Biomedical subjects
Publications and source records attributed to M C Harris.
Biventricular hypertrophy was noted at 24 weeks' gestation in a fetus with isolated cytochrome-c oxidase (COX) deficiency. Shock, caused by hypertrophic cardiomyopathy and severe pulmonary hypertension, led to the patient's death on day 6. His phenotype defines a new lethal variant of COX deficiency characterized by prenatal-onset cardiopulmonary pathophysiology.
Despite major improvements in infant intensive care, neonatal meningitis remains a devastating disease. Survivors of bacterial meningitis are at high-risk for life-long neurological handicaps, and despite a reduction in mortality, the morbidity of neonatal meningitis has not changed substantially over the last thirty years. A substantial improvement in outcome is unlikely to result from further refinements in ICU technology or new antibiotics. However, recent advancements in our understanding of the pathogenesis of meningitis and the pathophysiology of brain injury in meningitis may provide the opportunity to interrupt the mechanisms that allow bacteria to enter the central nervous system and initiate the inflammatory response. Strategies aimed at modulating the inflammatory response must be chosen carefully, so as not to disrupt normal host responses needed for the infant to recover from the infectious episode.
OBJECTIVE: In recent years, the increased prevalence of breastfeeding in conjunction with early discharge practices has increased the risk for marked hyperbilirubinemia in neonates. This has resulted in the potential for bilirubin brain injury in affected infants. The purpose of this study was to identify all infants >/=36 weeks' gestational age with bilirubin levels >25 mg/dL and evaluate them for early and late evidence of bilirubin brain injury. METHODS: We reviewed the charts of all infants (from 1993-1996) >/=36 weeks' gestational age who were readmitted to the hospital during the first week of life with bilirubin levels >25 mg/dL. Readmission records were reviewed for early signs of bilirubin encephalopathy. Magnetic resonance imaging (MRIs) and Brainstem auditory-evoked responses (BAERs) were reviewed for evidence of bilirubin toxicity. At follow-up, study infants had a complete neurodevelopmental examination, repeat MRIs, and behavioral hearing evaluations. RESULTS: From 1993 to 1996, we identified 6 term and near-term infants readmitted to the hospital within the first week of life with peak bilirubin values ranging from 26.4 mg/dL (451 micromol/L) to 36.9 mg/dL (631 micromol/L). Five of 6 infants had bilirubin values >30 mg/dL (513 micromol/L). All were exclusively breastfed or fed a combination of breast and bottle feedings. Five of 6 infants presented with abnormal neurologic signs. Four infants had initial MRIs, 3 of whom had increased signal intensity in the basal ganglia consistent with kernicterus. Two infants had abnormal BAERs; both also had abnormal MRIs. Five of 6 infants received exchange transfusions and all were treated with phototherapy and intravenous fluids. Follow-up examinations between 3 months and 2 years showed resolution of clinical signs in all but 1 infant. Four infants had a subsequent normal MRI and 1 had residual hearing impairment. One infant demonstrated severely abnormal developmental evaluations, as well as both an abnormal initial MRI and BAERs. Follow-up MRI showed evidence of encephalomalacia with changes not characteristic of kernicterus. CONCLUSIONS: We observed transient neurologic abnormalities in 5 of 6 infants readmitted to the hospital during the first week of life with marked hyperbilirubinemia. The abnormalities resolved following aggressive management using hydration, phototherapy, and exchange transfusion and may not correlate with long-term prognosis. Less aggressive therapy may be associated with residual neurologic abnormalities. We speculate that inadequate establishment of breastfeeding coupled with early discharge practices may play a role in the development of marked hyperbilirubinemia in these infants.
UNLABELLED: Neonates who require a central venous catheter (CVC) for prolonged vascular access experience high rates of catheter-related bloodstream infection (CRBSI). PURPOSE: A multicenter randomized clinical trial was undertaken to ascertain the efficacy of a novel chlorhexidine-impregnated dressing (Biopatch Antimicrobial Dressing) on the CVC sites of neonates for the prevention of catheter tip colonization, CRBSI, and bloodstream infection (BSI) without a source. Setting. Six level III neonatal intensive care units. Patients Studied. Neonates admitted to study units who would require a CVC for at least 48 hours. METHODS: Eligible infants were randomized before catheter placement to 1 of the 2 catheter site antisepsis regimens: 1) 10% povidone-iodine (PI) skin scrub, or 2) a 70% alcohol scrub followed by placement of a chlorhexidine-impregnated disk over the catheter insertion site. A transparent polyurethane dressing (Bioclusive Transparent Dressing) was used to cover the insertion site in both study groups. Primary study outcomes evaluated were catheter tip colonization, CRBSI, and BSI without an identified source. RESULTS: Seven hundred five neonates were enrolled in the trial, 335 randomized to receive the chlorhexidine dressing and 370 to skin disinfection with PI (controls). Neonates randomized to the antimicrobial dressing group were less likely to have colonized CVC tips than control neonates (15.0% vs 24.0%, relative risk [RR]: 0.6 95% confidence interval [CI]: 0.5-0.9). Rates of CRBSI (3.8% vs 3.2%, RR: 1.2, CI: 0.5-2.7) and BSI without a source (15.2% vs 14.3%, RR: 1.1, CI: 0.8-1.5) did not differ between the 2 groups. Localized contact dermatitis from the antimicrobial dressing, requiring crossover into the PI treatment group, occurred in 15 (15.3%) of 98 exposed neonates weighing </=1000 g. No neonates in the PI group developed contact dermatitis. CONCLUSION: The novel chlorhexidine-impregnated dressing, replaced weekly, was as effective as cutaneous disinfection with 10% PI and redressing the site every 3 to 7 days for preventing CRBSI and BSI without a source in critically ill neonates requiring prolonged central venous access. The risk of local contact dermatitis under the chlorhexidine dressing limits its use in low birth weight infants who require prolonged central access during the first 2 weeks of life.
The nicotinic receptor drug candidate, 3-(2,4-dimethoxybenzylidene)-anabaseine (also known as GTS-21; DMXBA), its hydroxy metabolites, and some related analogs were evaluated with the two-electrode voltage-clamp technique in mouse 5-hydroxytryptamine (5-HT)(3A) receptors expressed in Xenopus oocytes. Although DMXBA lacked partial agonist activity, its hydroxy-benzylidene metabolites and related analogs were partial agonists, displaying the following rank order of potency (EC(50)) and apparent efficacy: 5-HT, 0.9 +/- 0.06 microM (100% efficacy) > 3-(2-hydroxy,4-methoxybenzylidene)-anabaseine (2-OH-MBA), 2.0 +/- 0.3 microM (63% efficacy) > 3-(2,4-dihydroxybenzylidene)-anabaseine, 2.6 +/- 0.3 microM (63% efficacy) > 3-(2-methoxy,4-hydroxybenzylidene)-anabaseine, 17.2 +/- 1.0 microM (30% efficacy). To examine the influence of a benzylidene ring hydroxy substituent, the agonist actions of the three possible monohydroxy isomers were examined. The rank order of potency, based on EC(50) determinations, and apparent efficacy was: 3-(2-hydroxybenzylidene)-anabaseine, 20.3 +/- 2.6 microM (63% efficacy) > 3-(4-hydroxybenzylidene)-anabaseine, 32.3 +/- 5.9 microM (14% efficacy) > 3-(3-hydroxybenzylidene)-anabaseine (3-OH-BA) (no agonist activity). Both DMXBA and 3-OH-BA antagonized 5-HT-mediated currents, with IC(50) values of 15.7 +/- 0.9 and 27.5 +/- 4.7 microM, respectively. DMXBA demonstrated both competitive and noncompetitive forms of antagonism over the range of concentrations tested. These results suggest that a hydroxy substituent at the 2' position of the benzene ring is necessary and sufficient for partial agonist activity; substitution at the 4' position with a hydroxy or methoxy group further enhances agonist potency. Because 2-OH-MBA is a primary metabolite of DMXBA, it may contribute to the physiological, biochemical, and behavioral effects of the parent compound when administered in vivo.
The "one-pot" synthesis of triarylamines from an aniline and two different aryl halides is described. A catalytic system composed of Pd2(dba)3/P(t-Bu)2-o-biphenyl (1) is used to prepare a variety of triarylamines in a single flask by the coupling of an aniline with an aryl bromide and aryl chloride. The synthesis of triarylamines containing a heterocyclic aryl group is also described by employing a one-flask, two-step method. These methods can be used to synthesize both discrete triarylamines and a triarylamine library.
[equation--see text] The N-arylation of indoles, including a variety of substituted ones, has been carried out using bulky, electron-rich phosphines as the supporting ligand in combination with Pd(2)(dba)(3). Using this catalyst system, the efficient coupling of indole and a variety of substituted indoles with aryl iodides, bromides, chlorides, and triflates can be achieved.
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Mammals that use the ventilatory system as the principal means of increasing heat loss, i.e. that pant, show two fundamental changes in the control of breathing at raised temperatures. First, alveolar ventilation increases by more than, rather than in proportion to, the increase in CO2 production. Second, hypocapnia no longer causes apnoea. Rats do not use the ventilatory system as the principal means of increasing heat loss, so we have investigated whether rats also show these two changes at raised temperatures. Breathing was detected from diaphragmatic electromyogram (EMG) activity. Anaesthesia and hyperoxia were used to minimise behavioural and hypoxic drives to ventilation and arterial PCO2 (Pa,CO2) was controlled using mechanical ventilation. At 36.6 +/- 0.1 >C, breathing was absent as long as Pa,CO2 was held below a threshold level of 32.9 +/- 0.7 mm Hg (n = 14) under steady-state conditions. When body temperature in rats was raised above 37 >C, both fundamental changes in the control of breathing became apparent. First, at 39 >C the mean Pa,CO2 level during spontaneous breathing (39.6 +/- 5.4 mm Hg, n = 4) fell by 3.9 +/- 1.4 mm Hg (P < 0.05, Student's paired t test). Second, at 39.9 +/- 0.1 >C breathing was present when mean Pa,CO2 levels were only 18.2 +/- 1.5 mm Hg (n = 14), the lowest mean Pa,CO2 level we could achieve with mechanical ventilation. We calculate, however, that at 39.9 >C, the drive to breathe from the increased CO2 production alone would not sustain breathing below a Pa,CO2 level of 27.8 +/- 1.4 mm Hg (n = 13). In rats at raised body temperatures therefore a respiratory drive exists that is in addition to that related to the increase in CO2 production.
In mammals that use the ventilatory system as the principal means of increasing heat loss, raising body temperature causes the adoption of a specialised breathing pattern known as panting and this is mediated by the thermoregulatory system in the preoptic area of the hypothalamus. In these species an additional respiratory drive is also present at raised body temperature, since breathing can reappear at low Pa,CO2 levels, when stimulation of chemoreceptors is minimal. It is not known whether the preoptic area is also the source of this additional drive. Rats do not pant but do possess this additional respiratory drive at raised body temperatures. We have therefore tested whether the preoptic area of the hypothalamus is the source of this additional respiratory drive in rats. Urethane anaesthesia and hyperoxia were used in eleven rats to minimise behavioural and chemical drives to breathe. The presence of the additional respiratory drive was indicated if rhythmic diaphragmatic EMG activity reappeared during hypocapnia (a mean Pa,CO2 level of 21+/-2 mm Hg, n = 11), induced by mechanical ventilation. The additional respiratory drive was absent at normal body temperature (37¿C). When the temperature of the whole body was raised using an external source of radiant heat, the additional respiratory drive appeared at 40.6+/-0.5 degrees C (n = 3). In two further rats this drive was induced at normal body temperature by localised warming in the preoptic area of the intact hypothalamus. The additional respiratory drive appeared at similar temperatures to those in control rats in three rats following isolation of the hypothalamus from more rostral areas of the brain. In contrast, the additional respiratory drive failed to appear at these temperatures in three rats after isolating the hypothalamus from the caudal brainstem, by sectioning pathways medial to the medial forebrain bundle. Since the preoptic area is known to contain thermoreceptors and to receive afferents from peripheral thermoreceptors, the results show that this area is also the source of the additional respiratory drive at raised body temperature in anaesthetised rats.
Preterm infants have an increased incidence of infection, which is principally due to deficiencies in neonatal host defense mechanisms. Monocyte adherence is important in localizing cells at sites of infection and is associated with enhanced antimicrobial functions. We isolated cord blood monocytes from preterm and full-term infants to study their adhesion and immune functions, including superoxide (O2-) generation, degranulation, and cytokine secretion and their adhesion receptors. O2- production and degranulation were significantly diminished, by 28 and 37%, respectively, in adherent monocytes from preterm infants compared to full-term infants (P < 0. 05); however, these differences were not seen in freshly isolated cells. We also observed a significant decrease of 35% in tumor necrosis factor alpha secretion by lipopolysaccharide-stimulated adherent monocytes from preterm infants compared to full-term infants (P < 0.05); however, this difference was not observed in interleukin-1beta or interleukin-6 production by the monocytes. The cell surface expression of the CD11b/CD18 adhesion receptor subunits was significantly decreased (by 60 and 52%, respectively) in monocytes from preterm infants compared to full-term infants (P < 0. 01). The cascade of the immune response to infection involves monocyte upregulation and adherence via CD11b/CD18 receptors followed by cell activation and the release of cytokines and bactericidal products. We speculate that monocyte adherence factors may be important in the modulation of immune responses in preterm infants.
In urethane-anaesthetized rats, stimulation of carotid body chemoreceptors desynchronizes the cortical electroencephalogram and increases the sensitivity of thalamic and cortical somatosensory neurones to peripheral sensory nerve stimulation. Peripheral chemoreceptors were stimulated by injecting a bolus (30 ml) or infusing 100 ml of 0.18 M NaCl solution equilibrated with 100% CO2 into an internal carotid artery, the cortical electroencephalogram and ventilation were monitored routinely. This stimulus induced hyperventilation and desynchronization of the cortical electroencephalogram. Anaesthetized rats also showed spontaneous periodic increases in ventilation rate accompanied by changes of the cortical electroencephalogram from high-voltage low frequency to low-voltage high frequency which seemed to be identical with those evoked by stimulating chemoreceptors. The activity of identified somatosensory neurons in the thalamic ventrobasal complex, layer IV of the somatosensory cortex, or the cuneate nucleus was recorded extracellularly during and following chemoreceptor activation. Neurones in the ventrobasal thalamus and somatosensory cortex showed a decrease in latency and an increase in probability of discharge to supramaximal electrical stimulation of the forepaw which was more pronounced following infusion stimulation of the carotid body than following bolus stimulation. In contrast, neurons within the cuneate nucleus showed a slight increase in latency to onset and a decrease in the probability of firing following the same stimulus. The results indicate that stimulation of the carotid body chemoreceptors leads to an enhancement of the response of somatosensory neurons to their normal physiological input.
Experiments were performed to measure the apneic threshold for CO2 and its fundamental properties in anesthetized rats under steady-state conditions. Breathing was detected from diaphragmatic electromyogram activity. Mechanical hyperventilation resulted in apnea once arterial PCO2 (PaCO2) had fallen far enough. Apnea was not a reflex response to lung inflation because it did not occur immediately, was not prevented by vagotomy, and was reversed by raising PaCO2 without changing mechanical hyperventilation. The apneic threshold was measured by hyperventilating rats mechanically with O2 until apnea had occurred and then raising PaCO2 at constant hyperventilation until breathing reappeared. The mean PaCO2 level of the apneic threshold in 42 rats was 32.8 +/- 0.4 Torr. The level of the threshold did not depend on the volume at which the lungs were inflated. The level of the threshold, under steady-state conditions, was the same when approached from hypocapnia as from eupnea. The level of the threshold could be raised by 9 Torr by chronic elevation of the eupneic PaCO2 level by 18 Torr.
Immaturity of local innate defenses has been suggested as a factor involved in the pathophysiology of necrotizing enterocolitis (NEC). The mRNA of enteric human defensins 5 (HD5) and 6 (HD6), antibiotic peptides expressed in Paneth cells of the small intestine, have significantly lower levels of expression in fetal life compared with the term newborn and adult. In the current study, intracellular HD5 was demonstrated by immunohistochemistry at 24 wk of gestation, but at low levels, consistent with findings at the mRNA level. These data suggest that the low level enteric defensin expression, characteristic of normal intestinal development, may contribute to the immaturity of local defense, which predisposes the premature infant to NEC. To test if levels of defensin expression are altered in NEC, specimens from six cases of patients with NEC and five control subjects (four patients with atresia and one with meconium ileus) were analyzed to determine HD5 and HD6 mRNA levels by in situ hybridization. Compared with the control group, the level of enteric defensin expression per Paneth cell assessed by image analysis was increased 3-fold in cases of NEC (p = 0.02, analysis of variance and covariance). In addition, the number of Paneth cells was increased 2-fold in the small intestinal crypts of NEC specimens compared with those of control subjects (p < 0.01, covariance analysis). In healthy tissue, peptide levels within Paneth cells paralleled mRNA levels through development. In tissue from infants with NEC, the steady state level of intracellular peptide was not increased in conjunction with the observed rise in defensin mRNA. A straightforward interpretation of this finding is that HD5 is actively secreted in this setting and the Paneth cells maintain a constant steady state level of intracellular peptide, but the possibility of translational regulation of peptide expression is also consistent with these data. The associations between NEC and enteric defensin expression reported here offer support for future studies to address the role of these endogenous host defense factors in the pathophysiology of this disease.
The circulating insulin-like growth factor (IGF) axis consists of the IGF peptides, the IGF binding proteins (IGFBPs), and the IGFBP proteases. Little is known about the IGF axis in newborns, its possible perturbations in sick neonates, and the effect of nutrition on the IGF axis of such patients. The aims of this study were to define IGF axis parameters in the sera of hospitalized newborns and to correlate these parameters with the nutritional status of the infants. Serum samples obtained from twenty four hospitalized infants in the intensive care nursery were analyzed for IGF axis parameters. Insulin-like growth factor-I and IGFBP-3 by RIA were mostly within the normal range for age and were only minimally affected by gestational age. In comparison, 8 newborn infants with congenital growth hormone deficiency had IGFBP-3 levels which were below the normal range. Two infants on ECMO had elevated levels of IGFBP-3 by RIA. Western ligand blotting (WLB) demonstrated that IGFBP-2 was the major binding protein in infant serum and the 44 kDa IGFBP-3 in critically ill neonatal serum was approximately 10% of adult serum levels. IGFBP-3 by RIA in neonatal serum averaged approximately 25% of adult serum levels. Compatible with this discrepancy, a number of sick neonates had detectable levels of IGFBP-3 proteolytic activity and higher levels of IGFBP-3 fragments compared to normal adult serum in both the protease assays and Western immunoblotting. There was no correlation between any IGF axis parameter and nutritional status. In summary, sick hospitalized neonates display mostly normal IGF and IGFBP-3 levels, which are not correlated to nutritional intake. Thus serum IGFBP-3 levels maintain their diagnostic utility for growth hormone deficiency in critically ill neonates.
OBJECTIVE: To determine the effect of insurance status on the likelihood of interhospital transfer for neonates. DESIGN: Population-based retrospective cohort study. SETTING: All general acute care nonpediatric hospitals in the five counties of southeastern Pennsylvania. PATIENTS: Fifty-six thousand, seven hundred eighty-nine infants from 0 to 28 days of age admitted to or born in study hospitals between January 1 and December 31, 1991. INTERVENTION: None. MAINS OUTCOME MEASURE: Transfer to another general or specialty acute care hospital. RESULTS: The incidence (95% confidence interval) of interhospital transfer was 1.69% (1.60, 1.78). Uninsured infants were nearly twice as likely [relative risk (RR) = 1.96 (1.67, 2.31)] to be transferred as commercially insured infants, even when adjusted for the effects of prematurity, severity of illness, and the level of neonatal intensive care unit in the referring hospital. Similarly, infants with Medicaid were more likely to be transferred [RR = 1.20 (1.01, 1.43)] than similar commercially insured neonates. Uninsured and publicly insured infants were also more likely to be born premature [RR 1.49 (1.39, 1. 60)] than privately insured neonates, and were more likely to have both moderate [RR 1.11 (1.04, 1.23)] and high [RR 1.21 (1.11, 1.32)] illness severity on admission to the hospital than privately insured infants. CONCLUSIONS: Neonates with no insurance and those with Medicaid coverage were more likely to be transferred than infants with private insurance. These results are consistent with those of other investigators who have studied financially motivated patient transfers- so-called patient dumping-in nonpediatric populations of patients. Our study may represent the first documentation of this phenomenon in a pediatric population. Our results are also consistent with those of other investigators who have examined the effect of insurance status on maternal interhospital transfer, thus providing further evidence for the existence of financially motivated transfers within regional systems of perinatal care. Future investigation into the effect of economic factors on variation in the utilization of transport services, and on how transfer influences ultimate patient outcome, is needed as managed care health systems become more widespread.
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We sought to determine whether the detection of cytokines, produced during the inflammatory response, would aid in the diagnosis of meningitis in young infants. We measured cerebrospinal fluid (CSF) and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) in 62 infants less than 6 months of age whose condition was evaluated for meningitis. Twenty infants had culture-proved meningitis, 22 had aseptic meningitis, and 20 control infants had no evidence of meningitis. The CSF IL-6 levels were elevated in all 20 infants with bacterial meningitis and in 9 of 22 infants with aseptic meningitis but were undetectable in all control subjects. Furthermore, CSF IL-6 levels were 10 times greater in infants with bacterial versus aseptic meningitis (p < 0.001). Levels of TNF in CSF were detected in 12 of 20 infants with bacterial meningitis and were undetectable in infants with aseptic meningitis and in control infants (p < 0.02). Plasma IL-6 and TNF levels were unreliable for the detection of meningitis in this patient population. We conclude that the presence of IL-6 in the CSF reliably identifies infants with meningitis and that the presence of CSF TNF is a highly specific indicator of bacterial meningeal inflammation.