Raman spectroscopy and sciatic functional index (SFI) after low-level laser therapy (LLLT) in a rat sciatic nerve crush injury model.

Axonotmesis causes sensorimotor and neurofunctional deficits, and its regeneration can occur slowly or not occur if not treated appropriately. Low-level laser therapy (LLLT) promotes nerve regeneration with the proliferation of myelinating Schwann cells to recover the myelin sheath and the production of glycoproteins for endoneurium reconstruction. This study aimed to evaluate the effects of LLLT on sciatic nerve regeneration after compression injury by means of the sciatic functional index (SFI) and Raman spectroscopy (RS). For this, 64 Wistar rats were divided into two groups according to the length of treatment: 14 days (n = 32) and 21 days (n = 32). These two groups were subdivided into four sub-groups of eight animals each (control 1; control 2; laser 660 nm; laser 808 nm). All animals had surgical exposure to the sciatic nerve, and only control 1 did not suffer nerve damage. To cause the lesion in the sciatic nerve, compression was applied with a Kelly clamp for 6 s. The evaluation of sensory deficit was performed by the painful exteroceptive sensitivity (PES) and neuromotor tests by the SFI. Laser 660 nm and laser 808 nm sub-groups were irradiated daily (100 mW, 40 s, energy density of 133 J/cm2). The sciatic nerve segment was removed for RS analysis. The animals showed accentuated sensory and neurofunctional deficit after injury and their rehabilitation occurred more effectively in the sub-groups treated with 660 nm laser. Control 2 sub-group did not obtain functional recovery of gait. The RS identified sphingolipids (718, 1065, and 1440 cm-1) and collagen (700, 852, 1004, 1270, and 1660 cm-1) as biomolecular characteristics of sciatic nerves. Principal component analysis revealed important differences among sub-groups and a directly proportional correlation with SFI, mainly in the sub-group laser 660 nm treated for 21 days. In the axonotmesis-type lesion model presented herein, the 660 nm laser was more efficient in neurofunctional recovery, and the Raman spectra of lipid and protein properties were attributed to the basic biochemical composition of the sciatic nerve.

Differential Incidence of Tongue Base Cancer in Male and Female HPV16-Transgenic Mice: Role of Female Sex Hormone Receptors.

A growing proportion of oropharyngeal squamous cell carcinomas (OPSCC) are associated with infection by high-risk human papillomavirus (HPV). For reasons that remain largely unknown, HPV+OPSCC is significantly more common in men than in women. This study aims to determine the incidence of OPSCC in male and female HPV16-transgenic mice and to explore the role of female sex hormone receptors in the sexual predisposition for HPV+ OPSCC. The tongues of 30-weeks-old HPV16-transgenic male (n = 80) and female (n = 90) and matched wild-type male (n = 10) and female (n = 10) FVB/n mice were screened histologically for intraepithelial and invasive lesions in 2017 at the Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Portugal. Expression of estrogen receptors alpha (ERα) and beta (ERß), progesterone receptors (PR) and matrix metalloproteinase 2 (MMP2) was studied immunohistochemically. Collagen remodeling was studied using picrosirius red. Female mice showed robust ERα and ERß expression in intraepithelial and invasive lesions, which was accompanied by strong MMP2 expression and marked collagen remodeling. Male mice showed minimal ERα, ERß and MMP2 expression and unaltered collagen patterns. These results confirm the association of HPV16 with tongue base cancer in both sexes. The higher cancer incidence in female versus male mice contrasts with data from OPSCC patients and is associated with enhanced ER expression via MMP2 upregulation.

Recurrent respiratory papillomatosis: clinical characteristics and viral genotyping in a Brazilian population.

This study presents 25 cases of recurrent respiratory papillomatosis (RRP) that occurred in Sao Luis, Maranhao State, Northeast region, Brazil, between January 2007 and December 2018. Sociodemographic and clinical profile of patients as well as human papillomavirus (HPV) infection status were evaluated. Clinical and histopathological data were collected from the patients' medical records. For the HPV infection analysis, DNA was extracted and subjected to amplification by a nested polymerase chain reaction. Viral genotyping was performed by automated sequencing. The median age of patients was 12.40 ± 12.6. years, and the juvenile form of the disease (68%) was the predominant form of disease. Female participants were predominant (60%), and they were from cities located in the interior of the State (60%). The most common clinical manifestation was dysphonia; recurrence was observed in most cases (56%), and tracheostomy was necessary in seven patients (26.9%). When comparing the RRP forms, patients in the juvenile-RRP group had higher recurrence rates and need of tracheostomy than those in the adult-RRP group. The viral genotyping analysis revealed that 47.8% of patients had low-risk HPVs, whereas 13.1% had high-risk HPVs, and in 39.1% of patients the viral genotype was not obtained. HPV-6 was the most prevalent type and Juvenile-RRP was more prevalent in our population. HPV was present at a high rate, and HPV-6 was the predominant genotype. This study serves as the basis for further studies to be conducted in the Brazilian population. Our findings aid the better understanding of RRP, possibly suggesting some prognostic factors associated with the disease aggressiveness.

Morphological changes in the temporomandibular joints in women with fibromyalgia and myofascial pain: A case series.

Objective: This study investigated the temporomandibular joint (TMJ) morphological changes in women with fibromyalgia (FM) through clinical and tomographic evaluation.Methods: Ten women diagnosed with myofascial pain who were being treated for FM in a university hospital were included in this study. The data were collected through clinical examination and cone beam computed tomography evaluation of the TMJ in closed and open mouth positions.Results: All patients had crackling in the joint, a habit of grinding teeth during sleep, muscle stiffness, and tinnitus. The tomographic findings revealed a higher frequency of condylar bone wear, reduction of joint space, and posterior positioning of the mandibular condyle. The temporomandibular disorders with the highest prevalence were osteoarthritis and disc displacement with reduction.Conclusion: The findings suggest that women with FM have a high frequency of TMD related to the displacement of the articular disc, condyle position, and occurrence of osteoarthritis.

Morphological and histomorphometric evaluation of autogenous bone graft resorption in rabbits treated with alendronate sodium / Avaliação morfológica e histomorfométrica da reabsorção de enxertos ósseos autógenos em coelhos usuários de alendronato de sódio

Introduction: Different rates of resorption are mediated by osteoclasts that may be affected by bisphosphonates during bone graft repair. Bisphosphonates are drugs that act as inhibitors of bone resorption. Objective:The aim of the present study was to evaluate the rate of resorption of skullcap grafts in rabbits with and without the use of alendronate sodium. Material and method: Thirty two New Zealand rabbits were divided into two groups (control group and alendronate group) and divided again into four periods (7, 14, 30 and 60 days). The control group did not receive alendronate, while animals of the experimental group received 4 mg of alendronate sodium weekly after the surgery. An 8 mm diameter bone block was removed from the parietal bone and fixed by screws to the contralateral parietal bone. During the periods of 7, 14, 30 and 60 days, the animals had undergone euthanasia and samples were removed for further analysis. Morphological and histomorphometric tests were used to compare graft thicknesses and to evaluate the newly formed bone at the interface between the graft and receptor site. The Wilcoxon and Mann-Whitney tests were used for statistical analyses. Result: All grafts healed and integrated uneventfully and no statistically significant differences in resorption rates or bone deposition were detected after the final incorporation of the graft in both groups. Conclusion: Alendronate Sodium did not decrease the bone graft resorption rates, but there was a tendency for better results in the control group regarding the resorption and neoformation in autogenous calvarial bone grafts in rabbits.

Introdução: Durante o reparo de enxertos ósseos, diferentes taxas de reabsorção são mediadas pelos osteoclastos e podem ser afetadas pelos bisfosfonatos, que são drogas que agem como inibidores da reabsorção óssea. Objetivo: Avaliar a taxa de reabsorção dos enxertos ósseos de calota craniana de coelhos, com e sem o uso alendronato de sódio. Material e método: Trinta e dois coelhos Nova Zelândia foram divididos igualmente em 2 grupos (grupo controle e grupo alendronato de sódio) e subdivididos em 4 períodos (7, 14, 30 e 60 dias). O grupo controle não recebeu alendronato, enquanto os animais do grupo experimental receberam 4 mg de alendronato de sódio por semana, em dose única, após a cirurgia. Um bloco de osso de diâmetro de 8 mm foi retirado o osso parietal e fixado com parafuso no osso parietal contralateral. Após cirurgia, nos períodos de 7, 14, 30 e 60 dias, os animais foram eutanasiados e as peças removidas para análise. Análises morfológica e histomorfométrica foram utilizados para comparar a espessura do enxerto e para avaliar a interface de osso recém formado entre o enxerto ósseo e o sítio receptor. Os testes de Wilcoxon e Mann-Whitney foram utilizados para as análises estatísticas. Resultado: Todos os enxertos repararam e integraram sem intercorrências; não foram detectadas diferenças estatisticamente significativas nas taxas de reabsorção ou deposição óssea, após a incorporação final do enxerto em ambos os grupos. Conclusão: Alendronato de sódio parece não diminuir a taxa de reabsorção, porém houve uma tendência de resultados melhores no grupo controle tanto na reabsorção quanto na neoformação óssea em enxertos ósseos autógenos de calota craniana de coelhos.

Finite element analysis of bone stress after SARPE.

PURPOSE: This study investigated stress distribution in maxillas that underwent surgically assisted palatal expansion (SARPE). MATERIALS AND METHODS: Five maxillary models were built: no osteotomy (M1), Le Fort I osteotomy with a step in the zygomaticomaxillary buttress (M2), Le Fort I osteotomy with a step in the zygomaticomaxillary buttress and the pterygomaxillary disjunction (M3), Le Fort I osteotomy without a step (M4), and Le Fort I osteotomy with pterygomaxillary disjunction and no step (M5). Displacement coherence and maximum stress (MS) analyses were used for all models. RESULTS: Areas of tension spread to the maxilla and the region between the alveolar ridge and the palate and a critical point in the median suture for M2, M3, M4, and M5. In M2 and M4, MS spread farther toward and over the pterygoid process, contrary to what was found in M3 and M5. M3 had a better performance than the other models, and the tensile stress was interrupted by the posterior osteotomy, thus avoiding possible damage to the sphenoid bone or difficulties in expanding the posterior region of the maxilla. CONCLUSIONS: The steps in the zygomaticomaxillary buttress and the pterygomaxillary disjunction seem to be important to decrease the harmful dissipation of tensions during SARPE.

Complicações após expansão de maxila cirurgicamente assistida / Complications following surgically assisted maxillary expansion

Introdução: O tratamento da deficiência transversal de maxila, em adultos, exige a expansão de maxila cirurgicamente assistida. Diversas técnicas cirúrgicas são conhecidas para a realização desse procedimento, porém estas relacionam-se com complicações. Objetivo: Avaliar a incidência de complicações associadas ao procedimento de expansão de maxila cirurgicamente assistida. Material e Método: Trinta e três indivíduos com deficiência transversal de maxila foram submetidos ao procedimento de expansão pela técnica da osteotomia Le Fort I subtotal com degrau no pilar zigomático-maxilar, disjunção ptérigo-maxilar e osteotomia da sutura intermaxilar. Durante os períodos trans e pós-operatório, as complicações relacionadas ao procedimento e as distâncias interdentais foram registradas. Resultado: Doze homens e 21 mulheres, com idade média de 24,64 anos, submeteram-se ao procedimento. As mensurações das distâncias interdentais evidenciaram aumento das mesmas entre os períodos pré-operatório e pós-operatório de 2 meses. As complicações prevalentes foram sinusite (6%) e deslocamento associado à inclinação dental (6%). Conclusão: A expansão de maxila cirurgicamente assistida é um procedimento eficaz e de baixa morbidade para o tratamento da deficiência transversal de maxila em indivíduos adultos.

Introduction: The treatment of adult transverse maxillary deficiency is the surgically assisted maxillary expansion. Several surgical techniques have been described for this and complications have been related to these procedures. Objective: the aim of this study was evaluate the incidence of complications associated with surgically assisted maxillary expansion. Material and Method: 33 individuals undergone surgically assisted maxillary expansion by subtotal Le Fort I osteotomy with a step in the zygomatic-maxillary buttress and associated to pterigomaxillary disjunction and osteotomy of intermaxillary suture. Operative complications, post-operative complications and the distance between the upper teeth were recorded. Result: 12 men and 21 women with an average age of 24.64 years undergone the procedure. The interdental distances increased from preoperative to 2 months post-operative time. The prevalent complications were sinusitis (6%) and teeth displacement and inclination (6%). Conclusion: Surgically assisted maxillary expansion is an effective and low morbidity procedure to treat transverse maxillary deficiency in adults.

Avaliação ultra-estrutural, dimensional e mecânica de dois sistemas de fixação interna rígida de 2 mm / Ultra-structural dimensional and mechanical evaluation of two 2mm systems of internal rigid fixation

Introdução e objetivo: este trabalho teve como objetivo comparar dois materiais de fixação interna rígida utilizados em cirurgia maxilofacial, sob o ponto de vista ultra-estrutural, dimensional e mecânico. Materiais e Métodos: foram comparadas amostras de miniplacas de 2.0mm Neoortho® e Synthes®. As amostras foram avaliadas por Microscopia Eletrônica de Varredura (MEV) e Espectroscopia por Dispersão de Energia (EDS) para avaliação superficial e identificação de contaminantes. Avaliação macroscópica foi feita com paquímetros digitais e com micrômetro. Miniplacas foram submetidas a ensaio de acordo com as normas da American Society for Testing and Materials, Norma F382-99. Resultado: Como resultado do exame pelo MEV e EDS, observa-se a presença de contaminantes, manchamentos e rebarbas em ambas as amostras. Na análise dimensional, observou-se variabilidade nas medidas entre as marcas e maior variabilidade de dimensão nas miniplacas Neoortho®. Ao ensaio de flexão, observou-se discrepância entre as amostras, sendo a Synthes® com maior homogeneidade, mas ambas dentro do intervalo preconizado pela ASTM. Conclusão: a MEV demonstrou superfícies de titânio homogêneas e com debris de superfície oriundos da fabricação e manipulação dos materiais. Dimensionalmente as miniplacas apresentam variações quando comparadas, e estas podem influenciar diretamente os resultados do dos ensaios mecânicos, sendo que mesmo com as variações ambas estão de acordo com a norma da ASTM.

Introduction and objective: this study aimed to compare two rigid internal fixation materials used in maxillofacial surgery, from the ultra-structural, dimensional and mechanical points of view. Materials and Methods: we have compared samples of 2.0 mm miniplates produced by Neoortho® and Synthes®. The samples were analyzed by Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS) for evaluation and identification of surface contaminants. Macroscopic evaluation was made with digital calipers and micrometer. The miniplates were subjected totesting in accordance with the F382-99 standards of the American Society for Testing and Materials Standard. Result: examination by SEM and EDS revealed the presence of contaminants, staining and burrs in both samples. In dimensional analysis, there was variability in measurements between brands and greater variability in size of Neoortho® miniplates. In the bending test, it was observed discrepancy between the samples, showing the Synthes® greater uniformity, but both within the range recommended by ASTM. Conclusion: the SEM showed homogeneous titanium surfaces and surface debris deriving from the manufacture and handling of materials. From the dimensional point of view, the miniplates showed variations when compared to each other, and this may directly influence the results of the mechanical tests. However, even with variations both are in agreement with the standard ASTM..

Agenesia dentária reabilitada por meio de implante de superfície SLActive: relato de caso / Dental agenesis treated with SLActive implant: case report

Agenesia dentária é uma anomalia genética que caracteriza-se pela ausência total de um ou mais dentes. Ocorre em de 6% da população brasileira, geralmente no segundo pré-molar inferior e representa um desafio para a reabilitação, pois leva a alterações funcionais e estéticas. Nesse contexto, os implantes osseointegráveis ocupam lugar de destaque, dentre eles, os implantes de superfície SLActive®, que promovem aceleração no período de osseointegração, reduzindo esse tempo para 21 dias, além de melhor qualidade do osso neoformado ao redor dos implantes. Com altos índices de sucesso, mesmo quando submetidos a carga oclusal precoce ou imediata, tais implantes têm revolucionado a implantodontia moderna. O objetivo desse trabalho é relatar caso de agenesia dentária do segundo pré-molar inferior, reabilitado por meio de implante de superfície SLActive® e instalação da coroa protética definitiva na quinta semana pós-operatória.

Dental agenesis is a genetic abnormality characterized by total absence of one or more teeth. It affects about 6% of the population, affects preferably the second mandibular premolar and represents a challenge for rehabilitation because it leads to functional and esthetic problems. Currently, dental implants play a prominent role in rehabilitation, and the SLActive® implants stand out because they accelerate osseointegration, shorten it to 21 days, and ensure better quality of new bone around the implant. With high rates of success even when immediate or early loading is used, these implants have revolutionized modern Implantology. This report describes a case of dental agenesis of the second mandibular premolar treated using a SLActive® implant and a final prosthetic crown installed on the fifth postoperative week.

Does the Relationship between Retained Mandibular Third Molar and Mandibular Angle Fracture Exist? An Assessment of Three Possible Causes.

The objective of this study is to discuss problems associated with dental retention through three clinical cases of mandible fractures related to the presence of retained lower third molars, emphasizing the possibility of mandible fractures resulting from this or from the extraction procedure. The three evaluated patients had a fracture in the mandible angle. The third molars were present in all the cases, as was the relationship of the fracture with the teeth. After evaluating the three cases and reviewing literature, it is believed that the presence of the retained lower third molars and the surgical procedures for their extraction increase the risk of mandible angle fractures.

Evaluation of the mesio-buccal gingival sulcus depth of the upper central incisors in patients submitted to surgically assisted maxillary expansion.

UNLABELLED: PROPOSITION: The aim of this study was to evaluate the modifications that occurred in the mesio-buccal gingival sulcus depth of the upper central incisors during a 3-year post-operative period. METHODS: The mesio-buccal gingival sulcus depth of the upper central incisors of patients submitted to surgically assisted maxillary expansion (SAME) was measured by using a periodontal probe, both in the pre-operative period and in the 2-, 6-, 24-, and 36-month post-operative period. The results were submitted for statistical analysis by using ANOVA and Tukey's test with level of significance of 5%. RESULTS: The mesial gingival sulcus depths were statistically significant (P < 0.05) in the comparison between the pre-operative and both the 2- and 6-month post-operative periods, between the 2- and 24-month post-operative periods, and between the 2- and 36-month periods. CONCLUSION: The gingival sulcus depths increased during the initial post-operative periods. The SAME procedure increased the gingival sulcus depth of the upper central incisors.

Clinical evaluation of the alar base width of patients submitted to surgically assisted maxillary expansion.

UNLABELLED: PROPOSITION: The aim of this study was to evaluate both the presence and magnitude of the modifications occurred in the alar base width, in patients submitted to surgically assisted maxillary expansion (SAME). METHODS: The alar base width of 13 patients submitted to SAME followed by alar base suture and simple V-Y suture was measured by using direct measuring with digital paquimeter during regular periods: pre-operative and 2, 6, 24, and 36 months post-operative. Data were submitted to statistical analysis by using ANOVA and Tukey's test with level of significance of 5%. RESULTS: There was a statistically significant increase (P < 0.05) of the alar base width in the comparison between the pre-operative and the 6-, 24-, and 36-month post-operative periods. CONCLUSION: SAME procedure increased the alar base width even performing the alar bases sutures; however, despite the widening of 1.6 mm, the clinical result was not compromised and better than without the technique.

Avaliação histológica da reparação de área doadora de enxerto ósseo removido com motores elétrico e pneumático / Histological assessment of the restoration of bone graft areas after the removal with electric and pneumatic motors

Dentre as etapas da remoção de um enxerto ósseo, a ostectomia é uma manobra fundamental que pode interferir diretamente no processo de reparo ósseo de modo a exacerbar ou a minimizar a morbidade da área doadora. Teve-se por objetivo realizar uma análise histológica qualitativa da reparação tecidual de cavidades confeccionadas por meio da remoção de enxerto ósseo em tíbia de coelhos. Foram utilizados nove coelhos nos quais foram feitas cavidades padronizadas (6 x 12mm) com brocas cirúrgicas padrão montadas em dois diferentes equipamentos: na tíbia direita, utilizou-se motores de baixa rotação pneumático (Grupo I); na tíbia esquerda, motores de baixa rotação elétrico (Grupo II), todos com refrigeração constante. Os períodos de sacrifício preconizados foram de 2, 14 e 30 dias do pós-operatório. Em cada período, foram sacrificados três animais, procedendo-se à remoção de ambas as tíbias, de limitando a área a ser avaliada. Os espécimes foram submetidos ao processamento laboratorial de rotina e posteriormente foram realizadas análises por meio de microscopia óptica de luz...

The ostectomia is a basic surgical maneuver that can be to interfere in bone repair. This work aimed at achieving histological analysis qualitative of bone repair after removal bone graft from the rabbit tíbia using two different rotative instruments: pneumatic micromotor lower rotation and electric motor lower rotation. Were utilized nine rabbit and making standart cavity (6 x 12mm). In right tibia wereused pneumatic micromotor lower rotation (Group I); in left tibia were used electric motor lower rotation (Group II). Tree animals were sacrifice in period of 2, 14 and 30 days after surgery. The histological specimens were submitted at microscopy optical...

Estudo radiográfico digital indireto do efeito da expansão de maxila cirurgicamente assistida (EMCA) sobre o septo nasal / Indirect digital radiographic study about the effect of surgically assisted maxillary expansion (SAME) on the nasal septum

INTRODUÇÃO: a deficiência transversal da maxila é caracterizada pela atresia maxilar, palato ogival, apinhamento e rotação dos dentes, além da mordida cruzada posterior (uni ou bilateral). O tratamento dos pacientes com esta deficiência consiste no alargamento das bases ósseas maxilares. Nos pacientes com maturidade esquelética, a expansão da maxila é obtida através de procedimentos ortocirúrgicos (conhecidos como expansão de maxila cirurgicamente assistida - EMCA) que podem gerar efeitos sobre a cavidade e sobre o septo nasal. OBJETIVO: avaliar o comportamento do septo nasal frente aos procedimentos de EMCA. METODOLOGIA: foram avaliadas radiografias cefalométricas em norma póstero-anterior e radiografias oclusais totais de maxila, obtidas pela técnica convencional e posteriormente digitalizadas, de 16 pacientes submetidos à EMCA pela técnica de osteotomia Le Fort I subtotal. As radiografias foram obtidas no período pré-operatório (inicial) e pós-operatório mediato ou ao final da expansão e foram digitalizadas e mensuradas utilizando o programa DIGORA. Foram medidas, ainda, as distâncias entre os dentes (caninos, primeiro pré-molares, segundo pré-molares, primeiros molares e segundos molares). RESULTADOS: após a análise estatística pode-se constatar o aumento das distâncias interdentárias e intermaxilares, além do aumento da largura da porção basal da abertura piriforme e das distâncias entre a parede lateral da porção basal da abertura piriforme e o septo nasal. CONCLUSÃO: a EMCA é um procedimento eficaz, capaz de alargar a porção basal da abertura piriforme, que parece não influenciar no posicionamento do septo nasal.

INTRODUCTION: Maxillary transversal deficiency is characterized by constricted maxillary arch, dental crowding and rotation, along with posterior uni or bilateral crossbite. The treatment of this deficiency is based on the widening of maxillary bone. In skeletal mature patients the maxillary expansion is achieved by means of surgical-orthodontic procedures (known as surgically assisted maxillary expansion - SAME) that can cause some effects on the nasal cavity and septum. AIM: To evaluate the behavior of the nasal septum after the procedures of SAME. METHODS: Post-anterior cephalometric and maxillary occlusal radiographs, taken by conventional technique and therefore digitalized, were analyzed from 16 patients undergone SAME. For all patients, the SAME technique consisted of subtotal Le Fort I osteotomy. The radiographs were taken before the surgical procedure, right after (mediate post-operatory time) or after the expansion, and thereafter digitalized and measured using DIGORA program. Also, the distances between teeth (canines, first premolars, second premolars, first molars and second molars) were registered. RESULTS: The statistical treatment showed an increase in interdental and intermaxillary distances, along with an increase in the width of the base of piriform aperture and in the distances between the base of lateral wall of the piriform aperture and nasal septum. CONCLUSION: SAME is an efficient procedure that seems not to influence the septum position.

Utilização de microimplantes como ancoragem ortodôntica no tratamento das más-oclusões / The use of micro-implants for orthodontic anchorage in the treatment of malocclusions

Durante anos a Ortodontia e a Implantodontia buscam novas formas de abordagem ao tratamento das más-oclusões, utilizando formas de ancoragem mais simples. A indicação de microimplantes deve ser cautelosa, devendo ser considerado o custo, o tempo e a aplicação vantajosa ao caso de cada paciente.