Group B streptococcal infections in newborns.

Group B streptococcus (GBS) is the most common cause of neonatal infection in North America and is associated with morbidity and mortality. Prompt recognition and treatment of the infection is imperative. Diagnostic tests and treatment options vary, without clear research-based recommendations. Future trends should focus on GBS infection as a public health issue, with an emphasis on prevention.

Teaching residents in the neonatal intensive care unit: a non-traditional approach.

Because of the increasing constraints on the amount of time pediatric residents may train in the neonatal intensive care unit (NICU), concerns have been raised about the adequacy of their exposure to acute emergencies in the delivery room and their hands-on experience with sick neonates. Importantly, there are also concerns about the consistency and quality of supervision of PL-1 residents by second- and third-year residents, who themselves may not have had sufficient training in the NICU. To address these concerns, we have instituted an educational plan that links an experienced neonatal nurse practitioner (NNP) one-on-one with a PL-1 resident in a collaborative team. This plan differs from the traditional resident-to-resident supervisory model. An anonymous survey of our residents (n = 14) indicates enthusiastic endorsement of this new educational model. NNPs as first-line teachers in the NICU provide a new approach for residency training programs.

Thyroid function in very low birth weight infants.

OBJECTIVES: The purpose of this study was to test the hypothesis that low circulating thyroxine concentrations characteristic of very low birth weight (VLBW) neonates (< 1500 g) are the result of decreased protein binding of thyroid hormones and to elucidate the mechanism(s) responsible and possible significance thereof. DESIGN: Cross-sectional comparison of thyroid related measurements in cord blood specimens from VLBW infants and from full term infants. Longitudinal comparison in cord and 2- and 4-week blood specimens from VLBW infants. PATIENTS: Cord blood specimens were analysed from 47 VLBW and 45 full term infants weighing > or = 2500 g. Repeat analyses in venous bloods from 32 of the VLBW infants were analysed at 2 weeks of age and again at 4 weeks in 23. The first cohort of patients was studied in 1994 and comprised 28 VLBW and 24 full term infants (Cohort A). The studies were repeated in 1995-96 in 19 VLBW infants and 21 full term infants (Cohort B). MEASUREMENTS: T4, free T4 (FT4), T3, thyroxine binding globulin (TBG), and TSH were measured in cord blood and 2- and 4-week venous specimens from VLBW infants and in cord blood specimens of full term infants. Molar ratios of T4/TBG were calculated. RESULTS: (1) Cord blood TBG, T4 and T3 concentrations of VLBW infants were each 60% of those of term infants. TBG concentrations were 397 +/- 111 vs 680 +/- 172 nmol/l (P < 0.0005). T4 concentrations were 76 +/- 22 vs 139 +/- 26 nmol/l (P < 0.0005). FT4 concentrations were in the normal adult range in both neonatal groups. T4/TBG ratios did not differ between the neonatal groups but were significantly less than that of adults (P < 0.001). (2) TSH concentrations in VLBW infants at 2 and 4 weeks were less than 50% of cord blood values. At 2 weeks, TBG concentrations of VLBW infants were unchanged from cord blood concentrations but mean T4 concentration fell by 18% and T4/TBG ratios by 21% (P < 0.005). Mean FT4 rose by 78% (P < 0.02). The changes in mean T4 and FT4 were due largely to FT4 concentrations of 37-113 pmol/l and T4 concentrations of 13-48 nmol/l in 5 infants. These infants also had lower T4/TBG ratios and were smaller and more ill than the remainder of the cohort. The changes disappeared by 4 weeks in 3 of the 4 infants tested. CONCLUSIONS: Cord T4/TBG ratios are the same in very low birth weight and term infants and are significantly lower than in adult blood. These are more than compensated for in term infants by a 236% increase in thyroxine binding globulin concentrations. The lower thyroxine binding globulin concentrations in very low birth weight infants explain their much lower T4 concentrations. Cord FT4 concentrations of full term and very low birth weight infants are in the normal adult range. T4 concentrations are further depressed and free T4 concentrations elevated in the most ill very low birth weight infants at 2 weeks of age in a manner analogous to that of the 'sick euthyroid syndrome'.

Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus.

In the initial stages of influenza virus infection, the hemagglutinin (HA) protein of influenza virus mediates both adsorption and penetration of the virus into the host cell. Recently, we identified and characterized BMY-27709 as an inhibitor of the H1 and H2 subtypes of influenza A virus that specifically inhibits the HA function necessary for virus-cell membrane fusion (G.-X. Luo, R. Colonno, and M. Krystal, Virology 226:66-76, 1996). Studies presented herein show that the inhibition is mediated through specific interaction with the HA protein. This binding represses the low-pH-induced conformational change of the HA protein which is a prerequisite for membrane fusion. In an attempt to define the binding pocket within the HA molecule, a number of drug-resistant viruses have been isolated and characterized. Sequence analyses of the HA gene of these drug-resistant viruses mapped amino acid changes responsible for drug resistance to a region located near the amino terminus of HA2. In addition, we have identified inactive analogs of BMY-27709 which are able to compete out the inhibitory activity of BMY-27709. This finding suggests that inhibition of the HA-mediated membrane fusion by this class of compounds is not solely the result of binding within the HA molecule but requires specific interactions.

Prevalence of sleep-disordered breathing in ages 40-64 years: a population-based survey.

Previous research has offered widely varying prevalence estimates for sleep apnea in the population, leaving uncertain which breathing patterns are abnormal. To explore the distribution of sleep apnea in the population and its co-morbidities, random telephone dialing was used between 1990 and 1994 to recruit subjects for a prevalence survey of sleep-disordered breathing in San Diego adults. Events from which blood oxygen desaturations > or = 4% resulted were monitored with home recording instruments, usually for three consecutive nights. Among 190 women ages 40-64 years, a median of 4.3 desaturation events per hour of sleep were observed. A higher median of 6.7 events per hour was observed among 165 men. Frequencies were much higher among members of minority groups, leading to a standard estimate that 16.3% of U.S. Hispanics and racial minorities have > or = 20 events/hour as compared to 4.9% of non-Hispanic Whites ages 40-64. Obesity indicated by body-mass index was the most important demographic predictor of sleep-disordered breathing, followed by age, male gender, and ethnicity. Quality of well-being was not significantly impaired in subjects with more respiratory events; however, there was some increase in blood pressure and wake-within-sleep associated with sleep-disordered breathing. This survey indicates that sleep-disordered breathing is more common, especially among minorities, than had been previously believed, but less co-morbidity may be associated.

Evaluation of the neonatal nurse practitioner role: the next frontier.

The neonatal nurse practitioner (NNP) role at Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, has been in place since 1989. As part of the professional growth and development of this NNP group, the necessity for a useful evaluation instrument emerged. This instrument needed to be congruent with the job description, practice philosophy, and strong commitment to peer review. The literature search and institutional survey failed to uncover an acceptable option, so an evaluation instrument was developed, tested, and refined. This instrument captures the diverse scope of NNP practice and incorporates a continuum of novice to expert competencies based on the work of Patricia Benner. This evaluation mechanism has had a profound effect on our group, encouraging the development of a shared vision of the NNP role and stimulating professional growth.

Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus.

The influenza A virus M2 integral membrane protein has ion channel activity that can be inhibited by the antiviral drug amantadine. Recently, a spirene-containing compound, BL-1743 (2-[3-azaspiro (5,5)undecanol]-2-imidazoline), that inhibits influenza virus growth was identified (S. Kurtz, G. Lao, K. M. Hahnenberger, C. Brooks, O. Gecha, K. Ingalls, K.-I. Numata, and M. Krystal, Antimicrob. Agents Chemother. 39:2204-2209, 1995). We have examined the ability of BL-1743 to inhibit the M2 ion channel when expressed in oocytes of Xenopus laevis. BL-1743 inhibition is complete as far as can be measured by electrophysiological methods and is reversible, with a reverse reaction rate constant of 4.0 x 10(-3) s(-1). In contrast, amantadine inhibition is irreversible within the time frame of the experiment. However, BL-1743 inhibition and amantadine inhibition have similar properties. The majority of isolated influenza viruses resistant to BL-1743 are also amantadine resistant. In addition, all known amino acid changes which result in amantadine resistance also confer BL-1743 resistance. However, one BL-1743-resistant virus isolated, designated M2-I35T, contained the change Ile-35-->Thr. This virus is >70-fold more resistant to BL-1743 and only 10-fold more resistant to amantadine than the wild-type virus. When the ion channel activity of M2-I35T was examined in oocytes, it was found that M2-I35T is BL-1743 resistant but is reversibly inhibited by amantadine. These findings suggest that these two drugs interact differently with the M2 protein transmembrane pore region.

Thyroid function in very low birth weight infants: effects on neonatal hypothyroidism screening.

OBJECTIVES: To supply normative data for screening thyroxine (T4) and thyrotropin concentrations correlated with birth weight and age at screening of infants with birth weights ranging from 400 to 5500 gm, and to document the effects of screening of very low birth weight (VLBW) infants, because VLBW infants comprise 0.86% of surviving newborn infants and have very low total T4 concentrations with normal or elevated free T4 concentrations as a result of deficient protein binding of thyroid hormones. STUDY DESIGN: Both retrospective and prospective studies were used. We conducted retrospective analyses of screening of T4 and thyrotropin concentrations in 9,324 term, 18,946 low birth weight, and 3,450 VLBW infants in Massachusetts, and a prospective study of T4 and thyrotropin concentrations in 48 VLBW infants at 2 weeks of age. Forty of the infants also had hormone measurements at 4 weeks, 29 at 8 weeks of age, and 24 had analysis of cord blood samples. RESULTS: Median T4 concentrations for each weight group (in 250 gm increments) increased progressively and significantly up to 2500 gm. Of the surviving VLBW infants, 1.5% had screening T4 concentrations that were unmeasurably low (<3.9 nmol/L (0.3 microgram/dl)). The mean T4 concentration varied with age at screening, increasing from cord blood concentrations to a peak at 1 to 3 days of age and thereafter decreasing to a nadir at about 2 weeks in both low birth weight and VLBW infants. In VLBW infants the mean concentrations return to the level of 1 to 3 days by 4 to 8 weeks of age. The incidence of screening thyrotropin concentrations > or = 40 mU/L correlates inversely with weight. The incidence of early, transient hypothyroidism in VLBW infants defined by this thyrotropin concentration was eight times that in term infants. Two infants had late-onset, transient hypothyroidism at 2 and 7 weeks, respectively. CONCLUSIONS: The normative data related to birth weight and age at screening allow proper interpretation of VLBW results for primary T4 and primary thyrotropin screening programs. Screening of the concentrations of T4 and thyrotropin in VLBW increases the number of secondary measurements of T4 in a primary thyrotropin screening program and the number of secondary thyrotropin measurements in a primary T4 screening program by 6% and 9%, respectively. We recommend screening analyses for VLBW infants in the latter part of the first week of life and again at 2 and 4 to 6 weeks of age. This protocol would increase the number of screening analyses by 1.6%.

Practice model: development of a nurse-managed unit and the advanced practitioner role.

Health care reform has provided opportunities for the creation of nurse-managed centers and the expansion of an autonomous nursing role. This article describes a program established by Massachusetts General Hospital for cardiac patients that has reduced delays in transfer and improved access to the hospital from referral centers. The program merges a strong primary nursing staff with a new advanced practice nursing role to create an alternative to the traditional model of inpatient care.

Secretion of apolipoprotein B-containing lipoproteins from HeLa cells is dependent on expression of the microsomal triglyceride transfer protein and is regulated by lipid availability.

To elucidate the role of the microsomal triglyceride transfer protein (MTP) in lipoprotein assembly, MTP and apolipoprotein B-53 (apoB 53; the N-terminal 53% of apoB) were expressed in HeLa cells. The results showed that apoB-53 could be expressed in HeLa cells with or without expression of MTP. In contrast, efficient secretion of apoB-53 required expression of MTP. Ultracentrifugal density flotation analysis showed that apoB-53 was secreted predominantly as a particle with the density of high density lipoprotein. An essentially identical apoB-53 particle density distribution was obtained after transient expression of apoB-53 in McArdle RH-7777 rat hepatoma cells. The mass of apoB-53 secreted was greater, and the flotation density was lower, from cells fed lipid, suggesting that apoB secretion in HeLa cells was regulated by lipid availability, similar to what has been described for lipoprotein-producing cell lines. These results indicate that MTP is necessary and sufficient to direct the regulated secretion of apoB-53 in HeLa cells.

Cloning and mRNA expression analysis of a novel human protooncogene, c-mer.

A human B-lymphoblastoid lambda gt11 expression library was screened using anti-phosphotyrosine antibodies yielding complementary DNAs encoding active tyrosine kinases. The resulting clones were used to obtain the sequence of a novel 984 amino acid transmembrane tyrosine kinase. Analysis of the complementary DNA revealed extracellular immunoglobulin and fibronectin type III domains and the unusual kinase signature sequence KWIAIES; all are characteristic of the axl family of tyrosine kinases. The novel tyrosine kinase was not expressed in normal B- and T-lymphocytes but, unlike axl, was expressed in numerous neoplastic B- and T-cell lines. Transcripts for the novel receptor-like tyrosine kinase were detected in normal peripheral blood monocytes and bone marrow. One alternatively spliced transcript was detected which contained an insert in the membrane proximal region that could encode for a truncated, soluble receptor. Sequence comparison shows that the kinase may be the human protooncogene for the recently isolated chicken retroviral oncogene v-ryk (recently renamed v-eyk), a truncated tyrosine kinase whose expression by retroviral infection produced sarcomas in chickens. The intracellular domain of the human kinase shows 83% similarity and 71% identity to v-ryk. Since the ryk designation has been used to name another tyrosine kinase and an analysis of RNA expression demonstrated that this novel human kinase is expressed in monocytes and tissues of epithelial and reproductive origin, we have designated our novel protooncogene c-mer.

Mutations in the zinc-finger region of the yeast regulatory protein ADR1 affect both DNA binding and transcriptional activation.

The expression of the yeast ADH2 gene is controlled by the transcriptional activator ADR1, a zinc-finger protein that binds to an upstream activating sequence (UAS1) in the ADH2 promoter. We report here the isolation of seven mutations in the ADR1-5c allele, defining five different amino acid changes, that suppress the enhanced ADH2 expression caused by the ADR1-5c allele. Each of the mutations was shown to reduce the activation of ADH2 by a wild-type ADR1 gene, suggesting the mutations disrupt a domain important to the function of both the ADR1 and ADR1-5c proteins. All five amino acid changes occurred within the DNA-binding domain of ADR1 and were shown to severely inhibit the ability of ADR1 to bind UAS1 in vitro. These mutations were found, however, to also affect the ability of ADR1 to activate transcription independent of its ability to bind DNA. These results indicate that the DNA-binding region of ADR1 is involved in both transactivation and DNA binding.

Automatic sleep/wake identification from wrist activity.

The purpose of this study was to develop and validate automatic scoring methods to distinguish sleep from wakefulness based on wrist activity. Forty-one subjects (18 normals and 23 with sleep or psychiatric disorders) wore a wrist actigraph during overnight polysomnography. In a randomly selected subsample of 20 subjects, candidate sleep/wake prediction algorithms were iteratively optimized against standard sleep/wake scores. The optimal algorithms obtained for various data collection epoch lengths were then prospectively tested on the remaining 21 subjects. The final algorithms correctly distinguished sleep from wakefulness approximately 88% of the time. Actigraphic sleep percentage and sleep latency estimates correlated 0.82 and 0.90, respectively, with corresponding parameters scored from the polysomnogram (p < 0.0001). Automatic scoring of wrist activity provides valuable information about sleep and wakefulness that could be useful in both clinical and research applications.

Controlled trial of bright light for nonseasonal major depressive disorders.

Psychotropic drug-free hospitalized veterans with nonseasonal major depressive disorders or depressed forms of bipolar disorder were treated with light for 1 week. Twenty-five patients were randomly assigned to bright white light treatment (2000-3000 lux), and 26 patients were randomized to dim red light placebo control treatment. Unlike those treated with dim red light, those treated with bright white light showed declines in three measures of depression during treatment. Partial relapse appeared within 2 days. A global depression score showed a statistically significant (p = 0.02) difference favoring bright white light treatment. Two bright-light-treated patients became mildly hypomanic, but side effects were mild. Improvement was not correlated with patient expectations; indeed, patients expected somewhat greater benefit from the placebo. Patients treated in summer responded as well as those treated in winter. Baseline electroencephalogram (EEG) sleep stage data (e.g., rapid eye movement; REM latency) did not predict treatment responses. These 1-week treatment results suggest that bright light might produce benefits for patients with nonseasonal depression. Bright light should not be recommended for routine clinical application before additional assessments with longer treatment durations are done.

Theophylline delays human sleep phase.

Twelve healthy male volunteers were given theophylline 250 mg in order to test effects on 24-hr rhythms. Rhythms of sleep/wake and subjective sleepiness were delayed. Ingestion of xanthines such as theophylline in coffee, tea, colas and chocolate may contribute to some sleep disorders. Theophylline might likewise be useful in treating disorders of circadian oscillators.

Cefotaxime therapy. Evaluation of its effect on bacterial meningitis, CSF drug levels, and bactericidal activity.

Cefotaxime sodium was evaluated in the treatment of ten patients with bacterial meningitis. Seven of the patients were infected with unusual and difficult to eradicate pathogens. Eight of the ten patients had a favorable clinical response and rapid sterilization of their CSF. Trough CSF levels of cefotaxime (range, 5.6 to 44.3 micrograms/mL) and desacetylcefotaxime (3.7 to 44.0 micrograms/mL) were manyfold greater than the minimal bactericidal concentrations of the causative pathogens with the exception of the one Pseudomonas aeruginosa isolate. Trough CSF bactericidal titers ranged from 1:16 to 1:4,096 or more (median, 1:256) in the nine patients with susceptible pathogens. Trough cefotaxime and desacetylcefotaxime levels and bactericidal titers were maintained or actually increased over the course of therapy. Cefotaxime appears to be a promising new agent for the treatment of bacterial meningitis.

Cefotaxime therapy of serious bacterial infection in adults.

We evaluated the efficacy, safety, and tolerance of cefotaxime in 35 adults (25 with pleuropulmonary infections, 7 with genitourinary tract infections, and 3 with soft tissue infections). Of these 35 patients, 18 (51.4%) were seriously or critically ill. In vitro susceptibility testing revealed that 90.4% of the pathogens isolated were susceptible to cefotaxime (minimal inhibitory concentration, less than 8 micrograms/ml), 4.8% were intermediately susceptible (minimal inhibitory concentration, 8 to 32 micrograms/ml), and 4.8% were resistant (minimal inhibitory concentration, greater than 32 micrograms/ml). A total of 34 of the 35 patients (97%) were clinically and bacteriologically cured of their infections. Adverse reactions occurred in two patients, but these reactions did not require interruption of therapy.

An activity-based sleep monitor system for ambulatory use.

Wrist activity measured with a piezoceramic transducer was digitized and analyzed together with subjects' sleep/wake status to derive an optimal method for automatic computer sleep/wake scoring. Several algorithms for quantifying periods of activity were considered, and an algorithm that summed changes in activity level over a 2-s interval was found most sensitive. A computer program for scoring sleep/wake from the resulting digital activity records was then developed, and parameters derived by comparison with subjects' sleep/wake status as determined by EEG. EEG and activity sleep/wake scores agreed 94.46% of the time. A further prospective test of the automatic scoring system with new data yielded agreement of 96.02%. Finally, the data collection and recording functions were implemented in a wearable microprocessor-based digital activity monitor. The automatic scoring program was adjusted to use activity data collected by this monitor, and agreed 93.88% with EEG scoring. A prospective test with new data agreed 93.04% with EEG. Automatic scoring of activity data for sleep/wake is not only fast and accurate, but allows sleep to be monitored in non-laboratory situations. In addition, the score is objective and reliable, and free of scorer bias and drift.