Aviv D. Goldbart

Intranasal Steroids and Oral Leukotriene Modifier Therapy in Residual Sleep-Disordered Breathing After Tonsillectomy and Adenoidectomy in Children

OBJECTIVE. Tonsillectomy and adenoidectomy (T&A) is the primary therapeutic approach for sleep-disordered breathing (SDB) in children. However, residual mild SDB will be found in more than one third of these patients after T&A. We hypothesized that combined therapy with the leukotriene receptor antagonist montelukast and intranasal budesonide would result in normalization of residual SDB after T&A. METHODS. During the period of October 2002 to February 2005, children who underwent T&A for SDB underwent a routine postoperative (second) overnight polysomnographic evaluation (PSG) 10 to 14 weeks after T&A surgery. In children with residual apnea hypopnea index (AHI) >1 and <5/hour of total sleep time (TST), treatment with montelukast and intranasal budesonide aqueous solution was administered for a period of 12 weeks (M/B group), at which time a third PSG was performed. Children who had residual SDB and did not receive M/B therapy from their treating physicians were recruited as control subjects. RESULTS. Twenty-two children received M/B, and 14 children served as control subjects. Mean age, gender distribution, ethnicity, and BMI were similar in the 2 treatment groups. The mean AHI at the second PSG was 3.9 ± 1.2/hour of TST and 3.6 ± 1.4/hour of TST in M/B-treated and control patients, respectively. Similar nadir arterial oxygen saturation (87.3 ± 1.2%) and respiratory arousal index (4.6 ± 0.7/hour of TST) were recorded for both groups. However, the M/B group demonstrated significant improvements in AHI (0.3 ± 0.3/hour of TST), in nadir arterial oxygen saturation (92.5 ± 3.0%), and in respiratory arousal index (0.8 ± 0.7/hour of TST) on the third PSG, whereas no significant changes occurred over time in control subjects. CONCLUSIONS. Combined anti-inflammatory therapy that consists of oral montelukast and intranasal budesonide effectively improves and/or normalizes respiratory and sleep disturbances in children with residual SDB after T&A.

Montelukast for Children With Obstructive Sleep Apnea: A Double-blind, Placebo-Controlled Study

OBJECTIVES: Children with nonsevere obstructive sleep apnea (OSA) benefit from alternative therapeutic interventions such as leukotriene modifiers. We hypothesized that montelukast might improve OSA in children. We tested this hypothesis in a double-blind, randomized, placebo-controlled fashion. METHODS: Of 50 possible candidates, we recruited 46 children with polysomnographically diagnosed OSA. In this prospective, double-blind, randomized trial, children received daily oral montelukast at 4 or 5 mg (<6 or >6 years of age, respectively) or placebo for 12 weeks. Polysomnographic assessments, parent questionnaires, and radiographs to assess adenoid size were performed before and after therapy. RESULTS: Compared with the 23 children that received placebo, the 23 children that received montelukast showed significant improvements in polysomnographic measures of respiratory disturbance (obstructive apnea index), childrens symptoms, and adenoid size. The obstructive apnea index decreased by >50% in 65.2% of treated children. No attrition or side effects occurred. CONCLUSIONS: A 12-week treatment with daily, oral montelukast effectively reduced the severity of OSA and the magnitude of the underlying adenoidal hypertrophy in children with nonsevere OSA.

Intermittent hypoxic exposure during light phase induces changes in cAMP response element binding protein activity in the rat CA1 hippocampal region: water maze performance correlates.

Intermittent hypoxia (IH) during sleep, a characteristic feature of sleep-disordered breathing (SDB) is associated with time-dependent apoptosis and spatial learning deficits in the adult rat. The mechanisms underlying such neurocognitive deficits remain unclear. Activation of the cAMP-response element binding protein (CREB) transcription factor mediates critical components of neuronal survival and memory consolidation in mammals. CREB phosphorylation and DNA binding, as well as the presence of apoptosis in the CA1 region of the hippocampus were examined in Sprague-Dawley male rats exposed to IH. Spatial reference task learning was assessed with the Morris water maze. IH induced significant decreases in Ser-133 phosphorylated CREB (pCREB) without changes in total CREB, starting as early as 1 h IH, peaking at 6 h-3 days, and returning toward normoxic levels by 14-30 days. Double-labeling immunohistochemistry for pCREB and Neu-N (a neuronal marker) confirmed these findings. The expression of cleaved caspase 3 (cC3) in the CA1, a marker of apoptosis, peaked at 3 days and returned to normoxic values at 14 days. Initial IH-induced impairments in spatial learning were followed by partial functional recovery starting at 14 days of IH exposure. We postulate that IH elicits time-dependent changes in CREB phosphorylation and nuclear binding that may account for decreased neuronal survival and spatial learning deficits in the adult rat. We suggest that CREB changes play an important role in the neurocognitive morbidity of SDB patients.

INCREASING PREVALENCE OF PENICILLIN-RESISTANT PNEUMOCOCCAL INFECTIONS IN CHILDREN IN SOUTHERN ISRAEL : IMPLICATIONS FOR FUTURE IMMUNIZATION POLICIES

Although penicillin-resistant pneumococci (PR-PnC) are recognized as an increasing problem worldwide, data on the prevalence of these strains among pediatric patients are incomplete. The present study was conducted in southern Israel (1) to investigate the frequency of PR-PnC in invasive and middle ear infections in pediatric patients and (2) to assess the impact of resistance on the potential role of the candidate conjugate vaccines in preventing childhood PR-PnC infections. A total of 120 blood or cerebrospinal fluid isolates from 1987 to 1993 and 78 ear isolates from 1992 to 1993 were serogrouped and tested for susceptibility to antibacterial agents. The prevalence of PR-PnC among invasive isolates increased from 16% in the years 1987 to 1991 to 36% in 1992 to 1993 (P = 0.019). This increase was noted mainly for intermediately resistant strains (minimal inhibitory concentration, 0.12 to 1.0 micrograms/ml) whereas the prevalence of highly resistant strains was 3 and 2% for the 2 periods, respectively. The prevalence of PR-PnC among ear isolates in 1992 to 1993 was 42%. Resistance to other antimicrobial agents (one or more of the following: tetracycline, erythromycin, clindamycin and chloramphenicol) was found in 16 (8%) isolates, and multiple resistance (resistance to > or = 3 antibacterial agents) was found in 9 (5%) isolates. Sixty-five (99%) of the 66 resistant isolates belong to Serogroups 6, 14, 19 and 23. The prevalence of these 4 serogroups rose from 37% in 1987 to 1991 to 66% in 1992 to 1993 (P = 0.043). This rise was mainly because of Serogroup 23, the prevalence of which rose from 3% in 1987 to 1991 to 23% in 1992 to 1993 (P < 0.001). Eighty-five percent of all isolates belonging to Serogroup 23 were resistant to penicillin. Because Serogroups 6, 14, 19 and 23 are among the commonest pediatric pneumococcal strains, the newly developed conjugate pneumococcal vaccines contain these 4 serogroups. The selection of antibiotic-resistant strains has thus led to a change in the spectrum of serotypes causing invasive disease and to a situation of potential increase in vaccine coverage for the proposed pneumococcal conjugate vaccines.

High fat/refined carbohydrate diet enhances the susceptibility to spatial learning deficits in rats exposed to intermittent hypoxia

BACKGROUND Intermittent hypoxia during sleep (IH), as occurs in sleep disordered breathing (SDB), induces spatial learning deficits associated with regulation of transcription factors associated with learning and memory in the hippocampal CA1 region in rats. high fat refined carbohydrate diet (HF/RC) can induce similar deficits and associated changes in signaling pathways under normoxic conditions. METHODS Sprague-Dawley adult male rats were fed either with (HF/RC) or low fat/complex carbohydrate diet (LF/CC) starting at post-natal day 30 for 90 days, and were then exposed for 14 days during light phase (12 h/day) to either normoxia (RA) or IH (21% and 10% O2 alternations every 90 s). Place-training reference memory task deficits were assessed in the Morris water maze. Total and ser-133 phosphorylated CREB were assessed in different brain regions by Western blotting and immunostaining in rats exposed to normoxia or IH and to LF/CC or HF/RC. RESULTS Substantial decreases in CREB phosphorylation occurred in CA1 but not in motor cortex following either IH, HF/RC, and HF/RC + IH. Place-training reference memory task deficits were observed in rats exposed to IH and to HF/RC, and to a much greater extent in rats exposed to HF/RC + IH. CONCLUSIONS Nutritional factors alter recruitment of transcription factors, possibly via oxidative-related pathways, and modulate the vulnerability of the CA1 region of the hippocampus to the episodic hypoxia that characterizes SDB, thereby enhancing neurocognitive susceptibility in SDB patients.

The acute effects of water-pipe smoking on the cardiorespiratory system.

OBJECTIVE There are limited data on the acute effects of water-pipe tobacco smoking, commonly known as water-pipe smoking (WPS), on cardiopulmonary parameters. This study evaluated the acute effects of a single 30-min session of WPS on carboxyhemoglobin (COHb) levels, pulmonary function test results, vital signs, fractional exhaled nitric oxide (Feno) levels, and exhaled breath condensate (EBC) cytokine levels in volunteers in a domestic, open-air, group smoking setting. METHODS This prospective study evaluated the above-noted outcome parameters before and after 30 min of WPS. The primary outcome parameter was the change in COHb levels. RESULTS Forty-five volunteers (30 men, 15 women), aged 32.35 ± 15.33 years, were recruited. After one session of WPS, the COHb levels rose significantly, from 1.47% ± 0.57% (median 1.4) to 9.47% ± 5.52% (median 7.4), P < .001. Systolic and diastolic BP levels significantly increased after smoking (systolic, 119.52 ± 12.07 mm Hg vs 131.98 ± 17.8 mm Hg; diastolic, 74.84 ± 7.89 mm Hg vs 82.98 ± 12.52 mm Hg, respectively; P < .001). Heart rates increased from 80.39 ± 9.92 beats/min to 95.59 ± 17.41 beats/min, P < .001; and respiratory rates increased from 14.36 ± 1.63 breaths/min to 16.68 ± 2.24 breaths/min, P < .001. There were decreases in forced expiratory flow between 25% and 75% of FVC, peak expiratory flow rate, Feno levels, percentage of eosinophils in peripheral blood, and 8-isoprostane levels in EBC. CONCLUSIONS This study shows that one session of WPS causes acute biologic changes that might result in marked health problems. It adds to the limited evidence that WPS is harmful and supports interventions to control the continuing global spread of WPS, especially among youth. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01157832; URL: www.clinicaltrials.gov.

Glucocorticoid receptor subunit expression in adenotonsillar tissue of children with obstructive sleep apnea.

Tonsillectomy and adenoidectomy (T&A) is a frequent surgical procedure in children with obstructive sleep apnea (OSA). Many symptomatic children who do not fulfill the currently recommended criteria for T&A may benefit from topical intranasal steroid therapy. However, the expression of glucocorticoid receptor (GCR) expression in adenoid and tonsillar tissue is currently unknown. The objective of this study was to assess and compare expression patterns of the human GCR in children who undergo T&A for either recurrent throat infections (RI) or OSA. Adenotonsillar tissues from 36 children with OSA or RI were subjected to quantitative PCR using specific primers for GCR-α and GCR-β and to immunohistochemistry and Western blotting for protein expression of GCR isoforms. mRNA encoding for expression of both GCR-α and GCR-β was detected in the tonsils and adenoids of all children, with markedly higher relative abundance of the GCR-α. Furthermore, GCR-α mRNA expression was increased in OSA-derived adenoid and tonsil tissues compared with RI, whereas no differences emerged for GCR-β. Immunoblots confirmed these findings for the protein transcripts of these genes, and immunohistochemistry showed a specific topographic pattern of distribution for both receptors in tonsillar tissue. GCR-α and GCR-β are expressed in pediatric adenotonsillar tissue, are more abundant in OSA patients, and demonstrate a specific topographic pattern of expression. These findings along with the high GCR-α:GCR-β ratio suggest a favorable profile for topical steroid therapy in snoring children with adenotonsillar hypertrophy.

B-Type Natriuretic Peptide and Cardiovascular Function in Young Children With Obstructive Sleep Apnea

OBJECTIVE N-terminal pro-B-type natriuretic peptide (NT-proBNP), a marker of ventricular strain, and C-reactive protein (CRP), a marker of inflammation, are reportedly elevated in school-aged children with obstructive sleep apnea (OSA). We hypothesized that cardiovascular morbidity affects circulating markers and their echocardiographic and polysomnographic (PSG) correlates in young children with OSA. METHODS We assessed young children undergoing adenotonsillectomy (TA) for OSA by polysomnography, echocardiography, and serum CRP and NT-proBNP levels. RESULTS A total of 90 children with OSA (mean age 19 +/- 7 months; 71.2% male; BMI, z = 0.62 +/- 1.04) and 45 age- and sex-matched controls were included. Three months following TA, 72 children were reassessed for NT-proBNP and CRP. NT-proBNP level (pg/mL) was higher in subjects with OSA (189.1 +/- 112.7) vs control subjects (104.8 +/- 49.5; P = .006). Both NT-proBNP (187.8 +/- 114 vs 86 +/- 32.6; P = .002) and CRP levels (mg %) (0.49 +/- 0.41 vs 0.1 +/- 0.17; P < .05) decreased following TA. Doppler pulse wave measuring tricuspid regurgitation (TR), a reflection of pulmonary hypertension, correlated with CRP (r = 0.61, P < .01) but not NT-proBNP (r = -0.14, P = .53) levels. Left ventricle end-diastolic diameter (LVEDD) was at the maximal normal range (0.91 +/- 0.11), but did not correlate with CRP or NT-proBNP levels. Both CRP level and TR correlated with PSG variables reflecting nocturnal hypoxemia, whereas NT-proBNP level and LVEDD did not. Echocardiography in 40 children (out of 90) showed a decline in TR that was abnormal before TA and correlated with the decrease in CRP following TA. CONCLUSIONS NT-proBNP levels are increased in children with OSA and decrease following TA. Echocardiographic parameters suggesting increased pulmonary pressure in young children with OSA are related to nocturnal hypoxemia and systemic inflammation, which also decrease following therapy.

Green Tea Catechin Polyphenols Attenuate Behavioral and Oxidative Responses to Intermittent Hypoxia

RATIONALE The intermittent hypoxia (IH) that characterizes sleep-disordered breathing impairs spatial learning and increases NADPH oxidase activity and oxidative stress in rodents. We hypothesized that green tea catechin polyphenols (GTPs) may attenuate IH-induced neurobehavioral deficits by reducing IH-induced NADPH oxidase expression, lipid peroxidation, and inflammation. OBJECTIVES To assess the effects of GTP administered in drinking water on the cognitive, inflammatory, and oxidative responses to long-term (>14 d) IH during sleep in male Sprague-Dawley rats. METHODS Cognitive assessments were conducted in the Morris water maze. We measured levels and expression of malondialdehyde (MDA), prostaglandin E(2), p47(phox) subunit of NADPH oxidase, receptor for advanced glycation end products (RAGE), and glial fibrillary acidic protein expression in rodent brain tissue. MEASUREMENTS AND MAIN RESULTS GTP treatment prevented IH-induced decreases in spatial bias for the hidden platform during the Morris water maze probe trails as well as IH-induced increases in p47phox expression within the hippocampal CA1 region. In untreated animals, IH exposure was associated with doubling of cortical MDA levels in comparison to room air control animals, and GTP-treated animals exposed to IH showed a 40% reduction in MDA levels. Increases in brain RAGE and glial fibrillary acidic protein expression were observed in IH-exposed animals, and these increases were attenuated in animals treated with GTP. CONCLUSIONS Oral GTP attenuates IH-induced spatial learning deficits and mitigates IH-induced oxidative stress through multiple beneficial effects on oxidant pathways. Because oxidative processes underlie neurocognitive deficits associated with IH, the potential therapeutic role of GTP in sleep-disordered breathing deserves further exploration.

Effect of intermittent hypoxia on long-term potentiation in rat hippocampal slices

Intermittent hypoxia (IH) during sleep has been shown to induce apoptosis in a time-dependent manner and spatial learning deficits in adult rats. Recently, we have demonstrated that IH induced significant decreases in Ser-133-phosphorylated cAMP-response element-binding protein (pCREB) without changes in total CREB. The expression of cleaved caspase 3 in the hippocampal CA1, a marker of apoptosis, peaked at 3 days of IH and returned to normoxic values at 14 days of IH. In addition, biphasic changes in spatial task learning were correlated with the CREB phosphorylation time course. In the present study, the rat hippocampal slice preparation was used to evaluate the ability to induce and maintain a CA1 population spike long-term potentiation (PS-LTP) in room air (RA)-maintained and IH-exposed rats. A significant decrease in the ability to sustain PS-LTP for 15 min in slices prepared from IH-exposed rats for either 3 days (34% of total) or 7 days (51% of total) as compared to slices prepared from RA-maintained rats (76% of total) was observed. These results suggest that the diminishment in the ability of neuronal tissue to express and sustain PS-LTP is correlated with previously reported biphasic changes in CREB phosphorylation and programmed cell death.