A founder mutation in BBS2 is responsible for Bardet‐Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders

Innes AM, Boycott KM, Puffenberger EG, Redl D, MacDonald IM, Chudley AE, Beaulieu C, Perrier R, Gillan T, Wade A, Parboosingh JS. A founder mutation in BBS2 is responsible for Bardet‐Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders. Bardet‐Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome‐wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472‐2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population.     

Insensible water loss from the medtronic minimax oxygenator: an In Vitro study

The purposes of this study were to quantify the insensible water loss that occurs across the Medtronic Minimax oxygenator and to estimate the resultant rise in fluid sodium concentration.A Carmeda-coated extracorporeal membrane oxygenation circuit connected to a Medtronic Minimax Plus oxygenator was primed with normal saline and attached to a closed reservoir. The gas sweep was randomly assigned to one of three rates: 2, 5, or 10 LPM (liters per minute). Each sweep rate was run in triplicate. The sodium concentration of the circuit was assessed after 12 and 24 hours of each trial. At the end of each 24-hour run, the evaporative loss was calculated.The average insensible water losses were 6.9+/-0.4 ml/h, 16.6+/-1.5 ml/h, and 34.4+/-0.3 ml/h at gas sweep rates of 2, 5, and 10 LPM, respectively (p<0.0001). Daily evaporative water losses for the membrane can be estimated to be 82.7+/-2.2 ml for each 1 LPM of sweep gas flow for a normal saline pump flow of 300 ml/min. In a closed circuit, a faster sweep gas rate is associated with a more rapid rise in sodium concentration (p<0.0001).     

What is the mechanism of flow‐mediated arterial dilatation

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Use of high flow nasal cannula in critically ill infants, children, and adults: a critical review of the literature

Background

High flow nasal cannula (HFNC) systems utilize higher gas flow rates than standard nasal cannulae. The use of HFNC as a respiratory support modality is increasing in the infant, pediatric, and adult populations as an alternative to non-invasive positive pressure ventilation.

Objectives

This critical review aims to: (1) appraise available evidence with regard to the utility of HFNC in neonatal, pediatric, and adult patients; (2) review the physiology of HFNC; (3) describe available HFNC systems (online supplement); and (4) review ongoing and planned trials studying the utility of HFNC in various clinical settings.

Results

Clinical neonatal studies are limited to premature infants. Only a few pediatric studies have examined the use of HFNC, with most focusing on this modality for viral bronchiolitis. In critically ill adults, most studies have focused on acute respiratory parameters and short-term physiologic outcomes with limited investigations focusing on clinical outcomes such as duration of therapy and need for escalation of ventilatory support. Current evidence demonstrates that HFNC generates positive airway pressure in most circumstances; however, the predominant mechanism of action in relieving respiratory distress is not well established.

Conclusion

Current evidence suggests that HFNC is well tolerated and may be feasible in a subset of patients who require ventilatory support with non-invasive ventilation. However, HFNC has not been demonstrated to be equivalent or superior to non-invasive positive pressure ventilation, and further studies are needed to identify clinical indications for HFNC in patients with moderate to severe respiratory distress.     

The impact of infliximab infusion reactions on long-term outcomes in patients with Crohn's disease

Background Little is known about long‐term outcomes in patients who experience infusion reactions while receiving infliximab. Aim To investigate long‐term outcomes in patients who experience infusion reactions while receiving infliximab. Methods Retrospective electronic chart review of long‐term clinical outcomes. Results Clinical data on 287 patients who received infliximab infusions for Crohn’s disease were reviewed, of whom 51 developed at least one infusion reaction (18%). Ileo‐colonic disease (OR 2.2, 95% CI 1.1–4.4) and episodic infliximab (OR 2.4, 95% CI 1.2–4.7) were associated with a higher risk of infusion reactions in univariate analysis, but concomitant azathioprine/mercaptopurine therapy at the initiation of infliximab was associated with a reduced risk (OR 0.4, 95% CI 0.2–0.8). Only the effect of concomitant immunomodulators persisted on multivariate analysis. Patients who experienced infusion reactions were less likely to be in remission at 1 year (OR 0.6, 95% CI 0.3–1.2), 2 years (OR 0.4, 95% CI 0.2–0.8, P = 0.01), or 5 years (OR 0.4, 95% CI 0.1–1.3) and more likely to require surgery (OR 2.2, 95% CI 1.1–4.1, P = 0.01) than those who did not experience such reactions. Conclusions Patients who experienced infusion reactions to infliximab had a high rate of discontinuation of therapy in this cohort. Concomitant immunomodulators and maintenance therapy reduced the risk of infusion reactions.     

Total cavopulmonary anastomosis using atrial septal flap: technique and early results

Introduction The Fontan procedure has undergone many modifications to avoid atrial arrhythmias and thrombus formation. We used patient’s interatrial septum as a flap to direct the inferior venacaval blood to the superior venacava. Methods Seventeen patients, aged 1 to 17 years, underwent modified total cavopulmonary anastomosis. Interatrial septum was used to create the inner half of the atrial tunnel, outer half being formed by right atrial free wall. Post-operatively, all patients underwent echocardiography. Seven patients underwent 24 hour ambulatory Holter monitoring and 6 patients underwent cardiac catheterization and cineangiography. Results There was one early death due to low cardiac output. One patient had transient supraventricular arrhythmia. Two patients had singnificant pleural effusion. Holter Monitoring reveled sinus rhythm in all 7 patients studied. Follow up ranged from 18 to 60 months and patients were evaluated as they came for follow up. Long term follow up is currently being compiled. There was one late death from a non-cardiac cause. The remaining patients were in New York Heart Association (NYHA) Class I or II. All patients were in sinus rhythm. Echocardiography and cineangiography revealed absence of obstruction or leak. Conclusions Total cavopulmonary anastomosis using autogenous atrial septum is a useful modification for classical cavopulmonary anastomosis and provides good early results.     

Successful extracorporeal membrane oxygenation for respiratory failure in an infant with DiGeorge anomaly, following thymus transplantation

We report the first successful use of venovenous extracorporeal membrane oxygenation (ECMO) for refractory respiratory failure in an infant with DiGeorge anomaly, following thymus transplantation. A 23-month-old female with complete immune-incompetent DiGeorge anomaly 65 days after allogenic thymus transplantation was treated in our pediatric intensive care unit for acute respiratory failure secondary to bacterial sepsis. She subsequently developed acute hypercarbic respiratory failure unresponsive to conventional medical therapy. She was successfully managed with venovenous ECMO for 4 days, with complete resolution of her respiratory symptoms. This case demonstrates the complex decision making process regarding initiation of ECMO in patients with severe immunodeficiency.