The Role of the Cerebellum in the Zebra Finch Song Circuit

The cerebellum was originally thought to be a brain area used just for motor coordination, but it is now known to play a role in complex cognition. Some of these complex roles include aspects of human speech such as rhyming, silent rehearsal, and timing of speech. There are many similarities between human speech and songbird song including a babbling stage, the necessity of a tutor to copy, and specialized neural structures for learning and production; however, it is not clear whether the cerebellum plays a similar role in the songbird song circuit. In this experiment I examined the role of the cerebellum in the zebra finch song circuit. The song of male zebra finches is directed towards receptive females, and was recorded over several consecutive days. Surgeiy was then performed on the birds to disrupt the connection between the cerebellum and the rest of the brain. The songs were then recorded post surgery to deduce any cerebellum control on the song circuit. The results of the data show that after cerebellum lesion, birds were able to retain and faithfully reproduce their learned song; however their song had increased variability in its spectral qualities and additionally their song was longer in duration. These results are very similar to what is seen in humans with cerebellar dysarthria, which includes various deficiencies in speech that are seen after damage to the cerebellum. These data suggests that the cerebellum plays similar roles in the songbird song circuit, just as in human speech

A Protection Motivation Theory Approach to Home Wireless Network Security in New Zealand: Establishing If Groups of Concerned Wireless Network Users Exist And Exploring Characteristics of Behavioral Intention

Threats arising from wireless hacking have been recently acknowledged both within academic literature and in the mainstream media. Additionally, it has been reported that many users of wireless networks make no attempt to activate security measures on their networks. This report replicates and expands upon research found in Woon, Tan and Low (2005) in order to ascertain characteristics of home wireless network users in New Zealand. The first research area asks the question: aside from the people who activate and those who do not, are there also people who are worried about wireless security and those who are not? This was proven to be true and that there is indeed a subgroup of wireless router users in New Zealand who are worried about wireless security. The second research area seeks to determine what factors affect a person's intention to enable or not enable security features on a home wireless network. The results showed that: The more people notice an increase in the degree of risk posed by wireless hacking, the more they feel like they could autonomously enable security features. The more people feel vulnerable to threats of wireless hacking, the more they feel that they would need help in setting up security features on their wireless network. The more people feel susceptible to wireless hacking, the more they feel that enabling security features would require extra efforts of time and money on their part. In order to get users to secure wireless networks, they must be convinced that enabling security features will deter hacker attacks. In order to get users to secure networks they need to feel that they could actually enable security features by themselves without some form of human assistance to help them do it

Possibilities for RNA Interference in Developing Hepatitis C Virus Therapeutics

The discovery and characterization of the RNA interference (RNAi) pathway has been one of the most important scientific developments of the last 12 years. RNAi is a cellular pathway wherein small RNAs control the expression of genes by either degrading homologous RNAs or preventing the translation of RNAs with partial homology. It has impacted basic biology on two major fronts. The first is the discovery of microRNAs (miRNAs), which regulate almost every cellular process and are required for some viral infections, including hepatitis C virus (HCV). The second front is the use of small interfering RNAs (siRNAs) as the first robust tool for mammalian cellular genetics. This has led to the identification of hundreds of cellular genes that are important for HCV infection. There is now a major push to adapt RNAi technology to the clinic. In this review, we explore the impact of RNAi in understanding HCV biology, the progress in design of RNAi-based therapeutics for HCV, and remaining obstacles

Patient-controlled analgesia in the pediatric population: morphine versus hydromorphone

OBJECTIVE: Patient controlled analgesia (PCA) is commonly used to provide analgesia following surgical procedures in the pediatric population. Morphine and hydromorphone remain the most commonly used opioids for PCA. Although both are effective, adverse effects may occur. When these adverse effects are unremitting or severe, opioid rotation may be required. In this study, we retrospectively evaluated PCA use, the adverse effect profile, and the frequency of opioid rotation. METHODS: This retrospective study was performed at Nationwide Children’s Hospital (Columbus, OH). The hospital’s electronic registry was queried for PCA use delivering either morphine or hydromorphone from January 1, 2008 to December 31, 2010. RESULTS: A total of 514 patients were identified, that met study entry criteria. Of the 514 cases, 298 (56.2%) were initially started on morphine and 225 (43.8%) were initially started on hydromorphone. There were a total of 26 (5.1%) opioid changes in the cohort of 514 patients. Of the 26 switches, 23 of 298 (7.7%) were from morphine to hydromorphone, and 3 of 225 (1.3%) were from hydromorphone to morphine (P=0.0008). Of the 17 morphine-to-hydromorphone switches with adverse effects, pruritus (64.7%), and inadequate pain control (47.1%) were the most common side effects. The most common side effect resulting in a hydromorphone-to-morphine switch was nausea (66.7%). CONCLUSION: PCA switches from morphine-to-hydromorphone (88.5%) were more common than vice-versa (11.5%). The most common reasons for morphine-to-hydromorphone switch were pruritus and inadequate pain control. These data suggest that a prospective study is necessary to determine the side effect differences between morphine and hydromorphone in pediatric PCA

Tracking Inner City Substance Users from the Emergency Department: How Many Contacts Does It Take?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73960/1/j.1553-2712.2008.00033.x.pd

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease

Sickle cell disease (SCD) is the most common serious monogenic disease with 300,000 births annually worldwide. SCD is an autosomal recessive disease resulting from a single point mutation in codon six of the β-globin gene (HBB). Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) may potentially provide a curative treatment for SCD. We previously developed a CRISPR-Cas9 gene targeting strategy that uses high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce recombinant adeno-associated virus serotype 6 (rAAV6)-mediated HBB gene correction of the SCD-causing mutation in HSPCs. Here, we demonstrate the preclinical feasibility, efficacy, and toxicology of HBB gene correction in plerixafor-mobilized CD34+ cells from healthy and SCD patient donors (gcHBB-SCD). We achieved up to 60% HBB allelic correction in clinical-scale gcHBB-SCD manufacturing. After transplant into immunodeficient NSG mice, 20% gene correction was achieved with multilineage engraftment. The long-term safety, tumorigenicity, and toxicology study demonstrated no evidence of abnormal hematopoiesis, genotoxicity, or tumorigenicity from the engrafted gcHBB-SCD drug product. Together, these preclinical data support the safety, efficacy, and reproducibility of this gene correction strategy for initiation of a phase 1/2 clinical trial in patients with SCD

The Society for Pediatric Anesthesia recommendations for the use of opioids in children during the perioperative period

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149726/1/pan13639_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149726/2/pan13639.pd

Stem Cells Expressing Homing Receptors Could be Expanded From Cryopreserved and Unselected Cord Blood

We assessed the cytokine combinations that are best for ex vivo expansion of cord blood (CB) and the increment for cell numbers of nucleated cells, as well as stem cells expressing homing receptors, by an ex vivo expansion of cryopreserved and unselected CB. Frozen leukocyte concentrates (LC) from CB were thawed and cultured at a concentration of 1×105/mL in media supplemented with a combination of SCF (20 ng/mL)+TPO (50 ng/mL)+FL (50 ng/mL)±IL-6 (20 ng/mL)±G-CSF (20 ng/mL). After culturing for 14 days, the expansion folds of cell numbers were as follows: TNC 22.3±7.8~26.3±4.9, CFU-GM 4.7±5.1~11.7±2.6, CD34+CD38- cell 214.0±251.9~464.1±566.1, CD34+CXCR4+ cell 4384.5±1664.7~7087.2±4669.3, CD34+VLA4+ cell 1444.3±1264.0~2074.9±1537.0, CD34+VLA5+ cell 86.2±50.9~113.2±57.1. These results revealed that the number of stem cells expressing homing receptors could be increased by an ex vivo expansion of cryopreserved and unselected CB using 3 cytokines (SCF, TPO, FL) only. Further in vivo studies regarding the engraftment after expansion of the nucleated cells, as well as the stem cells expressing homing receptors will be required

AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy

Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans

Impact of chemotherapy for HIV-1 related lymphoma on residual viremia and cellular HIV-1 DNA in patients on suppressive antiretroviral therapy

The first cure of HIV-1 infection was achieved through complex, multimodal therapy including myeloablative chemotherapy, total body irradiation, anti-Thymocyte globulin, and allogeneic stem cell transplantation with a CCR5 delta32 homozygous donor. The contributions of each component of this therapy to HIV-1 eradication are unclear. To assess the impact of cytotoxic chemotherapy alone on HIV-1 persistence, we longitudinally evaluated low-level plasma viremia and HIV-1 DNA in PBMC from patients in the ACTG A5001/ALLRT cohort on suppressive antiretroviral therapy (ART) who underwent chemotherapy for HIV-1 related lymphoma without interrupting ART. Plasma HIV-1 RNA, total HIV-1 DNA and 2-LTR circles (2-LTRs) in PBMC were measured using sensitive qPCR assays. In the 9 patients who received moderately intensive chemotherapy for HIV-1 related lymphoma with uninterrupted ART, low-level plasma HIV-1 RNA did not change significantly with chemotherapy: median HIV-1 RNA was 1 copy/mL (interquartile range: 1.0 to 20) pre-chemotherapy versus 4 copies/mL (interquartile range: 1.0 to 7.0) post-chemotherapy. HIV-1 DNA levels also did not change significantly, with median prechemotherapy HIV-1 DNA of 355 copies/106 CD4+ cells versus 228 copies/106 CD4+ cells post-chemotherapy. 2-LTRs were detectable in 2 of 9 patients pre-chemotherapy and in 3 of 9 patients post-chemotherapy. In summary, moderately intensive chemotherapy for HIV-1 related lymphoma in the context of continuous ART did not have a prolonged impact on HIV-1 persistence. © 2014 Cillo et al