Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2.

Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene expression during hcIN development. Binding sites for different classes of transcription factors were enriched at CHD2 bound regions during differentiation, suggesting transcription factors that may cooperatively regulate stage-specific gene expression with CHD2. We also demonstrated that CHD2 haploinsufficiency altered CHD2 and H3K27ac coenrichment on chromatin and expression of associated genes, decreasing acetylation and expression of cell cycle genes while increasing acetylation and expression of neuronal genes, to cause precocious differentiation. Together, these data describe CHD2 direct targets and mechanisms by which CHD2 prevents precocious hcIN differentiation, which are likely to be disrupted by pathogenic CHD2 mutation to cause neurodevelopmental disorders.

Reproductive and developmental toxicity assessment of palbociclib, a CDK4/6 inhibitor, in Sprague-Dawley rats and New Zealand White rabbits.

Palbociclib is a selective inhibitor of the cyclin-dependent kinase (CDK) 4/6, approved for the treatment of breast cancer. We assessed the potential effects of oral administration of palbociclib on reproduction and development. There were no effects on female or male fertility indices; however, in the male there was seminiferous tubule degeneration in the testes and secondary findings in the epididymides, lower testicular and epididymal weights, sperm density and motility. Palbociclib was not teratogenic in rats or rabbits; however, in the presence of maternal toxicity (lower maternal body weight gain and food consumption), low fetal body weights were observed in rats and small forepaw phalanges were noted in rabbits. There were, however, no adverse effects on the F1 generation in a pre- and post-natal developmental toxicity study in the rat.

Measuring the equations of state in a relaxed magnetohydrodynamic plasma.

We report measurements of the equations of state of a fully relaxed magnetohydrodynamic (MHD) laboratory plasma. Parcels of magnetized plasma, called Taylor states, are formed in a coaxial magnetized plasma gun, and are allowed to relax and drift into a closed flux conserving volume. Density, ion temperature, and magnetic field are measured as a function of time as the Taylor states compress and heat. The theoretically predicted MHD and double adiabatic equations of state are compared to experimental measurements. We find that the MHD equation of state is inconsistent with our data.

Assessing the acquisition of core clinical skills through the use of serial standardized patient assessments.

PURPOSE: Students in many medical schools now undergo multiple standardized-patient-based assessments. In this study, the authors examine the ability of such serial assessments to detect interval learning. METHOD: Twenty-one students from the University of California, Irvine, College of Medicine, class of 1999, underwent a clinical skills appraisal after three months of their third-year instruction. After nine months, all 89 members of that class completed an OSCE. Subsequently, all 87 students in the class of 2000 also completed clinical skills assessments after their third and ninth months of third-year instruction. All of these exercises included identical or similar stations measuring history, physical examination, and communication skills. Communication skills were measured somewhat differently during some of the exercises, using checklists that were either "content-" or "process-"oriented. The authors compared the performances for all groups. RESULTS: Both classes demonstrated significant improvement in physical examination performance, while their history performances remained unchanged. According to the assessments, their communication skills deteriorated over the course of their third-year instruction. Repeated exposures to similar or identical cases on the serial assessments did not impact the students' performances. Both content- and process-oriented measures of communication skills yielded highly similar results. CONCLUSIONS: Serial assessments using standardized patients can detect interval changes in performance that are independent of repeated exposures to similar or identical cases. Changes detected using this approach may have important curricular implications.

Computer-generated recall letters for underimmunized children: how cost-effective?

OBJECTIVE: To evaluate the effectiveness and cost effectiveness of computer-generated recall letters to parents of children overdue for immunizations. METHODS: This randomized controlled trial included children of two facilities in a regional health maintenance organization. Parents of 20-month-olds who had not yet received a measles-mumps-rubella (MMR) immunization were identified via a computerized immunization tracking system. One half were mailed personalized letters that included the recommended immunization schedule and a request to call for an appointment; the other half served as a control group. Receipt of the MMR between 20 and 24 months of age was evaluated with the computerized tracking system. A telephone survey was conducted with parents whose children had not received the MMR by 24 months. Decision analysis was used to project the theoretical outcomes and costs of a recall letter policy for other populations. RESULTS: Among 20-month-old children 10% had not received the MMR; 289 families were included in the analysis. Of families who were mailed letters, 54% (82 of 153) received the MMR by 24 months of age, compared with 35% (47 of 136) of those in the control group (P = 0.001). The telephone survey was completed with 110 parents of children who still did not appear on the health plan computer as having received the MMR by 24 months. Fifteen percent said the child had received an immunization at an outside provider, and of the rest 62% said they had not been aware that an immunization was due. In the cost effectiveness analysis it was projected that recall letters would increase the immunization rate for the regional population of approximately 30000 children from 86% to 90% at a total cost of $5031 annually. The cost per additional child appropriately immunized was $4.04. In sensitivity analyses this cost effectiveness ratio varied depending on the baseline population coverage rate as well as the estimated effectiveness of recall letters. CONCLUSIONS: Computer-generated letters to recall children overdue for immunizations resulted in a higher proportion of children appropriately immunized in this setting. However, the strategy was not as cost-effective as intuition might suggest. Further studies in health maintenance organization (HMO) settings should compare the cost effectiveness of letters with other low cost strategies including automated telephone reminders.

Safety and immunogenicity of Chiron/Biocine recombinant acellular pertussis-diphtheria-tetanus vaccine in infants and toddlers.

OBJECTIVE: To evaluate the safety and immunogenicity of the recombinant acellular pertussis-diphtheria-tetanus (aPDT) vaccine (C-aPDT, Chiron/Biocine). STUDY DESIGN: This is a randomized blinded trial evaluating the safety and immunogenicity of the recombinant aPDT vaccine (C-aPDT, Chiron/Biocine) in 2000 infant recipients compared with 498 controls who received whole cell diphtheria-pertussis-tetanus (wDPT; Connaught) vaccine at 2, 4 and 6 months of age. In addition the safety and immunogenicity of the same C-aPDT vaccine were evaluated as a booster dose in a subset of the same population when given at 15 to 18 months of age and compared with licensed Lederle aPDT vaccine. RESULTS: The C-aPDT vaccine was associated with very few local or systemic reactions when compared with wDPT. In toddlers the local and systemic side effects observed were similar after either acellular vaccine. When the immunogenicity of the C-aPDT vaccine was compared with the wDPT (Connaught) in infancy, the vaccines were equivalent for anti-diphtheria response, the wDPT developed higher anti-tetanus response and the C-aPDT vaccine was significantly more immunogenic for all other antigens tested. In toddlers the C-aPDT acellular vaccine exhibited equal or improved immunogenicity for antigens tested as compared with Lederle aPDT except for a higher anti-filamentous hemagglutinin response with the Lederle aPDT vaccine. CONCLUSION: The Chiron/Biocine aPDT vaccine offers an improved safety profile as well as improved immunogenicity when compared with a licensed wDPT product.

The cost of childhood chickenpox: parents' perspective.

The development of a varicella vaccine has raised questions about the cost effectiveness of vaccination, but little information on the costs of chickenpox exists. The purpose of this study was to evaluate medical costs and the value of work loss among families whose children had chickenpox. Interviews were conducted with 179 families who made advice nurse calls or urgent care clinic visits to three clinics in the Northern California Kaiser Permanente Medical Care Plan. Two-thirds of working mothers and one-third of working fathers missed work to care for children with chickenpox. The mean value of the work lost because of chickenpox was $293/family or $183/chickenpox case. The estimated costs of nonprescription medications were $20/family or $12.50/chickenpox case. Children were sick enough to need to stay home for only one-third as many days as chicken actually stayed home because of school exclusion policies. These empiric results differ from previous estimates of the medical and work loss costs of varicella and should be included in analyses of the cost effectiveness of proposed vaccination programs.

Safety of combined oligosaccharide conjugate Haemophilus influenzae type b (HbOC) and whole cell diphtheria-tetanus toxoids-pertussis vaccine in infancy. The Kaiser Permanente Pediatric Vaccine Study Group.

The safety of the combined oligosaccharide conjugate Haemophilus influenzae (Hib) type b (HbOC) and whole cell diphtheria-tetanus toxoids-pertussis (DTP) vaccine (Tetramune, HbOC-DTP; Lederle) in infancy was evaluated in 6644 recipients of this vaccine and compared with 3914 recipients of separate injections of whole cell DTP and HbOC vaccines when given as a three dose regimen to infants at 2, 4 and 6 months of age in each group. Of the total number of infants in the study, a subset of 1435 were enrolled into the study and then randomly assigned to receive either the Hib-DPT combined vaccine or the separate components. This subset was used to assess local and systemic side effects which were evaluated utilizing telephone interviews 48 to 72 hours after vaccine. The remaining children in the study population were enrolled in a nonrandomized manner. For these children parents were offered the experimental Hib-DPT vaccine and refusers were given HbOC and DTP. Both of these groups of children as well as the randomized subset described above were used to assess rates of episodes of hospitalization, emergency room utilization and sudden infant death syndrome in HbOC-DTP recipients and children who received HbOC and DTP separately. Immunogenicity was evaluated in 123 children by collection of a single serum sample 30 days after the third dose of HbOC-DTP. The observed immunogenicity was comparable to that observed in other recent studies for HbOC and DTP component antigens. The profile of local and systemic side effects observed was virtually identical to that observed after DTP plus HbOC given separately.(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of succinyladenylate lyase activity and serum sialic acid as markers of malignancy.

A comparison was made of succinyladenylate lyase (SAMP lyase), total serum sialic (TSA), and lipid soluble serum sialic acid (LSA) as early markers of malignancy in three experimentally induced rat tumor models. Elevation of SAMP lyase in 3'-methyl-dimethylaminoazobenzene-induced hepatic tumors at 2 weeks corresponded with microscopic detection of preneoplastic lesions with elevation of LSA occurring 2 weeks later. Elevation of breast SAMP lyase concurred with macroscopic presence of dimethylbenzanthracene involved breast tumors with elevation of LSA occurring 12 weeks later. Neither colon SAMP lyase nor LSA increased in rats bearing colon tumors induced by dimethylhydrazine. The determination of TSA was not a reliable indicator of tumor presence for the three types of tumors investigated. Both SAMP lyase and LSA are very good early indicators of hepatic tumor with SAMP lyase an earlier indicator of breast tumor than LSA.

Time and cost comparison of four methods of filling piggyback bottles.

The time and cost required by four methods of filling piggyback bottles were compared. The four methods compared were (1) the traditional vacuum method, (2) the Wheaton Unispense Model II, (3) the Valleylab IV 6500 Formulator, and (4) the Instafil method. Batches of 20 bottles filled to 50-ml and 100-ml volumes were used to compare fill rates of all four methods. In addition, batches of 60 bottles filled to 100-ml volumes were used to compare the fill time of the Instafil and the IV 6500 Formulator methods. Relative cost factors were then computed for each method and used for comparison. The results showed the Instafil method to be the fastest method for batches of 20 to 60 bottles. The traditional method demonstrated the lowest overall cost, followed by the Instafil method. The authors recommend the use of the Instafil method for batches of 60 or less. For larger batches, an automated device like the Valleylab Formulator or the Wheaton Unispense may be more appropriate.