Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for ß-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures. METHODS: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes. DISCUSSION: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Effects of freezing and activation on membrane quality and DNA damage in Xenopus tropicalis and Xenopus laevis spermatozoa.

There is growing concern over the effect of sperm cryopreservation on DNA integrity and the subsequent development of offspring generated from this cryopreserved material. In the present study, membrane integrity and DNA stability of Xenopus laevis and Xenopus tropicalis spermatozoa were evaluated in response to cryopreservation with or without activation, a process that happens upon exposure to water to spermatozoa of some aquatic species. A dye exclusion assay revealed that sperm plasma membrane integrity in both species decreased after freezing, more so for X. laevis than X. tropicalis spermatozoa. The sperm chromatin dispersion (SCD) test showed that for both X. tropicalis and X. laevis, activated frozen spermatozoa produced the highest levels of DNA fragmentation compared with all fresh samples and frozen non-activated samples (P<0.05). Understanding the nature of DNA and membrane damage that occurs in cryopreserved spermatozoa from Xenopus species represents the first step in exploiting these powerful model organisms to understand the developmental consequences of fertilising with cryopreservation-damaged spermatozoa.

Cascade polycyclizations in natural product synthesis.

Cascade (domino) reactions have an unparalleled ability to generate molecular complexity from relatively simple starting materials; these transformations are particularly appealing when multiple rings are forged during this process. In this tutorial review, we cover recent highlights in cascade polycyclizations as applied to natural product synthesis, including pericyclic, heteroatom-mediated, cationic, metal-catalyzed, organocatalytic, and radical sequences.

Mortality due to SUDEP and status epilepticus.

Mortality in patients with epilepsy (PWE) is increased compared to the general population. For this reason the National Programme of Epilepsy Care, which was established under the Health Service Executive's National Director for Clinical Strategy and Programmes, identified a reduction in mortality from epilepsy as a key quality metric to monitor the success of the programme. The increased mortality is greatest in the first years after diagnosis where it is predominantly related to the underlying cause but there remains a persistent elevation in mortality rates especially amongst those with longstanding epilepsy. This group of patients is more likely to die from epilepsy, predominantly sudden unexpected death in epilepsy (SUDEP) or status epilepticus (SE). This paper identifies a number of studies on mortality in epilepsy from SE and SUDEP and uses this data to generate an estimate for annual mortality from SUDEP and SE in Ireland. These estimates indicate that mortality in patients with epilepsy due to SUDEP and SE account for between 48 and 162 deaths per year in Ireland and sources of mortality information currently available possibly underestimate the numbers involved especially if deaths due to non-convulsive status are included.

Wilcoxon-Mann-Whitney odds ratio: A statistical measure for ordinal outcomes such as EDSS.

BACKGROUND: In many clinical situations, ordinal scales afford the primary method of semi-quantifying patient outcomes. In the field of multiple sclerosis, the primary ordinal scale is the Expanded Disability Status Scale. Predominant methods of ordinal scale statistical analysis provide a p-value without effect size or rely heavily on the assumption of proportionality of odds, subjecting them to lack of power and error. The Wilcoxon-Manny-Whitney Odds is a statistical method which provides significant information such as p-value, effect size, number needed to treat, confidence intervals, and is largely assumption-free. However, its utility has not been demonstrated in the field of multiple sclerosis. METHODS: Three clinical studies in the field of multiple sclerosis were selected which utilized ordinal scale outcomes at group or individual levels. Data from these studies was extracted using WebPlotDigitizer, and a custom Wilxocon-Mann-Whitney Odds software was applied to each dataset to re-analyze the main outcomes of the studies. RESULTS: Re-analysis of the manuscript by Muraro et al., 2017 demonstrated that autologous stem cell transplantation for relapsing remitting multiple sclerosis resulted in a 65% chance of improving from any Expanded Disability Status Scale category, although not significant. Re-analysis of the manuscript by Songthammawat et al., 2019 demonstrated chance of improvement with intravenous methylprednisolone and concurrent plasma exchange was 185% versus 32% in intravenous methylprednisolone with add-on plasma exchange, although not significant. Re-analysis of Kister et al., 2012 demonstrated the chances of mobility or cognition scores generally favored decline at every 5-year increment of study, and although statistically significant, these were smaller effect sizes ranging from an 11% chance of improvement to a 66% chance of decline over a 5-year interval. DISCUSSION: The Wilcoxon-Mann-Whitney Odds simplifies ordinal data analysis with its robust largely assumption-free nature. In the place of numerous statistical tests, this single test provides effect size estimate, number needed to treat, p-values, and confidence intervals. Importantly, the Wilcoxon-Mann-Whitney Odds effect size calculation is intuitively applicable to both individual and population-levels. Further, the Wilcoxon-Mann-Whitney Odds allows intuitive description of the progression of large cohorts over time, and we were able to clearly convey the odds of mobility and cognitive decline over 30 years in a large multiple sclerosis cohort. Overall, the Wilcoxon-Mann-Whitney Odds is a powerful and robust statistical test with significant promise within the field of multiple sclerosis.

Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test.

The MS Functional Composite (MSFC) is a continuous scale of neurological disability for patients with multiple sclerosis (MS). Cognition is represented by the Paced Auditory Serial Addition Test (PASAT), although the Symbol Digit Modalities Test (SDMT) has been proposed as a promising alternative. MSFC scores were calculated using either the PASAT or the SDMT with the following reference populations: National Multiple Sclerosis Society (NMSS) Task Force, 400 MS patients, and 100 normal controls. A subgroup of 115 patients was followed longitudinally, with a test-retest interval of 2.3 +/- 1.2 years. Pearson correlations were calculated and analyses of variance (ANOVAs) were used to assess relationships among the MSFC components and composite scores, and differences in performance between patients and controls. Longitudinal changes were also assessed. Logistic regression was performed to determine which MSFC scores are most predictive of diagnosis, course, and work disability. All MSFCs had similar test-retest reliability and correlations with other measures including neurological disability, depression, and fatigue. The SDMT showed slightly better validity with respect to predicting diagnosis, course, and work disability, although the amount of variance accounted for was similar for each version of the MSFC. Our data, derived from a large sample of MS patients and normal controls, supports the validity of both PASAT and SDMT versions of the MSFC. Because the SDMT has slightly better predictive validity and has a relatively easier administration procedure, some clinicians and researchers may wish to replace the PASAT with the SDMT in future calculations of the MSFC using the calculation methods provided in this manuscript.

Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks.

BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Reduced Global Efficiency and Random Network Features in Patients with Relapsing-Remitting Multiple Sclerosis with Cognitive Impairment.

BACKGROUND AND PURPOSE: Graph theory uses structural similarity to analyze cortical structural connectivity. We used a voxel-based definition of cortical covariance networks to quantify and assess the relationship of network characteristics to cognition in a cohort of patients with relapsing-remitting MS with and without cognitive impairment. MATERIALS AND METHODS: We compared subject-specific structural gray matter network properties of 18 healthy controls, 25 patients with MS with cognitive impairment, and 55 patients with MS without cognitive impairment. Network parameters were compared, and predictive value for cognition was assessed, adjusting for confounders (sex, education, gray matter volume, network size and degree, and T1 and T2 lesion load). Backward stepwise multivariable regression quantified predictive factors for 5 neurocognitive domain test scores. RESULTS: Greater path length (r = -0.28, P < .0057) and lower normalized path length (r = 0.36, P < .0004) demonstrated a correlation with average cognition when comparing healthy controls with patients with MS. Similarly, MS with cognitive impairment demonstrated a correlation between lower normalized path length (r = 0.40, P < .001) and reduced average cognition. Increased normalized path length was associated with better performance for processing (P < .001), learning (P < .001), and executive domain function (P = .0235), while reduced path length was associated with better executive (P = .0031) and visual domains. Normalized path length improved prediction for processing (R 2 = 43.6%, G2 = 20.9; P < .0001) and learning (R 2 = 40.4%, G2 = 26.1; P < .0001) over a null model comprising confounders. Similarly, higher normalized path length improved prediction of average z scores (G2 = 21.3; P < .0001) and, combined with WM volume, explained 52% of average cognition variance. CONCLUSIONS: Patients with MS and cognitive impairment demonstrate more random network features and reduced global efficiency, impacting multiple cognitive domains. A model of normalized path length with normal-appearing white matter volume improved average cognitive z score prediction, explaining 52% of variance.

Development and validation of the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index.

BACKGROUND: Enthesitis is a recommended core domain for assessment of ankylosing spondylitis (AS), but no measurement has yet been validated according to Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) criteria. OBJECTIVE: The purpose of this study was to seek to validate an enthesitis index for patients with AS according to OMERACT criteria. METHODS: An enthesitis index was validated in two AS patient cohorts: (1) a longitudinal cohort (n = 223) and (2) 22 patients from three Canadian sites participating in a 24-week randomised placebo-controlled trial of adalimumab in AS. Construct validity was evaluated by correlation analysis with the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI) and quality of life instruments. Reproducibility was assessed by intraclass correlation coefficient (ICC), and responsiveness was assessed by Guyatt's effect size and standardised response mean. RESULTS: The most frequently affected sites were the greater trochanter and supraspinatus insertion ( approximately 20%). Patients with enthesitis had significantly greater scores for the BASDAI, BASFI, patient global, AS-specific quality of life index (ASQOL) and the Short Form 36 (SF-36) General Health Survey (p<0.001). The enthesitis score contributed significantly to variance in the BASDAI and BASFI. Interobserver ICCs were 0.96 in the longitudinal cohort and 0.89 and 0.77 in the adalimumab clinical trial cohort (for status and change score, respectively). Significant differences in change scores were evident for all patients after 24 weeks of adalimumab treatment, (p = 0.04), this being more significant when a subset of the most commonly affected entheses were analysed (p = 0.01). CONCLUSION: AS patients with enthesitis constitute a more severe subset of disease, and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index is feasible and reliable for measurement of this condition. Discrimination requires further study in larger trials.

High dose oral steroids commonly used to treat relapses in Canadian MS clinics.

BACKGROUND: Glucocorticoid treatment improves the speed of functional recovery of acute multiple sclerosis (MS) relapses but has not been shown to provide any long-term functional benefit. There is currently no convincing evidence that the clinical benefit is influenced by the route of administration or the dosage of glucocorticoid, or the particular glucocorticoid prescribed. Recent studies support similarities in the bioequivalence and in the clinical effect of high dose oral corticosteroids for MS relapses. OBJECTIVE: This survey aimed to determine the relapse treatment preferences of clinicians in Canadian MS clinics. METHODS: Members of the Canadian Network of MS Clinics are linked by an email server. A one page survey was distributed to the group to determine and report use of corticosteroids to manage MS relapses amongst Canadian MS specialists. RESULTS: Fifty-one clinicians from 17 MS clinics were surveyed. 32 (63%) surveys were returned representing 16 clinics. Five doses are most commonly prescribed, usually without a taper. Three or four doses and the use of a corticosteroid taper, however, are not uncommon. Gastric cytoprotection and sedatives are often prescribed for use as needed. CONCLUSION: This survey illustrates that when Canadian clinicians with expertise in managing MS treat MS relapses they choose high dose corticosteroids, either oral or i.v. The results therefore represent Canadian practice as these clinicians provide direct patient care and influence care by community neurologists. Until evidence clearly identifies a superior practice all options should be available to clinicians and their patients.

Comparison of Multiple Sclerosis Cortical Lesion Types Detected by Multicontrast 3T and 7T MRI.

BACKGROUND AND PURPOSE: Our aims were the following: 1) to compare multicontrast cortical lesion detection using 3T and 7T MR imaging, 2) to compare cortical lesion type frequency in relapsing-remitting and secondary-progressive MS, and 3) to assess whether detectability is related to the magnetization transfer ratio, an imaging marker sensitive to myelin content. MATERIALS AND METHODS: Multicontrast 3T and 7T MR images from 10 participants with relapsing-remitting MS and 10 with secondary-progressive MS. We used the following 3T contrast sequences: 3D-T1-weighted, quantitative T1, FLAIR, magnetization-transfer, and 2D proton-density- and T2-weighted. We used the following 7T contrast sequences: 3D-T1-weighted, quantitative T1, and 2D-T2*-weighted. RESULTS: Cortical lesion counts at 7T were the following: 720 total cortical lesions, 420 leukocortical lesions (58%), 27 intracortical lesions (4%), and 273 subpial lesions (38%). Cortical lesion counts at 3T were the following: 424 total cortical, 393 leukocortical (93%), zero intracortical, and 31 subpial (7%) lesions. Total, intracortical, and subpial 3T lesion counts were significantly lower than the 7T counts (P < .002). Leukocortical lesion counts were not significantly different between scanners. Total and leukocortical lesion counts were significantly higher in secondary-progressive MS, at 3T and 7T (P ≤ .02). Subpial lesions were significantly higher in secondary-progressive MS at 7T (P = .006). The magnetization transfer ratio values of leukocortical lesions visible on both scanners were significantly lower than the magnetization transfer ratio values of leukocortical lesions visible only at 3T. No significant difference was found in magnetization transfer ratio values between subpial lesions visible only at 7T and subpial lesions visible on both 3T and 7T. CONCLUSIONS: Detection of leukocortical lesions at 3T is comparable with that at 7T MR imaging. Imaging at 3T is less sensitive to intracortical and subpial lesions. Leukocortical lesions not visible on 7T T2*-weighted MRI may be associated with less demyelination than those that are visible. Detectability of subpial lesions does not appear to be related to the degree of demyelination.

Smooth-muscle myosin mutations in hereditary non-polyposis colorectal cancer syndrome.

We examined adenomas and cancers from hereditary non-polyposis colorectal cancer (HNPCC) syndrome patients for the presence of frameshift mutations in the smooth-muscle myosin gene, MYH11. Our results show that mutations in MYH11 occur more frequently in cancers than adenomas (P=0.008) and are dependent on microsatellite instability (MSI+).

Growth arrest in A549 cells during hyperoxic stress is associated with decreased cyclin B1 and increased p21(Waf1/Cip1/Sdi1) levels.

Exposure to high concentrations of oxygen has previously been shown to cause growth arrest in A549 cells, a distal lung epithelial cell line. We found that when A549 cells were exposed to 95% oxygen they underwent substantial growth inhibition. This was associated with induction of p21(Waf1/Cip1/Sdi1) protein and a decrease in cyclin B1 protein. Flow cytometry revealed that A549 cells exposed to hyperoxia had a significant decrease in the percentage of cells in G(1) and a modest but significant increase in the percentage of cells in S phase and G(2)/M, consistent with cells entering S phase. A549 cells in room air and hyperoxia were then treated with nocodazole, a mitotic inhibitor. Room air A549 cells treated with nocodazole showed a marked increase in G(2)/M consistent with mitotic arrest. In contrast, hyperoxic treated cells had a modest but significant decrease in G(1) but only a minimal increase in G(2)/M consistent with partial G(1)/S arrest and growth inhibition in S phase. To further investigate the role of p21(Waf1/Cip1/Sdi1) as a checkpoint regulator during hyperoxic growth inhibition, HCT116 cells with wild-type and null p21(Waf1/Cip1/Sdi1) were exposed to hyperoxia. Both wild-type p21(+/+) cells and null p21(-/-) cells underwent growth inhibition when exposed to hyperoxia. At 48 h the hyperoxic treated HCT116 p21(+/+) had a similar cell cycle distribution as the hyperoxic treated HCT116 p21(-/-) cells, suggesting that p21(Waf1/Cip1/Sdi1) may not be essential for growth arrest during hyperoxia. These findings suggest that hyperoxia causes partial growth arrest at different phases of the cell cycle but primarily in S phase, that hyperoxic growth arrest is associated with a decrease in cyclin B1 protein and that p21 induction may not be essential for hyperoxic growth arrest.

Induction of macrophage-like differentiation of HL-60 leukemia cells by tumor necrosis factor-alpha: potential role of fos expression.

Tumor necrosis factor-alpha (TNF-alpha) is a macrophage-derived cytokine elicited during cellular responses to various microbial infections. TNF-alpha exerts direct cytotoxicity toward some tumor cells in vitro and produces hemorrhagic tumor necrosis in vivo. In human promyelocytic HL-60 leukemia cells, human recombinant TNF-alpha (rTNF-alpha) exhibits a small early proliferative effect (within 48 h), followed by marked cytostatic activity at 96 h after the addition of rTNF-alpha. Cytostasis is contiguous with an induction of cell differentiation along the monocyte/macrophage lineage. The cell proliferation effects and the induction of the differentiated phenotype are preceded by an approximate 5-fold increase in c-fos mRNA levels within 90 min after rTNF-alpha treatment of log phase HL-60 cells. Nuclear in vitro transcription assays indicate that the effect of rTNF-alpha on c-fos mRNA abundance is controlled at the transcriptional level. We have also used a postembedding immunocolloidal gold electron microscopy technique to localize and semiquantitate pp55c-fos proto-oncoprotein levels in the nucleus of both control and rTNF-alpha-treated HL-60 leukemia cells. In response to rTNF-alpha, we have observed a rapid and transient accumulation of pp55c-fos in discrete nuclear substructures within 2 h after treatment. C-fos staining appears in clusters, which are preferentially localized over semi-condensed chromatin and interchromatin granules. These results suggest that pp55c-fos is involved in the signal transduction system initiated by rTNF-alpha during the induction of HL-60 differentiation.

The influence of small for gestational age status on outpatient bronchopulmonary dysplasia outcomes.

OBJECTIVE: To describe the characteristics of small for gestational age (SGA) and non-SGA infants with bronchopulmonary dysplasia (BPD) and to ascertain whether respiratory outcomes and health-care utilization patterns in these two populations differ. STUDY DESIGN: Three hundred and twenty-five infants with BPD born at <32 weeks gestation were recruited in the outpatient setting. Sociodemographic data and indicators of respiratory morbidity were collected via questionnaire and retrospective chart review. RESULT: SGA infants were on average 1 month older than non-SGA infants at discharge from the neonatal intensive care unit and were more likely to have a weight less than 10th percentile at first clinic visit. History of SGA was associated with increased risk of emergency department visits as well as with caregiver perception of poor weight gain. CONCLUSION: SGA status in infants with BPD is associated with increased health-care utilization, including length of initial hospitalization and emergency department visits.

Isovolemic hemodilution in stroke. A study in gerbils.

Isovolemic hemodilution has been reported to increase cerebral perfusion in humans and has been advocated as a treatment for acute cerebral infarction. This study examines the effect of isovolemic hemodilution with low-molecular-weight dextran on mortality and the incidence of neurological deficit in gerbils after internal carotid ligation. Sixty-four Mongolian gerbils were anesthetized with pentobarbital and the left internal carotid artery was ligated in both control and experimental animals. In the experimental group, blood was removed and an equal volume of dextran was injected to reestablish normal blood volume and lower hematocrit to a mean of 30.5. Control animals were not so treated. Animals were observed for neurological deficits for 24 hours after carotid ligation. The incidence of neurological deficit in control animals was 67%; it was 64% in the experimental group. Mortality within the first 24 hours was 28% in the controls and 75% in animals that were treated by hemodilution (p less than 0.001). Isovolemic hemodilution with dextran did not reduce the incidence of neurological deficit after carotid ligation in gerbils and was associated with a significant increase in mortality during the first 24 hours.

Ping-pong ball plombage for right postpneumonectomy syndrome in children.

BACKGROUND/PURPOSE: Right postpneumonectomy syndrome is a rare complication of pneumonectomy characterized by exertional dyspnea resulting from mediastinal shift into the empty hemithorax. Historically, this problem has been treated with thoracoplasty, muscle flap transposition, pericardial fixation, and plombage using a variety of materials. Significant postoperative complications have been reported with each of these methods. In an effort to avoid the problems known to be associated with other plombage materials, we have used sterilized ping-pong balls as plombage to treat the postpneumonectomy syndrome. METHODS: Two children with pneumonectomy syndrome were treated with ping-pong ball plombage. RESULTS: Symptoms improved immediately in both patients and postoperative chest x-rays in each showed a normal cardiac position. Neither child had a postoperative complication. Six-year follow-up chest films in both children have demonstrated some fluid filling of the ping-pong balls, but no clinical problems attributable to them have been noted. CONCLUSION: The authors conclude that ping-pong ball plombage appears to be a viable management option in children with right postpneumonectomy syndrome.

Pancreatoduodenectomy for neonatal myofibromatosis of the pancreas.

Myofibromatosis is a rare congenital disorder consisting of one or more fibrous nodules in the skin, soft tissues, bones, and internal organs. The authors report the unique case of a newborn who presented with obstructive jaundice caused by a single myofibroma in the head of the pancreas that was treated successfully by pancreatoduodenectomy on the eighth day of life.

Inhaled nitric oxide in congenital diaphragmatic hernia.

Pulmonary hypertension is a major complication of congenital diaphragmatic hernia (CDH). Inhaled nitric oxide (NO) is a selective pulmonary vasodilator because it produces vasodilatation of the pulmonary vasculature without systemic hypotension. In experimental and clinical studies, inhaled NO ameliorates pulmonary hypertension and improves gas exchange. The goal of the present study was to determine the extent to which infants with CDH respond to inhaled NO. Four newborn infants with CDH complicated by severe respiratory insufficiency and right-to-left shunting received inhaled NO. In three patients, postductal oxygenation improved in response to small concentrations of NO (5 to 10 ppm); two received NO after operative repair, and the third both before and after repair. However, tachyphylaxis developed in all cases within 1 to 6 days. A fourth patient received inhaled NO in an attempt at weaning from ECMO. He did not respond, remaining hypoxic despite 80 ppm NO, and continued to require ECMO. In the three patients who responded to inhaled NO, plasma nitrites and nitrates (stable oxidative end products of NO) accumulated over time, but not in the patient who did not respond. The accumulation of nitrite and nitrate in plasma may reflect alveolar-capillary NO absorption, and may identify patients who will respond to continued inhaled NO. Methemoglobin remained below 1.9% in all four babies. Selected infants with CDH may respond to NO, but the benefit may be temporary.

Balloon extraction of esophageal foreign bodies in children.

BACKGROUND: Whereas esophageal foreign bodies are commonly removed with rigid esophagoscopy under general anesthesia, selected foreign bodies also can be removed using a Foley catheter balloon under fluoroscopic control without anesthesia. The authors prefer to initially attempt removal of smooth, radiopaque esophageal foreign bodies using the balloon technique and then proceed to rigid esophagoscopy if unsuccessful. METHODS: The authors reviewed their 7-year experience with this approach in 276 children with esophageal foreign bodies. RESULTS: One hundred seventy-three children underwent attempted balloon extraction, and 146 of these underwent successful removal with this method. Fifteen remained lodged in the esophagus and were subsequently removed by esophagoscopy, and 12 passed into the stomach and were observed. The only complication was one episode of epistaxis that resolved. Success of the balloon method was not related to patient age, foreign body duration, location, or presenting symptoms. The use of more than 5 minutes of fluoroscopy time was associated with a low likelihood of successful extraction. CONCLUSION: The balloon extraction technique is a safe and effective alternative to rigid esophagoscopy for the removal of selected esophageal foreign bodies in children.