Autism Spectrum Disorder Prevalence Rates in the United States: Methodologies, Challenges, and Implications for Individual States

Many different studies have been conducted to determine the prevalence rates of Autism Spectrum Disorder (ASD) in the United States. The methodologies of these studies have varied, resulting in a multitude of publications with differing prevalence rates. Because there is such a wide range in the results of prevalence studies, it may be difficult for individual states to determine their rates. Accurate prevalence rates are important to obtain for many different reasons including increasing advocacy and awareness, increasing funding, and proper allocation of services for individuals with ASD and their families. Additionally, prevalence studies can be used to assess which groups are more at risk for ASD based off location and environmental factors. This paper describes different methodologies that can be utilized to determine ASD prevalence rates, the strengths and weaknesses of each method, and the challenges to determining accurate rates. This paper also includes the results from a study conducted in Nebraska to determine prevalence rates of ASD in the state. Implications for future prevalence studies are addressed and recommendations are provided

Expression of parathyroid hormone-related protein during immortalization of human peripheral blood mononuclear cells by HTLV-1: Implications for transformation

<p>Abstract</p> <p>Background</p> <p>Adult T-cell leukemia/lymphoma (ATLL) is initiated by infection with human T-lymphotropic virus type-1 (HTLV-1); however, additional host factors are also required for T-cell transformation and development of ATLL. The HTLV-1 Tax protein plays an important role in the transformation of T-cells although the exact mechanisms remain unclear. Parathyroid hormone-related protein (PTHrP) plays an important role in the pathogenesis of humoral hypercalcemia of malignancy (HHM) that occurs in the majority of ATLL patients. However, PTHrP is also up-regulated in HTLV-1-carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients without hypercalcemia, indicating that PTHrP is expressed before transformation of T-cells. The expression of PTHrP and the PTH/PTHrP receptor during immortalization or transformation of lymphocytes by HTLV-1 has not been investigated.</p> <p>Results</p> <p>We report that PTHrP was up-regulated during immortalization of lymphocytes from peripheral blood mononuclear cells by HTLV-1 infection in long-term co-culture assays. There was preferential utilization of the PTHrP-P2 promoter in the immortalized cells compared to the HTLV-1-transformed MT-2 cells. PTHrP expression did not correlate temporally with expression of HTLV-1 tax. HTLV-1 infection up-regulated the PTHrP receptor (PTH1R) in lymphocytes indicating a potential autocrine role for PTHrP. Furthermore, co-transfection of HTLV-1 expression plasmids and PTHrP P2/P3-promoter luciferase reporter plasmids demonstrated that HTLV-1 up-regulated PTHrP expression only mildly, indicating that other cellular factors and/or events are required for the very high PTHrP expression observed in ATLL cells. We also report that macrophage inflammatory protein-1α (MIP-1α), a cellular gene known to play an important role in the pathogenesis of HHM in ATLL patients, was highly expressed during early HTLV-1 infection indicating that, unlike PTHrP, its expression was enhanced due to activation of lymphocytes by HTLV-1 infection.</p> <p>Conclusion</p> <p>These data demonstrate that PTHrP and its receptor are up-regulated specifically during immortalization of T-lymphocytes by HTLV-1 infection and may facilitate the transformation process.</p

The ARF Tumor Suppressor Regulates Bone Remodeling and Osteosarcoma Development in Mice

The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf-/- mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf-/- mice had increased expression of OB genes while Arf-/- OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf-/- mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf-/- tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf+/- mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf-/- mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS

Protective effect of human amniotic fluid stem cells in an immunodeficient mouse model of acute tubular necrosis.

Acute Tubular Necrosis (ATN) causes severe damage to the kidney epithelial tubular cells and is often associated with severe renal dysfunction. Stem-cell based therapies may provide alternative approaches to treating of ATN. We have previously shown that clonal c-kit(pos) stem cells, derived from human amniotic fluid (hAFSC) can be induced to a renal fate in an ex-vivo system. Herein, we show for the first time the successful therapeutic application of hAFSC in a mouse model with glycerol-induced rhabdomyolysis and ATN. When injected into the damaged kidney, luciferase-labeled hAFSC can be tracked using bioluminescence. Moreover, we show that hAFSC provide a protective effect, ameliorating ATN in the acute injury phase as reflected by decreased creatinine and BUN blood levels and by a decrease in the number of damaged tubules and apoptosis therein, as well as by promoting proliferation of tubular epithelial cells. We show significant immunomodulatory effects of hAFSC, over the course of ATN. We therefore speculate that AFSC could represent a novel source of stem cells that may function to modulate the kidney immune milieu in renal failure caused by ATN

Weberian Militaries: Promotion and Appointment Systems as a Determinate of Military Effectiveness in Population Centric Counterinsurgency

This dissertation explains military effectiveness in executing population centric counterinsurgency (PCC) strategies. Why do some states conduct PCC effectively, while others attempt it, but fail to do so? Why are some states able to increase their effectiveness over the course of a campaign. In short, what are the determinates of PCC effectiveness? The dominant literature focuses on the effects of past formative wars on a military organization’s culture, the role of senior commanders, or the size of the military force and its ratio to the insurgent or civilian population. However, formative war based theories cannot explain within case variation, while commander and size based explanations are underspecified and underperform in empirical tests. Instead, this dissertation argues that PCC strategies create a principal-agent problem within the military organization. PCC requires subordinate units and soldiers to undertake dangerous activity, endure significant hardship, and forgo opportunities for personal gain, all in an environment of limited oversight. To prevent shirking and subverting of the strategy, militaries undertaking PCC require a command structure mirroring a Weberain bureaucracy, to include high levels of expertise, clear and well respected lines of hierarchical authority, and impersonal organizational and institutional loyalty. Expertise and hierarchy are necessary for monitoring, while impersonal loyalty is necessary to create a values and standards infused organizational culture that fosters agents self-motivated to achieve organizational ends. Merit based promotion and appointment systems are necessary to achieve this Weberian command structure. By contrast, promotion and appointment systems based on nepotism, cronyism, or patronage undermine these Weberian characteristics by ignoring expertise in leader selection, subverting formal chains of command, preventing monitoring and evaluation, and creating an organizational culture that privileges personal gain and loyalty to patrons over loyalty to the organizational mission. This dissertation probes the plausibility of the theory through two detailed case studies: the Huk Rebellion (1946-1956) and the Salvadoran Civil War (1979-1992). In the Philippines case, it uses longitudinal variation in the independent variable of promotion and appointment systems over the course of the war to demonstrate that changes in these systems cause a change in PCC effectiveness. In the Salvadoran case, it uses variation in the variables proposed in the dominant competing theories to show that by not accounting for promotion and appointment systems, those theories fall short in explaining PCC effectiveness

In Vivo Testing of Luciferase Substrate Analogs in an Orthotopic Murine Model of Human Glioblastoma

In vivo bioluminescent imaging using cells expressing Renilla luciferase is becoming increasingly common. Hindrances to the more widespread use of Renilla luciferase are the high autoluminescence of its natural substrate, coelenterazine, in plasma; the relatively high absorbance by tissue of the light emitted by the enzyme–substrate reaction; rapid clearance of the substrate; and significant cost. These factors, save for the cost, which has its own limiting effect on use, can combine to reduce the sensitivity of in vivo assays utilizing this reporter system, and methods of increasing light output or decreasing autoluminescence could be of great benefit. A number of analogs of coelenterazine are being investigated that may accomplish one or both of these goals. In this study, we report on the testing of two new substrate analogs, EnduRen™ and ViviRen™, manufactured by Promega Corporation, in an orthotopic murine model of human glioblastoma expressing Renilla luciferase. We have tested these analogs in this cell line, both in vitro and in vivo, and find that the substrate ViviRen results in significantly greater light output than the natural substrate or the other analog EnduRen. This new substrate could be valuable for studies where greater sensitivity is important

In Vivo Testing of Renilla

In vivo bioluminescent imaging using cells expressing Renilla luciferase is becoming increasingly common. Hindrances to the more widespread use of Renilla luciferase are the high autoluminescence of its natural substrate, coelenterazine, in plasma; the relatively high absorbance by tissue of the light emitted by the enzyme–substrate reaction; rapid clearance of the substrate; and significant cost. These factors, save for the cost, which has its own limiting effect on use, can combine to reduce the sensitivity of in vivo assays utilizing this reporter system, and methods of increasing light output or decreasing autoluminescence could be of great benefit. A number of analogs of coelenterazine are being investigated that may accomplish one or both of these goals. In this study, we report on the testing of two new substrate analogs, EnduRen™ and ViviRen™, manufactured by Promega Corporation, in an orthotopic murine model of human glioblastoma expressing Renilla luciferase. We have tested these analogs in this cell line, both in vitro and in vivo, and find that the substrate ViviRen results in significantly greater light output than the natural substrate or the other analog EnduRen. This new substrate could be valuable for studies where greater sensitivity is important