Abstract Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene ( HTT ), leading to mutant protein misfolding, ...aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete. We hypothesized that a combinatorial approach entailing drug and intrabody administration could enhance rescue of HD pathology in flies and that timing of treatment would affect outcomes. Feeding cystamine to adult HD flies expressing the intrabody resulted in a significant, additional rescue of photoreceptor neurodegeneration, but no additional benefit in longevity. Feeding cystamine during both larval and adult stages produced the converse result: longevity was significantly improved, but increased photoreceptor survival was not. We conclude that cystamine-intrabody combination therapies can be effective, reducing neurodegeneration and prolonging survival, depending on administration protocols.
Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson's disease (PD), and currently, the disease-modifying potential of the nicotine ...patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C, which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra (P=1 × 10(-7) for gene-smoking interaction on PD risk), and CG14691, which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2 × 10(-11) for nicotine-paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5 × 10(-10)). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.
Intracellular antibodies (intrabodies) and the chaperone, heat shock protein 70 (Hsp70), have each shown potential as therapeutics for neurodegenerative diseases in vitro and in vivo. Investigating ...combinational therapy in an established Drosophila model of Huntington's disease (HD), we show that Hsp70 and intrabody actually affect different aspects of the disease. Overexpression of human Hsp70 resulted in improved survival of HD flies to eclosion and prolonged adult life compared with intrabody treatment alone. An additive effect on adult survival was observed when the two therapies were combined. Intrabody was more successful at suppressing neurodegeneration in photoreceptors than was Hsp70. Furthermore, Hsp70 treatment alone did not block aggregation of mutant huntingtin, a process slowed by intrabody. Expression of each is restricted to the nervous system, which implies different neuronal populations respond distinctly to these treatments. Importantly, a role for endogenous Hsp70 in suppression of mutant huntingtin pathology was confirmed by a separate set of genetic studies in which HD flies deficient for Hsp70 showed significantly increased pathology. We conclude that a combinational approach of intrabody with enhanced Hsp70 expression is beneficial in addressing multiple pathologies associated with HD and has potential application for other neurodegenerative disorders.--McLear, J. A., Lebrecht, D., Messer, A., Wolfgang, W. J. Combinational approach of intrabody with enhanced Hsp70 expression addresses multiple pathologies in a fly model of Huntington's disease.
Huntington disease (HD) is a progressive neurodegenerative disease caused by an expansion of a polyglutamine sequence in mutant huntingtin (mhtt) that produces abnormal folding and aggregation that ...results in the formation of nuclear and cytoplasmic neuronal inclusion bodies. Although the precise role of mhtt aggregates in the pathogenesis is unclear, attempts to reduce accumulated mhtt protein have ameliorated the phenotype in multiple cellular and in vivo HD models. Here, we provide critical results on intracranial delivery of a single-chain Fv intrabody, C4, which targets the first 17 amino acids of the htt protein, a region of httExon1 that is increasingly being recognized as pivotal. To assess long-term efficacy and safety issues, we used adenoassociated viral vectors (AAV2/1) to deliver intrabody genes to the striatum of inbred B6.HDR6/1 mice. Treatment initiation at various stages of the disease showed that early treatment preserved the largest number of cells without nuclear aggregates and that the accumulation of aggregated material could be delayed by several months. Even when intrabody treatment was not initiated until the clinical disease stage, significant, albeit smaller, effects were seen. These data indicate that neuronal intrabodies against critical N-terminal epitopes can be safely and effectively delivered using AAV2/1 to delay the aggregation phenotype during a sustained period in this HD model, even when delivery is initiated after disease onset.
We conducted a meta-analysis on the effects of client preferences on treatment satisfaction, completion, and clinical outcome. Our search of the literature resulted in 34 empirical articles ...describing 32 unique clinical trials that either randomized some clients to an active choice condition (shared decision making condition or choice of treatment) or assessed client preferences. Clients who were involved in shared decision making, chose a treatment condition, or otherwise received their preferred treatment evidenced higher treatment satisfaction (ESd=.34; p<.001), increased completion rates (ESOR=1.37; ESd=.17; p<.001), and superior clinical outcome (ESd=.15; p<.0001), compared to clients who were not involved in shared decision making, did not choose a treatment condition, or otherwise did not receive their preferred treatment. Although the effect sizes are modest in magnitude, they were generally consistent across several potential moderating variables including study design (preference versus active choice), psychoeducation (informed versus uninformed), setting (inpatient versus outpatient), client diagnosis (mental health versus other), and unit of randomization (client versus provider). Our findings highlight the clinical benefit of assessing client preferences, providing treatment choices when two or more efficacious options are available, and involving clients in treatment-related decisions when treatment options are not available.
•We conduct a meta-analysis on the effects of treatment-related preferences.•Preferences are found to affect satisfaction, completion, and clinical outcome.•Preference effects are modest but consistent across potential moderator variables.•We discuss the benefit of assessing preferences and providing treatment choices.
This study examined cumulative risk, temperament traits, and their interplay as predictors of internalizing, externalizing, and sleep problems in at-risk toddlers. Participants were 104 low-income ...mother–toddler dyads recruited from women, infants, and children sites in a large city. The sample was primarily African American, and mothers were 21 years of age or younger at the child’s birth. The dyads were assessed when the toddlers were approximately 18 months old and again at 24 months of age. Though all toddlers were from low-income families with young mothers, the families varied in the degree to which other contextual risk factors were present. A cumulative risk index was calculated based on five contextual factors: maternal education, neighborhood dangerousness, social support, household overcrowding and single parenting. In multiple regressions, cumulative risk predicted sleep and externalizing problems. In addition, negative affectivity predicted all three domains of problem behaviors, effortful control predicted fewer externalizing problems, and surgency predicted fewer internalizing problems. Moreover, low negative affectivity buffered the association between cumulative risk and both internalizing and sleep problems. These findings suggest that it is important to consider children’s temperament traits in conjunction with the constellation of family risks when designing prevention programs to reduce the prevalence of behavior problems early in life.
Sigmoid sinus diverticula are relatively rare but typically cause pulsatile tinnitus (PT) in the involved ear. Occasionally, symptoms produced by blood flowing through the diverticulum are severe ...enough to necessitate recontouring the sigmoid sinus. Recently, a 59-year-old female was evaluated after years of worsening unilateral PT. CT angiography identified a 5 mm sigmoid sinus diverticulum near the sinodural angle. Given the severity of symptoms, the patient's diverticulum was surgically decompressed and recontoured using hydroxyapatite bone cement.
This study examined mental health problems among children of Iraqi refugees, most of whom were Christian. Exposure to potentially traumatic events was hypothesized to predict more symptoms of ...depression and traumatic stress. Moreover, youth reports of supportive relationships with parents and positive feelings about school were examined in relation to mental health problems. These promotive factors were expected to mitigate the hypothesized association between traumatic event exposure and mental health problems. Participants were 211 youth recruited from agencies and programs serving Iraqi refugees in a large metropolitan area in the United States. The hypotheses were partially supported. Youth who reported experiencing more potentially traumatic events endorsed more traumatic stress and depression symptoms. After accounting for exposure to potentially traumatic events and other covariates, youth who reported more positive feelings about school endorsed fewer symptoms of traumatic stress, and youth who reported more supportive relationships with parents endorsed fewer symptoms of depression. In addition, there was an interaction between potentially traumatic events and relationships with parents when predicting depression symptoms. Youth endorsed higher levels of depression symptoms when they reported less supportive relationships, regardless of the amount of traumatic event exposure, whereas youth endorsed lower levels of depression symptoms when they reported more supportive relationships with parents, but only at low levels of traumatic event exposure. Otherwise, the main effects were not qualified by interactions between potentially traumatic event exposure and the promotive factors. The findings from this study have implications for future research, policy, and practice with children of refugees.
Nestin-positive cells were targeted for pRb, p107 and p130 (pRb(f)) inactivation by expression of T(121), a truncated SV40 large T antigen that selectively binds to and inactivates pRb(f). Cre ...expression was initiated under GFAP control, resulting in T(121) expression restricted to neuroprogenitor cells beginning at embryonic day 11.5 (E11.5). Bi-transgenic embryos showed aberrant central nervous system (CNS) cell proliferation and apoptosis by E13.5. Defects in cortical development were evident with primary effects resulting in depletion of neural progenitors and aberrant cellular migration. Consequently, juvenile and adult brain morphology was reproducibly abnormal, including disorganization of neocortical, hippocampal and cerebellar regions. These aberrations resulted in behavioral phenotypes, including ataxia and seizures. The data indicate that inactivation of pRb(f) in radial glial cells, a population of neuroprogenitor cells, leads to specific disruptions in CNS patterning. The neuroprogenitor-restricted transgene expression provides a model in which to explore both developmental mechanisms and functional neurological outcomes.
Extrahepatic biliary obstruction (EHBO) was confirmed at surgery or necropsy in 22 cats. Biliary or pancreatic adenocarcinoma was diagnosed by histopathology in six cats and one cat had an ...undiagnosed mass in the common bile duct. The remaining 15 cats had at least one of a complex of inflammatory diseases including pancreatitis, cholangiohepatitis, cholelithiasis and cholecystitis. The most common clinical signs were jaundice, anorexia, lethargy, weight loss and vomiting. Hyperbilirubinaemia was present in all cases. Distension of the common bile duct and gall bladder was the most commonly observed finding on abdominal ultrasound. Nineteen cats underwent exploratory laparotomy for biliary decompression and diversion. Mortality in cats with underlying neoplasia was 100 per cent and, in those with non‐neoplastic lesions, was 40 per cent. Long‐term complications, in those that survived, included recurrence of cholangiohepatitis, chronic weight loss and recurrence of obstruction. Based on these findings, the prognosis for EHBO in cats must be considered guarded.
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