Further delineation of the facial 13q14 deletion syndrome in 13 retinoblastoma patients.

Thirteen years ago, Motegi and colleagues (J Med Genet 1987;24:696-697) summarized the specific facial phenotype of six Japanese retinoblastoma patients with interstitial 13q14 deletions. Among a series of 228 propositi with retinoblastoma referred to the Lausanne Retinoblastoma Clinic for treatment and genetic counseling between 1986 and 1997, 13 (5.7%) were diagnosed with a cytogenetic de-novo 13q14 deletion. We confirm the presence of the reported facial phenotype in our population of Caucasian patients and describe additional clinical traits, thus extending the facial phenotype associated with the 13q14 deletion. Del(13q14) comprises, among others, cranial anomalies, frontal bossing, deeply grooved and long philtrum, depressed and broad nasal bridge, bulbous tip of the nose, thick lower lip, thin upper lip, broad cheeks, and large ears and lobules. Recognition of this particular facial appearance was instrumental in the genetic diagnosis of 13q deletions and in the presymptomatic diagnosis of retinoblastoma in a significant number of our cases. Identification of this phenotype in a retinoblastoma patient allows for efficient diagnosis of recurrence in his progeny and/or sibship, while its ignorance will compromise genetic counseling due to the possible difficulties in detecting large deletions by standard molecular mutation analysis. Recognition of this syndrome in newborns without known familial risk for retinoblastoma is even more important as it is a clear warning sign that indicates immediate ophthalmic examination.

Origin of the relative afferent pupillary defect in optic tract lesions.

OBJECTIVE: To determine the percent decussation of pupil input fibers in humans and to explain the size and range of the log unit relative afferent pupillary defect (RAPD) in patients with optic tract lesions. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: Five patients with a unilateral optic tract lesion. METHODS: The pupil response from light stimulation of the nasal hemifield, temporal hemifield, and full field of each eye of 5 patients with a unilateral optic tract lesion was recorded using computerized binocular infrared pupillography. Six stimulus light intensities, separated by 0.5-log unit steps, were used; 12 stimulus repetitions were given for each stimulus condition. MAIN OUTCOME MEASURES: For each stimulus condition, the pupil response of each eye was characterized by plotting the mean pupil contraction amplitude as a function of stimulus light intensity. The percentage of decussating afferent pupillomotor input fibers was calculated from the ratio of the maximal pupil contractions elicited from each eye. The RAPD was determined pupillographically from full-field stimulation to each eye. RESULTS: In all patients, the pupil response from the functioning temporal hemifield ipsilateral to the tract lesion was greater than that from the functioning contralateral nasal hemifield. This temporal-nasal asymmetry increased with increasing stimulus intensity and was similar in hemifield and full-field stimuli, eventually saturating at maximal light intensity. The log unit RAPD did not correlate with the estimated percentage of decussating pupil fibers, which ranged from 54% to 67%. CONCLUSIONS: In patients with a unilateral optic tract lesion, the pupillary responses from full-field stimulation to each eye are the same as comparing the functioning temporal field with the functioning nasal field. The percentage of decussating fibers is reflected in the ratio of the maximal pupil contraction amplitudes resulting from stimulus input between the two eyes. The RAPD that occurs in this setting reflects the difference in light sensitivity between the intact temporal and nasal hemifields. Its magnitude does not correlate with the difference in the number of crossed and uncrossed axons, but its sidedness contralateral to the side of the optic tract lesion is consistent with the greater percentage of decussating pupillomotor input.

Treating tobacco use and dependence in clinical practice.

Physicians are in a unique position to advise smokers to quit by the ability to integrate the various aspects of nicotine dependence. This review provides an overview of the intervention strategies for smokers presented in a primary care setting. The strategies that are used for smoking cessation counselling differ according to the patient's readiness to quit. For smokers who do not intend to give up smoking, physicians should inform about tobacco use and the benefits of cessation. For smokers who are dissonant, physicians should use motivational strategies, such as discussing the barriers to successful cessation and their solutions. For smokers who are ready to quit, the physician should show strong support, help set a date to quit, prescribe pharmaceutical therapies for nicotine dependence, such as nicotine replacement therapy (i.e., gum, transdermal patch, nasal spray, mouth inhaler, lozenges, and micro and sublingual tablets) and/or bupropion (an atypical antidepressant thought to work by blocking the neural re-uptake of dopamine and/or noradrenaline), with instructions for use, and suggest behavioural strategies to prevent relapse. The efficacy of all of these pharmacotherapies is comparable, roughly doubling the cessation rates over control conditions.

Volitional assessment of respiratory muscle strength.

Respiratory muscle weakness may induce dyspnoea, secretion retention and respiratory failure. Assessing respiratory muscle strength is mandatory in neuromuscular diseases and in case of unexplained dyspnoea. A step by step approach is recommended, starting with simple volitional tests. Using spirometry, respiratory muscle weakness may be suspected on the basis of an abnormal flow-volume loop or a fall of supine vital capacity. When normal, maximal inspiratory and expiratory pressures against a near complete occlusion exclude significant muscle weakness, but low values are more difficult to interpret. Sniff nasal inspiratory pressure is a useful alternative because it is easy and it eliminates the problem of air leaks around the mouthpiece in patients with neuromuscular disorders. The strength available for coughing is easily assessed by measuring peak cough flow. In most cases, these simple non invasive tests are sufficient to confirm or to eliminate significant respiratory muscle weakness and help the timely introduction of ventilatory support or assisted cough techniques. In a minority of patients, a more complete evaluation is necessary using non volitional tests like cervical magnetic stimulation of phrenic nerves.

Allergic rhinitis in patients with asthma: the Swiss LARA (Link Allergic Rhinitis in Asthma) survey.

OBJECTIVE: To determine the characteristics of asthma (A) and allergic rhinitis (AR) among asthma patients in primary care practice. RESEARCH DESIGN AND METHODS: Primary care physicians, pulmonologists, and allergologists were asked to recruit consecutive asthma patients with or without allergic rhinitis from their daily practice. Cross-sectional data on symptoms, severity, treatment and impact on quality of life of A and AR were recorded and examined using descriptive statistics. Patients with and without AR were then compared. RESULTS: 1244 asthma patients were included by 211 physicians. Asthma was controlled in 19%, partially controlled in 27% and not controlled in 54%. Asthma treatment was generally based on inhaled corticosteroids (ICS) with or without long acting beta 2 agonists (78%). A leukotriene receptor antagonist (LTRA) was used by 46% of the patients. Overall, 950 (76%) asthma patients had AR (A + AR) and 294 (24%) did not (A - AR). Compared to patients with A - AR, A + AR patients were generally younger (mean age +/- standard deviation: 42 +/- 16 vs. 50 +/- 19 years, p < 0.001) and fewer used ICS (75% vs. 88%, p < 0.001). LTRA usage was similar in both groups (46% vs. 48%). Asthma was uncontrolled in 53% of A + AR and 57% of A - AR patients. Allergic rhinitis was treated with a mean of 1.9 specific AR medications: antihistamines (77%), nasal steroids (66%) and/or vasoconstrictors (38%), and/or LTRA (42%). Rhinorrhoea, nasal obstruction, or nasal itching were the most frequently reported AR symptoms and the greatest reported degree of impairment was in daily activities/sports (55%). CONCLUSIONS: Allergic rhinitis was more common among younger asthma patients, increased the burden of symptoms and the need for additional medication but was associated with improved asthma control. However, most asthma patients remained suboptimally controlled regardl-ess of concomitant AR.

Etude des niveaux de concentration d'hydrocarbures aromatiques polycycliques (HAPs) dans la poussière de bois et des marqueurs biologiques d'effets génotoxiques chez les travailleurs du bois

L'exposition aux poussières de bois est associé à un risque accru d'adénocarcinomes des fosses nasales et des sinus paranasaux (SNC, 'Sinonasal cancer') chez les travailleurs du bois. Les poussières de bois sont ainsi reconnues comme cancérogènes avérés pour l'homme par le Centre international de Recherche sur le Cancer (CIRC). Toutefois, l'agent causal spécifique et le mécanisme sous-jacent relatifs au cancer lié aux poussières de bois demeurent inconnus. Une possible explication est une co-exposition aux poussières de bois et aux Hydrocarbures Aromatiques Polycycliques (HAP), ces derniers étant potentiellement cancérogènes. Dans les faits, les travailleurs du bois sont non seulement exposés aux poussières de bois naturel, mais également à celles générées lors d'opérations effectuées à l'aide de machines (ponceuses, scies électriques, etc.) sur des finitions de bois (bois traités) ou sur des bois composites, tels que le mélaminé et les panneaux de fibres à densité moyenne (MDF, 'Medium Density Fiberboard'). Des HAP peuvent en effet être générés par la chaleur produite par l'utilisation de ces machines sur la surface du bois. Les principaux objectifs de cette thèse sont les suivants: (1) quantifier HAP qui sont présents dans les poussières générées lors de diverses opérations courantes effectuées sur différents bois (2) quantifier l'exposition individuelle aux poussières de bois et aux HAP chez les travailleurs, et (3) évaluer les effets génotoxiques (dommages au niveau de l'ADN et des chromosomes) due à l'exposition aux poussières de bois et aux HAP. Cette thèse est composée par une étude en laboratoire (objectif 1) et par une étude de terrain (objectifs 2 et 3). Pour l'étude en laboratoire, nous avons collecté des poussières de différents type de bois (sapin, MDF, hêtre, sipo, chêne, bois mélaminé) générées au cours de différentes opérations (comme le ponçage et le sciage), et ceci dans une chambre expérimentale et dans des conditions contrôlées. Ensuite, pour l'étude de terrain, nous avons suivi, dans le cadre de leur activité professionnelle, 31 travailleurs de sexe masculin (travailleurs du bois et ébenistes) exposés aux poussières de bois pendant deux jours de travail consécutifs. Nous avons également recruté, comme groupe de contrôle, 19 travailleurs non exposés. Pour effectuer une biosurveillance, nous avons collecté des échantillons de sang et des échantillons de cellules nasales et buccales pour chacun des participants. Ces derniers ont également rempli un questionnaire comprenant des données démographiques, ainsi que sur leur style de vie et sur leur exposition professionnelle. Pour les travailleurs du bois, un échantillonnage individuel de poussière a été effectué sur chaque sujet à l'aide d'une cassette fermée, puis nous avons évalué leur exposition à la poussière de bois et aux HAP, respectivement par mesure gravimétrique et par Chromatographie en phase gazeuse combinée à la spectrométrie de masse. L'évaluation des dommages induits à l'ADN et aux chromosomes (génotoxicité) a été, elle, effectuée à l'aide du test des micronoyaux (MN) sur les cellules nasales et buccales et à l'aide du test des comètes sur les échantillons de sang. Nos résultats montrent dans la poussière de la totalité des 6 types de bois étudiés la présence de HAP (dont certains sont cancérogènes). Des différences notoires dans les concentrations ont été néanmoins constatées en fonction du matériau étudié : les concentrations allant de 0,24 ppm pour la poussière de MDF à 7.95 ppm pour le mélaminé. Nos résultats montrent également que les travailleurs ont été exposés individuellement à de faibles concentrations de HAP (de 37,5 à 119,8 ng m-3) durant les opérations de travail du bois, alors que les concentrations de poussières inhalables étaient relativement élevés (moyenne géométrique de 2,8 mg m-3). En ce qui concerne la génotoxicité, les travailleurs exposés à la poussière de bois présentent une fréquence significativement plus élevée en MN dans les cellules nasales et buccales que les travailleurs du groupe témoin : un odds ratio de 3.1 a été obtenu pour les cellules nasales (IC 95% : de 1.8 à 5.1) et un odds ratio de 1,8 pour les cellules buccales (IC 95% : de 1.3 à 2.4). En outre, le test des comètes a montré que les travailleurs qui ont déclaré être exposés aux poussières de MDF et/ou de mélaminé avaient des dommages à l'ADN significativement plus élevés que les deux travailleurs exposés à la poussière de bois naturel (sapin, épicéa, hêtre, chêne) et que les travailleurs du groupe témoin (p <.01). Enfin, la fréquence des MN dans les cellules nasales et buccales augmentent avec les années d'exposition aux poussières de bois. Par contre, il n'y a pas de relation dose-réponse concernant la génotoxicité due à l'exposition journalière à la poussière et aux HAP. Cette étude montre qu'une exposition aux HAP eu bien lieu lors des opérations de travail du bois. Les travailleurs exposés aux poussières de bois, et donc aux HAP, courent un risque plus élevé (génotoxicité) par rapport au groupe témoin. Étant donné que certains des HAP détectés sont reconnus potentiellement cancérogènes, il est envisageable que les HAP générés au cours du travail sur les matériaux de bois sont un des agents responsables de la génotoxicité de la poussière de bois et du risque élevé de SNC observé chez les travailleurs du secteur. Etant donné la corrélation entre augmentation de la fréquence des MN, le test des micronoyaux dans les cellules nasales et buccales constitue sans conteste un futur outil pour la biosurveillance et pour la détection précoce du risque de SNC chez les travailleurs. - Exposures to wood dust have been associated with an elevated risk of adenocarcinomas of the Dasal cavity and the paranasal sinuses (sinonasal cancer or SNC) among wood workers. Wood dust is recognized as a human carcinogen by the International Agency for Research on Cancer. However, the specific cancer causative agent(s) and the mechanism(s) behind wood dust related carcinogenesis remains unknown. One possible explanation is a co-exposure to wood dust and polycyclic aromatic hydrocarbons (PAH), the latter being carcinogenic. In addition, wood workers are not only exposed to natural wood but also to wood finishes and composite woods such as wood melamine and medium density fiber (MDF) boards during the manipulation with power tools. The heat produced by the use of power tools can cause the generation of PAH from wood materials. The main objectives of the present thesis are to: (1) quantify possible PAH concentrations in wood dust generated during various common woodworking operations using different wood materials; (2) quantify personal wood dust concentrations and PAH exposures among wood workers; and (3) assess genotoxic effects (i.e., DNA and chromosomal damage) of wood dust and PAH exposure in wood workers. This thesis is composed by a laboratory study (objective 1) and a field study (objectives 2 and 3). In the laboratory study we collected wood dust from different wood materials (fir, MDF, beech, mahagany, oak, and wood melamine) generated during different wood operations (e.g., sanding and sawing) in an experimental chamber under controlled conditions. In the following field study, we monitored 31 male wood workers (furniture and construction workers) exposed to wood dust during their professional activity for two consecutive work shifts. Additionally, we recruited 19 non exposed workers as a control group. We collected from each participant blood samples, and nasal and buccal cell samples. They answered a questionnaire including demographic and life-style data and occupational exposure (current and past). Personal wood dust samples were collected using a closed-face cassette. We used gravimetrie analysis to determine the personal wood dust concentrations and capillary gas chromatography - mass spectrometry analysis to determine PAH concentrations. Genotoxicity was assessed with the micronucleus (MN) assay for nasal and buccal cells and with the comet assay for blood samples. Our results show that PAH (some of them carcinogenic) were present in dust from all six wood materials tested, yet at different concentrations depending on the material. The highest concentration was found in dust from wood melamine (7.95 ppm) and the lowest in MDF (0.24 ppm). Our results also show that workers were individually exposed to low concentrations of PAHs (37.5-119.8 ng m"3) during wood working operations, whereas the concentrations of inhalable dust were relatively high (geometric mean 2.8 mg m"3). Concerning the genotoxicity, wood workers had a significantly higher MN frequency in nasal and buccal cells than the workers in the control group (odds ratio for nasal cells 3.1 (95%CI 1.8-5.1) and buccal cells 1.8 (95%CI 1.3-2.4)). Furthermore, the comet assay showed that workers who reported to be exposed to dust from wooden boards (MDF and wood melamine) had significantly higher DNA damage than both the workers exposed to natural woods (fir, spruce, beech, oak) and the workers in the control group (p < 0.01). Finally, MN frequency in nasal and buccal cells increased with increasing years of exposure to wood dust. However, there was no genotoxic dose-response relationship with the per present day wood dust and PAH exposure. This study shows that PAH exposure occurred during wood working operations. Workers exposed to wood dust, and thus to PAH, had a higher risk for genotoxicity compared to the control group. Since some of the detected PAH are potentially carcinogenic, PAH generated from operations on wood materials may be one of the causative agents for the observed increased genotoxicity in wood workers. Since increased genotoxicity is manifested in an increased MN frequency, the MN assay in nasal and buccal cells may become a relevant biomonitoring tool in the future for early detection of SNC risk.

Patients at risk of complications of Staphylococcus aureus bloodstream infection.

Staphylococcus aureus is one of the most common causative pathogens of bloodstream infections (BSIs). In approximately one-half of patients with S. aureus BSI, no portal of entry can be documented. This group of patients has a high risk of developing septic metastases. Similarly, patient populations at high risk of S. aureus BSI and BSI-associated complications include patients receiving hemodialysis, injection drug users, patients with diabetes, and patients with preexisting cardiac conditions or other comorbidities. One of the most severe complications of S. aureus BSI is infective endocarditis, and S. aureus is now the most common cause of infective endocarditis in the developed world. Patients with methicillin-resistant S. aureus BSI or infective endocarditis have higher rates of mortality, compared with patients with methicillin-susceptible S. aureus infection. Nasal carriage is the most important source of S. aureus BSI. Better eradication and control strategies, including nasal decolonization and more-active antibiotics, are needed to combat S. aureus BSIs.

Transmission of MRSA and MSSA between humans and farm animals

Human nares are the main niche of Staphylococcus aureus, but farm animals can be also infected (cows) or colonized (pigs) constituting significant reservoir of this pathogen. Previous studies indicated that human and animal strains are quite distinct but the extent of cross-species specialization and transmission remains largely unknown. However, recent reports from several European countries as well as USA and Canada have indicated that employment in farming is an emerging risk factor for MRSA carriage. Pigs were found to be frequently colonized with MRSA, usually with a strain belonging to CC398. It is not known whether animal-human transmission was specific to this particular MRSA strain. S. aureus isolates from cow mastitis and pig colonization isolates were collected in parallel to nasal swab isolates from the animals' caretakers. The isolates were genotyped by AFLP, spatyping, and when appropriate by MLST. The isolates from cow mastitis were genetically uniform in comparison with human isolates. They were quite distinct from farmers\' carriage isolates, indicating pronounced hostspecialization. However, several cases where an infected cow and a colonized farmer had the same strain were detected, including one farm where two farmers were colonized and two cows were infected with MRSA belonging to CC398. Pig isolates were genetically more diverse than cow isolates. They were different from both human and cow isolates with one notable exception. Large fraction of pigs (20%) and pig caretakers (50%) were colonized with isolates belonging to CC398, majority of which were MSSA (2 cases of MRSA). These results indicate that host specialization in S. aureus is quite pronounced. Transmission between humans and farm animals was consequently quite rare. Both MSSA and MRSA strains belonging to otherwise pig-specific CC398 had increased capacity to colonize humans. Study of the genetic factors responsible for host specialization is underway.

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.

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.

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.

Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus.

Leishmaniaparasites cause a broad range of disease, with cutaneous afflictions being, by far, the most prevalent. Variations in disease severity and symptomatic spectrum are mostly associated to parasite species. One risk factor for the severity and emergence of leishmaniasis is immunosuppression, usually arising by coinfection of the patient with human immunodeficiency virus (HIV). Interestingly, several species ofLeishmaniahave been shown to bear an endogenous cytoplasmic dsRNA virus (LRV) of theTotiviridaefamily, and recently we correlated the presence of LRV1 withinLeishmaniaparasites to an exacerbation murine leishmaniasis and with an elevated frequency of drug treatment failures in humans. This raises the possibility of further exacerbation of leishmaniasis in the presence of both viruses, and here we report a case of cutaneous leishmaniasis caused byLeishmania braziliensisbearing LRV1 with aggressive pathogenesis in an HIV patient. LRV1 was isolated and partially sequenced from skin and nasal lesions. Genetic identity of both sequences reinforced the assumption that nasal parasites originate from primary skin lesions. Surprisingly, combined antiretroviral therapy did not impact the devolution ofLeishmaniainfection. TheLeishmaniainfection was successfully treated through administration of liposomal amphotericin B.