Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap.

The neurodevelopmental outcome of very low birth weight infants experiencing early-onset intraventricular hemorrhage (IVH) occurring within the first 6 postnatal hours was compared with that of their peers without early-onset IVH at 3 years corrected age. The 440 surviving preterm infants (birth weight 600 to 1,250 g) who had been enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH were evaluated with the Stanford-Binet Intelligence Scale and neurological examinations at 3 years corrected age. All study infants had echoencephalography between 5 and 11 hours of life, and testing is reported for all children residing in English monolingual households at 3 years corrected age (i.e., from the obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first 5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%) children without early-onset hemorrhage who were alive at 3 years corrected age (P<.001). Eleven of the 29 (38%) English monolingual children with early-onset IVH had Stanford-Binet intelligence quotient scores of less than 70, compared with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28 (25%) early IVH children were found to have cerebral palsy, compared with 20 of 241 (8%) children without early IVH (P = .01). These data suggest that infants who experience the early onset of IVH are at high risk for both cognitive and motor handicaps at 3 years corrected age.

Six new Eimeria species from vespertilionid bats of North America.

Twenty species of bats (Molossidae, Vespertilionidae) were collected from California, New Mexico, Oregon, South Carolina, Utah, and Baja California Norte (Mexico), and 29 of 404 (7%) animals, including Antrozous pallidus, Eptesicus fuscus, Myotis auriculus, Myotis californicus, Myotis ciliolabrum, Myotis evotis, Myotis lucifugus, Myotis thysanodes, Myotis vivesi, Myotis volans, Myotis yumanensis, and Nycticeius humeralis were infected with Eimeria spp., which represent 6 new species. Sporulated oocysts of a new species from A. pallidus are subspheroidal, 24.8 x 21.6 (22-27 x 19-24) microm with a polar granule and a large globular residuum. The oocyst wall is sculptured, with 2 layers, approximately 1.5 thick. Ovoidal sporocysts are 11.5 x 7.8 (9-13 x 7-10) microm, with Stieda body and residuum of many large granules. Sporulated oocysts of a new species from M. californicus are subspheroidal, 20.7 x 18.2 (19-23 x 16-20) microm, with 1-7 tiny polar granules, but without oocyst residuum. The oocyst wall is rough, with 2 layers, approximately 1.4 thick. Ovoidal sporocysts are 11.2 x 7.3 (10-12 x 7-8) microm, with Stieda body and a globular residuum. Sporulated oocysts of a second new species from M. californicus are subspheroidal, 23.1 x 20.7 (20-26 x 19-23) microm, with residuum and 1 polar granule, but a micropyle is absent. The oocyst wall is rough with 2 layers, approximately 1.5 thick. Ovoidal sporocysts are 12.5 x 7.2 (11-14 x 7-8) microm, with a Stieda body and residuum. Sporulated oocysts of a new species from M. ciliolabrum are subspheroidal, 24.9 x 20.1 (18-27 x 17-23) microm, with 1-2 polar granules, but without micropyle and residuum. The oocyst wall is rough with 2 layers, approximately 1.5 thick. Ellipsoidal sporocysts are 12.5 x 9.0 (8-14 x 7-10) microm, with Stieda and substieda bodies and residuum. Sporulated oocysts of a new species from M. evotis are subspheroidal, 21.3 x 18.6 (20-24 x 15-20) microm, with a prominent polar granule, but without micropyle and residuum. The oocyst wall is smooth with 2 layers, approximately 1.0 thick. Ovoidal sporocysts are 12.2 x 8.0 (11-13 x 7.5-9) microm, with Stieda and substieda bodies and residuum. Sporulated oocysts of the new species from N. humeralis are subspheroidal, 22.4 x 18 (21-24 x 17-20) microm, with 1-3 polar granules, but residuum and micropyle are absent. The oocyst wall is lightly sculptured with 2 layers, approximately 1.4 thick. Ovoidal sporocysts are 10.9 x 7.7 (9-12 x 6-8) microm, with Stieda body and residuum. Sporulated oocysts of E. pilarensis Scott and Duszynski, 1997 and those of at least 12 other morphological forms were seen in the other infected bats; these latter forms were seen in too few numbers to be adequately described as new species.

Eimeria from bats of Bolivia: two new species from vespertilionid bats.

Between 1985 and 1987, fecal samples were collected from 71 bats representing 14 species (Desmodontidae, Molossidae, Noctilionidae, Phyllostomidae, Vespertilionidae) from 8 localities in 3 states (Beni, Pando, Santa Cruz) in Bolivia, South America. Of these, 2 black myotid bats (Vespertilionidae), Myotis nigricans, and 1 tent-making bat (Phyllostomidae), Uroderma magnirostrum, had oocysts in their feces that represent undescribed species of Eimeria. The new species from M. nigricans (2/4, 50%) has sporulated oocysts that are subspheroidal, 18.9 x 16.9 (17-23 x 14-20) microm, without a micropyle; oocyst residuum of 6-8 spheroidal globules and 1 highly refractile polar granule are present. The oocyst wall has 2 layers (approximately 1.3 microm thick), with a rough outer layer. Ovoidal sporocysts are 10.1 x 7.4 (7-14 x 5-10) microm, with a Stieda body, substieda body, and a sporocyst residuum. The new eimerian species from U. magnirostrum (1/2, 50%) has sporulated oocysts that are subspheroidal to ellipsoidal, 23.8 x 20.8 (20-26 x 19-24) microm, without micropyle or oocyst residuum, but 1-3 polar granules are present. The oocyst wall has 2 layers (approximately 1.5 microm thick), with a rough, mammilated outer layer. Ovoidal sporocysts are 11.6 x 8.6 (10-12 x 7-10) microm, with a Stieda body, substieda body and a sporocyst residuum.

Formula supplementation with long-chain polyunsaturated fatty acids: are there developmental benefits?

OBJECTIVE: To evaluate the developmental outcomes of children who participated in an augmented randomized clinical trial of supplementing a standard infant formula with long-chain polyunsaturated fatty acids. DESIGN: Randomized clinical trial, augmented with a nonrandomized human milk comparison group. There were three randomized formula groups: standard formula, standard formula containing docosahexaenoic acid (DHA), and standard formula containing DHA and arachidonic acid. SETTING: Three clinical sites serving diverse populations: Kansas City, MO; Portland, OR; and Seattle, WA. PARTICIPANTS: A total of 274 healthy full-term infants were enrolled in the infant-feeding protocol; of these, 197 (72%) participated in assessments of developmental outcome. Formula Supplements. In the randomized trial, one group received a standard formula, another group received a formula that had been supplemented with DHA from fish oil, and a third group received a formula supplemented with both DHA and arachidonic acid from an egg phospholipid. OUTCOME MEASURES: Mental and Motor Scales of the Bayley Scales of Infant Development at 12 months of age; vocabulary and gesture communication scores from the MacArthur Communicative Development Inventories at 14 months of age. RESULTS: There were no statistically significant differences for either the Bayley Mental Scale or the Bayley Motor Scale, neither when the analysis was restricted to the three randomized formula groups nor when the analysis included all four groups. However, the DHA formula group had significantly lower scores on two of the MacArthur scales: the DHA group scored lower than the nonrandomized human milk comparison group on the Vocabulary Comprehension Scale, and the DHA group scored lower than the randomized control formula group on the Vocabulary Production Scale. Moreover, additional analyses both in the formula groups and in the human milk comparison group found significant negative correlations between DHA levels and vocabulary outcomes. CONCLUSION: We believe that additional research should be undertaken before the introduction of these supplements into standard infant formulas.

Eimeria from bats of the world: two new species from Myotis spp. (Chiroptera: Vespertilionidae).

Between 1986 and 1995, 548 fecal samples were collected from 41 species of bats (Molossidae, Mormoopidae, Phyllostomidae, Thyropteridae, and Vespertilionidae) from New Mexico, California, Baja California Sur (Mexico), and Bolivia. Of these, the feces of 28 (5%) bats, including Antrozous pallidus, Myotis ciliolabrum, Myotis lucifugus, and Myotis yumanensis (Vespertilionidae), contained oocysts representing at least 3 species of Eimeria. A new species of eimerian from M. lucifugus (3/27, 11%) and M. yumanensis (8/70, 11%) is described. Sporulated oocysts are ellipsoidal, 22.3 x 14.8 (18-25 x 13-16) microns with micropyle (approximately 2 microns) and polar granules (1-4), but an oocyst residuum is absent. The oocyst wall is slightly rough exteriorly and has 2 layers (total < or = 1 micron thick). Football-shaped sporocysts are 8.1 x 6.6 (8-11 x 5-7) microns, each with a Stieda body and granular sporocyst residuum present. A new eimerian from M. yumanensis (4/70, 6%) and M. ciliolabrum (1/12, 8%) also is described. Sporulated oocysts are spheroidal to subspheroidal, 15.0 x 14.1 (14-16 x 14-16) microns, with micropyle and oocyst residuum absent; a polar granule is present. The wall is smooth and has 2 layers (total < 1 micron thick). Sporocysts are football-shaped, 7.1 x 5.9 (6-9 x 5-7) microns, each with a Stieda body and sporocyst residuum. The sporulated oocysts of a third morphotype, found in A. pallidus (12/85, 14%), were indistinguishable from those of Eimeria arizonensis, a species typically found in murid rodents. The currently recognized species of bat Eimeria are listed, and a dichotomous key is provided.

Long-term perspective on premature infant outcome and contemporary intervention issues.

Despite improvements in survival rates for low birthweight (LBW) infants, the prevalence among survivors of major neurodevelopmental impairment seems relatively stable. Cerebral palsy, the most common major impairment, can usually be ruled out by 18 months corrected age. Minor impairments such as learning disabilities cannot be ruled out until much later. The efficacy of interventional services in this population was addressed by a national randomized trial. The intervention produced large treatment effects for heavier LBW infants and moderate effects for lighter infants. Five years later, modest residual effects were found for heavier LBW infants, but not for the lighter, suggesting that 0 to 3 services alone are not sufficient to prevent scholastic disadvantage in this population.

Results at age 8 years of early intervention for low-birth-weight premature infants. The Infant Health and Development Program.

OBJECTIVE: To reevaluate at age 8 years children who had participated during the first 3 years of life in a randomized clinical trial of special services for low-birthweight (LBW) premature infants. DESIGN: Follow-up of a randomized controlled trial of premature infants (< or = 37 weeks' gestation), stratified by 2 LBW groups (lighter [< or = 2000 g] and heavier [2001-2500 g]) and divided into intervention (n=377) and follow-up only (n=608) groups. SETTING: Eight sites serving diverse populations. PARTICIPANTS: At age 8 years, 874 children were assessed: 336 in the intervention group and 538 in the follow-up only group. INTERVENTION: The 3-year intervention consisted of home visits (birth to 3 years), child development center services (ages 1 to 3 years), and parent group meetings (ages 1 to 3 years). PRIMARY OUTCOME MEASURES: Cognitive functioning (Weschler Intelligence Scale for Children-III; Peabody Picture Vocabulary Test-Revised); academic achievement (Woodcock-Johnson Tests of Achievement-Revised); and parental reports of school performance, behavior (Child Behavior Checklist), and health (Child General Health Survey). RESULTS: At age 8 years, in the entire cohort and in the lighter LBW stratum, the intervention and follow-up only groups were similar on all primary outcome measures. Differences favoring the intervention group were found within the heavier LBW group: full-scale IQ score (4.4 points higher, P=.007), verbal IQ score (4.2 points higher, P=.01), performance IQ score (3.9 points higher, P=.02), mathematics achievement score (4.8 points higher, P=.04), and receptive vocabulary score (6.7 points higher, P=.001). On a physical functioning subscale, the whole intervention group received less favorable ratings, while the lighter LBW intervention group had lower maternal ratings assessing social limitations caused by behavior. CONCLUSION: Although at age 8 years there were modest intervention-related differences in the cognitive and academic skills of heavier LBW premature children, attenuation of the large favorable effects seen at 3 years was observed in both the heavier and lighter LBW groups. This indicates a need to develop additional intervention strategies for LBW premature children that can provide sustained benefits.

Neurodevelopmental outcome at 36 months' corrected age of preterm infants in the Multicenter Indomethacin Intraventricular Hemorrhage Prevention Trial.

OBJECTIVES: Low-dose indomethacin has been shown to prevent intraventricular hemorrhage (IVH) in very low birth weight neonates, and long-term neurodevelopmental follow-up data are needed to validate this intervention. We hypothesized that the early administration of low-dose indomethacin would not be associated with adverse cognitive outcome at 36 months' corrected age (CA). METHODS: We enrolled 431 neonates of 600 to 1250 g birth weight with no IVH at 6 to 12 hours in a randomized, prospective trial to determine whether low-dose indomethacin would prevent IVH. A priori, neurodevelopmental follow-up examinations, including the Stanford-Binet Intelligence Scale and Peabody Picture Vocabulary Test-Revised, and standard neurologic examinations were planned at 36 months' CA. RESULTS: Three hundred eighty-four of the 431 infants survived (192 [92%] of 209 infants receiving indomethacin versus 192 [86%] of 222 infants receiving saline), and 343 (89%) children were examined at 36 months' CA. Thirteen (8%) of the 166 infants who received indomethacin and 14 (8%) of 167 infants receiving the placebo were found to have cerebral palsy. There were no differences in the incidence of deafness or blindness between the two groups. For the 248 English-monolingual children for whom IQ data follow, the mean gestational age was significantly younger for the infants who received indomethacin than for those who received the placebo. None of the 115 infants who received indomethacin was found to have ventriculomegaly on cranial ultrasound at term, compared with 5 of 110 infants who received the placebo. The mean +/- SD Stanford-Binet IQ score for the 126 English-monolingual children who had received indomethacin was 89.6 +/- 18.92, compared with 85.0 +/- 20.79 for the 122 English-monolingual children who had received the placebo. Although maternal education was strongly correlated with Stanford-Binet IQ at 36 months' CA, there was no difference in educational levels between mothers of the infants receiving indomethacin and the placebo. CONCLUSIONS: Indomethacin administered at 6 to 12 hours as prophylaxis against IVH in very low birth weight infants does not result in adverse cognitive or motor outcomes at 36 months' CA.

Acute joint inflammation--mechanisms and mediators.

1. This review discusses factors contributing to acute joint inflammation, particularly sensory neuropeptides. 2. Mediators known to contribute importantly to the inflammatory process include cytokines, eicosanoids, complement and the kinin systems, histamine and 5-hydroxytryptamine and sensory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP). 3. The pro-inflammatory neurokinins, SP and CGRP, are present in nerves innervating joints and could significantly contribute to the increased vascular permeability and hyperaemia occurring in acute arthritis. 4. Although perhaps contributing to the pathogenesis of chronic inflammatory joint disease, there is little evidence for involvement of the sympathetic nervous system in acute models of inflammation.

Early intervention in low-birth-weight premature infants. Results through age 5 years from the Infant Health and Development Program.

OBJECTIVE: To evaluate the persistence of effects on health and development at age 5 years of the Infant Health and Development Program, an early childhood intervention that was provided to low-birth-weight (LBW) premature infants from neonatal discharge through age 3 years. DESIGN: Randomized, controlled, multicenter trial, stratified by two LBW groups: lighter (< or = 2000 g) and heavier (2001 to 2500 g). SETTING: Eight socioeconomically heterogeneous clinical sites. PARTICIPANTS: Of 985 eligible infants weighing 2500 g or less and at 37 weeks' or less gestational age, 377 infants were randomly assigned to the intervention group and 608 to the follow-up only group. About two thirds of the infants in each group were in the lighter LBW stratum, and one third were in the heavier LBW stratum. INTERVENTION: The intervention group received home visits (from neonatal discharge through age 3 years) as well as center-based schooling (from 1 to 3 years of age). Children in both groups received pediatric surveillance. MAIN OUTCOME MEASURES: Cognitive development, behavioral competence, and health status. RESULTS: At age 5 years, the intervention group had full-scale IQ scores similar to children in the follow-up only group. However, in the heavier LBW stratum, children in the intervention group had higher full-scale IQ scores (3.7 points higher; P = .03) and higher verbal IQ scores (4.2 points higher; P = .02). No significant differences between intervention and follow-up only groups in cognitive measures at age 5 years were noted in the lighter LBW infants. The intervention and follow-up groups were similar in behavior and health measures regardless of LBW stratum. CONCLUSION: The early childhood intervention provided in the first 3 years of life had effects on heavier LBW premature infants' IQ and verbal performance at age 5 years that were not observed for lighter LBW premature infants. The intervention did not affect health or behavior at age 5 years in either LBW stratum.

Excitation of soleus/gastrocnemius gamma-motoneurones by group II knee joint afferents is suppressed by group IV joint afferents in the decerebrate, spinalized cat.

Electrical stimulation sufficient to excite group II/III afferent fibres in the posterior articular nerve (PAN) of the cat knee joint facilitated gamma-motoneurone firing in filaments of the lateral gastrocnemius/soleus (LGS) nerve. Repetitive (0.5-2.0 Hz) electrical stimulation of the PAN, produced a short latency increase of gamma-motoneurone firing with a latency ranging from 8 to 35 ms. The shortest of these delays suggests a segmental link between group II knee joint afferents and lateral gastrocnemius/soleus gamma-motoneurones. This facilitation was diminished or abolished if the first stimulus was preceded by a conditioning stimulus which excited the group IV afferents in the PAN. This depression of facilitation was dependent on the interval between the test and conditioning stimuli and the interval which produced the greatest depression was consistent with the effect being due to group IV afferents. Inhibition of the facilitation did not significantly alter the on-going discharge rate of the gamma-motoneurones. This suggests that it was not due to direct inhibition of the motoneurones.

Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial.

OBJECTIVES: Parenchymal involvement of intraventricular hemorrhage (IVH) is a major risk factor for neurodevelopmental handicap in very low birth weight neonates. Previous trials have suggested that indomethacin would lower the incidence and severity of IVH in very low birth weight neonates. METHODS: We enrolled 431 neonates of 600- to 1250-g birth weight with no evidence for IVH at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that low-dose indomethacin (0.1 mg/kg intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would lower the incidence and severity of IVH. Serial cranial ultrasound examinations and echocardiographs were performed. RESULTS: There were no differences in the birth weight, gestational age, sex, Apgar scores, and percent of neonates treated with surfactant between the indomethacin and placebo groups. Within the first 5 days, 25 (12%) indomethacin-treated and 40 (18%) placebo-treated neonates developed IVH (P = .03, trend test). Only one indomethacin-treated patient experienced grade 4 IVH compared with 10 placebo-treated neonates (P = .01). Sixteen indomethacin-treated neonates and 29 control neonates died (P = .08); there was a difference favoring indomethacin with respect to survival time (P = .06). Eighty-six percent of all neonates had a patent ductus arteriosus on the first postnatal day; indomethacin was associated with significant ductal closure by the fifth day of life (P < .001). There were no differences in adverse events attributed to indomethacin between the two treatment groups. CONCLUSIONS: Low-dose prophylactic indomethacin significantly lowers the incidence and severity of IVH, particularly the severe form (grade 4 IVH). In addition, indomethacin closes the patent ductus arteriosus and is not associated with significant adverse drug events in very low birth weight neonates.

Prediction of the development of low birth weight preterm infants by a new neonatal medical index.

A new neonatal medical index (NMI) was used to predict the mental and motor development of low birth weight, preterm infants up to 3-years-old. The NMI is a summary score of only a few clinically salient items that are readily available on brief chart review. The sample consisted of 512 of 608 infants randomly assigned to the control group of the eight-site Infant Health and Development Program and on whom the complete set of developmental outcome measures was available. The developmental tests administered were the Bayley Scales at 12 and 24 months and the Stanford-Binet at 3 years. The findings indicated the NMI was predictive of later cognitive and motor development, and in infants born weighing less than 1500 g, the effects of neonatal medical complications continued to adversely influence these children's development to at least 3 years of age. In the heavier babies the developmental effects of sociodemographic factors predominated by 24 months and beyond.

Acute inflammation enhances substance P-induced plasma protein extravasation in the rat knee joint.

Acute inflammation of the rat knee joint was induced by intra-articular injection of 2% carrageenan. Intra-articular perfusion of the inflamed joint with substance P (SP) exacerbated the inflammatory condition as assessed by the degree of plasma protein extravasation into the synovial cavity. Protein extravasation induced by SP was enhanced and more persistent in the inflamed rat knee compared to normal animals. The time course of the response in the inflamed rat knee was related to SP concentration whilst the persistency of the response was positively correlated with the initial level of joint inflammation.

Time course of substance P-induced protein extravasation in the rat knee joint measured by micro-turbidimetry.

Intra-articular perfusion of the rat knee joint with substance P (SP) resulted in protein extravasation into the synovial cavity. This response was tested over a range of SP concentrations from 100 pM to 100 microM. The response was dose dependent from 10 nM to 10 microM, with each dose producing a steady rise of the protein content in the fluid aspirated from the synovial cavity for 12-16 min and then fell sharply again over an equivalent period despite continuing perfusion with SP. Concentrations below 10 nM gave rise to very brief increases in protein extravasation whose magnitude differed little over the range of 100 pM to 10 nM but differed significantly from control (saline) perfusion.

Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study.

Opioid analgesia requirements, distribution into breast milk, and influence on neonatal neurobehavior were evaluated in ten parturient-neonate pairs nursing after elective cesarean section during epidural anesthesia. Five patients received first a loading dose of intravenous meperidine after umbilical cord clamping, then patient-controlled analgesia (PCA) with intravenous meperidine, and finally meperidine tablets as needed. Five patients received morphine in the same manner. Treatment groups showed no differences with respect to neonatal Apgar scores or visual analog scale (VAS) pain or satisfaction scores at 24 and 48 h postpartum. Breast milk specimens, obtained at 12, 24, 36, 48, 72, and 96 h postpartum and analyzed for opioids and metabolites, showed persistently elevated normeperidine concentrations in the meperidine group. A blinded psychologist evaluated each infant once on the 3rd day of life with the Brazelton Neonatal Behavioral Assessment Scale (NBAS). A priori, the "alertness" and three "human orientation" outcomes of the NBAS were chosen for analysis as best measures of opioid-induced effects. On all four outcomes, neonates in the morphine group scored significantly higher (P less than 0.05) than neonates in the meperidine group. We conclude that post-cesarean delivery PCA with morphine provides equivalent maternal analgesia and overall satisfaction as that provided by PCA with meperidine, but with significantly less neurobehavioral depression among breast-fed neonates on the 3rd day of life.

Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very low birth weight neonates.

We admitted 36 preterm neonates (600 to 1250 gm birth weight) with normal 6-hour echoencephalograms to a randomized, placebo-controlled prospective trial to determine whether a low dose of indomethacin would prevent germinal matrix or intraventricular hemorrhage and permit adequate urinary output. Between the sixth and tenth postnatal hours, indomethacin (0.1 mg/kg) or placebo was administered intravenously every 24 hours for a total of three doses. Cardiac ultrasound studies to assess the status of the ductus arteriosus were performed at 6 postnatal hours and on day 5. Urinary output, serum electrolytes, serum indomethacin levels, and renal and clotting functions were monitored. No differences in birth weight, gestational age, or Apgar scores were noted between the two groups of infants. Two indomethacin-treated infants and three infants given placebo had significant urinary output difficulties, requiring that the study medication be withheld. Of 19 infants given indomethacin, two had germinal matrix or intraventricular hemorrhage, in comparison with 8 of 17 infants given saline solution (p = 0.02). Of the infants who had a left-to-right patent ductus arteriosus shunt before treatment, 64% of the indomethacin-treated and 33% of the saline solution-treated infants no longer had a patent ductus arteriosus on day 5. Ductal status appeared unrelated to the development of germinal matrix or intraventricular hemorrhage.