Background-Fetal long QT syndrome (LQTS) is associated with complex arrhythmias including torsades de pointes and 2°atrioventricular block. Sinus bradycardia has also been associated with fetal LQTS, but little is known of this rhythm manifestation. Our purpose was to characterize the fetal heart rate (FHR)/gestational age (GA) profile of fetal LQTS. Methods and Results-We ascertained fetal LQTS subjects by family history (Group 1) or fetal arrhythmia referral (Group 2). We compared FHR in LQTS subjects versus normal fetuses. To identify FHR predictors of LQTS, we calculated a bradycardia index as % of LQTS FHR recordings either Յ110 beats per minute (obstetric standard) or Յ3 rd percentile for GA. Among 42 LQTS subjects, 26 were in Group 1 and 16 in Group 2. There were 536 normal fetuses. The bradycardia index was only 15% for FHR Յ110 beats per minute, but 66% for FHR Յ3rd percentile for GA. Ten fetuses with complex arrhythmias also had severe and sustained sinus bradycardia throughout gestation. Identifying a fetal proband in Group 2 resulted in LQTS diagnosis in 9 unsuspected members of 6 families. Conclusions-FHR varies by GA in both normal and LQTS fetuses. Postnatal evaluation of neonates with FHR Յ3rd percentile for GA may improve ascertainment of LQTS in fetuses, neonates, and undiagnosed family members. (Circulation. 2012;126: 2688-2695.) Key Words: arrhythmias, cardiac Ⅲ fetus Ⅲ long-QT syndrome L ong QT syndrome (LQTS) is reported to have an incidence of 1 in 2500 individuals. Although QT interval prolongation may be an incidental finding, LQTS typically presents in adolescence or young adult life with syncope, sudden death, or cardiac arrest. 1,2 Less frequently, LQTS presents in the perinatal (fetal/neonatal) period; in this setting morbidity and mortality are high, and torsades de pointes (TdP) and 2°atrioventricular (AV) block are signature rhythms. [3][4][5][6] Sinus bradycardia is also a manifestation of fetal LQTS and is reported to be more common than TdP and 2°AV block. For example, as many as 44% to 66% of fetuses diagnosed with LQTS presented with sinus bradycardia at 26 to 40 weeks of gestation. 3,6 -8 In most reports, a fetal heart rate (FHR) Յ110 beats per minute (bpm) at any gestational age (GA) raised suspicion of LQTS. Indeed, FHR of Յ110 bpm at any GA is the obstetric definition of sinus bradycardia. 9 However, little is known of the sensitivity of this finding and how it relates to the subsequent diagnosis of LQTS. Clinical Perspective on p 2695It is well known that FHR in the normal fetus decreases during gestation from about 175 bpm at 10 weeks to 138 bpm at 40 weeks. This phenomenon is believed to be attributable to the increasing dominance of the parasympathetic nervous system on heart rate control as gestation progresses. 10,11 Despite the association between fetal bradycardia and LQTS, the FHR/GA profile, or the range of FHRs of subjects with LQTS, has not been defined. We wondered whether there might be a pathological FHR in the setting of 1:1 AV conduction that was below n...

Background Disorders of the Ras/MAPK pathway have an overlapping skeletal phenotype (eg. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and NF1 individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine derived cross-links of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Methods and Results Participants: [Noonan syndrome (n=14), Costello syndrome (n=21), and cardiofaciocutaneous (CFC) syndrome (n=14)]. Pyridinium cross-links from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by High Performance Liquid Chromotography. Three separate analyses of covariance (ANCOVA) were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. Conclusions The Dpd and the Dpd/Pyd ratio were elevated (p<0.0001) in all 3 conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.

Rationale Genetic testing for Long QT Syndrome (LQTS) is now a standard and integral component of clinical cardiology. A major obstacle to the interpretation of genetic findings is the lack of robust functional assays to determine the pathogenicity of identified gene variants in a high throughput manner. Objective The goal of this study was to design and test a high throughput in vivo cardiac assay to distinguish between disease-causing and benign KCNH2 (hERG1) variants, using the zebrafish as a model organism. Methods and Results We tested the ability of previously characterized LQTS hERG1 mutations and polymorphisms to restore normal repolarization in the kcnh2-knockdown embryonic zebrafish. The cardiac assay correctly identified a benign variant in 9 of 10 cases (negative predictive value 90%) while correctly identifying a disease-causing variant in 39/39 cases (positive predictive value 100%). Conclusion The in vivo zebrafish cardiac assay approaches the accuracy of the current benchmark in vitro assay for the detection of disease-causing mutations and is far superior in terms of throughput rate. Together with emerging algorithms for interpreting a positive LQTS genetic test, the zebrafish cardiac assay provides an additional tool for the final determination of pathogenicity of gene variants identified in LQTS genetic screening.

High-molecular-weight HA supplementation in culture medium had a dose-dependent effect on matrix production and thus chondrogenic differentiation of MSCs cultured on chitosan sponges. The addition of HA in the surrounding fluid during chondrogenesis should improve cartilage production and may be useful for producing engineered cartilage tissues.

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Management of home O2 in patients with bronchiolitis is a common in UT and CO. Weaning practices vary. Further research is needed.

OBJECTIVE To compare the anticollagenase efficacy of fresh feline, canine, and equine serum and plasma on in vitro corneal degradation. SAMPLE Grossly normal corneas from recently euthanized dogs, cats, and horses and fresh serum and plasma from healthy dogs, cats, and horses. PROCEDURES Serum and plasma were pooled by species and used for in vitro experiments. Corneas were collected and stored at -80°C. Sections of cornea were dried, weighed, and incubated in saline (0.9% NaCl) solution with clostridial collagenase and homologous fresh serum or plasma. Corneal degradation was assessed as the percentage of corneal weight loss and hydroxyproline concentration, compared with results for positive and negative control samples. RESULTS Homologous fresh serum and plasma significantly reduced the percentage of corneal weight loss, compared with results for positive control samples. No significant difference was found in percentage of corneal weight loss between incubation with serum or plasma for feline, canine, and equine corneas. Canine serum and plasma significantly reduced hydroxyproline concentrations, whereas inclusion of feline and equine serum or plasma did not, compared with results for positive control samples. Hydroxyproline concentrations were moderately correlated with percentage of corneal weight loss for feline samples and weakly correlated for equine samples, but they were not correlated for canine samples. CONCLUSIONS AND CLINICAL RELEVANCE In this study, the anticollagenase efficacy of fresh feline, canine, and equine serum was not different from that of plasma. Plasma should be an acceptable substitute for serum in the topical treatment of keratomalacia.

Background: Air pollution is associated with adverse health effects in individuals with chronic obstructive pulmonary disease (COPD). It is uncertain if and how individuals with COPD differ from former smokers without airflow obstruction in their response to naturally occurring episodes of particulate air pollution. We hypothesized that episodic temperature inversions with high particulate matter (PM) air pollution during the winter would be associated with increased pulmonary inflammation and oxidative stress, increased respiratory symptoms, and decreased lung function in individuals with COPD compared to controls. Methods: We conducted a panel study of former smokers, 16 with moderate-to-severe COPD and 12 without airflow obstruction as controls. We measured biomarkers (nitrite/nitrate (NOx), 8-isoprostane) in exhaled breath condensate (EBC), spirometry, and respiratory symptoms during periods of low and high PM 2.5 (PM < 2.5 microns in diameter). We compared differences between pollution and clean air days within the COPD and control groups using linear mixed effect models. Results: High PM 2.5 levels were associated with increased EBC NOx in participants with COPD (mean ratio 3.16, p = 0.007), but not in controls (mean ratio 0.49, p = 0.23, difference between groups p = 0.01). Respiratory symptoms significantly increased on pollution days in COPD participants but not in controls. We did not detect a difference in pulmonary function or EBC 8-isoprostane. Conclusions: Former smokers with COPD have a distinctive response to particulate air pollution episodes compared to former smokers without airflow obstruction, with increased airway inflammation and respiratory symptoms.