Differential MAP kinase activation and Na(+)/H(+) exchanger phosphorylation by H(2)O(2) in rat cardiac myocytes.

Bursts in reactive oxygen species production are important mediators of contractile dysfunction during ischemia-reperfusion injury. Cellular mechanisms that mediate reactive oxygen species-induced changes in cardiac myocyte function have not been fully characterized. In the present study, H(2)O(2) (50 microM) decreased contractility of adult rat ventricular myocytes. H(2)O(2) caused a concentration- and time-dependent activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38, and c-Jun NH(2)-terminal kinase (JNK) mitogen-activated protein (MAP) kinases in adult rat ventricular myocytes. H(2)O(2) (50 microM) caused transient activation of ERK1/2 and p38 MAP kinase that was detected as early as 5 min, was maximal at 20 min (9.6 +/- 1.2- and 9.0 +/- 1.6-fold, respectively, vs. control), and returned to baseline at 60 min. JNK activation occurred more slowly (1.6 +/- 0.2-fold vs. control at 60 min) but was sustained at 3.5 h. The protein kinase C inhibitor chelerythrine completely blocked JNK activation and reduced ERK1/2 and p38 activation. The tyrosine kinase inhibitors genistein and PP-2 blocked JNK, but not ERK1/2 and p38, activation. H(2)O(2)-induced Na(+)/H(+) exchanger phosphorylation was blocked by the MAP kinase kinase inhibitor U-0126 (5 microM). These results demonstrate that H(2)O(2)-induced activation of MAP kinases may contribute to cardiac myocyte dysfunction during ischemia-reperfusion.

Promoting education, mentorship, and support for pediatric research.

Pediatricians have an important role to play in the advancement of child health research and should be encouraged and supported to pursue research activities. Education and training in child health research should be part of every level of pediatric training. Continuing education and access to research advisors should be available to practitioners and academic faculty. Recommendations to promote additional research education and support at all levels of pediatric training, from premedical to continuing medical education, as well as suggestions for means to increase support and mentorship for research activities, are outlined in this statement.

Retrospective study of clinical observations on insect hypersensitivity and response to immunotherapy in allergic dogs.

A retrospective study was conducted to evaluate the importance of insect hypersensitivity in atopic dogs in the northeastern United States. Fifty (63%) of 79 dogs tested with 7 insect allergens, other than flea, had positive reactions to one or more insects. No dog had positive reactions to insects only. Forty-four dogs underwent immunotherapy. Thirty-one had insect antigens in their prescription mixture and 13 had only conventional environmental allergens. There was no statistical difference in the response rate between the 2 groups. Thus, testing with insect allergens did not decrease the number of dogs with negative skin tests, and including insect allergens in immunotherapy mixtures did not improve the response rate.

Proinflammatory and Th2-derived cytokines modulate CD40-mediated expression of inflammatory mediators in airway epithelia: implications for the role of epithelial CD40 in airway inflammation.

Cytokines produced by activated macrophages and Th2 cells within the lung play a key role in asthma-associated airway inflammation. Additionally, recent studies suggest that the molecule CD40 modulates lung immune responses. Because airway epithelial cells can act as immune effector cells through the expression of inflammatory mediators, the epithelium is now considered important in the generation of asthma-associated inflammation. Therefore, the goal of the present study was to examine the effects of proinflammatory and Th2-derived cytokines on the function of CD40 in airway epithelia. The results show that airway epithelial cells express CD40 and that engagement of epithelial CD40 induces a significant increase in expression of the chemokines RANTES, monocyte chemoattractant protein (MCP-1), and IL-8 and the adhesion molecule ICAM-1. Cross-linking epithelial CD40 had no effect on expression of the adhesion molecule VCAM-1. The proinflammatory cytokines TNF-alpha and IL-1beta and the Th2-derived cytokines IL-4 and IL-13 modulated the positive effects of CD40 engagement on inflammatory mediator expression in airway epithelial cells. Importantly, CD40 ligation enhanced the sensitivity of airway epithelial cells to the effects of TNF-alpha and/or IL-1beta on expression of RANTES, MCP-1, IL-8, and VCAM-1. In contrast, neither IL-4 nor IL-13 modified the effects of CD40 engagement on the expression of RANTES, MCP-1, IL-8, or VCAM-1; however, both IL-4 and IL-13 attenuated the effects of CD40 cross-linking on ICAM-1 expression. Together, these findings suggest that interactions between CD40-responsive airway epithelial cells and CD40 ligand+ leukocytes, such as activated T cells, eosinophils, and mast cells, modulate asthma-associated airway inflammation.

Varicella vaccine: progress 4 years after licensure.

The concerns raised by parents and physicians about varicella immunization are reasonable and need to be acknowledged. We believe, however, that the available information strongly suggests that these concerns should not impede implementation of universal immunization against varicella. In fact, some of these concerns are best resolved by universal immunization. Some people argue that only a small percentage of people with varicella will have a significant complication and therefore vaccinating all is unnecessary. Yet, a small percentage of 3.5 to 4 million cases per year is not an insignificant number. There is a precedent for changing immunization practice because of relatively small risks when the risks in question are serious. For example, immunization practice has changed because we have decided that 8 to 10 cases per year of vaccine-associated paralytic poliomyelitis (of 770 million doses) is unacceptable. Vaccination has been the most important health care advance of the past 40 years. Now that varicella can be added to the list of vaccine-preventable diseases, we can help our patients avoid both the common and the uncommon but much more severe complications of this disease, as well as the considerable economic burden. Although the chances that any individual will have a complication are small, if your patient is the statistic, the odds are meaningless. How can we continue to accept even mild disease from varicella, let alone severe complications, when the disease is now preventable by an effective, safe vaccine? Not immunizing patients puts them at medical risk and us at legal risk.

Kinetics of antibody response to Haemophilus influenzae type b vaccines. Pennridge Pediatric Associates.

Serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b (Hib) are effective in preventing or ameliorating invasive disease caused by this human pathogen. Polysaccharide and conjugate (saccharide covalently linked to protein carrier) vaccines have been developed which stimulate the production of such antibodies. The polysaccharide-specific antibody concentrations in the sera of vaccine-naïve adults and toddlers on days 1, 3, 7, 14 and 28 following immunisation with one dose of the Hib polysaccharide vaccine (PRP, polyribosylribitol phosphate) or an oligosaccharide-CRM197 conjugate vaccine (HbOC, HibTITER) were determined. Antibody responses occurred within 7 days of immunisation with the maximum response usually occurring 14 days post-immunisation, irrespective of vaccine or subject age. In this small study, a significant transient decline in pre-existing antibodies was observed only in the groups receiving the polysaccharide vaccine and not in the groups receiving HbOC vaccine. Because of the small magnitude of antigen-specific antibody decline and its transient nature, it is unlikely that this observation has clinical significance.

An acellular pertussis vaccine in healthy adults: safety and immunogenicity. Pennridge Pediatric Associates.

Recent data indicate that Bordetella pertussis can be an important cause of illness in adolescents and adults. In a randomized observer- and subject-blinded study, adults (> or = 18 years of age) received an acellular pertussis (aP) vaccine containing genetically inactivated pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN), or a saline placebo, and were monitored for safety and immunogenicity. IgG antibodies to PT, FHA, and PRN were measured by enzyme-linked immunosorbent assay (ELISA) and PT neutralization by a Chinese hamster ovary (CHO) cell assay. Local reactions, more common in the aP group, were mild and transient. One month after immunization, geometric mean ELISA antibody concentrations for the aP and placebo groups, respectively, were: anti-PT, 463 and 7.6; anti-FHA, 417 and 18; and anti-PRN, 855 and 14. The anti-PT neutralization titers for the aP and placebo groups were 1:3439 and 1:58 respectively. This aP vaccine is a safe and immunogenic candidate booster vaccine against pertussis for adults.

Efficacy of live, attenuated, human rotavirus vaccine 89-12 in infants: a randomised placebo-controlled trial.

BACKGROUND: Rotavirus is the most common cause of severe, dehydrating diarrhoea in infants worldwide. We assessed the safety, immunogenicity, and efficacy of a live, oral human rotavirus vaccine, 89-12, in US children in a randomised, placebo-controlled, double-blind multicentre trial. METHODS: 215 healthy infants were enrolled, of whom 213 were given two doses of 89-12 (containing 1x10(5) plaque-forming units) or placebo, and 213 were followed up through one rotavirus season. The frequency of side-effects was compared for 7 days after each dose of vaccine. Immune responses to rotavirus were assessed by serum and stool IgA, and by serum 89-12 neutralising titres. The primary outcome variable (protection from rotavirus disease) was evaluated by comparing the frequencies of rotavirus gastroenteritis in an intention-to-treat analysis. FINDINGS: Adverse reactions were mild. Low-grade fever (> or = 38.1 degrees C) after the first dose was the only side-effect significantly more common in the vaccine group than in the placebo group (21 [19%] vs 5 [5%], p=0.001). An immune response to vaccine was detected in 94.4% of vaccinees. Rotavirus disease occurred in 18 of 107 placebo recipients and two of 108 vaccine recipients (vaccine efficacy 89.0% [95% CI 65.4-94.5]). Ten infants in the placebo group but none in the vaccine group were presented for medical care. INTERPRETATION: The 89-12 rotavirus vaccine was safe and immunogenic and provided a high degree of protection against rotavirus disease. Further investigations of this vaccine are needed to confirm these findings in other settings.

Observations on the use of tetracycline and niacinamide as antipruritic agents in atopic dogs.

Tetracycline and niacinamide were administered in combination to 19 atopic dogs to determine their effectiveness in controlling pruritus. The pruritus was controlled successfully in only one dog. One dog experienced diarrhea that was severe enough to warrant stopping the medication.

The role of the neonatal nurse practitioner in post NICU follow-up.

This descriptive correlational study explored the role of neonatal nurse practitioners (NNPs) in postneonatal intensive care unit follow-up. A random sample of 505 NNPs completed a researcher-developed instrument pretested for reliability and validity. There was overwhelming agreement (96%) that a role exists for NNPs in follow-up. In total, 52% felt qualified to provide follow-up and 22% were currently in the role. NNPs with previous primary care experience (P = 0.010) were more involved in follow-up. NNPs with additional certification (P = 0.016) or previous primary care experience (P = 0.003) felt more qualified to provide follow-up care. Facilitators and barriers to the role were identified by NNPs providing follow-up care.

Efficacy of clindamycin hydrochloride capsules for the treatment of deep pyoderma due to Staphylococcus intermedius infection in dogs.

Clindamycin hydrochloride capsules (11 mg/kg body weight, q24 h) were administered orally to 20 dogs with deep staphylococcal pyoderma. Response to therapy was excellent in 100% of the dogs. Duration of therapy varied from 21 to 91 d, with an average duration of 45 d. Relapses occurred in 25% of the dogs within a 3-month period. One dog vomited when the clindamycin was given on an empty stomach. Under the conditions of the study, clindamycin was an effective, safe, and convenient antibiotic for the treatment of deep staphylococcal pyoderma in dogs.

Observations on the use of cyproheptadine hydrochloride as an antipruritic agent in allergic cats.

Cyproheptadine hydrochloride was administered to 20 presumed or proven allergic cats to determine its efficacy in controlling pruritus. Each cat received 2 mg, orally, every 12 h. The pruritus was satisfactorily controlled in 9 cats. Side effects were seen in 8 cats, and included polyphagia, sedation, vocalization, affectionate behavior, and vomiting.

Tetracycline and niacinamide for the treatment of sterile pyogranuloma/granuloma syndrome in a dog.

A sterile pyogranuloma/granuloma syndrome in a dog is described. Diagnosis was based on cytological examinations of the skin and lymph nodes and histopathological examinations of the skin and nictitans. Although the condition initially was responsive to large doses of glucocorticoids, it subsequently was treated successfully with tetracycline and niacinamide. The excellent responses of this dog suggest that this drug combination may be a viable therapeutic option for dogs in which glucocorticoids cannot be used.

Infant immunization with pneumococcal CRM197 vaccines: effect of saccharide size on immunogenicity and interactions with simultaneously administered vaccines.

Six pentavalent pneumococcal conjugate vaccines (Pn-CRM197) were evaluated among 400 infants. The vaccines differed in saccharide chain length (oligosaccharide [OS] or polysaccharide [PS]) and saccharide quantity (0.5, 2, or 5 microg). Subjects were randomized into groups 1-6 (Pn-CRM197 recipients) or 7 (controls) for immunization at 2, 4, and 6 months of age. Pn-CRM197 were well tolerated and elicited mean antibody concentrations that exceeded those in controls for all 5 capsular serotypes. PS formulations were generally more immunogenic than their OS counterparts. For PS vaccines, a dose-response was documented (5 microg > 2 microg > 0.5 microg), but the differences between the 5- and 2-microg formulations were insignificant. The mean anti-PRP antibody concentration was significantly higher among Pn-CRM197 recipients. It is concluded that PS vaccines are more immunogenic than OS vaccines. The improved immunogenicity from Haemophilus type b oligosaccharide conjugate (HbOC) vaccine when given with Pn-CRM197 suggests that a decreased dose of HbOC vaccine may be sufficient to elicit protection.

Dose titration study of live attenuated varicella vaccine in healthy children. Pennridge Pediatric Associates.

To approximate the effect of prolonged storage on safety and immunogenicity, healthy children were given a single dose of the currently marketed live attenuated varicella vaccine (3625 pfu) or of a partially heat-inactivated vaccine (1125 or 439 pfu). The 3 doses had similar antigen content (attenuated plus inactive virus particles). The vaccine was well tolerated. No significant differences in adverse reactions were observed. Although the seroconversion rates were excellent at each dose (> or = 98%), the higher doses resulted in significantly greater geometric mean antibody titers at 6 weeks (10.5 and 10.6 ELISA U/mL) compared with the 439 pfu dose (5.7 ELISA U/mL), P < or = .01. One year after immunization, differences in antibodies were similar to the 6-week postimmunization results. Results indicate that until the date of expiry, the vaccine's immunogenicity will be preserved and there will be no clinically important changes in type or frequency of adverse events.

A study of 5-day cefdinir treatment for streptococcal pharyngitis in children. Cefdinir Pediatric Pharyngitis Study Group.

OBJECTIVE: To compare the safety and efficacy of a 5-day regimen of cefdinir with those a conventional 10-day regimen of penicillin V for the treatment of streptococcal pharyngitis in children. DESIGN: Investigator-blind, randomized controlled trial. SETTING: Primary care, ambulatory. PATIENTS: Children aged 1 to 12 years with signs and symptoms of pharyngitis and a positive result on a rapid screening test for Streptococcus pyogenes (ie, a convenience sample). Four hundred eighty-two patients were enrolled in the study, and 440 were clinically and microbiologically evaluable. The most common reasons patients were nonevaluable were failure to return for specified visits and noncompliance with the administration of the medication; 2 patients receiving penicillin V discontinued use of the drug because of adverse events. INTERVENTION: Patients were randomized to receive either 7-mg/kg cefdinir, twice daily, for 5 days or 10-mg/kg penicillin V potassium, 4 times daily, for 10 days. MAIN OUTCOME MEASURES: The eradication of S pyogenes and the clinical cure of the signs and symptoms of pharyngitis, both determined 5 to 10 days after the completion of therapy. RESULTS: Streptococcus pyogenes was eradicated in 201 (90%) of the 224 patients receiving cefdinir and 155 (72%) of the 216 patients receiving penicillin V (95% confidence interval [CI], 10.7%-25.1%; P < .001). The clinical cure rates were 92% and 91% in the groups receiving cefdinir and penicillin V, respectively (95% CI, -4.5% to 6.1%; P = .80). Adverse events, regardless of the opinion of the investigator about their relationship to the study medication, occurred in 12.5% of the patients receiving cefdinir and 13.6% of the patients receiving penicillin V (P = .69). CONCLUSIONS: A 5-day regimen of cefdinir eradicated a higher proportion of S pyogenes than a 10-day regimen of penicillin V. No difference was noted between the regimens for clinical outcomes or adverse event rates.

Comparison of diphtheria-tetanus-two component acellular pertussis vaccines in United States and Japanese infants at 2, 4, and 6 months of age.

OBJECTIVE: We compared the diphtheria and tetanus toxoids and bicomponent acellular pertussis vaccine (DTaP) responses in Japanese and United States infants. DESIGN: This was a double-blind, comparative study. SETTING: Private pediatric practices in Japan and the U.S. participated. SUBJECTS: One hundred eighty-nine healthy 2-month old infants were tested. INTERVENTIONS: Infants were immunized at 2, 4, and 6 months of age. The Japanese formulation (DTaP-J) contained 20 micrograms of pertussis toxin (PT) and 20 micrograms of filamentous hemagglutinin (FHA); the U.S. formulation (DTaP-US) contained 23.4 micrograms of each antigen. Parents used a standard form to record average adverse experiences. Serum was obtained before the first immunization, 2 months after the second immunization, and 1 month after the third immunization. MEASUREMENTS: Differences in DTaP-J and DTaP-US were evaluated in Japanese infants immunized subcutaneously (s.c.). Differences due to ethnicity and to route of administration were compared in U.S. infants immunized with DTaP-US s.c. or intramuscularly (i.m.). An indirect enzyme-linked immunosorbent assay was used to determine immunoglobulin G antibody responses to PT, FHA, and tetanus toxoid. Neutralizing antibody to PT was measured by a Chinese hamster ovary call assay. Diphtheria antitoxin was assayed by serum neutralization on VERO cells. RESULTS: Statistical differences (P < .05) in adverse events included less fatigue after immunization with DTaP-US compared with DTaP-J. Erythema of more than 2.5 cm was more frequent, but erythema less than 2.5 cm was less frequent in Japanese infants compared with U.S. infants. Fewer Japanese infants were febrile ( > 38 degrees C), tired, or irritable. Subcutaneous immunization resulted in a greater frequency of erythema and induration. The DTaP-US resulted in an equivalent response to PT and a greater response to FHA. More Japanese infants demonstrated at least a fourfold response over preimmunization antibody values to FHA. In U.S. infants, antibody responses to the contained pertussis antigens were equivalent after i.m. and s.c. administration. Compared with Japanese infants receiving DTaP-J s.c., U.S. infants receiving DTaP-US i.m. had equivalent responses to PT and a greater response to FHA. CONCLUSIONS: United States infants receiving an i.m. injection of a U.S. -produced bicomponent DTaP vaccine produced antibody responses to the contained pertussis antigens at least equal to those of Japanese infants receiving a similar bicomponent DTaP vaccine shown to be effective in older Japanese children.

Reactogenicity and immunogenicity of a three-component acellular pertussis vaccine administered as the primary series to 2, 4 and 6 month old infants in the United States.

Five hundred and fifty-seven infants received either an acellular pertussis (DTaP) vaccine containing pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) or one of two commercially available whole-cell pertussis (DTP) vaccines at 2, 4 and 6 months. One month after the third immunization, IgG antibody values to pertussis toxoid, filamentous hemagglutinin and PRN were significantly greater following DTaP than either DTP (P < 0.05). When reactions within 48 h after all three doses of vaccine were combined, fever 101 degrees, > or = moderate fussiness, > or = moderate pain, swelling 10 mm, and erythema 10 mm occurred less often after DTaP compared with DTP-Connaught (P < 0.001). The same adverse events were also less after DTaP compared with DTP-Lederle (P < 0.05), except for erythema 10 mm. This three-component DTaP vaccine produced fewer adverse events and greater antibody values to PT, FHA and PRN in comparison with either licensed DTP vaccine when given as the primary series.

Safety and cellular and humoral immune responses of a booster dose of varicella vaccine 6 years after primary immunization.

Four hundred nineteen children and adolescents immunized with live varicella vaccine 4-6 years earlier were enrolled in a study to evaluate the safety and immune response to a booster dose containing approximately 3300 pfu of virus. Of the subjects, 99% (414/419) maintained antibody to varicella zoster virus (VZV) with a geometric mean titer of 25.7 and mean stimulation index (SI) for VZV-specific lymphoproliferation response of 40.3 +/- 5.3 (SE). Some 7-10 days after the booster immunization, seropositivity rates increased to 100% (302/302), and GMT was 143.6 (anamnestic response). At 6 weeks after the booster inoculation, a subset of subjects had 100% seropositivity (74/74) with a GMT of 218.8 and an SI of 58.6. After 3 months, seropositivity was 100% (358/358), GMT was 119.0, and SI was 61.4.