Auditory neuropathy (AN) is a condition in which transmission of sound to the brain is abnormal. This is reflected as an electrophysiologic profile of normal otoacoustic emissions (OAE), with abnormal auditory brainstem evoked responses (ABR). Functionally speech perception is impaired and management strategies remain controversial. AN can be missed if high-risk newborns are screened for hearing loss with only OAE testing. The rate of sensorineural hearing loss (SNHL) in high-risk nursery infants is 10 times greater compared with normal term newborns. Therefore, we hypothesize that infants from the neonatal intensive care unit (NICU) are at significantly higher risk for AN than normal term infants.Objective: The objective of this study is to establish a prevalence rate and characterize risk factors for NICU graduates who demonstrate the AN electrophysiologic profile.Study Design: This retrospective study examined infants admitted to the NICU at Kapi'olani Medical Center for Women and Children in Honolulu, HI from 1999 through 2003. Infants were screened with automated ABR. Diagnostic testing and OAE were performed before discharge if the ABR was abnormal. Hospital courses of 24 AN, 71 SNHL and 95 gestational age (GA)-matched control infants with normal hearing were reviewed.Result: With a SNHL prevalence of 16.7/1000, the rate for AN was 5.6/1000 NICU infants. Compared to infants with SNHL, infants with AN were significantly younger (GA 28.3±4.8 AN vs 32.9±5.2 weeks SNHL, P<0.0001) and smaller (BW 1318±894 AN vs 1968±1006 g SNHL).Nearly two-thirds of the AN infants were ELBW and had significantly longer hospital stays compared to SNHL infants of the same birth weight group. Exposure to furosemide, aminoglycosides, vancomycin or dexamethasone was associated with increased AN but not SNHL. Peak bilirubin level correlated with SNHL but not AN.Conclusion: Low birth weight NICU infants are at significant risk for AN. ELBW infants are at significantly higher risk for both AN and SNHL.Infants admitted to the NICU should be routinely screened by automated ABR and if abnormal, further evaluation should be started before hospital discharge. Early identification of AN will result in better understanding of this disorder and lead to the development of appropriate intervention strategies.
The widespread presence of the Na-K-2Cl (NKCC) cotransporter protein suggests that chronic administration of inhibitors may result in adverse effects. Inhibition of the NKCC cotransporter by loop diuretics is felt to underlie the diuretic and the pulmonary smooth muscle relaxant effects of this drug class. However, the fundamental regulation of salt and water movement by this cotransporter suggests that it may also mediate cell volume changes occurring during cell cycle progression. Thus we hypothesized that NKCC cotransporter inhibition by loop diuretics would decrease cellular proliferation. Normal human bronchial smooth muscle cells (BSMC) showed a significant concentration-dependent decrease in cell counts after 7 days of exposure to both bumetanide (n=5-10) and furosemide (n=6-16) compared with controls. Proliferation was similarly inhibited in normal human lung fibroblasts (n=5-9). To determine whether this was due to loss of cells, we performed apoptosis assays on BSMC. Both annexin V-propidium iodide staining (n=5-10) and single cell gel electrophoresis assays (n=4) were negative for necrosis and apoptosis in BSMC exposed to 10 microM bumetanide. Subsequent analysis of the cell cycle by flow cytometry showed that bumetanide-exposed BSMC were delayed in G1 phase compared with controls (n=4-8). This is the first evidence for loop diuretic inhibition of airway smooth muscle cell proliferation. NKCC cotransporter inhibition impeded G1-S phase transition without facilitating cell death. Thus although inhibition by loop diuretics relaxes airway smooth muscle, the NKCC cotransporter may have a more important role in cell proliferation regulation.
The use of fish oil–based lipid emulsions (FOLE) in the treatment of intestinal failure–associated liver disease (IFALD) remains investigational. Additional evidence for safety and efficacy, particularly in the neonatal and pediatric populations, is needed. Retrospective chart review was conducted on 10 infants with short bowel syndrome who received FOLE for IFALD. Direct bilirubin concentrations normalized in surviving subjects within 4.1 to 22.7 weeks of starting treatment. Although earlier initiation of FOLE was not associated with more rapid normalization of direct bilirubin concentrations, it trended toward a significant correlation with reduced length of hospital stay (P = .058). The reduction in direct bilirubin levels and transition from parenteral to enteral feeding were statistically significant within 6 weeks of initiating the FOLE. Subjects did not have impaired growth and did not develop an essential fatty acid deficiency. These infants were discharged from the hospital 7.9 to 42.3 weeks after starting FOLE treatment, and 2 infants had transitioned completely off parenteral nutrition at discharge. In this study, FOLE appeared to be a safe and effective treatment for IFALD in infants with short bowel syndrome. Future studies are necessary to determine whether FOLE can help to prevent or shorten the duration of cholestasis.
This study tested the hypothesis that airway relaxation to furosemide is mediated via the Na-K-2Cl cotransporter. If this mechanism exists in airway smooth muscle like in vascular smooth muscle, changes in airway relaxation should be associated with changes in Na-K-2Cl cotransporter function, and both should be substrate dependent. Tracheal rings from newborn guinea pigs were bathed in standard (STD) or varying low Cl- concentration ([Cl-]) N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). Isometric relaxation to 300 microM furosemide or 10(-8) to 10(-5) M salbutamol was measured. Airway segments were incubated with rubidium-86 (86Rb) in STD or varying low [Cl-] HEPES, with and without 300 microM furosemide or 25 microM salbutamol. Furosemide was unable to reduce 86Rb uptake at 10 mM [Cl-], although relaxation was still observed in 10 mM [Cl-]. Salbutamol did not affect 86Rb uptake. This study demonstrated that there is a furosemide-sensitive Na-K-2Cl cotransporter in newborn guinea pig trachea. However, the effect of furosemide on cotransporter function did not always directly correspond to differences in relaxation, suggesting that the Na-K-2Cl cotransporter may play a major, but not exclusive, role in furosemide-induced airway relaxation.
This study tested the hypothesis that inhaled nitric oxide (NO) and combined NO and hyperoxia will result in less pulmonary dysfunction and delay onset of respiratory signs compared with hyperoxia-exposed newborn guinea pigs (GPs). GPs were exposed to room air (n = 14), 95% O(2) (n = 36), 20 parts per million (ppm) NO (n = 14), or combined 20 ppm NO and 95% O(2) (NO/O(2), n = 13) for up to 5 days. Data evaluated included latency interval for onset of respiratory distress, pressure volume curves, lung histology, and bronchoalveolar lavage (BAL) polymorphonuclear cells (PMNs), proteolytic activity, and total protein. NO-exposed GPs did not develop respiratory distress and had no evidence of pulmonary dysfunction. O(2)-exposed GPs developed respiratory distress after 1-5 days (median 4.0) vs. 3-5 days (median 5.0) for NO/O(2) exposure (P < 0.05). BAL from O(2)-exposed GPs showed increased PMNs compared with NO/O(2)-exposed GPs. O(2)- and NO/O(2)-exposed GPs had comparable reduced lung volumes, lung histology, and increased BAL proteinase activity and total protein. In summary 1) O(2) exposure resulted in multiple measures of pulmonary dysfunction in newborn GPs, 2) 5-day exposure to NO produced no noticeable respiratory effects and pulmonary dysfunction, and 3) short-term exposure (=5 days) to NO/O(2) delayed onset of respiratory distress and neither exacerbated nor attenuated pulmonary dysfunction compared with O(2) exposure alone.
Significant adverse perinatal effects of maternal methamphetamine use have been reported, but little is known about factors influencing methamphetamine screening test results during the perinatal period. We tested the hypothesis that gestational age would affect quantitative recovery of methamphetamine in meconium and amniotic fluid. Time-bred guinea pigs received an intraperitoneal (i.p.) injection of 1 mg/kg methamphetamine at either 44 days (0.65 of term, n = 5), 50 days (0.74, n = 8), 56 days (0.82, n = 9) or 63 days (0.93, n = 4) gestation. At 1 or 7 days after i.p. methamphetamine, meconium and amniotic fluid were collected for quantitative methamphetamine assay by gas chromatography-mass spectrometry. Recovery from amniotic fluid and meconium 1 day after injection was influenced by gestational age. Greater values in amniotic fluid and meconium and a higher percentage of positive samples were seen in older fetuses. Collectively at all gestational ages, combined testing of amniotic fluid and meconium yielded detectable methamphetamine or its metabolites in 87% of guinea pigs 1 day after injection. However, methamphetamine was not detectable 1 week after injection in any sample (n = 63) at either 0.74 or 0.82 of term except for one positive amniotic fluid sample. Finally, demethylation of methamphetamine to amphetamine was higher in older fetuses. In summary, these results suggest that in guinea pigs: (1) gestational age may be an important consideration in interpreting quantitative methamphetamine recovery in perinatal samples; (2) amniotic fluid testing may be useful as an early indicator of fetal exposure; (3) timing of sample collection affects detection rate in amniotic fluid and meconium, and (4) combined testing of amniotic fluid and meconium may increase the probability of detecting positive samples at younger gestations.
Inhibition of the Na-K-2Cl (NKCC) cotransporter by loop diuretics is associated with airway relaxation, but there has been no direct evidence for the expression of this protein in airway smooth muscle. Thus we hypothesized that a NKCC cotransporter is present and functional in airway smooth muscle cells. Monoclonal and polyclonal antibodies were used first to demonstrate the presence of a NKCC cotransporter protein in isolated human fetal trachea and normal human bronchial smooth muscle cells (BSMC) by Western blotting. The cotransporter protein was then localized by immunohistochemical staining to airway smooth muscle cells in culture and in situ. The localization was confirmed by indirect immunofluorescence and laser confocal microscopy in the BSMC. Cotransporter function in BSMC was also confirmed in vitro by bumetanide-mediated inhibition of rubidium uptake. Our present findings thus document the presence of a functional NKCC cotransporter in human airway smooth muscle, providing a basis for defining the role of this ion cotransporter in airway smooth muscle function.
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