better explained by the mean minimum temperatures of the coldest month than by annual precipitation at the place of origin. Analyses of the relationships between delta(13)C and growth or survival revealed a distinct pattern for the Mediterranean population, with low delta(13)C (and WUE) associated with the lowest growth potential and reduced survival. There were significant negative correlations between delta(13)C and height or survival in the Atlantic group. Variation in polycyclism was correlated with annual precipitation at the place of origin. Some Atlantic populations maintained a high growth potential while experiencing moderate water stress. A detailed knowledge of the relationships between growth, survival and delta(13)C in contrasting environments will enhance our ability to select populations for forestry or conservation.

Background and Objectives: Disseminated strongyloidiasis is a clinical form of presentation associated with states of severe immunosuppression, as in AIDS, hematological malignancies and in treatment for immunosuppression (especially with high doses of corticosteroids). It usually mimics severe sepsis and still brings a significant challenge related to the diagnosis and treatment. Therefore exceedingly high mortality rates remain unchanged in the past decades. Initially, the diagnosis depends on the clinical suspicion and on the identification of the larva in an organic fluids or tissues. The cutaneous involvement, albeit rare, is typical and can provide an important clue for the diagnostic hypothesis. The emergence of ivermectin for oral use changed significantly the treatment for strongyloidiasis; however, there are still shortcomings for the utilization in critically ill patients. Shock, ileus and hypoperfusion states are associated with difficulties in the absorption that result in erratic systemic levels. Reports of good results with parenteral administration of ivermectin raised the prospect that this therapeutic modality be more effective. However, questions about dosage and safety remain unanswered. The aim of the present article is to review the medical literature on the clinical aspects of disseminated strongyloidiasis., Contents: A systematic review of the literature was performed by searching the PubMed database within the last 30 years. Search terms were: disseminated strongyloidiasis, strongyloides and hyperinfection e ivermectin., Conclusions: The article highlights the diagnostic and therapeutic aspects emphasizing the importance of the clinical suspicion for the institution of appropriated therapy.

A non-ambulatory dog with tetraparesis following a pain episode that had evolved over 2 months was submitted for medical treatment and diagnosed with intervertebral disk disease at C3-C4 and dorsal extradural compression at C1-C2 and C3-C4 using myelography and computed tomography. The dog experienced ambulation recovery after 15 days of treatment with only electroacupuncture and Chinese herbal medicine, with marked improvement occurring after only 10 treatments. Six months of followup demonstrated that the dog was stable and had no recurrence of symptoms. Therefore, it was concluded that the combination of electroacupuncture and Chinese herbal medicine was responsible for motor rehabilitation.

We studied the growth hormone receptor (GHR) gene in 6 patients with Laron syndrome (LS) from 4 unrelated families. Exons 2 to 10 were amplified by PCR using specific intronic pairs of primers. The PCR products were directly sequenced. Our results showed that all 6 patients carried a homozygous GAG>GAA mutation in codon 180 of exon 6. This mutation did not change the translated amino acid, but created an abnormal splice site deleting 8 amino acids from the extracellular domain of GHR. Members of all 4 kindreds with the E180splice mutation were genotyped for 4 polymorphic intragenic sites: The retention or exclusion of exon 3, single nucleotide polymorphisms present in exons 6 and 10, and intron 9 polymorphic site. All 6 patients presented the same haplotype. The E180splice mutation was first described in a population of Spanish descendants from the Andes of Southern Ecuador. This mutation was also found in oriental Jewish patients from Israel. Our families share the same intron-9 haplotype observed in Ecuadorian and Israeli patients. We conclude that the E180splice mutation is an important cause of LS in Brazil and there is probably a founder effect since our patients, Ecuadorian and Israeli patients share the same haplotype in intron 9.