Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors.

BACKGROUND: Activation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors. MATERIALS AND METHODS: Using accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers. RESULTS: Forty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action. CONCLUSIONS: MSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.

Human Activities Attract Harmful Mosquitoes in a Tropical Urban Landscape.

Knowledge of the interrelationship of mosquito communities and land use changes is of paramount importance to understand the potential risk of mosquito disease transmission. This study examined the effects of land use types in urban, peri-urban and natural landscapes on mosquito community structure to test whether the urban landscape is implicated in increased prevalence of potentially harmful mosquitoes. Three land use types (park, farm, and forest nested in urban, peri-urban and natural landscapes, respectively) in Klang Valley, Malaysia, were surveyed for mosquito larval habitat, mosquito abundance and diversity. We found that the nature of human activities in land use types can increase artificial larval habitats, supporting container-breeding vector specialists such as Aedes albopictus, a dengue vector. In addition, we observed a pattern of lower mosquito richness but higher mosquito abundance, characterised by the high prevalence of Ae. albopictus in the urban landscape. This was also reflected in the mosquito community structure whereby urban and peri-urban landscapes were composed of mainly vector species compared to a more diverse mosquito composition in natural landscape. This study suggested that good environmental management practices in the tropical urban landscape are of key importance for effective mosquito-borne disease management.

Text-message responsiveness to blood glucose monitoring reminders is associated with HbA1c benefit in teenagers with Type 1 diabetes.

AIMS: To evaluate an 18-month text-messaging intervention in teenagers with Type 1 diabetes and to assess factors associated with text responsiveness and glycaemic benefit. METHODS: Teenagers with diabetes (N = 147), aged 13-17 years, received two-way text reminders at self-selected times to check blood glucose levels and reply with blood glucose results. RESULTS: At baseline, the participants (48% boys, 78% white, 63% pump-treated) had a mean ± sd age of 14.9 ± 1.3 years, diabetes duration of 7.1 ± 3.9 years and HbA1c concentration of 69 ± 12 mmol/mol (8.5 ± 1.1%). The mean proportion of days with ≥1 blood glucose response declined over time (0-6 months, 60 ± 26% of days, 7-12 months, 53 ± 31% of days, 13-18 months, 43 ± 33% of days). Over 18 months, 49% responded with ≥1 blood glucose result on ≥50% of days (high responders). Regression analysis controlling for baseline HbA1c revealed no significant change in HbA1c from baseline to 18 months in high responders (P = 0.54) compared with a significant HbA1c increase in low responders (+0.3%, P = 0.01). In participants with baseline HbA1c ≥64 mmol/mol (≥8%), high responders were 2.5 times more likely than low responders to have a clinically significant [≥5.5 mmol/mol (≥0.5%)] HbA1c decrease over 18 months (P < 0.05). In participants with baseline HbA1c <64 mmol/mol(<8%), high responders were 5.7 times more likely than low responders to have an 18-month HbA1c <58 mmol/mol (<7.5%; P < 0.05). CONCLUSIONS: Teenagers with Type 1 diabetes who responded to text reminders on ≥50% of days over 18 months experienced clinically significant glycaemic benefit. There remains a need to tailor interventions to maintain teenager engagement and optimize improvements.

River flow, zooplankton and dominant zooplanktivorous fish dynamics in a warm-temperate South African estuary.

The possible links between river flow, zooplankton abundance and the responses of zooplanktivorous fishes to physico-chemical and food resource changes are assessed. To this end, the seasonal abundance, distribution and diet of the estuarine round-herring Gilchristella aestuaria and Cape silverside Atherina breviceps were studied in the Kariega Estuary. Spatio-temporal differences were determined for selected physico-chemical variables, zooplankton abundance and zooplanktivorous fish abundance and distribution. Results indicated that, following a river flood event in winter (>30 m3  s-1 ), altered physico-chemical conditions occurred throughout the estuary and depressed zooplankton stocks. Abundance of G. aestuaria was highest in spring, with this species dominant in the upper and middle zones of the estuary, while A. breviceps was dominant in summer and preferred the middle and lower zones. The catch per unit of effort of both zooplanktivores also declined significantly following the flooding, thus suggesting that these fishes are reliant on zooplankton as a primary food source for healthy populations. Copepods dominated the stomach contents of both fish species, indicating a potential for strong interspecific competition for food, particularly in the middle reaches. Temporal differences were evident in dietary overlap between the two zooplanktivorous fish species and were correlated with river flow, zooplankton availability and fish distribution. The findings of this study emphasize the close trophic linkages between zooplankton and zooplanktivorous fishes under changing estuarine environmental conditions, particularly river flow and provide important baseline information for similar studies elsewhere in South Africa and the rest of the world.

Preliminary evidence for the organisation of a bacterial community by zooplanktivores at the top of an estuarine planktonic food web.

As part of a larger investigation, the effect of apex predation on estuarine bacterial community structure, through trophic cascading, was investigated using experimental in situ mesocosms. Through either the removal (filtration) or addition of specific size classes of planktonic groups, four different trophic scenarios were established using estuarine water and its associated plankton. One such treatment represented a "natural" scenario in which stable apex predatory pressure was qualified. Water samples were collected over time from each of the treatments for bacterial community evaluation. These samples were assessed through pyrosequencing of the variable regions 4 and 5 of the bacterial 16S rRNA gene and analysed at the species operational taxonomic unit (OTU) level using a community procedure. The blue-green group dominated the samples, followed by Proteobacteria and Bacteroidetes. Samples were the most similar among treatments at the commencement of the experiment. While the bacterial communities sampled within each treatment changed over time, the deviation from initial appeared to be linked to the treatment trophic scenarios. The least temporal deviation-from-initial in bacterial community was found within the stable apex predatory pressure treatment. These findings are consistent with trophic cascade theory, whereby predators mediate interactions at multiple lower trophic levels with consequent repercussions for diversity.

Evaluation of correlation between dose and clinical outcomes in subcutaneous immunoglobulin replacement therapy.

The importance of serum immunoglobulin (Ig)G concentration in IgG replacement therapy for primary immunodeficiency diseases is established in certain settings. Generally, IgG is infused via the intravenous (IVIG) or subcutaneous (SCIG) route. For IVIG infusion, published data demonstrate that higher IgG doses and trough levels provide patients with improved protection from infection. The same conclusions are not yet accepted for SCIG; data from two recent Phase III studies and a recent post-hoc analysis, however, suggest the same correlation between higher SCIG dose and serum IgG concentration and decreased incidence of infection seen with IVIG. Other measures of clinical efficacy have not been considered similarly. Thus, combined analyses of these and other published SCIG studies were performed; a full comparison of the 13 studies was, however, limited by non-standardized definitions and reporting. Despite these limitations, our analyses indicate that certain clinical outcomes improve at higher SCIG doses and associated higher serum IgG concentrations, and suggest that there might be opportunity to improve patient outcomes via SCIG dose adjustment.

Study design and baseline description of the BMI2 trial: reducing paediatric obesity in primary care practices.

OBJECTIVES: This study will test the efficacy of motivational interviewing (MI) conducted by primary care providers and dieticians among children ages 2-8 years old with a body mass index (BMI) ≥ 85th and ≤ 97th percentile. METHODS: Forty-two practices from the American Academy of Pediatrics, Pediatric Research in Office Settings Network were assigned to one of three groups. Group 1 (usual care) measures BMI percentile at baseline, and at 1- and 2-year follow-ups and receives standard health education materials. Group 2 providers deliver three proactive MI counselling sessions with a parent of the index child in Year 1 and one additional 'booster' visit in Year 2. Group 3 adds six MI counselling sessions from a trained dietician. The primary outcome is the child's BMI percentile at 2-year follow-up. Secondary outcomes include parent report of the child's screen time, physical activity, intake of fruits and vegetables, and sugar-sweetened beverages. RESULTS: We enrolled 633 eligible children whose mean BMI percentile was 92.0 and mean age of 5.1. The cohort was 57% female. Almost 70% of parents reported a household income of ≥ $40,000 per year, and 39% had at least a college education. The cohort was 63% white, 23% Hispanic, 7% black and 7% Asian. Parent self-reported confidence that their child will achieve a healthy weight was on average an 8 (out of 10). CONCLUSION: To date, several aspects of the study can inform similar efforts including our ability to use volunteer clinicians to recruit participants and their willingness to dedicate their time, without pay, to receive training in MI.

C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks--final results of the I.M.P.A.C.T.2 study.

BACKGROUND: The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks. METHODS: I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies. RESULTS: During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient. CONCLUSIONS: A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.

Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease.

Subcutaneous administration of intravenous immunoglobulin G (IgG) preparations provides an additional level of patient convenience and more options for patients with poor venous access or a history of intravenous IgG reactions. An open-label, pharmacokinetic trial (n = 32) determined the non-inferiority of the subcutaneous versus intravenous route of 10% caprylate/chromatography purified human immune globulin intravenous (IGIV-C; Gamunex®) administration by comparing the steady-state area under the concentration-versus-time curve (AUC) of total plasma IgG in patients with primary immunodeficiency disease. Patients on stable IGIV-C received two intravenous infusions (administered 3 or 4 weeks apart). Seven to 10 days after the second intravenous infusion, all patients switched to a weekly infusion of subcutaneous IGIV-C, with the dose equal to 137% of the previous weekly equivalent intravenous dose, for up to 24 weeks. Samples for pharmacokinetic analysis were collected during steady state for intravenous and subcutaneous IGIV-C treatments. The AUC(0-) τ geometric least-squares mean ratio was 0·89 (90% confidence interval, 0·86-0·92) and met the criteria for non-inferiority. The overall mean steady-state trough concentration of plasma total IgG with subcutaneous IGIV-C was 11·4 mg/ml, 18·8% higher than intravenous IGIV-C (9·6 mg/ml). Subcutaneous IGIV-C was safe and well tolerated. Subcutaneous IGIV-C infusion-site reactions were generally mild/moderate and the incidence decreased over time. No serious bacterial infections were reported. Weekly subcutaneous IGIV-C infusion using 137% of the weekly equivalent intravenous immunoglobulin dose provides an AUC comparable to intravenous administration, thus allowing patients to maintain the same IgG preparation/formulation if switching between intravenous and subcutaneous infusions.

Subcutaneous immunoglobulin: opportunities and outlook.

Immunoglobulin (Ig) administration via the subcutaneous (s.c.) route has become increasingly popular in recent years. The method does not require venous access, is associated with few systemic side effects and has been reported to improve patients' quality of life. One current limitation to its use is the large volumes which need to be administered. Due to the inability of tissue to accept such large volumes, frequent administration at multiple sites is necessary. Most studies conducted to date have investigated the use of subcutaneous immunoglobulin (SCIg) in patients treated previously with the intravenous (i.v.) formulation. New data now support the use of s.c. administration in previously untreated patients with primary immunodeficiencies. SCIg treatment may further be beneficial in the treatment of autoimmune neurological conditions, such as multi-focal motor neuropathy; however, controlled trials directly comparing the s.c. and i.v. routes are still to be performed for this indication. New developments may further improve and facilitate the s.c. administration route. For example, hyaluronidase-facilitated administration increases the bioavailability of SCIg, and may allow for the administration of larger volumes at a single site. Alternatively, more concentrated formulations may reduce the volume required for administration, and a rapid-push technique may allow for shorter administration times. As these developments translate into clinical practice, more physicians and patients may choose the s.c. administration route in the future.

Fluticasone propionate/salmeterol hydrofluoroalkane via metered-dose inhaler with integrated dose counter: Performance and patient satisfaction.

Currently, patients have to keep track of doses to determine when to replace their metered-dose inhalers (MDIs). This study evaluated the performance and patient satisfaction of a novel MDI with an integrated dose counter. In an open-label study at 38 outpatient centres, patients > or =12 years old with asthma or chronic obstructive pulmonary disease (COPD) received two actuations of fluticasone propionate/salmeterol 125/25 microg (115/21 microg ex-actuator) hydrofluoroalkane (ADVAIR) HFA) via MDI with counter twice a day until all 120 actuations were completed. Concordance between counter and diary recordings in patients who reported use of > or =90% of labelled actuations (completer population, n = 228) was high (discrepancy rate of 0.94%) and the incidence of device firing without changes in counter readings was low (0.13%). Mean expected actuations based on canister weights (114) were slightly lower than mean counter (121) and diary reported actuations (120). Upon study completion, 95% of patients were satisfied with the dose counter and 92% agreed it would help prevent them from running out of medication. Safety assessments (intent-to-treat population, n = 237) indicated that the drug was well tolerated. This integrated MDI counter may help patients maintain better disease control by enabling them to accurately track their medication supply.

Outbreak of Serratia marcescens infections following injection of betamethasone compounded at a community pharmacy.

BACKGROUND: In June 2001, following the report of 4 patients with Serratia marcescens meningitis who received epidural injections of betamethasone compounded at a community pharmacy, we initiated an outbreak investigation. METHODS: All patients who received injections of betamethasone from the production lot common to the 4 patients were evaluated. A case patient was defined as a patient who received compounded betamethasone and had S. marcescens isolated from a sterile site or clinical and laboratory evidence of infection. We cultured all recovered betamethasone, environmental specimens from the pharmacy, and medications recovered from an ambulatory surgery center. The California Board of Pharmacy reviewed the procedures used to prepare the betamethasone. RESULTS: We identified 11 patients with culture-confirmed S. marcescens (8 patients) or clinical infection (3 patients) following injection of compounded betamethasone from 25 May through 31 May 2001. Case patients had meningitis (5 patients, with 3 deaths), epidural abscesses (5 patients), or an infected hip (1 patient). S. marcescens was isolated from 35 (69%) of 51 betamethasone vials recovered, from pharmacy specimens of 1% carboxymethylcellulose stock solution, from pharmacy surfaces, and from multiple parenteral materials used at the ambulatory surgery center. Pulsed-field gel electrophoresis patterns of S. marcescens isolates of representative specimens from patients, the betamethasone, the pharmacy, and the ambulatory surgery center were identical. Deficient practices in compounding of betamethasone included inadequate autoclaving temperatures and failure to perform terminal sterilization. CONCLUSIONS: This outbreak of serious S. marcescens infection followed improper compounding of betamethasone in a community pharmacy. Enforceable national standards for pharmaceutical compounding are needed to reduce the risk of such outbreaks.

Changes in haemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection.

Interferon alpha and ribavirin (RBV) combination therapy is associated with decreases in haemoglobin (Hb) concentrations and anaemia. The aim of this analysis was to better characterize the magnitude and frequency of Hb changes and risk factors. This retrospective analysis evaluated treatment-related changes in Hb in 677 patients who participated in either of two interferon alpha-2b plus RBV studies for chronic hepatitis C virus (HCV) infection. Study 1 included 192 interferon alpha-naïve patients randomized to receive RBV 1000-1200 mg/day plus interferon alpha-2b 3 million IU daily or three times weekly for 48 weeks. Study 2 included 485 interferon alpha-experienced patients randomized to receive RBV 1000-1200 mg daily plus interferon alpha-2b 3 million IU daily or three times weekly for 4 weeks, followed by three times weekly dosing for 44 weeks. More than 50% of all patients experienced a decrease in Hb > or =30 g/L. Women were 4.4 times as likely as men to experience a Hb level of <100 g/L; however, men were at a 40% higher risk to experience a Hb decline of >30 g/L from baseline. Daily use of interferon alpha-2b did not impact the magnitude of Hb decrease. In this pooled analysis, RBV dose reduction resulted in increases in Hb concentration of approximately 10 g/L. Lower baseline creatinine clearance, higher baseline Hb levels and increased age were independently associated with increased risk of Hb decreases of >27.7%. Lower baseline weight was not associated with increased risk of Hb decrease. Substantial Hb decreases occur frequently with interferon alpha/RBV combination therapy. Sex, the magnitude of the Hb decline and renal function are potentially important factors to consider in patients receiving RBV. Further research is needed to determine the impact on virological response and to develop strategies to manage the medical consequences.

Comparative immunolocalization of the plasma membrane calcium pump and calbindin D28K in chicken retina during embryonic development.

The immunolocalization of the plasma membrane calcium pump (PMCA) was studied in 4-week-old chick retina in comparison with calbindin D28K (CaBP) immunostaining. We have demonstrated that the monoclonal anti-PMCA antibody SF10 from human erythrocyte plasma membrane cross-reacts with a Ca2+ pump epitope of the cells from the neural retina. The immunolocalization of both proteins was also studied during the embryonic development of the chicken retina. At age 4.5 days, the cells of the retina were faintly immunoreactive to PMCA and CaBP antibodies, but the lack of cellular aggregation and differentiation did not allow discrimination between the two proteins. A clear difference in the localization was seen from the tenth day of development through post-hatching with slight variation. PMCA localized mainly in the outer and inner plexiform layers, in some cells in the ganglion layer, in the nerve fiber layer and slightly in the photoreceptor cells. CaBP was intensely stained in cones, cone pedicles and some amacrine cells. The number of CaBP positive amacrine cells declined after hatching. A few ganglion cells and several nerve fibers were CaBP immunoreactive. The role of these proteins in the early stages of retinal development is unknown, but the results suggest that Ca2+ homeostasis in the retina is well regulated, probably to avoid excessive accumulation of Ca2+, which often leads to neurodegeneration.

Earlier onset of puberty in girls: relation to increased body mass index and race.

OBJECTIVE: A recent study conducted by the Pediatric Research in Office Settings network provided evidence that girls in the United States, especially black girls, are starting puberty at a younger age than earlier studies had found, but the reasons for this are not known. Because nutritional status is known to affect timing of puberty and there is a clear trend for increasing obesity in US children during the past 25 years, it was hypothesized that the earlier onset of puberty could be attributable to the increasing prevalence of obesity in young girls. Therefore, the objective of this study was to reexamine the Pediatric Research in Office Settings puberty data by comparing the age-normalized body mass index (BMI-ZS; a crude estimate of fatness) of girls who had breast or pubic hair development versus those who were still prepubertal, looking at the effects of age and race. RESULTS: For white girls, the BMI-ZS were markedly higher in pubertal versus prepubertal 6- to 9-year-olds; for black girls, a smaller difference was seen, which was significant only for 9-year-olds. Higher BMI-ZS also were found in girls who had pubic hair but no breast development versus girls who had neither pubic hair nor breast development. A multivariate analysis confirms that obesity (as measured by BMI) is significantly associated with early puberty in white girls and is associated with early puberty in black girls as well, but to a lesser extent. CONCLUSIONS: The results are consistent with obesity's being an important contributing factor to the earlier onset of puberty in girls. Factors other than obesity, however, perhaps genetic and/or environmental ones, are needed to explain the higher prevalence of early puberty in black versus white girls.

Impact of the change to inactivated poliovirus vaccine on the immunization status of young children in the United States: a study from pediatric research in office settings and the National Medical Association.

OBJECTIVE: To determine whether the change from an all oral poliovirus vaccine (OPV) schedule to an inactivated poliovirus vaccine (IPV)-containing schedule has adversely affected the immunization status of young children in the United States. METHODS: Immunization data were abstracted from the medical records of children 8 to 35 months old seen consecutively for any reason in the offices of practicing pediatricians who are members of the Pediatric Research in Office Settings network of the American Academy of Pediatrics or the National Medical Association. Data on up to 120 eligible children were collected in each practice between March 1998 and January 2000. Patients were classified as fully immunized at 8 months old if they had received 3 diphtheria-tetanus-pertussis, 2 Haemophilus influenzae type b, 2 hepatitis B, and 2 poliovirus vaccines. Study children who were >/=12 months of age at the time that data were collected were categorized as being fully immunized at 12 months if they had received the same vaccines before their first birthday. To assess the effect of type of poliovirus vaccines on these outcomes, study patients were classified as being in an IPV or OPV group based on the initial type of vaccine received. Logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for IPV as a predictor of being fully immunized at 8 and 12 months of age, after adjusting for race/ethnicity of the patient, maternal education level, year of birth, and method of payment for vaccines. In addition, the effect of clustering of children within practices was accounted for by the use of generalized estimation equation techniques. RESULTS: Data were analyzed on 13 520 children from 177 practices in 42 states; 79.4% of patients were fully immunized at 8 months of age, and 88.7% of those eligible were fully immunized at 12 months of age. A total of 6910 patients (51.1%) were classified as OPV recipients, wheras 5282 (39.1%) received IPV. In addition, 1328 children (9.8%) were documented as having received poliovirus vaccine, but the particular type could not be determined. Compared with OPV recipients and after controlling for the confounding variables and the effect of clustering within practices, children in the IPV group were as likely as were OPV recipients to be fully immunized at 8 months of age (OR: 1.04; 95% CI: 0.88,1.23). At 12 months of age, the OR for IPV as a predictor of being fully immunized was 1.08 (95% CI: 0.90,1.30). When compared with OPV recipients, adjusted ORs for children in the undetermined poliovirus vaccine type group being fully immunized at 8 and 12 months of age were 0.84 (95% CI: 0.68,1.04) and 0.84 (95% CI: 0.67,1.07), respectively. CONCLUSIONS: The results of this national study indicate that the implementation of an IPV-containing poliovirus vaccine schedule has not had an adverse effect on the immunization status of young children who were vaccinated in the offices of practicing pediatricians.

Response by B cell precursors to pre-B receptor assembly: differences between fetal liver and bone marrow.

The expression of different sets of immunoglobulin specificities by fetal and adult B lymphocytes is a longstanding puzzle in immunology. In the past few years it has become clear that production of mu heavy chain and subsequent assembly with surrogate light chain to form the pre-B cell receptor complex is critical to promote development of adult B cell precursors in mouse bone marrow. Recently we found that instead of promoting pre-B cell expansion as in adult bone marrow, this complex inhibits pre-B cell growth in fetal liver, providing a previously unrecognized mechanism for alteration of the B cell repertoire with age. The consequence is very distinct primary repertoires for development of fetal B1 cells and adult bone marrow B2 cells.