Developmental stages and estimated prevalence of coexisting mental health and neurodevelopmental conditions and service use in youth with intellectual disabilities, 2011-2012.

BACKGROUND: Few studies exist on mental health and neurodevelopmental conditions and service use among youth with intellectual disabilities (IDs), which makes it difficult to develop interventions for this population. The objective of the study is to (1) estimate and compare the prevalence of mental health and neurodevelopmental conditions in youth with and without ID across three developmental stages and (2) estimate and compare mental health service use in youth with and without ID across three developmental stages. METHODS: We conducted secondary data analysis using cross-sectional data collected from caregivers completing the 2011-2012 National Survey of Children's Health. The data set represents a nationally representative sample of youth (0-17 years) in the USA with one child from each household being randomly selected. Data were collected from caregivers in 50 states, Washington D.C. and the US Virgin Islands. We restricted the sample to parents of youth between 3-17 years (N = 81 510). RESULTS: Compared with youth without ID, youth ages 3-17 with ID had a statistically significantly higher prevalence of (1) mental health and neurodevelopmental conditions and (2) mental health care use and medication use for mental health and neurodevelopmental issues (other than attention deficit disorder/attention deficit hyperactivity disorder). Clinically significant differences in coexisting conditions and service use were also found across developmental stages. CONCLUSIONS: Youth with ID are at greater risk of having coexisting mental health and neurodevelopmental conditions than youth without ID and are more likely to receive treatment. Therefore, clinicians should consider mental health and neurodevelopmental conditions and the unique needs of youth by developmental stage when tailoring interventions for youth with ID.

Twenty-five years of progress: the view from NIMH and NINDS.

As directors of two NIH institutes supporting neuroscience research, we explore the gap between 25 years of stunning progress in fundamental neuroscience and the persistent needs of those with brain disorders. We conclude that closing this gap will require a more detailed comprehension of brain function, a rethinking of how we approach translational science, a focus on human neurobiology, and a continuing commitment to build a diverse, innovative neuroscience workforce. In contrast to many other areas of medicine, we lack basic knowledge about our organ of interest. The next phase of progress on brain disorders will require a significantly deeper understanding of fundamental neurobiology.

The NIH toolbox: setting a standard for biomedical research.

This special issue of Neurology(®) marks the unveiling of a multi-year effort to develop the NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox). Constructed based on state-of-the-art psychometric research and novel testing methods, this approach to functional neurologic measurement is as innovative in concept as it is in design. This initiative and the resulting set of instruments, supported through the NIH Blueprint for Neuroscience Research (NIH Blueprint) and built by a development team of more than 250 scientists from almost 100 academic institutions, promises to provide long overdue economies of scale and efficiency to the clinical research enterprise. The NIH Toolbox achieves that end by providing psychometrically sound, cutting-edge, adaptable measures that enable uniformity of measurement, data sharing, and integration of findings in the research setting.

A call for transparent reporting to optimize the predictive value of preclinical research.

The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the methodological reporting of animal studies in grant applications and publications. The main workshop recommendation is that at a minimum studies should report on sample-size estimation, whether and how animals were randomized, whether investigators were blind to the treatment, and the handling of data. We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators, reviewers, funding agencies and journal editors. Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress.

Effect of co-infusion of dextrose-containing solutions on red blood cell haemolysis during packed red cell transfusion.

AIM: Transfusion guidelines prohibit co-infusion of maintenance intravenous fluid solutions, with significant consequences for neonatal clinical care. This study investigated co-infusion-related haemolysis in an in vitro model closely resembling clinical practice. METHODS: Packed red blood cells (PRBCs, n=8) were co-infused at 5 and 10 ml/h with dextrose 5%, 10% and intravenous amino acid solution (synthamin). Free haemoglobin (fHb), as a measure of haemolysis, was measured by spectrophotometry and presented as % haemolysis and total fHb content (µmol/l). RESULTS: Following co-infusion, there was no significant increase in PRBC haemolysis with either type of solution co-infused (p=0.82) or infusion rate (p=0.5). Neither macroscopic nor microscopic agglutination was observed during co-infusion for any type of solution co-infused. CONCLUSIONS: Co-infusion does not result in increased haemolysis, with total fHb significantly lower than currently accepted safe thresholds for fHb. Adherence to current guidelines may place undue restrictions on current transfusion practice in neonatal intensive care.

The 3rd Judith Hoyer Lecture in epilepsy, December 2, 2005 opening remarks.

On December 2, 2005, Dr. Jeffrey L. Noebels presented the third lecture in a series highlighting the promise of epilepsy research. Opening remarks were provided by Dr. Story C. Landis, Director of the National Institute of Neurological Disorders and Stroke, and by Representative Steny Hoyer (D-MD). The lecture series is held in memory of Mrs. Judith Hoyer, an active member of the Board of Directors of the Epilepsy Foundation (EF) and the late wife of Rep. Hoyer. Mrs. Hoyer spent her life both helping families to cope with epilepsy and promoting research into a cure and a better quality of life for those with the disorder. The purpose of the lecture is to raise awareness of epilepsy among researchers and the public and provide intellectual stimulation that will encourage continuing progress toward finding a cure for epilepsy.

Response to: "Rescuing the NIH before it is too late".

We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs.

Role of beta(1)-integrins and their associated tetraspanin molecules in fibronectin-enhanced megakaryopoiesis.

BACKGROUND: We have shown previously that fibronectin (FN) together with megakaryocyte (Mk) growth and development factor (MGDF) enhanced generation of Mk progenitors determined by colony-forming unit (CFU)-Mk assay. MGDF can activate beta(1)-integrins on progenitor cells and increase binding to FN. We studied the role of beta(1)-integrin-tetraspanin complexes by which FN may enhance megakaryopoiesis. METHODS: Cord blood CD34(+) cells were cultured for up to 8 days in serum-free medium containing IL-3, IL-6 and SCF with or without MGDF in the presence or absence of FN. Immunofluorescence flow cytometry was used to monitor changes in beta(1)-integrin-tetraspanin complexes. CFU-Mk assay was used to assess Mk commitment. RESULTS: The cocktail of cytokines irrespective of the presence of MGDF altered the percentage expression of beta(1)-integrins CD49d and CD49e on CD34(+) cells. CD49d expression fell initially (98% to 15%) and then rose to 75%, whereas CD49e progressively increased over the 8 days of culture, from 5.4% to 22%. However, with the addition of FN, similar changes in the expression of beta(1)-integrins were observed but the expression was maintained at a higher level. MGDF and FN increased expression of tetraspanin molecules, CD63 and CD151, as well as their co-expression with the beta(1)-integrins on both the CD34(+) and CD34(-) cells (e.g. and increase from 0% to 80% co-expression of CD49d and CD151 on CD34(+)). Blocking of beta(1)-integrins or the tetraspanin CD151 with the respective MAb reduced Mk progenitor generation in a stromal cell model. DISCUSSION: FN enhanced Mk progenitor generation through modulation of beta(1)-integrin-tetraspanin complexes, such as CD151/CD49d.

Enhanced expansion and maturation of megakaryocytic progenitors by fibronectin.

BACKGROUND: Megakaryopoiesis occurs as a result of a complex interaction between hemopoietic cells, stromal cells, hemopoietic growth factors and extracellular matrix (ECM). Megakaryocyte growth and development factor (MGDF) or thrombopoietin is the main growth factor that induces megakaryocyte commitment. The role of adhesion proteins in the generation of megakaryocytic progenitors has not been well studied. METHODS: We isolated CD34(+) cells from umbilical cord (UC) blood and cultured them in serum-free medium containing IL-3, IL-6, SCF and MGDF, with or without fibronectin. Cultures were sampled at Days 4 and 8 for cell count, immunophenotyping by flow cytometry, and megakaryocyte colony-forming units (CFU-Mk) assay. RESULTS: Fibronectin in synergy with MGDF increased both total and CD34(+) cell count. Immunophenotyping of the CD34(+) and CD34(-) cells showed that the percentage expression of CD61 and CD41a on CD34(-) cells was increased by fibronectin compared with CD34(+) cells by Day 8 of culture. The CFU-Mk assay confirmed that fibronectin increased generation of megakaryocytic progenitors by 2.4-fold by Day 8 of culture, but the absolute number was less than that of Day 4 culture. The cells in the CFU-Mk colonies derived from culture containing fibronectin were larger than those from cytokine-only culture. CONCLUSION: It was concluded that the addition of fibronectin to the culture system enhanced MGDF, induced ex vivo expansion of megakaryocytic progenitors from CD34(+) cells, as well as increasing their maturation towards later stages of megakaryocyte differentiation.

Immune escape mechanisms of childhood ALL and a potential countering role for DC-like leukemia cells.

BACKGROUND: Pre-B ALL cells generally elicit a weak immune host response, due to poor expression of co-stimulatory molecules and/or suppression of immune function. A possible way to enhance immunogenicity of pre-B ALL cells is to convert them to DC-like cells. METHODS: To study the effect of ALL cells on T-cell function, ALL cells were incubated with T adult cells activated by OKT3 MAb. Liquid culture of de novo pre-B ALL cells for 7 days, in a medium containing IL-1alpha, IL-3, IL-7, Flt 3 ligand (L) and tumor-necrosis factor alpha (TNF-alpha) produced DC-like cells. These were evaluated for morphology, viability, phenotype, as measured by flow cytometry, and function, including MLR. RESULTS: Pre-B ALL cell-lines NALM-6, BALM and de novo pre-B ALL cells failed to stimulate T cells, but suppressed stimulated T cells. The DC-like cells displayed characteristic features of DCs: filiform cytoplasmic projections, and phenotypic expression of co-stimulatory molecules CD80/86, MHC Class I and II molecules, CD83 and CD1a. Genetic monoclonality study confirmed their leukemic origin. In a 5-day MLR culture, the DC-like cells potently activated allogeneic adult and cord CD4+ and CD8+ T cells. Furthermore, both CD4+ and CD8+ T cells were primed towards a Type I. No such effect was seen with unmanipulated de novo pre-B ALL cells. DISCUSSION: DC-like cells can be generated from childhood pre-B ALL cells and are potent stimulators of adult and naïve cord CD8+ T cells via CD4+ cells. These cells may form part of an immunotherapy strategy to overcome tolerance to ALL cells.

HIV-1 Nef blocks transport of MHC class I molecules to the cell surface via a PI 3-kinase-dependent pathway.

HIV causes a chronic infection by evading immune eradication. A key element of HIV immune escape is the HIV-1 Nef protein. Nef causes a reduction in the level of cell surface major histocompatibility complex class I (MHC-I) protein expression, thus protecting HIV-infected cells from anti-HIV cytotoxic T lymphocyte (CTL) recognition and killing. Nef also reduces cell surface levels of the HIV receptor, CD4, by accelerating endocytosis. We show here that endocytosis is not required for Nef-mediated downmodulation of MHC-I molecules. The main effect of Nef is to block transport of MHC-I molecules to the cell surface, leading to accumulation in intracellular organelles. Furthermore, the effect of Nef on MHC-I molecules (but not on CD4) requires phosphoinositide 3-kinase (PI 3-kinase) activity. We propose that Nef diverts MHC-1 proteins into a PI 3-kinase-dependent transport pathway that prevents expression on the cell surface.

Comparison of methods for assessment of minimal residual disease in childhood B-lineage acute lymphoblastic leukemia.

The level of minimal residual disease (MRD) early in treatment of acute lymphoblastic leukemia (ALL) strongly predicts the risk of marrow relapse. As a variety of methods of varying complexity have been separately used for detecting and quantifying MRD, we compared the prognostic utility of three methods measurement of blast percentage on day 14 of treatment, detection of monoclonality on day 14 or day 35, and measurement of MRD by PCR-based limiting dilution analysis on day 14 or day 35. The study group comprised 38 children aged 1-15 with Philadelphia-negative B-lineage ALL who were uniformly treated and followed until relapse or for a minimum of 5 years. We also studied some of the technical factors which influence the ability to detect MRD. Measurement of blast percentage on day 14 by an expert morphologist, detection of monoclonality on day 35, and PCR-based measurement of MRD levels on days 14 and 35 all showed significant ability to divide patients into prognostic groups. Measurement of blast percentage on day 14 by routine morphology or detection of monoclonality on day 14 were not useful. The quality of DNA samples varied greatly, as determined by amplifiability in the PCR. However, virtually all amplifiable leukemic targets in a sample were detectable which suggests that the level of detection achieved by limiting dilution analysis is essentially determined by the amount of DNA which it is practicable to study. We conclude that quantification of MRD at the end of induction provides the full range of prognostic information for marrow relapse but is complex; detection of monoclonality on day 35 is simple and has good positive predictive value; and quantification of MRD on day 14 merits further study. PCR-based methods for measurement of MRD levels should incorporate a correction for variation in DNA amplifiability.

Age of calf at weaning of spring-calving beef cows and the effect on cow and calf performance and production economics.

Over a 5-yr period, spring-calving cows were used in a carry-over design experiment to evaluate effects of calf age at weaning on cow and calf performance and production economics. Weaning management groups were early (n = 60, calf age 150 d, EW), traditional (n = 60, calf age 210 d, NW), and late (n = 60, calf age 270 d, LW). Cow body condition score (BCS) and weights at the last weaning date were different (P < .05) for EW (5.8, 583 kg), NW (5.5, 560 kg), and LW (5.2, 541 kg) management groups. Pregnancy rates among groups were similar. Days on feed for groups differed (P = .001) and was 247 for EW, 204 for NW, and 164 d for LW steers. Average daily gain in the feedlot differed (P = .01) among groups and averaged 1.5 kg for LW, 1.4 kg for NW, and 1.3 kg for EW steers. Dry matter intake while steers were in the feedlot was greater (P = .001) for LW than for NW and EW calves. Hot carcass weight was greater (P = .01) for EW (328 kg) and NW (332 kg) calves than for LW (321 kg) steers, and fat depth was greater (P = .05) for EW and NW steers than for LW steers. When carcass data for the NW and LW steers were adjusted to the fat depth of EW steers, carcass characteristics among groups were similar. Net income per steer at slaughter for the feedlot phase was greater (P < .001) for the EW ($75.36) and NW ($62.16) steers than for the LW ($10.09) steers. Again, when carcass data for the NW and LW steers were adjusted to the same fat depth of the EW steers, net income differences among groups were reduced. Replacement heifers were developed in a drylot and costs were higher (P < .001) for the EW than for NW and LW heifers. Annual cow costs were greater (P < .10) for the LW ($443.45) than for the EW ($410.09) and NW ($421.35) groups. Break-even for each system on a steer financial basis was not different between the NW and LW groups, and both the NW and LW groups had lower (P = .08) break-evens than the EW group. Age of the calf at weaning affects cow weight and BCS. Net income in each system is influenced by cow costs, month of the year that steer calves are purchased into the feedlot and finished steers are sold, month of the year cull cows are marketed, and replacement heifer development costs.