Effect of young sibling visitation on respiratory syncytial virus activity in a NICU.

OBJECTIVE: To determine whether the restriction of young sibling (<13 years) visitation in the neonatal intensive care unit (NICU) during the respiratory syncytial virus (RSV) season was associated with a reduction in the rate of RSV infection among NICU patients. STUDY DESIGN: A retrospective chart review of all RSV positive infants from the 2001-2010 RSV seasons. The 2001-2006 RSV seasons (group 1) contained 639 admissions and the 2007-2010 (group 2, with sibling restriction) contained 461 admissions. Groups were compared by using the Fisher's Exact Test. RESULTS: There was a reduction of RSV positive infants from 6.7% in Group 1 to 1.7% in Group 2 (P<0.0001). There was a reduction of symptomatic infants from the number of infants with symptomatic RSV infection from 23/639 infants with young sibling visitation to 2/461 (P<0.001). CONCLUSION: Exclusion of young sibling visitors <13 years of age during RSV season was associated with a significant reduction in the number of RSV positive infants in the NICU.

Percutaneous transport in relation to stratum corneum structure and lipid composition.

Despite the acknowledged importance of the stratum corneum in limiting water loss and in controlling skin permeability, the basis for these functions remains unknown. To pinpoint those factor(s) of importance for cutaneous barrier function, we correlated the thickness, number of cell layers, and lipid composition of leg vs. abdominal stratum corneum samples with penetration of 3H-water and 14C-salicylic acid across the same tissue sample. Viable upper epidermal sheets were obtained by incubating fresh autopsy or amputation full-thickness skin with staphylococcal exfoliatin. Each sheet was divided into 3 portions. The first piece was mounted in a diffusion cell for penetration studies. The second stratum corneum sample was frozen sectioned, stained with the fluorochrome, ANS, and measured with a micrometer eyepiece. The 3rd piece was pooled with other leg (n = 6) and abdomen (n = 15) specimens for determination of lipid weight percent. In all cases, leg stratum corneum was congruent to 2 times more permeable than abdominal stratum corneum to water and slightly more permeable to salicylic acid, as well. Penetration of both substances correlated inversely with lipid weight % of leg (mean = 3.0%) vs. abdomen (mean = 6.8%), but neither the penetration of water nor of salicylic acid was influenced by the number of cell layers or the thickness of the stratum corneum. We conclude that: differences in the thickness and the number of cell layers in the stratum corneum are insufficient to account for differences in percutaneous transport across leg and abdomen, and that total lipid concentration may be the critical factor governing skin permeability.

Antibody response to measles and rubella vaccine by children with HIV infection.

To determine the immunogenicity of the measles and rubella components of the measles, mumps, and rubella virus (MMR) vaccine in human immunodeficiency virus (HIV)-infected children, we compared their response to that of uninfected controls. Sera were collected from HIV-infected patients and HIV seroreverters followed in our clinic and tested as close to 2 months post-MMR vaccination as possible. Specific IgG to both rubella and measles were measured by enzyme-linked immunosorbent assay. Of 20 children with HIV, 11 responded with adequate levels of antibody to measles. In the seroreverters, 12 of 13 responded. Of the measles responders, the median antibody level was significantly lower in the HIV-infected group than in the seroreverter group. In addition, HIV-infected responders tested at 9-15 months after vaccination demonstrated a significant decline in measles antibody levels. Although there was not a difference between the two cohorts in the proportion of patients who responded to the rubella component of the vaccine, there was a significant difference in the median antibody level of the responders of the two groups. We did not find a statistical difference in CD4 counts between responders and nonresponders. Alternate strategies will need to be established to prevent measles in HIV-infected children.

Seroreversion in human immunodeficiency virus-exposed but uninfected infants.

The goal of this study was to describe seroreversion (SR) in a cohort of human immunodeficiency virus-exposed but uninfected infants. Groups of patients who seroreverted very early or late were examined for salient clinical and immunologic characteristics of the mother or infant. The mean time (+/- s.d.) to seroreversion by enzyme-linked immunoabsorbent assay (ELISA) was 50.1 +/- 14.8 weeks, or 11.6 months (n = 84); the range of times to antibody loss by ELISA was 17.9 to 82.0 weeks. The mean time to seroreversion by Western blot was 68.3 +/- 12.6 weeks, or 15.8 months (n = 51), with a range of 44.9 to 94.1 weeks. Initial anti-human immunodeficiency virus titer as measured by cord blood ELISA optical density (OD) was found to relate significantly to mean time to seroreversion. No relationship to time to seroreversion was demonstrated for gestational age, maternal or neonatal serum immunoglobulin concentrations, maternal CD4 cell counts, maternal alcohol consumption, infantile diarrhea or failure to thrive. The lengthy time to seroreversion seen here demonstrates the 1994 revised Centers for Disease Control and Prevention definition of human immunodeficiency virus infection (based on seropositivity by both ELISA and confirmatory tests persisting beyond 18 months of age) to be accurate in our population. We recommend Western blot testing be used as confirmation for positive ELISAs only after 18 months of age.

Thymic size on chest radiograph and rapid disease progression in human immunodeficiency virus 1-infected children.

BACKGROUND: Early infection of the thymus, an organ central to the ontogeny of the immune system, has been proposed as a cause of rapid progression in pediatric HIV disease. OBJECTIVE: To test the hypothesis that small thymic volume is associated with rapid disease progression in HIV-infected children. DESIGN: Three pediatric radiologists established criteria for rating the size of the thymic profile on chest radiographs. All available baseline chest radiographs were reviewed in a random sequence, with radiologists blinded to study subjects' clinical status. A consensus was reached on whether the thymus was normal or small for age. SETTING: A prospective multicenter study of the natural history of HIV-1 infection in children, the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted Human Immunodeficiency Virus Infection (P2C2) Study. PATIENTS: Fifty-eight HIV-infected children and 38 control children (uninfected but born to HIV-infected women) for whom chest radiographs in the first year of life were available. MAIN OUTCOME MEASURE: Rapid progression of HIV disease, defined as CDC Clinical Category C (severely symptomatic) or Immunologic Category 3 (severe immunosuppression) by 1 year of age. RESULTS: The mean age at the time of chest radiography was 3.5 months. Ten (17%) HIV-infected children had reduced thymic profile size, whereas no controls did (P = 0.006). Of the 58 (59%) HIV-infected children 34 were classified as rapid progressors, and 9 (26%) of them had reduced thymus size, compared with 1 (4%) of the non-rapid progressor children [odds ratio, 8.28; 95% confidence interval (CI), 1.0, 70.5; P = 0.035]. Baseline mean CD4+ count was 1642 (95% CI 1322 to 2009) cells/microl for those with normal thymus and 740 (95% CI 380 to 1275) cells/microl for those with reduced thymus (P = 0.007). CONCLUSION: Early thymic involution is associated with rapidly progressive disease in HIV-infected children.

Prophylaxis against possible human immunodeficiency virus exposure after nonoccupational needlestick injuries or sexual assaults in children and adolescents.

BACKGROUND: Nonoccupational human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) for adults has been described, although the Centers for Disease Control and Prevention, Atlanta, Ga, offer no specific recommendations. There is limited information about its use in children and adolescents. OBJECTIVE: To describe the current practices of physicians in pediatric infectious disease (PID) and pediatric emergency medicine (PEM) departments regarding nonoccupational HIV PEP for children and adolescents. DESIGN: Survey. PARTICIPANTS: Directors of all PID and PEM departments with fellowship programs in the United States and Canada between July and November 1998. MAIN OUTCOME MEASURES: General questions regarding HIV PEP and questions concerning 2 scenarios (5-year-old with a needlestick injury and a 15-year-old after sexual assault). RESULTS: The return rate was 67 (78%) of 86 for PID and 36 (75%) of 48 for PEM physicians. Fewer than 20% of physicians reported institutional policies for nonoccupational HIV PEP; 33% had ever initiated nonoccupational HIV PEP. In both scenarios, PID physicians were more likely than PEM physicians to recommend or offer HIV PEP in the first 24 hours after the incident (55 [83%] of 66 vs 20 [56%] of 36 for needlestick injuries [odds ratio, 4.0; 95% confidence interval, 1.6-10.1] and 47 [72%] of 65 vs 16 [50%] of 32 for sexual assault [odds ratio, 2.6; 95% confidence interval, 1.1-6.3]). Seven different antiretroviral agents in single, dual, or triple drug regimens administered for 2 to 12 weeks were suggested. CONCLUSIONS: Although few physicians reported institutional policies, and only one third had ever initiated HIV PEP, many would offer or recommend HIV PEP for children and adolescents within 24 hours after possible HIV exposure. A wide variation of regimens have been suggested. There is a need for a national consensus for nonoccupational HIV PEP.

Effect of diffusional lag time on multicompartmental pharmacokinetics for transepidermal infusion.

A simple proof is given to demonstrate that the lag time to reach steady state from transepidermal infusion is the sum of the diffusional and pharmacokinetic lag times.

Pharmacokinetics of skin penetration.

A model for estimating in vivo skin permeability coefficients is presented. Explicit expressions are derived for the permeability coefficient in terms of excretion rates and tissue absorption. The excretion rate has a linear asymptotic limit from which the permeability coefficient can be determined. The usefulness of the model is demonstrated with existing literature data.

Increased skin permeability for lipophilic molecules.

Treatment of the epidermis with surfactants can markedly increase the transport of polar molecules but only marginally increases the transport of nonpolar (lipophilic) molecules. Thus, other vehicle systems are needed to increase the transport of lipophilic molecules. One method to accomplish this increased transport is to add small quantities of polar lipids to a base vehicle containing propylene glycol. The transport of nonpolar materials such as salicylic acid can be increased by an order of magnitude by the addition of small amounts of fatty acids or alcohols to a formulation. The effect of this mixed system is much greater than the effect of any of the agents alone.

Finite dose pharmacokinetics of skin penetration.

A model for estimating in vivo skin permeability coefficients for finite doses is presented. The ratio of the maximum value of the excretion rate to the steady-state flux is a function of the thickness of the applied vehicle and the vehicle-skin partition coefficient. The decay rate of the excretion is a function of skin-vehicle parameters for large doses and, under certain conditions, can even reduce to the total excretory rate constant as the dose is decreased.

Application of diffusion theory to the relationship between partition coefficient and biological response.

A diffusion model for transport through multilaminates is studied as a possible way to predict the optimal biological response of a set of congeners with respect to the oil-water partition coefficient, P. The model predicts the bilinear form typical of biological response data and, unlike the earlier kinetic model, also relates the results to physical processes, predicts the structure with the optimal response in terms of diffusion constants, and shows such an optimum prior to steady state for an infinite dose. Diffusion through an oil-water multilaminate causes extraordinary separation of permeating species based on partition coefficient and diffusion constant for times shorter than the lag time.

Kinetic analysis of relationship between partition coefficient and biological response.

Both nonequilibrium and equilibrium models were proposed to explain the optimal biological response to a set of congeners with respect to the oil-water partition coefficient (P). A detailed analysis of the kinetic model proposed by Hansch demonstrates the bilinear form of the model, with the initial slope of the logarithm of the concentration for 50% receptor binding versus log P having a slope of greater than one. This result is in contrast to the equilibrium model for an initial slope of less than one. Thus, a criterion is established for deciding whether equilibrium or nonequilibrium processes apply.

Mechanisms of corneal drug penetration. III: Modeling of molecular transport.

A model relating the parameters of permeability coefficient in the cornea with partition coefficient and molecular weight of the penetrating species is presented. The development of the model is unique in that it includes the availability of a "pore" pathway with the corresponding kinetic data to substantiate this premise. The "pore" pathway is applied to small hydrophilic compounds and assumes that an aqueous diffusional space is available for transport of these compounds. This is in contrast to an alternate "partitioning" mechanism which is the most probable route of transport for larger or more lipophilic entities. The model is consistent with published data from this and other laboratories.

Effect of fatty acids and alcohols on the penetration of acyclovir across human skin in vitro.

The cutaneous penetration of acyclovir can be significantly increased from a propylene glycol base vehicle by adding small amounts of a polar lipid such as oleic acid. These results are consistent with those found for salicylic acid, and the large increases in acyclovir penetration could potentially lead to better topical treatment of herpes simplex.

Limits on optimizing ocular drug delivery.

The problem of optimizing ocular bioavailability of topically applied ophthalmic drugs is discussed. A formula for drug concentration in the tear film is derived using well-known pharmacokinetic relationships and a first-order drug decay model for the tear film. The time integral of the tear film concentration is then related to ocular bioavailability. The results of this analysis show that: (1) high corneal permeability (corresponding to lipophilic compounds) produces the highest bioavailability; (2) the bioavailability of drugs with high corneal permeability is relatively unaffected by drug volume; and (3) by making the dosage volume sufficiently small, a bioavailability improvement factor of approximately 4 can be obtained for drugs with low corneal permeability.

Percutaneous computed tomography lymphography in the rabbit by subcutaneously injected nanoparticulates.

RATIONALE AND OBJECTIVES: Surgical lymphangiography is infrequently used in staging cancer because of its inherent limitations. Radiopaque nanoparticulates target lymph nodes draining interstitial tissues and could make percutaneous lymphography feasible. METHODS: Experimental nanoparticulate contrast agent formulations were injected subcutaneously in the forepaw or hindpaw of normal rabbits or rabbits with induced reactive nodal hyperplasia. Axillary and popliteal nodes were imaged with thin-section computed tomography (CT) using quantitative methods to measure node enhancement. Dose-response (0.1-2.0 ml) and time course (4 hr to 10 weeks) of enhancement were assessed. RESULTS: Nodal enhancement above 100 Hounsfield units was consistently obtained. Enhancement was significantly related to dose and peaked at 10 hr with slow washout over the observation period. Nodes with reactive hyperplasia were larger and had heterogeneous enhancement patterns distinctly different from normal nodes. CONCLUSION: Percutaneous CT lymphography effectively depicts the macroscopic intranodal architecture in rabbits.

Nanoparticulate computed tomography contrast agents for blood pool and liver-spleen imaging.

RATIONALE AND OBJECTIVES: We investigated the properties of a group of iodine-containing, insoluble compounds formulated as nanoparticles for use as potential blood pool and liver-spleen contrast agents. METHODS: High-resolution, quantitative computed tomography (CT) was performed prior to and at intervals following the intravenous administration of the contrast agents to rabbits. Time-density characteristics for three organs were evaluated. RESULTS: Excellent enhancement of blood (< or = 232 Hounsfield units [HU]), liver (< or = 263 HU), and spleen (< or = 350 HU) was achieved at the administered dose of 3.0 ml/kg. The composition of the agents influenced the biodistribution, as well as the residence time in blood, and time to peak enhancement in liver. CONCLUSION: Iodinated nanoparticulate compounds are promising CT contrast agents. Development of agents with desirable pharmacokinetic and biodistribution profiles may permit application-specific contrast enhancement.

Acquired immunodeficiency syndrome: a new population of children at risk.

Cases of AIDS in children have been described since 1982. Diagnosis is more complex in children than in adults owing to the more varied clinical presentations and the difficulty in interpretation of laboratory tests. Our current understanding of HIV infection in children is reviewed, as well as the controversies regarding medical, psychosocial, and public health issues.