Huntingtin Decreases Susceptibility to a Spontaneous Seizure Disorder in FVN/B Mice.

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is caused by a trinucleotide CAG repeat expansion in the HTT gene that codes for the protein huntingtin (HTT in humans or Htt in mice). HTT is a multi-functional, ubiquitously expressed protein that is essential for embryonic survival, normal neurodevelopment, and adult brain function. The ability of wild-type HTT to protect neurons against various forms of death raises the possibility that loss of normal HTT function may worsen disease progression in HD. Huntingtin-lowering therapeutics are being evaluated in clinical trials for HD, but concerns have been raised that decreasing wild-type HTT levels may have adverse effects. Here we show that Htt levels modulate the occurrence of an idiopathic seizure disorder that spontaneously occurs in approximately 28% of FVB/N mice, which we have called FVB/N Seizure Disorder with SUDEP (FSDS). These abnormal FVB/N mice demonstrate the cardinal features of mouse models of epilepsy including spontaneous seizures, astrocytosis, neuronal hypertrophy, upregulation of brain-derived neurotrophic factor (BDNF), and sudden seizure-related death. Interestingly, mice heterozygous for the targeted inactivation of Htt (Htt+/- mice) exhibit an increased frequency of this disorder (71% FSDS phenotype), while over-expression of either full length wild-type HTT in YAC18 mice or full length mutant HTT in YAC128 mice completely prevents it (0% FSDS phenotype). Examination of the mechanism underlying huntingtin's ability to modulate the frequency of this seizure disorder indicated that over-expression of full length HTT can promote neuronal survival following seizures. Overall, our results demonstrate a protective role for huntingtin in this form of epilepsy and provide a plausible explanation for the observation of seizures in the juvenile form of HD, Lopes-Maciel-Rodan syndrome, and Wolf-Hirschhorn syndrome. Adverse effects caused by decreasing huntingtin levels have ramifications for huntingtin-lowering therapies that are being developed to treat HD.

Implementation of a Humanoid Robot as an Innovative Approach to Child Life Interventions in a Children's Hospital: Lofty Goal or Tangible Reality?

INTRODUCTION: This study reports the findings on how Child life specialists (CLSs) implemented an innovative approach to providing therapeutic support to pediatric patients. METHODS: Part of a larger study that uncovered themes about CLSs' experiences while working with MEDi®, this study reports the reflections that CLSs have about the process of implementation. Seven CLSs participated in semi-structured interviews. Content analysis was conducted on interview data and three themes were generated. RESULTS: The first was in regards to the adoption process whereby CLS challenges, successes, and surprises were revealed. Second, CLSs explained how using MEDi® aligned with the roles and responsibilities of their profession. The third area of understanding was in CLS explanation of the friendly emotional impact MEDi® seems to have on the hospital environment. CONCLUSION: Child life specialists are encouraged to use the MEDi® robot to support children at the bedside.

Children's Pain During IV Induction: A Randomized-Controlled Trial With the MEDi® Robot.

OBJECTIVE: This study examined the impact of a humanoid robot (MEDi®) programmed to teach deep breathing as a coping strategy, on children's pain and fear as primary and secondary outcomes, respectively, during intravenous (IV) line placement. The completion of IV induction was also examined as an exploratory outcome. METHODS: In this randomized controlled, two-armed trial, 137 children (4-12 years) were recruited in Short Stay Surgery at a tertiary pediatric hospital. Patients were randomly assigned to standard care (SC) with Ametop© only (N = 60) or SC and robot-facilitated intervention (N = 59) before induction. Pain and fear before, during, and after IV insertion were rated by patients and observers. RESULTS: No significant differences were found between groups and there were no changes over time for pain or fear (ps > .05). Exploratory analyses show that patients in the MEDi® group were 5.04 times more likely to complete IV induction, compared to SC, Fisher's exact test: X2 (1) = 4.85, p = .04, φc = 0.22, odds ratio = 5.04, 95% CI [1.06, 24.00]. CONCLUSION: This study was the first to examine children's IV induction experience when provided MEDi® support. Reasons for nonsignificance, limitations, and research suggestions were made.

Perspectives of Child Life Specialists After Many Years of Working With a Humanoid Robot in a Pediatric Hospital: Narrative Design.

BACKGROUND: Child life specialists (CLSs) play an important role in supporting patients and their families during their visits to a children's hospital. Although CLSs are equipped with considerable expertise to support families during some of the most difficult moments of their lives, we introduced an additional resource to them in the form of a humanoid robot named MEDi. OBJECTIVE: The aim of this study is to explore the experiences of CLSs using a robot to support children. METHODS: We interviewed 7 CLSs who had worked with this robot for several years. The transcribed interviews were analyzed using open and axial coding. RESULTS: The first main theme that emerged was the process of navigating from fear to friendship in learning to use a humanoid robot for therapeutic support. The second major theme was MEDi as a source of connection and support to children. CLSs' perceptions of MEDi as an adaptable resource and working with the limits of MEDi constituted the last 2 themes. CONCLUSIONS: These descriptions show how CLSs can incorporate a robot into their practice.

Children's Fear and Pain During Medical Procedures: A Quality Improvement Study With a Humanoid Robot.

BACKGROUND: Pediatric patients undergo a variety of painful medical procedures. PURPOSE: The goal of this quality improvement study was to introduce a humanoid robot (MEDi®) programmed with strategies, such as distraction and deep breathing, at inpatient and outpatient units to determine any preliminary effects on children's pain and fear during medical procedures. METHODS: A nonrandomized two-group pre- and posttest design was used to compare pain and fear of children before and after intervention versus standard care. A total of 46 children aged 2-15 years undergoing various medical procedures in a pediatric hospital, and their parents completed the Children's Fear Scale and the Faces Pain Scale-Revised. The former was used both before and after the procedure, while the latter only after the procedure. RESULTS: Children (n = 18), who interacted with the robot before and during a procedure, and their parents reported significantly lower levels of fear and pain than did children (n = 28) and their parents in standard care, ps < .05. CONCLUSIONS: The use of a humanoid robot programmed with psychological strategies to support coping may enhance children's experiences of care for pain management.

Compliance to clinical pathways in the management of suspected pulmonary embolus: are there cost implications?

This study investigated the cost implications of poor compliance to established guidelines for management of suspected pulmonary embolism (PE) in two NSW public hospitals. A retrospective audit showed that the prevalence of PE overall was 9.9% (4.3% in the low-risk groups) in 436 patients. An estimated total of $32 454 (14%) was spent on unnecessary tests.

Testicular degeneration in Huntington disease.

Huntington disease (HD) is an adult onset, neurodegenerative disorder that results from CAG expansion in the HD gene. Recent work has demonstrated testicular degeneration in mouse models of HD and alterations in the hypothalamic-pituitary-gonadal (HPG) axis in HD patients. Here, we show that HD patients have specific testicular pathology with reduced numbers of germ cells and abnormal seminiferous tubule morphology. In the YAC128 mouse model, testicular degeneration develops prior to 12 months of age, but at 12 months, there is no evidence for decreased testosterone levels or loss of GnRH neurons in the hypothalamus. This suggests that testicular pathology results from a direct toxic effect of mutant huntingtin in the testis and is supported by the fact that huntingtin is highly expressed in the affected cell populations in the testis. Understanding the pathogenesis of HD in the testis may reveal common critical pathways which lead to degeneration in both the brain and testis.

Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain.

The YAC128 mouse model of Huntington disease (HD) exhibits motor abnormalities, cognitive dysfunction and selective neuropathology which are similar to the human disease. Backcrossing YAC128 mice from the FVB/N strain onto the C57BL/6 strain and the 129 strain revealed that striatal volume loss and motor dysfunction are penetrant on all three genetic backgrounds. The severity of HD-like phenotypes in these mice is modulated by strain and this variation is not accounted for by differences in mutant huntingtin expression. In contrast, nuclear localization of mutant htt is modulated by strain and is correlated with the severity of neuropathology. Differences in phenotypic severity between the strains provide the opportunity to identify modifier genes which could impact the pathogenesis of HD. Importantly, the demonstration of penetrance across all three strains permits examining the effect of specific genes on the phenotypic severity in YAC128 mice without necessarily backcrossing onto the FVB/N strain background.

Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease.

BACKGROUND: Huntington disease (HD) is an adult onset neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. Htt function is essential for embryonic survival as well as normal function during the postnatal period. In addition to having roles in transcription and transport, recent evidence demonstrates that wild-type htt is neuroprotective in vivo. To determine whether treatment with wild-type htt would be beneficial in HD, we crossed the YAC128 mouse model of HD with mice that over-express wild-type htt (YAC18 mice) to generate YAC128 mice that over-express wild-type htt (YAC18/128 mice). RESULTS: YAC18/128 mice were found to express mutant htt at the same level as YAC128 mice and wild-type htt at the same level as YAC18 mice. YAC18/128 mice show no significant behavioural improvement compared to YAC128 mice in the rotarod test of motor coordination or in an automated open field test. In the brain, YAC18/128 mice show no significant improvement in striatal volume, striatal neuronal numbers or striatal DARPP-32 expression compared to YAC128 mice. In contrast, striatal neuronal cross-sectional area showed significant improvement in YAC18/128 mice compared to YAC128 mice. CONCLUSION: While the over-expression of wild-type htt results in a mild improvement in striatal neuropathology in YAC128 mice, our findings suggest that treatment with wild-type htt may not be sufficient to ameliorate the symptoms of HD in this model.

Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin.

Cleavage of huntingtin (htt) has been characterized in vitro, and accumulation of caspase cleavage fragments represents an early pathological change in brains of Huntington's disease (HD) patients. However, the relationship between htt proteolysis and the pathogenesis of HD is unknown. To determine whether caspase cleavage of htt is a key event in the neuronal dysfunction and selective neurodegeneration in HD, we generated YAC mice expressing caspase-3- and caspase-6-resistant mutant htt. Mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant htt mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid (QA), and staurosporine. These results are consistent with proteolysis of htt at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of htt proteolysis and excitotoxicity in HD.

Body weight is modulated by levels of full-length huntingtin.

Huntington disease is an adult-onset neurodegenerative disorder that is caused by the expansion of a polyglutamine tract within the Huntingtin (htt) protein. Wild-type htt has been shown to be involved in transcription, transport and cell survival. Here, we demonstrate that increased expression of full-length wild-type htt in mice is associated with a dose-dependent increase in body weight which results from an increase in both total fat mass and fat-free mass. Conversely, we show that a reduction in the levels of wild-type htt is associated with decreased body weight. Examination of individual organ weights revealed that the weight of the heart, liver, kidneys, lungs and spleen increased with the over-expression of wild-type htt, whereas the brain and testis were unaltered. On the basis of these initial findings, we examined mice that over-express full-length mutant htt to determine the effect of polyglutamine expansion on this novel function of wild-type htt. We found that over-expression of full-length mutant htt, but not an N-terminal fragment of mutant htt, also increased body weight and organ weight, except in the brain and testis where mutant htt appears to be toxic. In these mice, the majority of weight gain could be accounted for by increases in total fat mass. Further investigation of the weight gain phenotype revealed that the increases in weight were not accounted for by increased food consumption relative to body weight. Overall, we demonstrate that increased levels of both wild-type and mutant full-length htt are associated with increased body weight.

Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models.

Huntington disease (HD) is a devastating neuropsychiatric disease caused by expansion of a trinucleotide repeat (CAG) in the HD gene. Neuropathological changes include the appearance of N-terminal huntingtin fragments, decreased brain weight and apoptotic neuronal loss in a select subset of neurons located in the striatum. There is still controversy over whether homozygosity for the mutation in HD is associated with a more severe phenotype. In humans, resolution of this issue has been complicated by the small number of homozygous patients and difficulty in the definition of reliable phenotypic endpoints. In order to definitively determine whether there is a correlation between phenotypic severity and expression levels of mutant huntingtin, we undertook a behavioral and neuropathological assessment of YAC128 mice with varying levels of mutant huntingtin. The results reveal a clear relationship between levels of mutant huntingtin and phenotype defined by earlier age of onset, more rapid progression, enhanced striatal volume loss, acceleration of nuclear huntingtin fragment accumulation and increased sensitivity to NMDAR-mediated excitotoxicity. These results provide clear evidence in vivo supporting a more severe phenotype associated with increased levels of mutant huntingtin as seen in homozygotes for HD.

Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease.

Huntington disease (HD) is an adult onset neurodegenerative disorder characterized by selective atrophy and cell loss within the striatum. There is currently no treatment that can prevent the striatal neuropathology. Transglutaminase (TG) activity is increased in HD patients, is associated with cell death, and has been suggested to contribute to striatal neuronal loss in HD. This work assesses the therapeutic potential of cystamine, an inhibitor of TG activity with additional potentially beneficial effects. Specifically, we examine the effect of cystamine on striatal neuronal loss in the YAC128 mouse model of HD. We demonstrate here for the first time that YAC128 mice show a forebrain-specific increase in TG activity compared with wild-type (WT) littermates which is decreased by oral delivery of cystamine. Treatment of symptomatic YAC128 mice with cystamine starting at 7 months prevented striatal neuronal loss. Cystamine treatment also ameliorated the striatal volume loss and striatal neuronal atrophy observed in these animals, but was unable to prevent motor dysfunction or the down-regulation of dopamine and cyclic adenosine monophsophate-regulated phosphoprotein (DARPP-32) expression in the striatum. While the exact mechanism responsible for the beneficial effects of cystamine in YAC128 mice is uncertain, our findings suggest that cystamine is neuroprotective and may be beneficial in the treatment of HD.

Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease.

Huntington disease (HD) is an adult-onset neurodegenerative disorder that is characterized by selective degeneration in the striatum. There are currently no treatments that can prevent the progressive decline of motor and cognitive function in HD. In parallel with a human clinical trial, we examined the efficacy of ethyl-EPA treatment in the YAC128 mouse model of HD. Oral delivery of ethyl-EPA to symptomatic YAC128 mice beginning at 7 months of age increased membrane EPA levels 3-fold (P < 0.001) and resulted in a modest but significant improvement in motor dysfunction by 12 months of age as measured by open-field activity (P = 0.01) and performance on the rotarod (P = 0.05). At this age, ethyl-EPA-treated YAC128 mice showed no improvement in striatal volume, striatal neuron counts, striatal neuronal cross-sectional area, or striatal DARPP-32 expression compared to untreated YAC128 mice, thereby indicating no reduction of striatal neuropathology. This result is congruent with modest motor benefits observed in HD patients treated with ethyl-EPA. Overall, this work demonstrates the feasibility of experimental therapeutics in the YAC128 mouse model and suggests that experiments in these mice may be predictive for future human clinical trials.

Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease.

Huntington disease (HD) is an adult-onset neurodegenerative disease caused by a toxic gain of function in the huntingtin (htt) protein. The contribution of wild-type htt function to the pathogenesis of HD is currently uncertain. To assess the role of wild-type htt in HD, we generated YAC128 mice that do not express wild-type htt (YAC128-/-) but express the same amount of mutant htt as normal YAC128 mice (YAC128+/+). YAC128-/- mice perform worse than YAC128+/+ mice in the rotarod test of motor coordination (P = 0.001) and are hypoactive compared with YAC128+/+ mice at 2 months (P = 0.003). Striatal neuropathology was not clearly worse in YAC128-/- mice compared with YAC128+/+ mice. There was no significant effect of decreased wild-type htt on striatal volume, neuronal counts or DARPP-32 expression but a modest worsening of striatal neuronal atrophy was evident (6%, P = 0.03). The testis of YAC128+/+ mice showed atrophy and degeneration, which was markedly worsened in the absence of wild-type htt (P = 0.001). YAC128+/+ mice also showed a male specific deficit in survival compared with WT mice which was exacerbated by the loss of wild-type htt (12-month-male survival, P < 0.001). Overall, we demonstrate that the loss of wild-type htt influences motor dysfunction, hyperkinesia, testicular degeneration and impaired lifespan in YAC128 mice. The mild effect of wild-type htt on striatal phenotypes in YAC128 mice suggests that the characteristic striatal neuropathology in HD is caused primarily by the toxicity of mutant htt and that replacement of wild-type htt will not be an adequate treatment for HD.

Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease.

Huntington's disease (HD) is an adult-onset neurodegenerative disorder involving motor dysfunction, cognitive deficits, and psychiatric disturbances that result from underlying striatal and cortical dysfunction and neuropathology. The YAC128 mouse model of HD reproduces both the motor deficits and selective degeneration observed in the human disease. However, the presence of cognitive impairment in this model has not been determined. Here, we report mild cognitive deficits in YAC128 mice that precede motor onset and progressively worsen with age. Rotarod testing revealed a motor learning deficit at 2 months of age that progresses such that by 12 months of age, untrained YAC128 mice are unable to learn the rotarod task. Additional support for cognitive dysfunction is evident in a simple swimming test in which YAC128 mice take longer to find the platform than wild-type (WT) controls beginning at 8 months of age. YAC128 mice also have deficits in open-field habituation and in a swimming T-maze test at this age. Strikingly, in the reversal phase of the swimming T-maze test, YAC128 mice take twice as long as WT mice to locate the platform, indicating a difficulty in changing strategy. At 12 months of age, YAC128 mice show decreased prepulse inhibition and habituation to acoustic startle. The clear pattern of cognitive dysfunction in YAC128 mice is similar to the symptoms and progression of cognitive deficits in human HD and provides both the opportunity to examine the relationship between cognitive dysfunction, motor impairment, and neuropathology in HD and to assess whether potential therapies for HD can restore cognitive function.

Epidemiology and genetics of rheumatoid arthritis.

The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5-1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan. These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases. The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-gamma and other cytokines). Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein-Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive. There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.