Gene Therapy for Parkinson's Disease

Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field

The Effects on Saturated Fat Purchases of Providing Internet Shoppers with Purchase- Specific Dietary Advice: A Randomised Trial

OBJECTIVES: The supermarket industry now services many customers through online food shopping over the Internet. The Internet shopping process offers a novel opportunity for the modification of dietary patterns. The aim of this study was to evaluate the effects on consumers' purchases of saturated fat of a fully automated computerised system that provided real-time advice tailored to the consumers' specific purchases recommending foods lower in saturated fat. DESIGN: This study was a blinded, randomised controlled trial. SETTING: The study was conducted in Sydney, New South Wales, Australia. PARTICIPANTS: The participants were consumers using a commercial online Internet shopping site between February and June 2004. INTERVENTIONS: Individuals assigned to intervention received fully automated advice that recommended specific switches from selected products higher in saturated fat to alternate similar products lower in saturated fat. Participants assigned to control received general non-specific advice about how to eat a diet lower in saturated fat. OUTCOME MEASURES: The outcome measure was the difference in saturated fat (grams per 100 g of food) in shopping baskets between the intervention and control groups. RESULTS: There were 497 randomised participants, mean age 40 y, each shopping for an average of about three people. The amount of saturated fat in the foods purchased by the intervention group was 0.66% lower (95% confidence interval 0.48–0.84, p < 0.001) than in the control group. The effects of the intervention were sustained over consecutive shopping episodes, and there was no difference in the average cost of the food bought by each group. CONCLUSIONS: Fully automated, purchase-specific dietary advice offered to customers during Internet shopping can bring about changes in food purchasing habits that are likely to have significant public health implications. Because implementation is simple to initiate and maintain, this strategy would likely be highly cost-effective

Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study

Background Children with intellectual disability frequently have multiple co-morbid neuropsychiatric conditions and poor physical health. Genomic testing is increasingly recommended as a first-line investigation for these children. We aim to determine the effect of genomics, inheritance, and socioeconomic deprivation on neuropsychiatric risk in children with intellectual disability of genetic origin as compared with the general population. Methods IMAGINE is a prospective cohort study using online mental health and medical assessments in a cohort of 3407 UK participants with intellectual disability and pathogenic genomic variants as identified by the UK's National Health Service (NHS). Our study is on a subset of these participants, including all children aged 4–19 years. We collected diagnostic genomic reports from NHS records and asked primary caregivers to provide an assessment of their child using the Development and Well-Being Assessment (DAWBA), the Strengths and Difficulties Questionnaire (SDQ), the Adaptive Behaviour Assessment System 3 (ABAS-3), and a medical history questionnaire. Each child was assigned a rank based on their postcode using the index of multiple deprivation (IMD). We compared the IMAGINE cohort with the 2017 National Survey of Children's Mental Health in England. The main outcomes of interest were mental health and neurodevelopment according to the DAWBA and SDQ. Findings We recruited 2770 children from the IMAGINE study between Oct 1, 2014 and June 30, 2019, of whom 2397 (86·5%) had a basic assessment of their mental health completed by their families and 1277 (46·1%) completed a medical history questionnaire. The mean age of participants was 9·2 years (SD 3·9); 1339 (55·9%) were boys and 1058 (44·1%) were girls. 355 (27·8%) of 1277 reported a seizure disorder and 814 (63·7%) reported movement or co-ordination problems. 1771 (73·9%) of 2397 participants had a pathogenic copy number variant (CNV) and 626 (26·1%) had a pathogenic single nucleotide variant (SNV). Participants were representative of the socioeconomic spectrum of the UK general population. The relative risk (RR) of co-occurring neuropsychiatric diagnoses, compared with the English national population, was high: autism spectrum disorder RR 29·2 (95% CI 23·9–36·5), ADHD RR 13·5 (95% CI 11·1–16·3). In children with a CNV, those with a familial variant tended to live in more socioeconomically deprived areas than those with a de novo variant. Both inheritance and socioeconomic deprivation contributed to neuropsychiatric risk in those with a CNV. Interpretation Children with genomic variants and intellectual disability are at an increased risk of neuropsychiatric difficulties. CNV variant inheritance and socioeconomic deprivation also contribute to the risk. Early genomic investigations of children with intellectual disability could facilitate the identification of the most vulnerable children. Additionally, harnessing parental expertise using online DAWBA assessments could rapidly identify children with exceptional needs to child mental health services

HIV treatment with dolutegravir and doravirine: rationale for selection and clinical outcomes in a highly treatment experienced population

Dolutegravir and doravirine are individually safe and effective antiretroviral therapy (ART) components, but their combined use has not been studied in clinical trials and is not recommended in HIV treatment guidelines. We noted persons with HIV (PWH) receiving dolutegravir with doravirine at our Washington, DC, infectious disease clinic and undertook a service evaluation to understand why providers selected this ART, whether HIV virologic suppression was achieved and identify adverse effects of concomitant use. Case registry and prescriptions data identified 21 PWH receiving concomitant dolutegravir and doravirine with mean follow-up 576.1 days (range 413-751); frequent reasons for switching were multiple ART resistance (57.1%), proton pump inhibitor usage (28.6%) and renal failure (28.6%), with 52.4% switched from protease inhibitor or cobicistat-boosted regimens. Dolutegravir with doravirine alone was prescribed for 60%, and additional ART in 40%. During 12 months follow-up mean CD4 was 585.9 (baseline 570.7) with undetectable viral load in 77.8% (baseline 66.7%). No discontinuations for drug-related adverse events or virologic failure occurred. Dolutegravir with doravirine was well tolerated in small numbers of highly treatment experienced PWH at our clinic, achieving virologic suppression in most. Establishing the efficacy and safety of dolutegravir with doravirine for HIV treatment in randomized trials remains important

Strongyloides and COVID-19: Challenges and Opportunities for Future Research

is a soil transmitted helminth endemic to tropical and subtropical areas that can persist for decades in immunocompetent human hosts as a chronic asymptomatic infection. The use of corticosteroids, a mainstay of treatment for patients hospitalized with severe coronavirus disease (COVID-19), can trigger a life-threatening Strongyloides hyperinfection syndrome and disseminated disease. We identified 22 previously published cases of strongyloidiasis occurring in individuals with COVID-19, with one death reported among the seven patients who had Strongyloides hyperinfection syndrome. A total of seventeen patients had previously received corticosteroids, and of the five with no prior corticosteroid use, one presented with hyperinfection syndrome. We identify the key challenges in the diagnosis and treatment of Strongyloides within the context of COVID-19, including our imprecise knowledge of the global distribution of Strongyloides, the overlapping symptoms and signs of COVID-19 and Strongyloides hyperinfection syndrome, the limited utility of eosinophilia as a clinical marker for strongyloidiasis in this setting, the lack of validated algorithms to screen for Strongyloides prior to corticosteroid use, and the paucity of treatment options for critically ill patients with COVID-19 who cannot take oral ivermectin. Future research should focus on improved diagnostic methods and population prevalence estimates, optimizing the approaches for Strongyloides screening in persons with COVID-19 (including clinical trial participants and strategies for resource-limited settings) and better defining the role of pre-emptive treatment

The effects on saturated fat purchases of providing internet shoppers with purchase-specific dietary advice: a randomised trial

The supermarket industry now services many customers through online food shopping over the Internet. The Internet shopping process offers a novel opportunity for the modification of dietary patterns. The aim of this study was to evaluate the effects on consumers\u27 purchases of saturated fat of a fully automated computerised system that provided real-time advice tailored to the consumers\u27 specific purchases recommending foods lower in saturated fat. The supermarket industry now services many customers through online food shopping over the Internet. The Internet shopping process offers a novel opportunity for the modification of dietary patterns. The aim of this study was to evaluate the effects on consumers\u27 purchases of saturated fat of a fully automated computerised system that provided real-time advice tailored to the consumers\u27 specific purchases recommending foods lower in saturated fat. The reports conclusion was that fully automated, purchase-specific dietary advice offered to customers during Internet shopping can bring about changes in food purchasing habits that are likely to have significant public health implications. Because implementation is simple to initiate and maintain, this strategy would likely be highly cost-effective. Published in PLOS Clinical Trials.&nbsp

Development of an ex-vivo co-culture system to model pulpal infection by Streptococcus anginosus group bacteria

Introduction: Streptococcus anginosus group (SAG) bacteria are opportunistic pathogens and a major cause of pulpal infection and subsequent abscess formation. Understanding of the processes involved in SAG oral infections has been limited by the lack of an appropriate model system. Methods: Cocultures of SAG bacteria and mammalian tooth slices were maintained using a combination of Dulbecco modified eagle medium and brain-heart infusion broth at 60 rpm, 37°C, 5% CO2 for 4, 8, or 24 hours before histologic examination or staining with acridine orange/ethidium bromide. Tooth slices were also incubated as described with SAG bacteria stained with fluorescein diacetate. Pulps were extirpated from infected and sterile cultured tooth slices, messenger RNA was extracted and converted to complementary DNA, and polymerase chain reaction were performed for genes encoding tumor necrosis factor α, interleukin 1β, and interleukin-6. Results: SAG bacteria were able to adhere directly to the central region of the pulpal matrix in small foci that were associated with a localized matrix breakdown. Acridine orange–ethidium bromide staining and cell counts indicated a decrease in mammalian cell viability with increasing incubation times in the presence of SAG bacteria. The increased expression of tumor necrosis factor α and interleukin 1β was detected in infected tooth slices. Conclusions: A novel ex vivo model system has been developed that allows coculture of SAG bacteria with a 3-dimensional organotypic tooth slice. The model allows observation of bacterial growth patterns and subsequent responses from host tissues. Therefore, it may be of future use in testing the efficacy of both antimicrobial and anti-inflammatory treatments for use in endodontic therapy

Development of an ex vivo coculture system to model pulpal infection by Streptococcus anginosus group bacteria

Introduction: Streptococcus anginosus group (SAG) bacteria are opportunistic pathogens and a major cause of pulpal infection and subsequent abscess formation. Understanding of the processes involved in SAG oral infections has been limited by the lack of an appropriate model system. Methods: Cocultures of SAG bacteria and mammalian tooth slices were maintained using a combination of Dulbecco modified eagle medium and brain-heart infusion broth at 60 rpm, 37°C, 5% CO2 for 4, 8, or 24 hours before histologic examination or staining with acridine orange/ethidium bromide. Tooth slices were also incubated as described with SAG bacteria stained with fluorescein diacetate. Pulps were extirpated from infected and sterile cultured tooth slices, messenger RNA was extracted and converted to complementary DNA, and polymerase chain reaction were performed for genes encoding tumor necrosis factor α, interleukin 1β, and interleukin-6. Results: SAG bacteria were able to adhere directly to the central region of the pulpal matrix in small foci that were associated with a localized matrix breakdown. Acridine orange–ethidium bromide staining and cell counts indicated a decrease in mammalian cell viability with increasing incubation times in the presence of SAG bacteria. The increased expression of tumor necrosis factor α and interleukin 1β was detected in infected tooth slices. Conclusions: A novel ex vivo model system has been developed that allows coculture of SAG bacteria with a 3-dimensional organotypic tooth slice. The model allows observation of bacterial growth patterns and subsequent responses from host tissues. Therefore, it may be of future use in testing the efficacy of both antimicrobial and anti-inflammatory treatments for use in endodontic therapy

Characterization of the Genes Encoding the Cytosolic and Plastidial Forms of ADP-Glucose Pyrophosphorylase in Wheat Endosperm

In most species, the synthesis of ADP-glucose (Glc) by the enzyme ADP-Glc pyrophosphorylase (AGPase) occurs entirely within the plastids in all tissues so far examined. However, in the endosperm of many, if not all grasses, a second form of AGPase synthesizes ADP-Glc outside the plastid, presumably in the cytosol. In this paper, we show that in the endosperm of wheat (Triticum aestivum), the cytosolic form accounts for most of the AGPase activity. Using a combination of molecular and biochemical approaches to identify the cytosolic and plastidial protein components of wheat endosperm AGPase we show that the large and small subunits of the cytosolic enzyme are encoded by genes previously thought to encode plastidial subunits, and that a gene, Ta.AGP.S.1, which encodes the small subunit of the cytosolic form of AGPase, also gives rise to a second transcript by the use of an alternate first exon. This second transcript encodes an AGPase small subunit with a transit peptide. However, we could not find a plastidial small subunit protein corresponding to this transcript. The protein sequence of the purified plastidial small subunit does not match precisely to that encoded by Ta.AGP.S.1 or to the predicted sequences of any other known gene from wheat or barley (Hordeum vulgare). Instead, the protein sequence is most similar to those of the plastidial small subunits from chickpea (Cicer arietinum) and maize (Zea mays) and rice (Oryza sativa) seeds. These data suggest that the gene encoding the major plastidial small subunit of AGPase in wheat endosperm has yet to be identified