Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G presenting as childhood-onset severe myopathy: threshold determination through segregation study.

Mitochondrial tRNA(Leu(UUR)) mutation m.3302A > G is associated with respiratory chain complex I deficiency and has been described as a rare cause of mostly adult-onset slowly progressive myopathy. Five families with 11 patients have been described so far; 5 of them died young due to cardiorespiratory failure. Here, we report on a segregation study in a family with an index patient who already presented at the age of 18 months with proximal muscular hypotonia, abnormal fatigability, and lactic acidosis. This early-onset myopathy was rapidly progressive. At 8 years, the patient is wheel-chair bound, requires nocturnal assisted ventilation, and suffers from recurrent respiratory infections. Severe complex I deficiency and nearly homoplasmy for m.3302A > G were found in muscle. We collected blood, hair, buccal swabs and muscle biopsies from asymptomatic adults in this pedigree and determined heteroplasmy levels in these tissues as well as OXPHOS activities in muscle. All participating asymptomatic adults had normal OXPHOS activities. In contrast to earlier reports, we found surprisingly little variation of heteroplasmy levels in different tissues of the same individual. Up to 45% mutation load in muscle and up to 38% mutation load in other tissues were found in non-affected adults. The phenotypic spectrum of tRNA(Leu(UUR)) m.3302A > G mutation seems to be wider than previously described. A threshold of more than 45% heteroplasmy in muscle seems to be necessary to alter complex I activity leading to clinical manifestation. The presented data may be helpful for prognostic considerations and counseling in affected families.

Genetic and Antigenic Analysis of Adenovirus Type 3 Strains Showing Intermediate Behavior in Standard Seroneutralization Test

During an epidemiological survey of acute respiratory infection in Rio de Janeiro, among 208 adenovirus isolates, we found two strains that we were not able, by a standard neutralization procedure, to distinguish between type 3 or 7. However, DNA restriction pattern for the two strains with different enzymes were analyzed and showed a typical Ad3h profile. Using a cross-neutralization test in which both Ad3p and Ad7p antisera were used in different concentration against 100 TCID50 of each adenovirus standard and both isolates, we were able to confirm that the two isolates belong to serotype 3. An hemagglutination inhibition test also corroborated the identification of both strains as adenovirus type 3. Comparing Ad3h and Ad3p genome, we observed 16 different restriction enzyme sites, three of which were located in genomic regions encoding polypeptides involved in neutralization sites

Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients.

INTRODUCTION: Mutations in the TMEM70 are the most common cause of nuclear ATP synthase deficiency resulting in a distinctive phenotype characterized by severe neonatal hypotonia, hypertrophic cardiomyopathy (HCMP), facial dysmorphism, severe lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria (3-MGA). METHODS AND RESULTS: We collected 9 patients with genetically confirmed TMEM70 defect from 8 different families. Six were homozygous for the c.317-2A>G mutation, 2 were compound heterozygous for mutations c.317-2A>G and c.628A>C and 1 was homozygous for the novel c.701A>C mutation. Generalized hypotonia, lactic acidosis, hyperammonemia and 3-MGA were present in all since birth. Five patients presented acute respiratory distress at birth requiring intubation and ventilatory support. HCMP was detected in 5 newborns and appeared a few months later in 3 additional children. Five patients showed a severe and persistent neonatal pulmonary hypertension (PPHN) requiring Nitric Oxide (NO) and/or sildenafil administration combined in 2 cases with high-frequency oscillatory (HFO) ventilation. In 3 of these patients, echocardiography detected signs of HCMP at birth. CONCLUSIONS: PPHN is a life-threatening poorly understood condition with bad prognosis if untreated. Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient. This report further expands the clinical and genetic spectrum of the syndrome indicating PPHN as a frequent and life-threatening complication regardless of the type of mutation. Moreover, in these children PPHN appears even in the absence of an overt cardiomyopathy, thus representing an early sign and a clue for diagnosis.

Pandemic influenza control in Europe and the constraints resulting from incoherent public health laws.

Background With the emergence of influenza H1N1v the world is facing its first 21st century global pandemic. Severe Acute Respiratory Syndrome (SARS) and avian influenza H5N1 prompted development of pandemic preparedness plans. National systems of public health law are essential for public health stewardship and for the implementation of public health policy[1]. International coherence will contribute to effective regional and global responses. However little research has been undertaken on how law works as a tool for disease control in Europe. With co-funding from the European Union, we investigated the extent to which laws across Europe support or constrain pandemic preparedness planning, and whether national differences are likely to constrain control efforts. Methods We undertook a survey of national public health laws across 32 European states using a questionnaire designed around a disease scenario based on pandemic influenza. Questionnaire results were reviewed in workshops, analysing how differences between national laws might support or hinder regional responses to pandemic influenza. Respondents examined the impact of national laws on the movements of information, goods, services and people across borders in a time of pandemic, the capacity for surveillance, case detection, case management and community control, the deployment of strategies of prevention, containment, mitigation and recovery and the identification of commonalities and disconnects across states. Results Results of this study show differences across Europe in the extent to which national pandemic policy and pandemic plans have been integrated with public health laws. We found significant differences in legislation and in the legitimacy of strategic plans. States differ in the range and the nature of intervention measures authorized by law, the extent to which borders could be closed to movement of persons and goods during a pandemic, and access to healthcare of non-resident persons. Some states propose use of emergency powers that might potentially override human rights protections while other states propose to limit interventions to those authorized by public health laws. Conclusion These differences could create problems for European strategies if an evolving influenza pandemic results in more serious public health challenges or, indeed, if a novel disease other than influenza emerges with pandemic potential. There is insufficient understanding across Europe of the role and importance of law in pandemic planning. States need to build capacity in public health law to support disease prevention and control policies. Our research suggests that states would welcome further guidance from the EU on management of a pandemic, and guidance to assist in greater commonality of legal approaches across states.

Electroencephalogram changes during inhalation with nitric oxide in the pediatric intensive care patient--a preliminary report.

OBJECTIVES: Although endogenous nitric oxide (NO) is an excitatory mediator in the central nervous system, inhaled NO is not considered to cause neurologic side effects because of its short half-life. This study was motivated by a recent case report about neurologic symptoms and our own observation of severe electroencephalogram (EEG) abnormalities during NO inhalation. DESIGN: Blind, retrospective analyses of EEGs which were registered before, during, and after NO inhalation. EEG was classified in a 5-point rating system by an independent electroencephalographer who was blinded to the patients' clinical histories. Comparisons were made with the previous evaluation documented at recording. Other EEG-influencing parameters such as oxygen saturation, hemodynamics, electrolytes, and pH were evaluated. SETTING: Pediatric intensive care unit of a tertiary care university children's hospital. PATIENTS: Eleven ventilated, long-term paralyzed, sedated children (1 mo to 14 yrs) who had EEG or clinical assessment before NO treatment and EEG during NO inhalation. They were divided into two groups according to the NO-indication (e.g., congenital heart defect, acute respiratory distress syndrome). MEASUREMENTS AND MAIN RESULTS: All 11 patients had an abnormal EEG during NO inhalation. EEG-controls without NO showed remarkable improvement. EEG abnormalities were background slowing, low voltage, suppression burst (n = 2), and sharp waves (n = 2) independent of patients' age, NO-indication, and other EEG-influencing parameters. CONCLUSIONS: These preliminary data suggest the occurrence of EEG-abnormalities after application of inhaled NO in critically ill children. We found no correlation with other potential EEG-influencing parameters, although clinical state, medication, or hypoxemia might contribute. Comprehensive, prospective, clinical assessment regarding a causal relationship between NO-inhalation and EEG-abnormalities and their clinical importance is needed.

Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus SEMICYUC-SENPE: Obese patient

As a response to metabolic stress, obese critically-ill patients have the same risk of nutritional deficiency as the non-obese and can develop protein-energy malnutrition with accelerated loss of muscle mass. The primary aim of nutritional support in these patients should be to minimize loss of lean mass and accurately evaluate energy expenditure. However, routinely used formulae can overestimate calorie requirements if the patient's actual weight is used. Consequently, the use of adjusted or ideal weight is recommended with these formulae, although indirect calorimetry is the method of choice. Controversy surrounds the question of whether a strict nutritional support criterion, adjusted to the patient's requirements, should be applied or whether a certain degree of hyponutrition should be allowed. Current evidence suggested that hypocaloric nutrition can improve results, partly due to a lower rate of infectious complications and better control of hyperglycemia. Therefore, hypocaloric and hyperproteic nutrition, whether enteral or parenteral, should be standard practice in the nutritional support of critically-ill obese patients when not contraindicated. Widely accepted recommendations consist of no more than 60-70% of requirements or administration of 11-14 kcal/kg current body weight/day or 22-25 kcal/kg ideal weight/day, with 2-2.5 g/kg ideal weight/day of proteins. In a broad sense, hypocaloric-hyperprotein regimens can be considered specific to obese critically-ill patients, although the complications related to comorbidities in these patients may require other therapeutic possibilities to be considered, with specific nutrients for hyperglycemia, acute respiratory distress syndrome (ARDS) and sepsis. However, there are no prospective randomized trials with this type of nutrition in this specific population subgroup and the available data are drawn from the general population of critically-ill patients. Consequently, caution should be exercised when interpreting these data.

Regional consumption of antibiotics : a demand system approach

Through this paper. we have attempted to model the demand for different classes of antibiotics used for respiratory infections in outpatient care in Switzerland using a spatial version of the linear approximate Almost Ideal Demand System (AIDS) model. This model takes spatial dependency into account by means of spatial lags of antibiotic budget shares. We control for the health status of patients and the potential harmful effects of antibiotic use in terms of bacterial resistance. Elasticities to socioeconomic determinants of consumption and own- and cross-price elasticities between different groups of antibiotic have also been computed in this paper. Significant cross-price elasticities are found between newer or more expensive generations and older or less expensive generations of antibiotics. (C) 2009 Elsevier B.V. All rights reserved.

Plasmodium falciparum gametocyte carriage, sex ratios and asexual parasite rates in Nigerian children before and after a treatment protocol policy change instituting the use of artemisinin-based combination therapies

The effects of artemisinin-based combination therapies (ACTs) on transmission of Plasmodium falciparum were evaluated after a policy change instituting the use of ACTs in an endemic area. P. falciparum gametocyte carriage, sex ratios and inbreeding rates were examined in 2,585 children at presentation with acute falciparum malaria during a 10-year period from 2001-2010. Asexual parasite rates were also evaluated from 2003-2010 in 10,615 children before and after the policy change. Gametocyte carriage declined significantly from 12.4% in 2001 to 3.6% in 2010 (@@χ² for trend = 44.3, p < 0.0001), but sex ratios and inbreeding rates remained unchanged. Additionally, overall parasite rates remained unchanged before and after the policy change (47.2% vs. 45.4%), but these rates declined significantly from 2003-2010 (@@χ² for trend 35.4, p < 0.0001). Chloroquine (CQ) and artemether-lumefantrine (AL) were used as prototype drugs before and after the policy change, respectively. AL significantly shortened the duration of male gametocyte carriage in individual patients after treatment began compared with CQ (log rank statistic = 7.92, p = 0.005). ACTs reduced the rate of gametocyte carriage in children with acute falciparum infections at presentation and shortened the duration of male gametocyte carriage after treatment. However, parasite population sex ratios, inbreeding rates and overall parasite rate were unaffected.

Compliance with guidelines-recommended processes in pneumonia: impact of health status and initial signs

Initial care has been associated with improved survival of community-acquired pneumonia (CAP). We aimed to investigate patient comorbidities and health status measured by the Charlson index and clinical signs at diagnosis associated with adherence to recommended processes of care in CAP. We studied 3844 patients hospitalized with CAP. The evaluated recommendations were antibiotic adherence to Spanish guidelines, first antibiotic dose <6 hours and oxygen assessment. Antibiotic adherence was 72.6%, first dose <6 h was 73.4% and oxygen assessment was 90.2%. Antibiotic adherence was negatively associated with a high Charlson score (Odds ratio [OR], 0.91), confusion (OR, 0.66) and tachycardia ≥100 bpm (OR, 0.77). Delayed first dose was significantly lower in those with tachycardia (OR, 0.75). Initial oxygen assessment was negatively associated with fever (OR, 0.61), whereas tachypnea ≥30 (OR, 1.58), tachycardia (OR, 1.39), age >65 (OR, 1.51) and COPD (OR, 1.80) were protective factors. The combination of antibiotic adherence and timing <6 hours was negatively associated with confusion (OR, 0.69) and a high Charlson score (OR, 0.92) adjusting for severity and hospital effect, whereas age was not an independent factor. Deficient health status and confusion, rather than age, are associated with lower compliance with antibiotic therapy recommendations and timing, thus identifying a subpopulation more prone to receiving lower quality care.

Viral aetiology of common colds of outpatient children at primary care level and the use of antibiotics

Although antibiotics are ineffective against viral respiratory infections, studies have shown high rates of prescriptions worldwide. We conducted a study in Brazil to determine the viral aetiologies of common colds in children and to describe the use of antibiotics for these patients. Children up to 12 years with common colds were enrolled from March 2008-February 2009 at a primary care level facility and followed by regular telephone calls and medical consultations. A nasopharyngeal wash was obtained at enrollment and studied by direct fluorescence assay and polymerase chain reaction for nine different types of virus. A sample of 134 patients was obtained, median age 2.9 years (0.1-11.2 y). Respiratory viruses were detected in 73.9% (99/134) with a coinfection rate of 30.3% (30/99). Rhinovirus was the most frequent virus (53/134; 39.6%), followed by influenza (33/134; 24.6%) and respiratory syncytial virus (8/134; 13.4%). Antibiotic prescription rate was 39.6% (53/134) and 69.8% (37/53) were considered inappropriate. Patients with influenza infection received antibiotics inappropriately in a greater proportion of cases when compared to respiratory syncytial virus and rhinovirus infections (p = 0.016). The rate of inappropriate use of antibiotics was very high and patients with influenza virus infection were prescribed antibiotics inappropriately in a greater proportion of cases.

Modulation of TCR avidity of primary HIV-1-specific CD8 T-cell responses by early and potent antiviral therapy responses

Background: CD8 T-cells play a critical role in antiviral immunity. However, mechanisms of virus control and immune correlates of protection are still not fully understood. Among other factors, TCR avidity (antigen sensitivity) is thought to play a critical role. Whereas there is a large consensus that high TCR avidity T-cell responses are correlated to higher efficacy against cancer and acute viral infections, it may be not the case in chronic persistent viral infections. Methods: TCR avidity (measured by the effect concentration 50% [EC50]) of HIV-1-specific CD8 T-cell responses directed against optimal epitopes was investigated in different cohorts of HIV-1- infected subjects (n¼114) including early acute and chronic (progressive and non-progressive) HIV-1-infection. Overall, TCR avidity was investigated in 245 HIV-1-specific CD8 T-cell responses. The relationships between TCR avidity, T-cell differentiation and functional profile including cytokine secretion, proliferation and cytotoxic potential (determined by polychromatic flow cytometry) were analyzed. Results: HIV-1-specific CD8 T-cell responses from patients with acute infection had significantly lower TCR avidity as compared to patients with chronic (progressive or non-progressive) HIVinfection (P¼0.03 and 0.003, respectively). These differences remained significant when the analyses were restricted to common epitopes (same epitopes restricted by the same class I HLA). Interestingly, some patients treated during acute infection underwent spontaneous treatment interruption. Re-exposure to high viral load induced two major effects: a) the increase in TCR avidity of pre-existing high avidity (EC50<0.01) T-cell responses (P<0.02) and b) the generation of new T-cell responses with higher TCR avidity as compared to the average pre-existing T-cell responses. Conclusion: These results suggest that high TCR avidity T-cell responses are selected during the course of HIV-1 infection and that one of the potential driving mechanisms is continuous exposure to HIV-1 antigens. These results advance our understanding of the relationship between TCR avidity and Ag exposure of antiviral memory CD8 T-cells.

Què saben els pares dels infants de 0-3 anys, sobre l'ús del rentat nasal i els inhaladors amb cambra?

Aquest estudi insisteix en la importància de l’educació sanitària dirigida als pares per tald’assegurar l’eficàcia del tractament a administrar i consolidar els coneixements i habilitats del progenitors per tal de que aquests puguin dur a terme les tècniques requerides de forma adequada.Destacar la necessitat de conscienciar a tots els professionals de la salut, sobretot els quepassen més temps amb els familiars, de la importància que té la seva competència comeducador en l’àmbit de la salut.Evidenciar la importància de fer una avaluació continuada dels coneixements i les habilitatsadquirides pels cuidadors principals, sobre com dur a terme les tècniques del rentat de nas iadministració de la medicació inhalada amb cambra i mascareta, per detectar-ne els possibleserrors i poder posar-hi mesures correctores per pal·liar-los.Constatar la utilitat de preguntar i esbrinar “in situ” què saben els progenitors sobre lestècniques a avaluar (rentat de nas i administració de la medicació inhalada amb cambra i mascareta), abans de donar qualsevol explicació o iniciar l’educació sanitària per detectar lesnecessitats específiques de cada pare o mare i poder individualitzar el procés educatiu

Can neurally adjusted ventilatory assist (NAVA) improve patient-ventilator interaction? A preliminary study

INTRODUCTION. NAVA is a new spontaneous-assisted ventilatory mode based on thedetection of diaphragmatic electrical activity (Eadi) and its feedback to adjust ventilatorsettings. NAVA uses the Eadi, an expression of the respiratory center's activity, to initiatepressurization, set the level of pressure support and cycle the ventilator into exhalation.Therefore, NAVA should theoretically allow near-perfect synchronization between the patientand the ventilator. However there are few data documenting these effects in intensive carepatients.OBJECTIVES. To determine whether NAVA can improve patient-ventilator synchronycompared to standard pressure support (PS) in intubated intensive care patients.METHODS. Comparative study of patient-ventilator interaction during PS with cliniciandetermined ventilator settings and NAVA with NAVA gain (proportionality factor betweenEadi and the amount of delivered inspiratory pressure) set as to obtain the same peak airwaypressure as the total pressure obtained in PS. A 20 min continuous recording with eachventilatory mode was performed allowing determination of trigger delay (Td), patient neuralinspiratory time (Tin), duration of pressurization by the ventilator (Tiv), excess durationof pressurization (Ti excess = Tiv - Tin/Tin 9 100) and number of asynchrony events byminute: non-triggering breaths, auto-triggering, double triggering, premature and delayedcycling.Results are given in mean ± SD. p is considered significant if\0.05.RESULTS. Preliminary results (mean ± SD): five patients (age 75 ± 12 years, 1 M/4F,BMI 25.7 ± 4.1 kg m-2), two pts with COPD, 1 with restrictive disease, initial settings: PS14.6 ± 1.7 cm H2O, PEEP 6.4 ± 1.5 cm H2O, NAVA gain 2.8 ± 1.3PS NAVA % reduction NAVAversus PSTd (ms) 210.4 ± 63.0 51.8 ± 12.1* 74.5 ± 5.0Ti excess (%) 12.9 ± 19.6 2.2 ± 0.6 70.8 ± 37.8n asynchrony/minute 7.6 ± 6.4 4.1 ± 3.7* 47.5 ± 17.0Respiratory rate (min-1) 16.8 ± 2.6 20.4 ± 4.7 NA* p\0.05CONCLUSION. Compared to standard PS, NAVA improves patient ventilator interaction byreducing Td and the overall incidence of asynchrony events. There is also a strong trend inreducing delayed cycling. This ongoing trial should provide evidence that NAVA can indeedimprove patient-ventilator synchrony in intubated patients undergoing PS.REFERENCE(S). 1. Sinderby C, Navalesi P et al (1995) Neural control of mechanicalventilation in respiratory failure. Nat Med 5(12):1433-1436.2. Colombo D, Cammarota G et al (2008) Physiologic response to varying levels of pressuresupport and neurally adjusted ventilator assist in patients with acute respiratory failure.Intensive Care Med 34(11):2010-2018.

Passive smoking in babies: The BIBE Study (Brief Intervention in babies. Effectiveness)

Background: There is evidence that exposure to passive smoking in general, and in babies in particular, is an important cause of morbimortality. Passive smoking is related to an increased risk of pediatric diseases such as sudden death syndrome, acute respiratory diseases, worsening of asthma, acute-chronic middle ear disease and slowing of lung growth.The objective of this article is to describe the BIBE study protocol. The BIBE study aims to determine the effectiveness of a brief intervention within the context of Primary Care, directed to mothers and fathers that smoke, in order to reduce the exposure of babies to passive smoking (ETS).Methods/DesignCluster randomized field trial (control and intervention group), multicentric and open. Subject: Fathers and/or mothers who are smokers and their babies (under 18 months) that attend pediatric services in Primary Care in Catalonia.The measurements will be taken at three points in time, in each of the fathers and/or mothers who respond to a questionnaire regarding their baby's clinical background and characteristics of the baby's exposure, together with variables related to the parents' tobacco consumption. A hair sample of the baby will be taken at the beginning of the study and at six months after the initial visit (biological determination of nicotine). The intervention group will apply a brief intervention in passive smoking after specific training and the control group will apply the habitual care.Discussion: Exposure to ETS is an avoidable factor related to infant morbimortality. Interventions to reduce exposure to ETS in babies are potentially beneficial for their health. The BIBE study evaluates an intervention to reduce exposure to ETS that takes advantage of pediatric visits. Interventions in the form of advice, conducted by pediatric professionals, are an excellent opportunity for prevention and protection of infants against the harmful effects of ETS.

Mechanical ventilation and clinical practice heterogeneity in intensive care units: a multicenter case-vignette study.

BACKGROUND: Observational studies on mechanical ventilation (MV) show practice variations across ICUs. We sought to determine, with a case-vignette study, the heterogeneity of processes of care in ICUs focusing on mechanical ventilation procedures, and whether organizational patterns or physician characteristics influence practice variations. METHODS: We conducted a cross-sectional multicenter study using the case-vignette methodology. Descriptive analyses were calculated for each organizational pattern and respondent characteristics. An Index of Qualitative Variation (IQV, from 0, no heterogeneity, to a maximum of 1) was calculated. RESULTS: Forty ICUs from France (N = 33) and Switzerland (N = 7) participated; 396 physicians answered our case-vignettes. There was major heterogeneity of management processes related to MV within and across centers (mean IQV per center 0.51, SD 0.09). We observed the lowest variability (mean IQV per question < 0.4) for questions related to intubation procedure, ventilation of acute respiratory distress syndrome and the use of the semirecumbent position. We observed a high variability (mean IQV per question > 0.6) for questions related to management of endotracheal tube or suctioning, management of sedation and analgesia, and respect of autonomy. Heterogeneity was independent of respondent characteristics and of the presence of written procedures. There was a correlation between the processes associated with the highest variability (mean IQV per question > 0.6) and the annual volume of ICU admission (r = 0.32 (0.01 to 0.58)) and MV (r = 0.38 (0.07 to 0.63)). Within ICUs there was a large heterogeneity regarding knowledge of a local written procedure. CONCLUSIONS: Large clinical practice variations were found among ICUs. High volume centers were more likely to have heterogeneous practices. The presence of a local written procedure or respondent characteristics did not influence practice variation.