Umakanth Khatwa

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Significance This paper provides unique insights into mechanism-based therapeutics for Rett syndrome (RTT), a devastating neurodevelopmental disorder. This clinical trial was based on pioneer preclinical work from the laboratory of M.S. Outcome measures include clinical instruments, standardized behavioral measures, and biomarkers, the latter being not only objective but also applicable to experimental studies. We believe this work will a have major impact on the understanding and treatment of RTT, as well as other neurodevelopmental disorders. Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Changes in Gastric and Lung Microflora With Acid Suppression Acid Suppression and Bacterial Growth

IMPORTANCE The use of acid suppression has been associated with an increased risk of upper and lower respiratory tract infections in the outpatient setting but the mechanism behind this increased risk is unknown. We hypothesize that this infection risk results from gastric bacterial overgrowth with subsequent seeding of the lungs. OBJECTIVES To determine if acid-suppression use results in gastric bacterial overgrowth, if there are changes in lung microflora associated with the use of acid suppression, and if changes in lung microflora are related to full-column nonacid gastroesophageal reflux. DESIGN, SETTING, AND PARTICIPANTS A 5-year prospective cohort study at a tertiary care center where children ages 1 to 18 years were undergoing bronchoscopy and endoscopy for the evaluation of chronic cough. Acid-suppression use was assessed through questionnaires with confirmation using an electronic medical record review. MAIN OUTCOMES AND MEASURES Our primary outcome was to compare differences in concentration and prevalence of gastric and lung bacteria between patients who were and were not receiving acid-suppression therapy. We compared medians using the Wilcoxon signed rank test and determined prevalence ratios using asymptotic standard errors and 95% confidence intervals. We determined correlations between continuous variables using Pearson correlation coefficients and compared categorical variables using the Fisher exact test. RESULTS Forty-six percent of patients taking acid-suppression medication had gastric bacterial growth compared with 18% of untreated patients (P = .003). Staphylococcus (prevalence ratio, 12.75 [95% CI, 1.72-94.36]), Streptococcus (prevalence ratio, 6.91 [95% CI, 1.64-29.02]), Veillonella (prevalence ratio, 9.56 [95% CI, 1.26-72.67]), Dermabacter (prevalence ratio, 4.78 [95% CI, 1.09-21.02]), and Rothia (prevalence ratio, 6.38 [95% CI, 1.50-27.02]) were found more commonly in the gastric fluid of treated patients. The median bacterial concentration was higher in treated patients than in untreated patients (P = .001). There was no difference in the prevalence (P > .23) of different bacterial genera or the median concentration of total bacteria (P = .85) in the lungs between treated and untreated patients. There were significant positive correlations between proximal nonacid reflux burden and lung concentrations of Bacillus (r = 0.47, P = .005), Dermabacter (r = 0.37, P = .008), Lactobacillus (r = 0.45, P = .001), Peptostreptococcus (r = 0.37, P = .008), and Capnocytophagia (r = 0.37, P = .008). CONCLUSIONS AND RELEVANCE Acid-suppression use results in gastric bacterial overgrowth of genera including Staphylococcus and Streptococcus. Full-column nonacid reflux is associated with greater concentrations of bacteria in the lung. Additional studies are needed to determine if acid suppression-related microflora changes predict clinical infection risk; these results suggest that acid suppression use may need to be limited in patients at risk for infections.

The presence of pepsin in the lung and its relationship to pathologic gastro‐esophageal reflux

Background  Pepsin has been proposed as a biomarker of reflux‐related lung disease. The goal of this study was to determine (i) if there is a higher reflux burden as measured by pH‐MII in patients that are pepsin positive in the lung, and (ii) the sensitivity of pepsin in predicting pathologic reflux by pH, MII, and EGD.

MMP-8 promotes polymorphonuclear cell migration through collagen barriers in obliterative bronchiolitis.

Increased levels of MMP‐8 (neutrophil collagenase) have been reported in OB, but the biological role of MMP‐8 in OB is not known. MMP‐8 is an interstitial collagenase highly expressed by polymorphonuclear leukocytes, which are prominent in early OB. Here, we show that MMP‐8 promotes migration of PMNs through the collagen‐rich matrix in a mouse heterotopic airway transplant model of OB. Overall, MMP‐8−/− mice had significantly fewer PMNs in the airway lumen 2 and 14 days post‐transplantation, and the percentage of PMNs traversing the matrix to the lumen was decreased markedly in the MMP‐8−/− compared with WT mice at 14 days. There were significantly more PMNs outside of the lumen in the ECM in the MMP‐8−/− mice compared with WT mice. In vitro, significantly fewer MMP‐8−/− PMNs migrated through 3D cross‐linked collagen gels than WT PMNs. MMP inhibitor GM6001 was also able to impede migration of WT PMNs through collagen gels. The decreased migration was likely a result of pericollagenase activity of MMP‐8, as WT PMNs expressing MMP‐8 were not able to migrate effectively through collagen that was resistant to the collagenase. Protection from OB was seen in the MMP‐8−/− mice, as the airway lumen had significantly less obliteration and collagen deposition, suggesting that MMP‐8 plays an important role in the pathogenesis of OB.

16S community profiling identifies proton pump inhibitor related differences in gastric, lung and oropharyngeal microflora

OBJECTIVES To test the hypothesis that proton pump inhibitor (PPI) use results in changes in gastric microflora which, through full column reflux, results in lung and oropharyngeal microflora changes. STUDY DESIGN We performed a prospective, cross-sectional cohort study of 116 children (57 off and 59 on PPIs) undergoing simultaneous bronchoscopy and upper endoscopy for the evaluation of chronic cough. We performed 16S sequencing on gastric, bronchoalveolar lavage, and oropharyngeal fluid. Fifty patients also underwent multichannel intraluminal impedance testing. RESULTS Streptococcus was more abundant in the gastric fluid of patients taking PPIs, and there was a significant correlation with PPI dose (mg/kg/d) and abundance of gastric Streptococcus (P = .01). There was also a significant difference in the abundance of oropharyngeal Streptococcus in patients treated with PPI. Eight unique bacterial genera were found in the gastric and lung fluid but not in the oropharyngeal suggesting exchange between the 2 sites and 2 of the 8 (Lactococcus, Acinetobacter) were more abundant in patients with more full column reflux, suggesting direct aspiration. Principal component analysis revealed greater overlap between gastric and lung than oropharyngeal microflora. CONCLUSIONS PPI use was associated with differences in gastric, lung, and oropharyngeal microflora. Although microflora exchange can occur between all 3 sites, gastric and lung microflora are more closely related, and the mechanism of exchange between sites may be aspiration of full column reflux.

Management of undescended testis.

The term cryptorchidism indicates a testis, which has failed to descend to the scrotum and is located at any point along the normal path of descent or at an ectopic site. Hormones play a pivotal role in testicular descent except during the migration to the level of internal inguinal ring. Cryptorchidism is present in about 4.5% of newborns with a higher incidence in preterms. The incidence decreases to 1.2% by the first year. It is classified as palpable and impalpable. The most common site of an ectopic testis is superficial inguinal pouch. Retractile testis is often bilateral and most common in boys between 5 and 6 years of age. Hypospadias and inguinal hernias are the most common associated anomalies seen with undescended testis. A thorough clinical examination helps in arriving at the etiology. A short hCG stimulation test helps to exclude anorchia. Different imaging techniques are of little help in diagnosis and require the help of an experienced radiologist. Laparoscopy has an important role in the diagnosis and management of undescended testis. The common complications include torsion and atrophy of testis. Infertility is seen in about 40% of unilateral and 70% of bilateral cryptorchidism. Undescended testis is 20 to 40 times more likely to undergo malignant transformation than normal testis. Both hCG and GnRH have been used with limited success in these children. All boys with cryptorchidism should be referred to a pediatric surgeon before 2 years of age. These children should be followed up every year after surgery to identify testicular tumors.

Hyperpolarized 3He MR imaging of the lung: normal range of ventilation defects and PFT correlation in young adults.

Objective To prospectively investigate the number, location, and size of ventilation defects and correlate these findings with pulmonary function tests (PFTs) when performing hyperpolarized helium-3 (HP 3He) magnetic resonance imaging (MRI) of the lung in healthy young adults. Materials and Methods Six healthy adult female volunteers underwent standard PFT and MRI of the lungs after inhalation of HP 3He. HP 3He MR images were evaluated by 4 reviewers in consensus. Number, location, and size of ventilation defects were recorded. Locations of ventilation defects included the right upper lobe, right middle lobe, right lower lobe, left upper lobe, left lower lobe, and lingula. Ventilation defects were localized into central, middle, or peripheral portions of the lungs. Size of ventilation defects was categorized with a maximum diameter of either ≤3 cm or >3 cm. HP 3He MRI findings were correlated with PFT results. Results The study cohort comprised 6 healthy, young adult female volunteers (mean age 22.5 y, range: 20-25 y) who underwent both PFT and HP 3He MRI. Five (83.3%) out of 6 volunteers had at least 1 ventilation defect (mean=2.3; range: 1-4; 95% confidence interval: 1.3-3.8 defects/patient). Among a total of 14 ventilation defects observed from 5 healthy, young adult volunteers, ventilation defects were observed in left lower lobe in 6 (42.9%), right lower lobe in 3 (21.4%), right upper lobe in 3 (21.4%), and left upper lobe in 2 (14.3%) patients. No ventilation defects were observed in the right middle lobe and lingula. All observed ventilation defects were less than 3 cm in size and peripherally located. There was no correlation between number, location, or size of ventilation defects and PFT results. Conclusions Small (≤3 cm) peripherally located ventilation defects can be seen in the majority of healthy, young adult volunteers, and should not be mistaken as abnormalities when evaluating HP 3He MRI. These ventilation defects are located in the peripheral upper lobes and lower lobes (lower lobes>upper lobes) while sparing right middle lobe and lingula. The number, location, and size of ventilation defects on HP 3He MRI were not correlated with PFT results in the normal range, which suggests HP 3He MRI may be more sensitive than PFT for evaluating small ventilation defects in young adults.

The utility of endoscopy and multichannel intraluminal impedance testing in children with cough and wheezing

Gastroesophageal reflux (GER) has been implicated as a causal factor in respiratory disease but prior studies have focused on the role of acid alone in the genesis of symptoms. Prior studies have relied on pH probe testing but this is blind to non‐acid reflux which has been implicated in the genesis of extraesophageal symptoms. The objective of this prospective, cross‐sectional study is to determine the utility of gastroesophageal reflux testing, including multichannel intraluminal impedance with pH (pH‐MII) and upper gastrointestinal endoscopy (EGD), in the child with intractable cough and wheezing. We hypothesize that there is a high rate of pathologic reflux testing in these patients.

Restless legs syndrome and periodic limb movements disorder in the pediatric population

Purpose of review Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) are common neurological disorders in childhood which are usually underdiagnosed. As many pediatricians and pediatric pulmonologists with interest in sleep medicine will be encountering children with RLS and PLMS in their practice, we feel a comprehensive review of these disorders from a pediatric perspective would be very important in understanding basic pathophysiology, clinical features in early diagnosis, and effective management. Recent findings There has recently been increased awareness about these disorders in children, and the American Academy of Sleep Medicine has recently published pediatric specific diagnostic criteria. There have also been exciting discoveries into the basic pathophysiology of these conditions which have helped to better understand these disorders. Genetics plays a very important role in their development, and current management strategies have been very successful in treatment of these conditions. Summary RLS occurs in 1 out of 120 school-age children. In many children, diagnosis is not even suspected as these children present with atypical symptoms and associated comorbid conditions. In this review, we will discuss RLS and PLMS in the pediatric population and briefly review their pathophysiology, clinical presentation, risk factors, neurobehavioral consequences, and newer diagnostic criteria along with recent advances in their management.

Obstructive sleep apnea in infancy: A 7-year experience at a pediatric sleep center

To investigate the common indications for polysomnogram (PSG) associated co‐morbid conditions, evaluation strategies, treatment options, and outcomes in a series of infants diagnosed with obstructive sleep apnea (OSA) by a PSG.