MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Salmeterol for the prevention of high-altitude pulmonary edema.

BACKGROUND: Pulmonary edema results from a persistent imbalance between forces that drive water into the air space and the physiologic mechanisms that remove it. Among the latter, the absorption of liquid driven by active alveolar transepithelial sodium transport has an important role; a defect of this mechanism may predispose patients to pulmonary edema. Beta-adrenergic agonists up-regulate the clearance of alveolar fluid and attenuate pulmonary edema in animal models. METHODS: In a double-blind, randomized, placebo-controlled study, we assessed the effects of prophylactic inhalation of the beta-adrenergic agonist salmeterol on the incidence of pulmonary edema during exposure to high altitudes (4559 m, reached in less than 22 hours) in 37 subjects who were susceptible to high-altitude pulmonary edema. We also measured the nasal transepithelial potential difference, a marker of the transepithelial sodium and water transport in the distal airways, in 33 mountaineers who were prone to high-altitude pulmonary edema and 33 mountaineers who were resistant to this condition. RESULTS: Prophylactic inhalation of salmeterol decreased the incidence of high-altitude pulmonary edema in susceptible subjects by more than 50 percent, from 74 percent with placebo to 33 percent (P=0.02). The nasal potential-difference value under low-altitude conditions was more than 30 percent lower in the subjects who were susceptible to high-altitude pulmonary edema than in those who were not susceptible (P<0.001). CONCLUSIONS: Prophylactic inhalation of a beta-adrenergic agonist reduces the risk of high-altitude pulmonary edema. Sodium-dependent absorption of liquid from the airways may be defective in patients who are susceptible to high-altitude pulmonary edema. These findings support the concept that sodium-driven clearance of alveolar fluid may have a pathogenic role in pulmonary edema in humans and therefore represent an appropriate target for therapy.

Clinical features for diagnosis of pneumonia in children younger than 5 years: a systematic review and meta-analysis.

BACKGROUND: Pneumonia is the biggest cause of deaths in young children in developing countries, but early diagnosis and intervention can effectively reduce mortality. We aimed to assess the diagnostic value of clinical signs and symptoms to identify radiological pneumonia in children younger than 5 years and to review the accuracy of WHO criteria for diagnosis of clinical pneumonia. METHODS: We searched Medline (PubMed), Embase (Ovid), the Cochrane Database of Systematic Reviews, and reference lists of relevant studies, without date restrictions, to identify articles assessing clinical predictors of radiological pneumonia in children. Selection was based on: design (diagnostic accuracy studies), target disease (pneumonia), participants (children aged <5 years), setting (ambulatory or hospital care), index test (clinical features), and reference standard (chest radiography). Quality assessment was based on the 2011 Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. For each index test, we calculated sensitivity and specificity and, when the tests were assessed in four or more studies, calculated pooled estimates with use of bivariate model and hierarchical summary receiver operation characteristics plots for meta-analysis. FINDINGS: We included 18 articles in our analysis. WHO-approved signs age-related fast breathing (six studies; pooled sensitivity 0·62, 95% CI 0·26-0·89; specificity 0·59, 0·29-0·84) and lower chest wall indrawing (four studies; 0·48, 0·16-0·82; 0·72, 0·47-0·89) showed poor diagnostic performance in the meta-analysis. Features with the highest pooled positive likelihood ratios were respiratory rate higher than 50 breaths per min (1·90, 1·45-2·48), grunting (1·78, 1·10-2·88), chest indrawing (1·76, 0·86-3·58), and nasal flaring (1·75, 1·20-2·56). Features with the lowest pooled negative likelihood ratio were cough (0·30, 0·09-0·96), history of fever (0·53, 0·41-0·69), and respiratory rate higher than 40 breaths per min (0·43, 0·23-0·83). INTERPRETATION: Not one clinical feature was sufficient to diagnose pneumonia definitively. Combination of clinical features in a decision tree might improve diagnostic performance, but the addition of new point-of-care tests for diagnosis of bacterial pneumonia would help to attain an acceptable level of accuracy. FUNDING: Swiss National Science Foundation.

Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial.

Background: Previous studies have presented contradictory data concerning obstructive sleep apnoea syndrome (OSAS), lipid oxidation and nitric oxide (NO) bioavailability. This study was undertaken to (1) compare the concentration of 8-isoprostane and total nitrate and nitrite (NOx) in plasma of middle-aged men with OSAS and no other known co-morbidity and healthy controls of the same age, gender and body mass index; and (2) test the hypothesis that nasal continuous positive airway pressure (CPAP) therapy attenuates oxidative stress and nitrate deficiency. Methods: A prospective, randomised, placebo controlled, double-blind, crossover study was performed in 31 consecutive middle-aged men with newly diagnosed OSAS and 15 healthy control subjects. Patients with OSAS were randomised to receive sham CPAP or effective CPAP for 12 weeks. Blood pressure, urinary catecholamine levels and plasma 8-isoprostane and NOx concentrations were obtained before and after both treatment modalities. Results: Patients with OSAS had significantly higher 8-isoprostane levels (median (IQR) 42.5 (29.2-78.2) vs 20.0 (12.5-52.5) pg/ml, p = 0.041, Mann-Whitney test) and lower NOx levels (264 (165-650) vs 590 (251- 1465) mmol/l, p = 0.022) than healthy subjects. Body mass index, blood pressure and urinary catecholamines were unchanged by CPAP therapy, but 8-isoprostane concentrations decreased (38.5 (24.2-58.7) pg/ml at baseline vs 22.5 (16.2-35.3) pg/ml on CPAP, p = 0.0001) and NOx levels increased (280 (177-707) vs 1373 (981-1517) mmol/l, p = 0.0001) after CPAP. Conclusions: OSAS is associated with an increase in oxidative stress and a decrease in NOx that is normalised

Tomografia computadorizada helicoidal dos seios paranasais na criança: avaliação das sinusopatias inflamatórias

Neste estudo foi feita avaliação retrospectiva de 71 casos selecionados de pacientes pediátricos, maiores de um ano e menores de sete anos, que realizaram exame de tomografia computadorizada helicoidal dos seios paranasais no período de março de 1997 a abril de 1998, apresentando quadro clínico de sinusopatia inflamatória aguda recorrente e sinusopatia inflamatória crônica. Foram correlacionados os quadros clínicos com os achados da tomografia computadorizada helicoidal, avaliando a pneumatização dos seios paranasais, os complexos óstio-meatais, as variações anatômicas, o estado da superfície mucosa e a extensão lesional. Os achados tomográficos de maior prevalência foram o velamento total ou parcial de uma ou mais cavidades paranasais (92,9%), seguido da hipertrofia da mucosa de revestimento (67,6%). Houve, na maioria dos casos, associação entre a sinusopatia inflamatória e a obstrução dos complexos óstio-meatais (53,5%). As variações anatômicas foram identificadas já a partir de um ano, com predomínio dos desvios do septo nasal (14,1%), estando correlacionadas às sinusopatias inflamatórias em cerca de 71% dos pacientes.

Displasia craniometafisária: relato de caso

Apresentamos um caso de uma criança com dois anos e oito meses de idade,acometida pela forma recessiva da displasia craniometafisária. São enfatizados os achados clínico-radiológicos, bem como seus principais diagnósticos diferenciais, baseados em dados de breve revisão literária.

Comprometimento órbito-craniano por tumores malignos sinonasais: estudo por tomografia computadorizada

Tumores malignos das cavidades sinonasais são raros e freqüentemente diagnosticados em estágio avançado da doença. A extensão destes tumores para locais críticos como a órbita e o crânio gera dificuldades no tratamento destas lesões. Dez pacientes com neoplasia maligna sinonasal, sem qualquer tratamento prévio e com evidência radiológica de extensão órbito-craniana, foram estudados por tomografia computadorizada. Dos dez tumores, cinco (50%) foram neoplasias epiteliais, tendo sido a mais comum o carcinoma epidermóide (três casos). O sítio de origem tumoral mais comum foi o seio etmoidal, em quatro pacientes (40%), seguido pelo seio maxilar (30%) e pela fossa nasal (30%). Dezesseis órbitas foram comprometidas, já que seis pacientes (60%) apresentaram acometimento orbitário tumoral bilateral. Os tumores se estenderam mais freqüentemente para as órbitas através de erosão da parede medial e do soalho orbitários. A maioria das órbitas teve todos os compartimentos acometidos. Extensão dos tumores para a cavidade craniana foi mais comum através do teto etmoidal (70%) e teto orbitário (30%). A fossa craniana anterior foi acometida em oito casos (80%), seguida pela fossa craniana média (40%) e pelo lobo frontal (excluindo-se a fossa anterior) (30%). Trinta e sete regiões da face foram acometidas pelos dez tumores, excluindo-se o sítio de origem da neoplasia e a região órbito-craniana, corroborando a grande extensão loco-regional do tumor no momento do diagnóstico.

Long-term outcomes following functional endoscopic sinus surgery in Samter's triad.

OBJECTIVE: This study aimed to assess the long-term outcome of functional endoscopic sinus surgery for Samter's triad patients using an objective visual analogue scale and nasal endoscopy. METHOD: Using a retrospective database, 33 Samter's triad patients who underwent functional endoscopic sinus surgery were evaluated pre- and post-operatively between 1987 and 2007 in Hospital of La Chaux-de-Fonds, Switzerland. RESULTS: A total of 33 patients participated in the study, and the mean follow-up period was 11.6 years (range 1.2-20 years). Patients were divided into two groups based on visual analogue scale scores of the five parameters with the greatest difference in intensity of symptoms between the beginning and end of follow up. Group 1 included patients with a mean visual analogue scale score of 6 and below at the end of follow up and group 2 included patients with a mean visual analogue scale score of more than 6. The only statistically significant difference noted between the two groups was the endonasal findings: stage III-IV polyposis was present in 1 out of 24 patients (4 per cent) in group 1 and in 5 out of 9 patients (56 per cent) in group 2. CONCLUSION: The results of our study indicate that functional endoscopic sinus surgery helps stabilise disease progression. Stage III-IV polyposis had a significant adverse effect on long-term outcome.

Identification of pyridine analogs as new predator-derived kairomones.

In the wild, animals have developed survival strategies relying on their senses. The individual ability to identify threatening situations is crucial and leads to increase in the overall fitness of the species. Rodents, for example have developed in their nasal cavities specialized olfactory neurons implicated in the detection of volatile cues encoding for impending danger such as predator scents or alarm pheromones. In particular, the neurons of the Grueneberg ganglion (GG), an olfactory subsystem, are implicated in the detection of danger cues sharing a similar chemical signature, a heterocyclic sulfur- or nitrogen-containing motif. Here we used a "from the wild to the lab" approach to identify new molecules that are involuntarily emitted by predators and that initiate fear-related responses in the recipient animal, the putative prey. We collected urines from carnivores as sources of predator scents and first verified their impact on the blood pressure of the mice. With this approach, the urine of the mountain lion emerged as the most potent source of chemical stress. We then identified in this biological fluid, new volatile cues with characteristic GG-related fingerprints, in particular the methylated pyridine structures, 2,4-lutidine and its analogs. We finally verified their encoded danger quality and demonstrated their ability to mimic the effects of the predator urine on GG neurons, on mice blood pressure and in behavioral experiments. In summary, we were able to identify here, with the use of an integrative approach, new relevant molecules, the pyridine analogs, implicated in interspecies danger communication.

Avaliação radiográfica da adenóide em crianças: métodos de mensuração e parâmetros da normalidade

A radiografia da nasofaringe (ou radiografia do cavum) ainda é o exame por imagem mais usado para a avaliação do tamanho da adenóide. Dada a variedade e a complexidade dos métodos de mensuração preconizados, muitos radiologistas preferem a avaliação subjetiva, que pode ser imprecisa e não-acurada. Esta revisão enumera e descreve os diversos métodos de mensuração radiográfica da adenóide propostos na literatura, considerando praticidade, acurácia e precisão, com o objetivo de indicar os mais adequados para a prática cotidiana.

Prevalência, classificação e características do refluxo cecoileal diagnosticado pelo enema opaco

OBJETIVO: Verificar, retrospectivamente, a prevalência do refluxo cecoileal diagnosticado pelo enema opaco, caracterizar sua distribuição etária e sexual e classificá-lo conforme o grau de intensidade. MATERIAIS E MÉTODOS: Foram revistos 715 enemas opacos, incluindo 268 homens e 447 mulheres com idade média de 54 anos. RESULTADOS: Dos 715 casos examinados, 46,5% apresentaram refluxo cecoileal, sendo 45% do tipo leve, 37,5% do tipo moderado e 17,5% do tipo severo. Refluxo cecoileal esteve presente em 48,3% das mulheres e em 43,6% dos homens. A distribuição percentual do refluxo cecoileal por faixa etária mostrou 46,1% nos indivíduos com menos de 21 anos, 42,1% nos indivíduos entre 21-40 anos, 49,8% nos indivíduos entre 41-60 anos e 44,7% nos indivíduos com mais de 60 anos. CONCLUSÃO: Refluxo cecoileal foi achado relativamente freqüente em nosso material, correspondendo os graus moderado e severo a 25% do material examinado. Aparentemente, não há associação entre seu surgimento e sexo ou idade. A etiopatogenia e conseqüências do refluxo cecoileal são ainda pouco conhecidas. Alguns estudos sugerem que o comprometimento de componentes da junção ileocecal, como os ligamentos, pode favorecer seu aparecimento. Entre as conseqüências prováveis, incluem-se a contaminação e alteração motora ileais, resultantes do material refluído do ceco.

Mutations in the heat-shock protein A9 (HSPA9) gene cause the EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia.

We and others have reported mutations in LONP1, a gene coding for a mitochondrial chaperone and protease, as the cause of the human CODAS (cerebral, ocular, dental, auricular and skeletal) syndrome (MIM 600373). Here, we delineate a similar but distinct condition that shares the epiphyseal, vertebral and ocular changes of CODAS but also included severe microtia, nasal hypoplasia, and other malformations, and for which we propose the name of EVEN-PLUS syndrome for epiphyseal, vertebral, ear, nose, plus associated findings. In three individuals from two families, no mutation in LONP1 was found; instead, we found biallelic mutations in HSPA9, the gene that codes for mHSP70/mortalin, another highly conserved mitochondrial chaperone protein essential in mitochondrial protein import, folding, and degradation. The functional relationship between LONP1 and HSPA9 in mitochondrial protein chaperoning and the overlapping phenotypes of CODAS and EVEN-PLUS delineate a family of "mitochondrial chaperonopathies" and point to an unexplored role of mitochondrial chaperones in human embryonic morphogenesis.

Diagnóstico por imagem dos tumores da nasofaringe

A nasofaringe é a parte mais superior das vias aéreas superiores. Seu limite superior é a base do osso esfenóide e occipital, situa-se anteriormente às duas primeiras vértebras cervicais e à frente do clivo. Seus limites laterais são formados pelas margens do músculo constritor superior da faringe e pela fáscia faringobasilar, recessos faríngeos, toro tubário e tuba auditiva. O limite inferior é um plano horizontal que passa pelo palato duro e pelo músculo palatofaríngeo. Anteriormente, comunica-se com a cavidade nasal via coana posterior. Mede cerca de 2,0 cm de diâmetro ântero-posterior e cerca de 4,0 cm de extensão crânio-caudal. O carcinoma de células escamosas compreende aproximadamente 70% a 98% de todas as neoplasias malignas da nasofaringe em adultos. Este tipo de tumor apresenta alta incidência na população asiática, sendo mais comum entre os homens e o terceiro mais comum entre as mulheres. A manifestação clínica do carcinoma da nasofaringe depende do tamanho da lesão e da sua localização, sendo que as lesões de pequenas dimensões são geralmente assintomáticas. A tomografia computadorizada e a ressonância magnética desempenham papel essencial e complementar no estadiamento e no tratamento dos pacientes portadores de câncer da nasofaringe.

Variações anatômicas do complexo ostiomeatal: achados tomográficos em 200 pacientes

OBJETIVO: O objetivo deste trabalho foi verificar a freqüência e os tipos de variações anatômicas do complexo ostiomeatal. MATERIAIS E MÉTODOS: Foram revisadas 200 tomografias computadorizadas de pacientes com suspeita clínica de sinusopatia. RESULTADOS: Observamos um ou mais tipos de variações anatômicas em 83,5% dos pacientes, as mais freqüentes envolvendo o corneto médio (84%) e o septo nasal (34%). Outras variantes anatômicas comuns encontradas foram a presença de aeração do agger nasi e células etmoidais infra-orbitárias (células de Haller). CONCLUSÃO: As variações anatômicas do complexo ostiomeatal anterior são muito corriqueiras. As mais freqüentes envolvem o corneto médio e o septo nasal.

Schwannoma of the inferior turbinate: case report and review of literature

Schwannomas of the sinonasal tract are rare entities that are amenable to local resection. We present a 69 year old woman with a schwannoma of the inferior turbinate that was successfully resected. Schwannomas arising from the inferior turbinate are very infrequent.