Estrogen replacement raises rat CRP without evidence of complement activation

Given current controversies regarding anti- and pro-inflammatory effects of estrogen, there is a need to explore relationships between gonadal hormones and inflammation using appropriate animal models. It has been proposed that rats are not appropriate for such research since, contrary to the effect of estrogen in humans, earlier animal studies had reported that estrogen downregulates serum C-reactive protein (rCRP) levels in the rat. With these considerations in mind, we re-examined the effects of estrogen withdrawal and replacement on CRP expression and complement activation in the rat. F-344 rats underwent bilateral ovariectomy or sham surgery at 9-10 months of age. Four months later, ovariectomized rats were treated with traditional high-dose 17beta-estradiol (Hi-E2) capsules, lower-dose (Lo-E2) 17beta-estradiol capsules, or placebo capsules for 7 days prior to sacrifice. Levels of plasma rat C-reactive protein (rCRP) were significantly lower in ovariectomized vs. sham-operated animals (415.5 +/- 10.6 vs. 626.6 +/- 23.0 mg/L, p < 0.001). Estrogen replacement significantly raised rCRP levels in ovariectomized animals (690.0 +/- 28.0 mg/L in Lo-E2 and 735.5 +/- 35.8 mg/L in Hi-E2, respectively, p < 0.001). Plasma rCRP levels correlated significantly with both hepatic rCRP (r = 0.79, p < 0.001) and serum estradiol (r = 0.70, p < 0.001) levels. However, no significant differences were observed in indices of complement activation (C4b/c) or CRP-complement complex generation (rCRP-C3 complex). In the mature female rat, ovariectomy reduces and estrogen replacement raises rCRP. Effects of estrogen on plasma rCRP induction are mediated, at least in part, through hepatic mechanisms and do not appear to require or be associated with complement activation.     

Extracellular granzyme A, complexed to proteoglycans, is protected against inactivation by protease inhibitors

Granzyme A (GrA) and B (GrB) together with perforin are the main constituents of cytotoxic granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The cytotoxic proteins are released to deliver a lethal hit during contact between the CTL or NK cell and target cell. With the use of an enzyme-linked immunosorbent assay for antigenic levels, we showed in a recent study that plasma of patients with activated CTLs and NK cells contain elevated levels of extracellular GrA. In this study, we determined the form and proteolytic capacity of this extracellular GrA detected in plasma. With the use of various assays, we show that part of the extracellular GrA circulates in the mature conformation and is bound to proteoglycans that protect it against inactivation by protease inhibitors, such as antithrombin III and alpha-2-macroglobulin, whereas another part of GrA circulates as a complex with antithrombin III. Finally, with the use of a novel assay for active GrA, we demonstrate that some plasma samples with high levels of extracellular GrA contain active GrA. These results suggest that various forms of extracellular GrA occur in vivo and that the regulation of GrA activity may be modified by proteoglycans. These data support the notion that granzymes may exert extracellular functions distant from the site of CTL or NK cell interaction with their target cells. (Blood. 2000;95:1465-1472)     

Very-low-birthweight children and speech and language development.

Very low birthweight (VLBW) is often considered to be a risk factor for speech and language disorders, yet data are equivocal. The present study compared speech and language comprehension and production between 249 very-low-birthweight (VLBW: less than 1.5 kg) and 363 normal-birthweight 8-year-olds, randomly sampled in a geographic area. Mean performance for the entire group of VLBW children and for the group when 24 VLBW children with major neurologic abnormalities were excluded, was significantly lower than for controls on the majority of speech and language measures. Further analyses addressed the clinical significance of these statistically significant differences. Test scores were converted to standard scores and grouped according to standard deviation intervals, thus portraying each child's performance in terms of the magnitude of discrepancy from each test's mean. When the 24 children with major neurological abnormalities were excluded, no significant differences between the VLBW and control children were observed. Using discrepancy between WISC-R performance IQ and language to define specific language impairment (SLI), a higher percentage of control than VLBW children were identified as having SLI. Neonatal risk factors did not differentiate between VLBW children with or without SLI. A higher proportion of VLBW than control children did present subnormal language associated with IQ less than 85, hearing deficits, and/or major neurological impairments. Thus, SLI is not more common among VLBW than control children. Language deficits accompanied by more general developmental problems, however, are more frequent.     

Differential effects of intrauterine and postnatal brain growth failure in infants of very low birth weight

We investigated the contribution of brain growth failure to outcome in infants of very low birth weight (VLBW; less than 1.5 kg) who were appropriate for gestational age (AGA; n = 379) or small for gestational age (SGA; n = 102). Growth was assessed at birth, term, and 8 and 20 months' corrected age and results of a Bayley Mental Developmental Index (MDI) and neurologic examination were evaluated at 20 months of age. Both groups had similar 20-month MDI scores (93 vs 90) and similar rates of neurologic impairment (14% vs 10%). More SGA infants (25%) than AGA infants (14%) had a subnormal head circumference at 8 months' corrected age, indicating failure to catch up in head growth. Subnormal head size at 8 months predicted the 20-month MDI score for both groups. However, multivariate analysis indicated that, whereas subnormal 8-month head size was directly associated with the MDI score in AGA children, in SGA children 8-month head size was not significantly related to the MDI score when neonatal illness, neurologic impairment, socioeconomic status, and race were controlled for. We conclude that in AGA VLBW infants, subnormal head size at 8 months results from major neonatal illness and has adverse later effects. In SGA infants, subnormal head size at 8 months has many causes, including growth retardation in utero, which may not have an adverse effect on outcome; if subnormal head size is superimposed with neonatal illness, a poorer outcome is likely.     

Severity of necrotizing enterocolitis: influence on outcome at 2 years of age

The long-term outcome of very low birth weight (VLBW) infants with necrotizing enterocolitis has been reported to be similar to that of other VLBW infants. To examine the influence of disease severity on outcome, the growth and neurodevelopment of survivors of necrotizing enterocolitis were evaluated when the babies were 20 months' corrected age. Between 1975 and 1983, 1506 VLBW infants were admitted to the hospital, and necrotizing enterocolitis developed in 84 (5.6%). Forty infants (48%) survived to be 20 months' corrected age, and complete follow-up data were available for 36. Survivors were classified by modified Bell's criteria into four groups by increasing severity of disease; 13 had mild necrotizing enterocolitis (stage IIA, IIB), and 23 had severe necrotizing enterocolitis (stage IIIA, IIIB). The 36 survivors were compared with 766 surviving VLBW infants without necrotizing enterocolitis. There were no perinatal or socioeconomic differences between groups. Compared with infants with stage II necrotizing enterocolitis at 20 months, infants with stage III necrotizing enterocolitis had a higher rate of subnormal body weight (39% vs 15%) and subnormal head circumference (30% vs 0%). Thirty-three percent of necrotizing enterocolitis survivors had significant neurodevelopmental impairment; the majority of impaired infants (10 of 12) were survivors of stage III necrotizing enterocolitis. These findings highlight the importance of continued evaluations for medical and neurodevelopmental sequelae.     

Effects of oleoresin capsicum pepper spray on human corneal morphology and sensitivity

PURPOSE: To examine the potential harmful effects on corneal structure, innervation, and sensitivity of a spray containing the neurotoxin capsaicin (oleoresin capsicum, OC). METHODS: Ten police officers who volunteered for the study were exposed to OC. Clinical signs were assessed. Corneal sensitivity was measured using a Cochet-Bonnet or a noncontact esthesiometer that provides separate measurements of mechanical, chemical, and thermal sensitivity. Tear fluid nerve growth factor (NGF) was measured. Corneal cell layers and subbasal nerves were examined by in vivo confocal microscopy. The subjects were examined before application and 30 minutes, 1 day, 1 week, and 1 month after OC exposure. RESULTS: OC spray produced occasional areas of focal epithelial cell damage that healed within 1 day. Each eye showed conjunctival hyperemia and in two subjects, mild chemosis. All except one eye had unchanged best corrected visual acuity (BCVA). A transient decrease (day 1) of mechanical sensitivity was observed with the Cochet-Bonnet esthesiometer. With the gas esthesiometer, mechanical sensitivity remained below normal values for 7 days. Chemical sensitivity to CO2 was high for as much as 1 day and decreased below normal 1 week later, whereas sensitivity to cold was unaffected. Two subjects had measurable tear NGF that increased after exposure. Basal epithelial cell morphology suggested temporary corneal epithelial swelling, whereas keratocytes, endothelial cells, and subbasal nerves remained unchanged. CONCLUSIONS: Although OC causes immediate changes in mechanical and chemical sensitivity that may persist for a week, a single exposure to OC appears harmless to corneal tissues. The changes are possibly associated with damage of corneal nerve terminals of mainly unmyelinated polymodal nociceptor fibers.     

How small is too small? Considerations in evaluating the outcome of the tiny infant

An aggressive approach to the obstetric and neonatal care of the pregnant mother and her infant in the late second trimester has led to an increase in survival. Surviving infants have a high rate of neonatal morbidity, including bronchopulmonary dysplasia and intraventricular hemorrhage. No long-term follow-up reveals handicap rates of 22 to 35 per cent, with multiple sensory and neurodevelopmental handicaps. With current methods of care, the biologic threshold of extrauterine survival is 23 to 24 weeks' gestation, or a birth weight of 500 to 600 gm. There is no simple arithmetical answer to the question of "how small is too small?" It should be apparent from the information presented in this article that the state of the art is constantly in flux. New developments have, to date, continued to decrease the threshold of viability. Application of the full weight of the available technology results in only a few infants of less than 23 to 24 weeks' gestation or with birth weights of less than 500 to 600 gm surviving. The future continues to lie in the development of the methodology to prolong the sojourn in utero, rather than in dramatic biophysical, biochemical, and technologic advances.     

Transcutaneous oxygen tension during nonnutritive sucking in preterm infants

The effects of nonnutritive sucking on transcutaneous oxygen tension, heart rate, and respiratory rate were studied sequentially in 14 sleeping preterm infants breathing room air. Transcutaneous oxygen tension increased during nonnutritive sucking in infants between 32 and 35 weeks postconceptional age, but not in those between 36 and 39 weeks. This response was not associated with a change in respiratory rate or sleep state, although heart rate tended to increase. These data offer further support for the beneficial effects of nonnutritive sucking in preterm infants.     

Multicenter evaluation of SonoVue for improved endocardial border delineation

OBJECTIVES: Two multicenter studies were conducted to evaluate the safety and efficacy of SonoVue as a contrast agent for enhanced left ventricular endocardial border delineation (LVEBD), and to compare the efficacy of SonoVue and Albunex in adult patients with a suboptimal, nonenhanced echocardiogram. BACKGROUND: The use of contrast to enhance echocardiographic assessment of LVEBD is well-established. SonoVue is a new microbubble contrast agent that contains sulfur hexafluoride. METHODS: Patients were randomized to receive four injections of SonoVue (0.5, 1, 2, and 4 ml), or two injections of Albunex and two injections of hand-agitated saline (0.08 and 0.22 ml/kg). Echocardiographic images were evaluated at the study centers and by four blinded, offsite reviewers for degree of left ventricle opacification (LVO), duration of contrast enhancement, and LVEBD. RESULTS: LVO scores were significantly higher for all doses of SonoVue. Patients with complete LVO ranged from 34%-87% for SonoVue and from 0%-16% for Albunex. The mean duration of useful contrast effect ranged from 0.8-4.1 minutes for SonoVue and < 15 seconds for Albunex. Mean increases in LVEBD scores ranged from 3.8-18.2 for SonoVue and 0.1-4.3 for Albunex. SonoVue (cumulative 7.5 ml dose) was well-tolerated, with a safety profile similar to that observed in the control group. CONCLUSIONS: SonoVue is superior to Albunex for improving visualization of endocardial borders in patients with suboptimal noncontrast echocardiograms. Optimal increases in LVEBD, LVO, and duration of useful contrast effect were observed at the 2.0 ml dose of SonoVue.     

A case of melioidosis of the breast present at screening mammography

A previously well 54-year-old woman presented for screening mammography with a 3-day history of an inflamed lump in her right breast. She was subsequently admitted to hospital with acute melioidosis where right breast abscesses were drained. Following recovery and discharge, she was reviewed at the mammographic screening unit where her previous abnormal mammogram was found to be due to melioidosis. To our knowledge this is the first reported case of melioidosis of the breast and its appearance on mammography and ultrasound are described.