Identifying prodromal symptoms at high specificity for Parkinson's disease.

Introduction: To test drugs with the potential to prevent the onset of Parkinson's disease (PD), it is key to identify individuals in the general population at high risk of developing PD. This is often difficult because most of the clinical markers are non-specific, common in PD but also common in older adults (e.g., sleep problems). Objective: We aimed to identify the clinical markers at high specificity for developing PD by comparing individuals with PD or prodromal PD to healthy controls. Methods: We investigated motor and non-motor symptoms (Movement Disorder Society Unified Parkinson's Disease Rating Scale Part 1 and 2 items) in 64 prodromal PD and 422 PD individuals calculating the odds ratios, adjusting for age and gender, for PD and prodromal PD versus 195 healthy controls. Symptoms at high specificity were defined as having an adjusted odds ratio ≥ 6. Results: Constipation had an adjusted odds ratio, 6.14 [95% CI: 2.94-12.80] showing high specificity for prodromal PD, and speech difficulties had an adjusted odds ratio, 9.61 [95% CI: 7.88-48.81] showing high specificity for PD. The proportion of participants showing these specific markers was moderate (e.g., prevalence of constipation was 43.75% in prodromal PD, and speech difficulties was 33.89% in PD), suggesting these symptoms may make robust predictors of prodromal PD and PD, respectively. Discussion: Clinical markers at high specificity for developing PD could be used as tools in the screening of general populations to identify individuals at higher risk of developing PD.

De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region.

By 2050, it is predicted that antimicrobial resistance will be responsible for 10 million global deaths annually, more deaths than cancer, costing the world economy $100 trillion. Clearly, strategies to address this problem are essential as bacterial evolution is rendering our current antibiotics ineffective. The discovery of an allosteric binding site on the established antibacterial target DNA gyrase offers a new medicinal chemistry strategy. As this site is distinct from the fluoroquinolone binding site, resistance is not yet documented. Using in silico molecular design methods, we have designed and synthesised a novel series of biphenyl-based inhibitors inspired by a published thiophene-based allosteric inhibitor. This series was evaluated in vitro against Escherichia coli DNA gyrase and E. coli topoisomerase IV with the most potent compounds exhibiting IC50 values towards the low micromolar range for DNA gyrase and only ∼2-fold less active against topoisomerase IV. The structure-activity relationships reported herein suggest insights to further exploit this allosteric site, offering a pathway to overcome developing fluoroquinolone resistance.

Hoehn and Yahr Stage and Striatal Dat-SPECT Uptake Are Predictors of Parkinson's Disease Motor Progression.

Currently, no treatments available for Parkinson's disease (PD) can slow PD progression. At the early stage of the disease, only a subset of individuals with PD progress quickly, while the majority have a slowly progressive form of the disease. In developing treatments that aim to slow PD progression, clinical trials aim to include individuals who are likely to progress faster, such that a treatment effect, if one exists, can be identified easier and earlier. The aim of the present study was to identify baseline predictors of clinical progression in early PD. We analyzed 12-month data acquired from the PASADENA trial Part 1 (NCT03100149, n = 76 participants who were allocated to the placebo arm and did not start symptomatic therapy) and the Parkinson's Progression Markers Initiative (PPMI) study (n = 139 demographically and clinically matched participants). By using ridge regression models including clinical characteristics, imaging, and non-imaging biomarkers, we found that Hoehn and Yahr stage and dopamine transporter single-photon emission computed tomography specific binding ratios (Dat-SPECT SBR) in putamen ipsilateral to the side of motor symptom onset predicted PD progression at the early stage of the disease. Further studies are needed to confirm the validity of these predictors to identify with high accuracy individuals with early PD with a faster progression phenotype.

The Long Non-Coding RNA H19 Drives the Proliferation of Diffuse Intrinsic Pontine Glioma with H3K27 Mutation.

Diffuse intrinsic pontine glioma (DIPG) is an incurable paediatric malignancy. Identifying the molecular drivers of DIPG progression is of the utmost importance. Long non-coding RNAs (lncRNAs) represent a large family of disease- and tissue-specific transcripts, whose functions have not yet been elucidated in DIPG. Herein, we studied the oncogenic role of the development-associated H19 lncRNA in DIPG. Bioinformatic analyses of clinical datasets were used to measure the expression of H19 lncRNA in paediatric high-grade gliomas (pedHGGs). The expression and sub-cellular location of H19 lncRNA were validated in DIPG cell lines. Locked nucleic acid antisense oligonucleotides were designed to test the function of H19 in DIPG cells. We found that H19 expression was higher in DIPG vs. normal brain tissue and other pedHGGs. H19 knockdown resulted in decreased cell proliferation and survival in DIPG cells. Mechanistically, H19 buffers let-7 microRNAs, resulting in the up-regulation of oncogenic let-7 target (e.g., SULF2 and OSMR). H19 is the first functionally characterized lncRNA in DIPG and a promising therapeutic candidate for treating this incurable cancer.

Unlocking history through automated virtual unfolding of sealed documents imaged by X-ray microtomography.

Computational flattening algorithms have been successfully applied to X-ray microtomography scans of damaged historical documents, but have so far been limited to scrolls, books, and documents with one or two folds. The challenge tackled here is to reconstruct the intricate folds, tucks, and slits of unopened letters secured shut with "letterlocking," a practice-systematized in this paper-which underpinned global communications security for centuries before modern envelopes. We present a fully automatic computational approach for reconstructing and virtually unfolding volumetric scans of a locked letter with complex internal folding, producing legible images of the letter's contents and crease pattern while preserving letterlocking evidence. We demonstrate our method on four letterpackets from Renaissance Europe, reading the contents of one unopened letter for the first time. Using the results of virtual unfolding, we situate our findings within a novel letterlocking categorization chart based on our study of 250,000 historical letters.

Patterns of routine primary care for osteoarthritis in the UK: a cross-sectional electronic health records study.

OBJECTIVE: To determine common patterns of recorded primary care for osteoarthritis (OA), and patient and provider characteristics associated with the quality of recorded care. DESIGN: An observational study nested within a cluster-randomised controlled trial. SETTING: Eight UK general practices who were part of the Management of Osteoarthritis in Consultations study. PARTICIPANTS: Patients recorded as consulting within the eight general practices for clinical OA. PRIMARY OUTCOMES: Achievement of seven quality indicators of care (pain/function assessment, information provision, exercise/weight advice, analgesics, physiotherapy), recorded through an electronic template or routinely recorded in the electronic healthcare records, was identified for patients aged ≥45 years consulting over a 6-month period with clinical OA. Latent class analysis was used to cluster patients based on care received. Clusters were compared on patient and clinician-level characteristics. RESULTS: 1724 patients (median by practice 183) consulted with clinical OA. Common patterns of recorded quality care were: cluster 1 (38%, High) received most quality indicators of care; cluster 2 (11%, Moderate) had pain and function assessment, and received or were considered for other indicators; cluster 3 (17%, Low) had pain and function assessment, and received or were considered for paracetamol or topical non-steroidal anti-inflammatory drugs; cluster 4 (35%, None) had no recorded quality indicators. Patients with higher levels of recorded care consulted a clinician who saw more patients with OA, consulted multiple times and had less morbidity. Those in the High cluster were more likely to have recorded diagnosed OA and have knee/hip OA. CONCLUSIONS: Patterns of recorded care for OA fell into four natural clusters. Appropriate delivery of core interventions and relatively safe pharmacological options for OA are still not consistently recorded as provided in primary care. Further research to understand clinical recording behaviours and determine potential barriers to quality care alongside effective training for clinicians is needed. TRIAL REGISTRATION NUMBER: ISRCTN06984617; Results.

An important relationship.

I met Louise (below right) in 2009. She was 18 and a nursing student on the children's ward at the Royal Surrey County Hospital, Guildford. I was 15 and had been admitt ed by my children's home aft er a suicide att empt. I was not medically unwell so I found being on the ward distressing.

Neonatal gene therapy of MPS I mice by intravenous injection of a lentiviral vector.

Mucopolysaccharidosis type I (MPS I) is a lysosomal glycosaminoglycan (GAG) storage disorder caused by deficiency of alpha-l-iduronidase (IDUA). In this study, we evaluated the potential to perform gene therapy for MPS I by direct in vivo injection of a lentiviral vector, using an IDUA gene knockout murine model. We compared the efficacy in newborn versus young adult MPS I mice of a single intravenous injection of the lentiviral vector. The extent of transduction was dose-dependent, with the liver receiving the highest level of vector, but other somatic organs reaching almost the same level. The phenotypic manifestations of disease were partially improved in the mice treated as young adults, but were nearly normalized at every end-point measured in the mice treated as neonates. In the neonatally treated mice, the expressed IDUA activity resulted in decreased GAG storage, prevention of skeletal abnormalities, a more normal gross appearance, and improved survival. Most strikingly, significant levels of IDUA enzyme were produced in the brain of mice treated as neonates, with transduction of neurons at high levels. The sustained expression of enzymatically active IDUA in multiple organs had a significant beneficial effect on the phenotypic abnormalities of MPS I, which may be translated to clinical gene therapy of patients with Hurler disease.

Vitamin E does not protect against neonatal ethanol-induced cerebellar damage or deficits in eyeblink classical conditioning in rats.

BACKGROUND: Rodent studies have shown that heavy binge-like ethanol (EtOH) exposure during the brain growth spurt [postnatal days (PD) 4-9] causes cerebellar neuronal loss and deficits in cerebellar-mediated eyeblink classical conditioning (ECC). Oxidative stress has been implicated in EtOH-mediated brain damage, and studies using vitamin E have reported amelioration of EtOH-induced tissue damage, including protection in rats against EtOH-induced cerebellar Purkinje cell (PC) loss on PD 4 to 5. The purpose of this study was to determine whether dietary supplementation with vitamin E concurrent with binge EtOH exposure on PD 4 to 9 in rats would attenuate the cerebellar cell death and ECC deficits. METHODS: Rat pups were given one of five different neonatal treatments: (1) intubation with EtOH in milk formula (twice daily, total dose 5.25 g/kg/day), (2) intubation with EtOH in milk formula supplemented with vitamin E (12.26 mg/kg/feeding), (3) intubation with milk formula that contained vitamin E only, (4) sham intubations, or (5) normally reared unintubated controls. Between PD 26 and 33, subjects received short-delay ECC for 3 consecutive days. Unbiased stereological cell counts were performed on cerebellar PCs of left cerebellar lobules I to VI and neurons of the interpositus nucleus. In a separate study with PD 4 pups, the effects of vitamin E on EtOH-induced expression of caspase-3 active subunits were assessed using Western blot analysis. RESULTS: EtOH-treated groups showed significant deficits in acquisition of conditioned eyeblink responses and reductions in cerebellar PCs and interpositus nucleus neurons compared with controls. Vitamin E supplementation failed to protect against these deficits. Vitamin E also failed to protect against increases in caspase-3 active subunit expression induced by acute binge EtOH exposure on PD 4. CONCLUSIONS: In contrast to the previously reported neuroprotective potential of antioxidants on EtOH-mediated cerebellar damage, vitamin E supplementation did not diminish EtOH-induced structural and functional damage to the cerebellum in this model of binge EtOH exposure during the brain growth spurt in rats.

Concept of treatment in supracondylar humeral fractures.

This opinion of treatment for children's supracondylar humeral fractures discusses techniques of fracture reduction and stabilization. A useful method of external visualization of the fracture is reviewed. The article discusses the treatment of 95 fractures in children using crossed and two lateral pin techniques.