Slow, programmed maturation of the immunoglobulin HCDR3 repertoire during the third trimester of fetal life.

The mean distribution of lengths in the third complementarity-determining region of the heavy chain (HCDR3) serves as a measure of the development of the antibody repertoire during ontogeny. To determine the timing and pattern of HCDR3 length maturation during the third trimester of pregnancy, the mean distribution of HCDR3 lengths among variable-diversity-joining-constant-mu (VDJC(mu)) transcripts from the cord blood was analyzed from 138 infants of 23 to 40 weeks' gestation, including 3 sets of twins, 2 of which were of dizygotic origin. HCDR3 maturation begins at the start of the third trimester; follows a slow, continuous expansion over a 5-month period; and is unaffected by race or sex. The range and mean distribution of lengths may vary in dizygotic twins, indicating individual rates of development. The mean HCDR3 length distribution in 10 premature infants with documented bacterial sepsis was then followed for 2 to 12 weeks after their first positive blood culture. HCDR3 spectrotype analysis demonstrated oligoclonal B-cell activation and expansion after sepsis, but maturation of the repertoire was not accelerated even by the systemic exposure to external antigen represented by bacteremia. Antibody repertoire development appears to be endogenously controlled and adheres to an individualized developmental progression that probably contributes to the relative immaturity of the neonatal immune response.

Level of maternal antibody required to protect neonates against early-onset disease caused by group B Streptococcus type Ia: a multicenter, seroepidemiology study.

Because of the difficulty of conducting efficacy trials of vaccines against group B streptococcus (GBS), the licensure of these vaccines may have to rely on studies that measure vaccine-induced antibody levels that correlate with protection. This study estimates the level of maternal antibody required to protect neonates against early-onset disease (EOD) caused by GBS type Ia. Levels of maternal serum IgG GBS Ia antibodies, measured by ELISAs in 45 case patients (neonates with EOD caused by GBS Ia) and in 319 control subjects (neonates colonized by GBS Ia but without EOD) born at > or =34 weeks gestation were compared. The probability of developing EOD declined with increasing maternal levels of IgG GBS Ia antibody (P = .03). Neonates whose mothers had levels of IgG GBS Ia antibody > or =5 microg/mL had an 88% lower risk (95% confidence interval, 7%-98%) of developing type-specific EOD, compared with those whose mothers had levels < 0.5 microg/mL. A vaccine that induces IgG GBS Ia antibody levels > or =5 microg/mL in mothers can be predicted to confer a high degree of type-specific immunity to EOD to their infants.

The effectiveness of risk-based intrapartum chemoprophylaxis for the prevention of early-onset neonatal group B streptococcal disease.

OBJECTIVE: Our purpose was to evaluate the effectiveness of a risk-based intrapartum antibiotic prophylaxis strategy for the prevention of early-onset neonatal group B streptococcal disease. STUDY DESIGN: Cases and controls were selected from infants born to women with one or more risk factors: preterm labor or rupture of membranes, prolonged rupture of membranes (>18 hours), fever during labor, or previous child with group B streptococcal disease. Cases were matched with controls by birth hospital and gestational age. Data abstracted from medical records were analyzed to estimate the effectiveness of intrapartum antibiotic prophylaxis. RESULTS: We analyzed data from 109 cases and 207 controls. Nineteen (17%) case versus 69 (33%) control mothers received an acceptable regimen of intrapartum antibiotic prophylaxis. In adjusted analyses, the effectiveness of intrapartum antibiotic prophylaxis was 86% (95% confidence interval, 66%-94%). When the first dose of antibiotics was given > or =2 hours before delivery, the effectiveness increased to 89% (95% confidence interval, 70%-96%); when it was given within 2 hours of delivery, the effectiveness was 71% (95% confidence interval, -8%-92%). Effectiveness was lowest in mothers with intrapartum fever (72%, 95% confidence interval, -9%-93%). On the basis of a 70% prevalence of maternal risk factors expected among cases in the absence of intrapartum antibiotic prophylaxis, we estimate that the risk-based strategy could reduce early-onset group B streptococcal disease by 60%. CONCLUSIONS: The risk-based approach to intrapartum antibiotic prophylaxis is effective in preventing early-onset group B streptococcal disease. To achieve the maximum preventive effect, the first dose of antibiotics should be administered at least 2 hours before delivery.

Effect of cigarette smoke extract on neonatal porcine vascular smooth muscle cells.

RATIONALE: Cigarette smoke exposure in the perinatal period increases the risk of various prenatal and postnatal complications, including sudden infant death syndrome (SIDS) and persistent pulmonary hypertension of the newborn (PPHN). We investigated the cellular effects of cigarette smoke extract (CSE) in the developing vasculature. METHODS: Vascular smooth muscle cells (VSMC) were isolated from neonatal porcine carotid arteries, splenic arteries, and main and resistance pulmonary arteries. Effects of CSE on VSMC proliferation, viability, apoptosis, and media nitrates and nitrites were evaluated. The effects of known constituents of CSE (nicotine, benzopyrene, acrolein, acetaldehyde), aged CSE, CSE with added hemoglobin, devolatilized CSE, CSE with added dithiothreitol (DTT), and reduced glutathione (GSH) on cell proliferation and viability were assessed. RESULTS: CSE caused a dose- and time-dependent decrease in neonatal VSMC numbers isolated from all four sites, mainly as a result of increased cell necrosis and not apoptosis. Nitrates and nitrites were below the threshold of detection. Nicotine and benzopyrene did not affect cell counts, while acrolein and acetaldehyde decreased cell counts in a dose-dependent manner. Addition of hemoglobin, devolatilization, and the addition of DTT or GSH slightly decreased CSE inhibition. CONCLUSIONS: CSE causes necrosis of neonatal VSMC, and this toxicity is mediated mainly by volatile components such as acrolein and acetaldehyde, possibly in association with nitric oxide and carbon monoxide.

Antibiotic susceptibility profiles for group B streptococci isolated from neonates, 1995-1998.

Antibiotic susceptibility profiles were analyzed for 119 invasive and 227 colonizing strains of group B streptococci isolated from neonates at 6 US academic centers. All strains were susceptible to penicillin, vancomycin, chloramphenicol, and cefotaxime. The rate of resistance to erythromycin was 20.2% and to clindamycin was 6.9%. Resistance to erythromycin increased in 1997. Type V strains were more resistant to erythromycin than were type Ia (P=.003) and type Ib (P=.004) strains and were more resistant to clindamycin than were type Ia (P<.001), type Ib (P=.01), and type III (P=.001) strains. Resistance rates varied with geographic region: in California, there were high rates of resistance to erythromycin and clindamycin (32% and 12%, respectively), and low rates in Florida (8.5% and 2.1%, respectively). Penicillin continues to be the drug of choice for treatment of group B streptococcus infection. For women who are penicillin intolerant, however, the selection of an alternative antibiotic should be guided by contemporary resistance patterns observed in that region.

Antibiotic susceptibility profile of group B streptococcus acquired vertically.

OBJECTIVE: To determine the contemporary antibiotic susceptibility profile of vertically acquired group B streptococcal isolates. METHODS: Susceptibility to ampicillin, penicillin G, erythromycin, clindamycin, cefazolin, and gentamicin was assessed by two methods, minimal inhibitory concentration and disc diffusion. RESULTS: The susceptibility profiles of 119 colonizing and eight invasive strains of group B streptococcus isolated from January 1996 to September 1997 at two hospitals in Birmingham, Alabama-University of Alabama at Birmingham and Cooper Green-were studied. Minimal inhibitory concentration determinations indicated that all colonizing strains were susceptible or moderately susceptible to ampicillin and penicillin G. Resistance was noted by at least one strain to each of the other antibiotics; all were resistant to gentamicin, whereas 27 (21%) were resistant to erythromycin, five (4%) to clindamycin, and one (1%) to cefazolin. All of the eight invasive strains were susceptible or moderately susceptible to ampicillin, penicillin G, clindamycin, and cefazolin; one (13%) was resistant to erythromycin, and all were resistant to gentamicin. Disc diffusion results generally were concordant with minimal inhibitory concentration results, although by disc diffusion fewer isolates were classified as susceptible, and more as moderately susceptible, to ampicillin and penicillin G than by minimal inhibitory concentration. CONCLUSION: Universal susceptibility of group B streptococcus to members of the penicillin family supports the continued use of penicillin G or ampicillin for early onset neonatal group B streptococcal disease prevention. For patients allergic to beta-lactam agents, clindamycin (4% resistance) may be a better alternative than erythromycin (21% resistance).

Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Septicemia is a major antecedent of morbidity and mortality in very low birth weight (501- to 1500-g) infants. Our purpose was to determine prospectively the incidence, clinical presentation, laboratory features, risk factors, morbidity and mortality associated with late onset septicemia in infants 501 to 1500 g. METHODS: Clinical data were prospectively collected for 2416 infants enrolled in a multicenter trial to determine the efficacy of intravenous immunoglobulin in preventing nosocomial infections. Septicemia was confirmed by positive blood culture in 395 symptomatic infants. Multivariate analyses of factors associated with septicemia were performed. RESULTS: Sixteen percent of VLBW infants developed septicemia at a median age of 17 days. Factors associated with septicemia by logistic regression included male gender, lower gestational age and birth weight and decreased baseline serum IgG concentrations. Increasing apnea (55%), feeding intolerance, abdominal distension or guaiac-positive stools (43%), increased respiratory support (29%), lethargy and hypotonia (23%) were the dominant presenting features of septicemia. An abnormal white blood cell count (46%), unexplained metabolic acidosis (11%) and hyperglycemia (10%) were the most common laboratory indicators. Septicemic infants, compared with nonsepticemic infants, had significantly increased mortality (21% vs. 9%), longer hospital stay (98 vs. 58 days) and more serious morbidity, including severe intraventricular hemorrhage, bronchopulmonary dysplasia and increased ventilator days (P < 0.001). CONCLUSIONS: Late onset septicemia is common in very low birth weight infants, and the rate is inversely proportional to gestational age and birth weight. Septicemia is more common in males and those with low initial serum IgG values. A set of clinical signs (apnea, bradycardia, etc.) and laboratory values (leukocytosis, immature white blood cells and neutropenia) increase the probability of late onset sepsis, but they have poor positive predictive value.

Capsular polysaccharide types of group B streptococcal isolates from neonates with early-onset systemic infection.

The distribution of serotypes of group B streptococci (GBS) isolated from 67 infants with early-onset sepsis are described. Case-infants were assembled from 13 hospitals across the United States from 15 July 1995 to 5 February 1997 through prospective active surveillance. The distribution of GBS serotypes was Ia, 40%; Ib, 9%; II, 6%; III, 27%; V, 15%; and nontypeable, 3%. Type V occurred more frequently in the northeast region (New York and New Jersey) than in other regions (29% vs. 9%, P = .06). Conversely, type III occurred significantly less frequently in the northeast region than other regions (10% vs. 35%, P = .04). GBS types Ia, III, and V accounted for 82% of the isolates. This report supports previous observations about the emergence of GBS type V, but our data caution that conclusions about serotype distributions based on one geographic location or on a small number of patients may not be generally applicable. Continued monitoring seems necessary for the design of a GBS vaccine.

Endotoxin induces biphasic alterations in small intestinal myoelectric activity in fasted newborn piglets.

Previous studies have shown that i.v. endotoxin infusion causes gastrointestinal dysfunction and intestinal injury in piglets. The aim of this study was to investigate the effects of endotoxin on intestinal myoelectric activity in newborn swine and to correlate this with gastrointestinal and hemodynamic events. Three pairs of electrodes were implanted in the jejunal wall of piglets, and after recovery, intestinal myoelectric activity was continuously recorded in the conscious, fasted condition. The intestinal myoelectric activity on the control day showed regular, repeating migrating myoelectric complex (MMC) cycles, each of which was composed of the classic phases I, II, and III. Mean cycle duration was 67.0 +/- 18.7 min (+/- SD), and phase III comprised 9.1 +/- 2.2% of each cycle. On the next day, infusion of 30 micrograms/kg endotoxin caused an initial, prolonged quiescent period and delayed the appearance of the first postendotoxin phase III complex. After the quiescent period, there was a period of irregular spiking activity followed by several shortened MMC cycles (47.9 +/- 22.7 min, p < 0.01 versus control) with a prolongation of the percentage of time spent in phase III (15.4 +/- 11.3%, p < 0.01). Endotoxin thus produced biphasic alterations in intestinal myoelectric activity characterized by an initial quiescence followed by increased gastrointestinal smooth muscle activity. Animals developed diarrhea, hypotension, and tachycardia about 1 h after endotoxin infusion in temporal association with increased spiking activity and MMC cycling. These studies are the first to show this biphasic response to endotoxin.

Delayed thromboxane or tumor necrosis factor-alpha, but not leukotriene inhibition, attenuates prolonged pulmonary hypertension in endotoxemia.

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.

Effects of cholinergic blockade on hemodynamic disturbances and intestinal lesions in endotoxic shock in newborn piglets.

The parasympathetic nervous system actively participates in the regulation of pathophysiologic responses in circulatory shock. To determine the effects of cholinergic blockade in endotoxic shock in newborn piglets, 16 chronically instrumented newborn piglets were infused with 10 mg/kg of endotoxin over 10 min. Eight animals were injected intravenously with 10 mg/kg of anisodamine, an anticholinergic drug, 10 min before endotoxin and then with escalating doses of 2, 5, 10, and 20 mg/kg every 10 min, beginning 60 min after endotoxin. The other eight animals were given saline as a control. Endotoxin infusion caused elevations in mean pulmonary artery pressure and vascular resistance index and an initial increase in systemic artery pressure followed by hypotension. Heart rate was stable for 45 min and then increased. Cardiac index fell from a baseline of 173 +/- 20 (mean +/- S.E.) to 136 +/- 23 mL.min-1.kg-1 60 min after endotoxin. Pretreatment with anisodamine increased heart rate from 163 +/- 15 to 289 +/- 10 beats.min-1 and cardiac index from 195 +/- 15 to 238 +/- 14 mL.min-1.kg-1 before endotoxin infusion. These variables remained at higher levels than in the control group until 60 min after endotoxin infusion; thereafter, the two groups were similar. The changes in pulmonary and systemic artery pressures were not significantly altered by anisodamine. After 60 min, additional doses of anisodamine caused no significant hemodynamic responses, and the differences between the two groups were not significant. Arterial plasma thromboxane B2 levels rose immediately and tumor necrosis factor-alpha levels increased 60 min after endotoxin infusion; no significant differences were noted between groups at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network.

BACKGROUND: Nosocomial infections are a major cause of morbidity and mortality in premature infants. As a rule, their low serum gamma globulin levels at birth subsequently decline to hypogammaglobulinemic values; hence, prophylactic administration of intravenous immune globulin may reduce the rate of hospital-acquired infections. METHODS: In this prospective, multicenter, two-phase controlled trial, 2416 infants were stratified according to birth weight (501 to 1000 g and 1001 to 1500 g) and randomly assigned to an intravenous immune globulin group (n = 1204) or a control group (n = 1212). Control infants were given placebo infusions during phase 1 of the study (n = 623) but were not given any infusions during phase 2 (n = 589). Infants weighing 501 to 1000 g at birth were given 900 mg of immune globulin per kilogram of body weight, and infants weighing 1001 to 1500 g at birth were given a dose of 700 mg per kilogram. The immune globulin infusions were repeated every 14 days until the infants weighed 1800 g, were transferred to another center, died, or were sent home from the hospital. RESULTS: Nosocomial infections of the blood, meninges, or urinary tract occurred in 439 of the 2416 infants (18.2 percent): 208 (17.3 percent) in the immune globulin group and 231 (19.1 percent) in the control group (relative risk, 0.91; 95 percent confidence interval, 0.77 to 1.08). Septicemia occurred in 15.5 percent of the immune globulin recipients and 17.2 percent of the controls. During phase 1 the rate of nosocomial infections was 13.4 percent in the immune globulin group and 17.8 percent in the control group; the respective rates during phase 2 were 21.0 percent and 20.4 percent. The predominant organisms included gram-positive cocci (53.0 percent), gram-negative bacilli (22.4 percent), and candida species (16.0 percent). Adverse reactions were rarely observed during the infusions. Immune globulin therapy had no effect on respiratory distress syndrome, bronchopulmonary dysplasia, intracranial hemorrhage, the duration of hospitalization, or mortality. The incidence of necrotizing enterocolitis was 12.0 percent in the immune globulin group and 9.5 percent in the control group. CONCLUSIONS: Prophylactic use of intravenous immune globulin failed to reduce the incidence of hospital-acquired infections in very-low-birth-weight infants.

Thromboxane and pulmonary morphometry in the development of the pulmonary hypertensive response to group B streptococcus.

OBJECTIVE: To clarify the mechanism of the development of a severe pulmonary hypertensive response to group B streptococcus. DESIGN: Prospective, randomized controlled trial. SUBJECTS: Twelve chronically instrumented and six age-matched uninstrumented newborn piglets. INTERVENTIONS: Six animals received eight injections of group B streptococcus over an 11-day period (control group). Six additional animals (pretreatment group) were given 3 mg/kg of dazmegrel, a thromboxane synthase blocking agent, before each dose of group B streptococcus to prevent the pulmonary hypertensive response and to control for any secondary arterial remodeling. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements, pulmonary arterial morphometry, and thromboxane concentrations were examined in the instrumented animals. Lungs from the uninstrumented piglets were examined to determine morphometric norms for this population. The animals given only group B streptococcus developed a significant pulmonary hypertensive response after five daily doses (+6.8 +/- 2.0 [SEM] mm Hg, p < .05) which became pronounced after eight doses (+13.2 +/- 1.0 mm Hg). Pulmonary hypertension was not observed in the pretreatment group when dazmegrel was given; however, on the final day in this group, dazmegrel was withheld before group B streptococcus dosing and a significant pulmonary hypertensive response was observed (+20 +/- 1.6 mm Hg). The medial thickness of pulmonary arteries was not different between the two groups nor when compared with that of six normal, uninstrumented animals. Plasma thromboxane B2 concentrations were determined from blood samples taken before and after group B streptococcus infusion at the first, seventh and eighth (final) dosing. Thromboxane concentrations increased significantly on days 7 and 8 in the control group (578 +/- 312 to 752 +/- 372 pg/mL, 638 +/- 201 to 1462 +/- 295 pg/mL, respectively) and on day 8 in the pretreatment group (545 +/- 160 to 705 +/- 187 pg/mL). CONCLUSIONS: We conclude that the development of potentiated pulmonary hypertension is not due to pulmonary arterial remodeling, but is associated with increased thromboxane production.

Comparison of the effect of three doses of a synthetic surfactant on the alveolar-arterial oxygen gradient in infants weighing > or = 1250 grams with respiratory distress syndrome. American Exosurf Neonatal Study Group II.

The effect of a 50% increment or decrement in the recommended 5 ml/kg dose of a commercially available surfactant (Exosurf Neonatal) on the alveolar-arterial oxygen gradient was investigated in a multicenter, double-blind, placebo-controlled rescue trial conducted at 15 hospitals in the United States. Two doses of three different volumes (2.5, 5.0, and 7.5 ml/kg) were compared with two 5.0 ml/kg doses of air in 281 infants weighing > or = 1250 gm who had respiratory distress syndrome requiring mechanical ventilation and an arterial/alveolar oxygen ratio < 0.22. The first dose was given between 2 and 24 hours of age, and the second dose was given 12 hours later to all infants who still required mechanical ventilation. Infants were stratified at entry by gender and the magnitude of the arterial/alveolar oxygen ratio. The air placebo arm of the study was terminated early when reductions in mortality rates were proved in another rescue trial of this surfactant in infants with the same birth weights. For the first 48 hours, administration of a 2.5 ml/kg dose of surfactant provided less improvement in the alveolar-arterial oxygen gradient than doses of 5.0 and 7.5 ml/kg, which were equivalent. Similar results were observed in mean airway pressure (p < 0.05). There were no significant differences among the three dosage groups in mortality rate, air leak, bronchopulmonary dysplasia, and other complications of prematurity. There were no pulmonary hemorrhages in any group. Reflux of surfactant occurred more frequently in the 5.0 and 7.5 ml/kg groups. These results indicate that more sustained improvements in oxygenation are provided, with equal safety, by the standard two 5.0 ml/kg rescue doses of this surfactant than by the 2.5 ml/kg dose. No further benefit is gained from two larger doses given 12 hours apart.

Age-related differences in responses to endotoxin infusion in unanesthetized piglets.

Newborn endotoxic shock syndrome is associated with high morbidity and mortality, yet presents with different clinical manifestations than in older patients. To determine the influence of age on hemodynamic and metabolic responses to endotoxin, we developed a chronically instrumented endotoxic shock model using eight 1-3-day-old and seven 2-3-week-old piglets. Three days after surgery, 10 mg/kg of endotoxin was infused intravenously over 10 min in the younger group, and 5-10 mg/kg was given to the older animals. Two older piglets died immediately after infusion of 5 mg/kg of endotoxin, and five of the seven died within 4 hr, while all eight younger animals lived longer than 4 hr. Pulmonary artery pressure increased significantly after endotoxin in both groups, and there were no differences between groups. Systemic artery pressure and cardiac index fell by 44 +/- 10% and 70 +/- 15%, respectively, 5 min after endotoxin infusion in the older group, while these values did not change significantly in the younger group. Endotoxin infusion also caused greater elevation in pulmonary vascular resistance index in the older animals. In the later phase, which began 30 min after endotoxin, both groups displayed systemic hypotension and pulmonary hypertension, and the groups did not differ from one another in this regard. With progression of endotoxic shock, more severe metabolic acidosis developed in the older animals than in the younger animals. Plasma thromboxane B2 levels in the older group were about double those in younger piglets. Plasma 6-keto-PGF1 alpha and TNF alpha levels in both groups were similar and were significantly increased in the later phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Capsular type-specific polysaccharide partially inhibits group B Streptococcus-induced pulmonary hypertension.

Capsular type-specific polysaccharide is thought to be an important pathogenetic factor in Group B streptococcus (GBS) sepsis. To determine the effects of capsular type-specific polysaccharide on GBS-induced hemodynamic responses, anesthetized infant piglets were infused for 3 h with three related GBS Type lb strains that express different amounts of capsular type-specific polysaccharide. A larger capsule strain and a smaller capsule strain were isolated from an infected infant and its mother, respectively. A capsule-deficient mutant was then made from the larger capsule strain by transposon insertion mutagenesis. The smaller capsule strain and capsule-deficient mutant caused similar elevations in mean pulmonary artery pressure and pulmonary vascular resistance index and reductions in cardiac index. The larger capsule strain caused moderate pulmonary hypertension, but this response was smaller than for the other two GBS strains. Further comparisons in responses between the large capsule strain and its capsule-deficient mutant were then performed using unanesthetized piglets. The mutant caused significantly greater pulmonary hypertension and arterial plasma thromboxane B2 levels than the large capsule strain. The pulmonary hypertension induced by both strains was reversed by dazmegrel, a thromboxane A2 synthase inhibitor. These results suggest that (1) capsular type-specific polysaccharide is not an essential component in the generation of acute hemodynamic responses; (2) expression of large amounts of capsular type-specific polysaccharide on the organism surface partially inhibits GBS-induced pulmonary hypertension; and (3) the inhibition of the pulmonary responses is due to reduced thromboxane A2 release.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes insipidus associated with symptomatic congenital cytomegalovirus infection.

We report five infants with congenital cytomegalovirus infection in whom diabetes insipidus developed before initiation of treatment with ganciclovir. Four of five infants required treatment with desmopressin. Magnetic resonance imaging of the brain showed no destruction of the hypothalamus or pituitary gland in any infant. Cortisol levels and results of thyroid function studies were normal in all infants.

Low-dose aspirin therapy to prevent preeclampsia.

OBJECTIVE: Our aim was to test the hypothesis that acetylsalicylate (aspirin) treatment reduces the incidence or severity of pregnancy-associated hypertension. STUDY DESIGN: Patients were nulliparous, healthy, and with a singleton gestation at between 20 and 22 weeks' gestation. A sample size of 600 patients was calculated on the basis of p < or = 0.05 and 90% power of observation. A 2-week placebo-controlled "run-in" was used to select compliant patients. Randomization occurred at 24 weeks, with 60 mg of aspirin or placebo treatment from randomization to delivery. RESULTS: Follow-up was maintained on 99% of the patients. The randomized patients had a 94% pill compliance index. At randomization, serum thromboxane medians were similar in both groups. Thromboxane B2 levels in the aspirin group decreased significantly from baseline at 29 to 31 weeks, 34 to 36 weeks, and at delivery as compared with an overall increase in the placebo group. Preeclampsia developed in five of 302 women (1.7%) who received aspirin versus 17 of 302 (5.6%) who received the placebo (p = 0.009). Preeclampsia was severe in one aspirin and in six placebo recipients (p = 0.06). CONCLUSION: Daily ingestion of 60 mg of aspirin beginning at 24 weeks' gestation significantly reduced the occurrence of preeclampsia.

Role of capsule in pulmonary hypertension induced by group B streptococcus.

The type-specific polysaccharide capsule of group B streptococcus (GBS) is thought to be an important factor in the pathogenesis of disease. We used an acutely instrumented piglet model to assess the hemodynamic effects of rapid infusions of two heat-killed GBS type Ib strains isolated from the spinal fluid of an infant with late-onset meningitis and from the vaginal culture of his mother. These strains expressed different amounts of capsule, as determined by buoyant density centrifugation and electron micrographs, and they produced different hemodynamic effects in the piglets. The mother's strain, which had a smaller capsule, caused significantly higher increases in pulmonary artery pressure and vascular resistance than did the infant's strain, which had a larger capsule. Transposon mutants were then made from the infant's isolate to further study the role of capsule in pulmonary hypertension. Two mutants lacking detectable capsular type-specific polysaccharide were compared with the original isolate and with an isogenic mutant containing transposons but having a large capsule. The nonencapsulated mutants caused significantly higher changes in pulmonary artery pressure and resistance than did the encapsulated strains. Pulmonary hypertension may play a role in the pathophysiology of GBS sepsis, but the presence of a large capsule may partially cloak the hemodynamically active component(s) of the bacteria. The lower initial host response to heavily encapsulated GBS may play a role in pathogenesis by helping the organisms avoid host defense mechanisms.