Low temperature remote plasma sputtering of indium tin oxide for flexible display applications

Tin doped indium oxide (ITO) has been directly deposited onto a variety of flexible materials by a reactive sputtering technique that utilises a remotely generated, high density plasma. This technique, known as high target utilisation sputtering (HiTUS), allows for the high rate deposition of good quality ITO films onto polymeric materials with no substrate heating or post deposition annealing. Coatings with a resistivity of 3.8 ×10−4 Ωcm and an average visible transmission of greater than 90% have been deposited onto PEN and PET substrate materials at a deposition rate of 70 nm/min. The electrical and optical properties are retained when the coatings are flexed through a 1.0 cm bend radius, making them of interest for flexible display applications

Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series.

BACKGROUND: The causes of phenotypic heterogeneity in familial Alzheimer's disease with autosomal dominant inheritance are not well understood. We aimed to characterise clinical phenotypes and genetic associations with APP and PSEN1 mutations in symptomatic autosomal dominant familial Alzheimer's disease (ADAD). METHODS: We retrospectively analysed genotypic and phenotypic data (age at symptom onset, initial cognitive or behavioural symptoms, and presence of myoclonus, seizures, pyramidal signs, extrapyramidal signs, and cerebellar signs) from all individuals with ADAD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London, UK. We examined the frequency of presenting symptoms and additional neurological features, investigated associations with age at symptom onset, APOE genotype, and mutation position, and explored phenotypic differences between APP and PSEN1 mutation carriers. The proportion of individuals presenting with various symptoms was analysed with descriptive statistics, stratified by mutation type. FINDINGS: Between July 1, 1987, and Oct 31, 2015, age at onset was recorded for 213 patients (168 with PSEN1 mutations and 45 with APP mutations), with detailed history and neurological examination findings available for 121 (85 with PSEN1 mutations and 36 with APP mutations). We identified 38 different PSEN1 mutations (four novel) and six APP mutations (one novel). Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations (mean age 43·6 years [SD 7·2] vs 50·4 years [SD 5·2], respectively, p<0·0001); within the PSEN1 group, 72% of age at onset variance was explained by the specific mutation. A cluster of five mutations with particularly early onset (mean age at onset <40 years) involving PSEN1's first hydrophilic loop suggests critical functional importance of this region. 71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers (n=14; p=0·037). Myoclonus and seizures were the most common additional neurological features; individuals with myoclonus (40 [47%] with PSEN1 mutations and 12 [33%] with APP mutations) were significantly more likely to develop seizures (p=0·001 for PSEN1; p=0·036 for APP), which affected around a quarter of the patients in each group (20 [24%] and nine [25%], respectively). A number of patients with PSEN1 mutations had pyramidal (21 [25%]), extrapyramidal (12 [14%]), or cerebellar (three [4%]) signs. INTERPRETATION: ADAD phenotypes are heterogeneous, with both age at onset and clinical features being influenced by mutation position as well as causative gene. This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms, and of examining different mutation types separately in future research. FUNDING: Medical Research Council and National Institute for Health Research

A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders

Mutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioral variant FTD, primary progressive aphasia, and pure ALS. We describe the clinical, anatomical, and pathological features of a patient who developed corticobasal syndrome (CBS)/progressive nonfluent aphasia (PNFA) overlap. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic-rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with four out of seven siblings developing either dementia or ALS in their 50s and 60s. The patient died at the age of 71 and the brain was donated for postmortem analysis. Histopathological examination showed frontotemporal lobar degeneration TDP-43 type A pathology. Genetic screening did not reveal a mutation in the GRN, MAPT, or C9orf72 genes, but exome sequencing revealed a novel p.E703X mutation in the TBK1 gene. Although segregation data were not available, this loss-of-function mutation is highly likely to be pathogenic because it is predicted to disrupt TBK1/optineurin interaction and impair cellular autophagy. In conclusion, we show that TBK1 mutations can be a cause of an atypical parkinsonian syndrome and screening should be considered in CBS patients with a family history of dementia or ALS

Presence of Helicobacter pylori in betel chewers and non betel chewers with and without oral cancers

<p>Abstract</p> <p>Background</p> <p>Betel chewing has been shown to predispose to periodontal disease and oral cancer. Studies show that people with gum disease are more likely to test positive for <it>Helicobacter pylori (H. pylori)</it>. It is not known if the lesions produced by betel quid and the resulting, chemical changes predispose to colonization by <it>H. pylori</it>. Further the role of this organism in oral cancer is not known. Our objective was to determine the presence of <it>H. pylori </it>in oral lesions of thirty oral cancer patients and to determine the presence of IgG antibodies to <it>H. pylori </it>in oral cancer patients who are betel chewers and non betel chewers, healthy betel chewers and healthy non-betel chewers and to compare the presence of <it>H</it>. <it>pylori </it>in these four groups. This case control study was conducted at the Cancer Institute Maharagama and the Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayewardenepura.</p> <p>Methods</p> <p>One hundred and seventy three subjects, of whom fifty three were patients presenting with oral cancer to the Cancer Institute Maharagama, sixty healthy betel chewers and sixty healthy non-betel chewers from the Religious and Welfare Service Centre Maharagama were tested for <it>H. pylori </it>by serology. Thirty oral biopsies from oral cancer patients were cultured under microaerophilic condition to isolate <it>H. pylori</it>. The statistic used was Chi-square test.</p> <p>Results</p> <p>Of the fifty-three oral cancer patients, forty-four were betel chewers. Among the 53 oral cancer patients examined, ten of forty-four (10/44 = 22.7%) patients who are betel chewers and four of nine (4/9 = 44.4%) patients who are non-betel chewers were detected positive for IgG antibody against <it>H. pylori</it>. In the healthy group (betel chewers and non betel chewers) ten (16.7%) of the healthy betel chewers tested positive for <it>H. pylori </it>by serology. None of the healthy non-betel chewers tested positive for <it>H. pylori</it></p> <p>Fourteen [26.4%] of oral cancer patients tested positive for <it>H. pylori </it>by serology, of which two were also culture positive (Only thirty samples were cultured). The presence of <it>H. pylori </it>in betel chewers (with or without cancer) compared to non-betel chewers was statistically significant. (Chi-square test p < 0.05) The use of tobacco and areca nut in betel chewers was significant with the presence of <it>H. pylori </it>(p < 0.05).</p> <p>Conclusion</p> <p>There is a significant higher proportion of <it>H. pylori </it>in betel chewers compared to non-betel chewers but not between oral cancer patients compared to patients without oral cancer. Hence Betel chewing may predispose to colonisation with <it>H. pylori </it>in the digestive tract through swallowing the quid or during betel chewing.</p

Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome

IMPORTANCE: Patients with atypical parkinsonian syndromes (APS), including progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA), may be difficult to distinguish in early stages and are often misdiagnosed as Parkinson’s disease (PD). The diagnostic criteria for PSP have been updated to encompass a range of clinical subtypes, but have not been prospectively studied. OBJECTIVE: To define the distinguishing features of PSP and CBS, and to assess their usefulness in facilitating early diagnosis and separation from PD. DESIGN, SETTING, PARTICIPANTS: Cohort study which recruited APS and PD patients from movement disorder clinics across the UK from September 2015 to December 2018, and will follow up patients over 5 years. APS patients were stratified into PSP-Richardson syndrome, PSP-subcortical (including PSP-parkinsonism and PSP-progressive gait freezing cases), PSP-cortical (including PSP-frontal and PSP/CBS overlap cases), MSA-parkinsonism, MSA-cerebellar, CBS-Alzheimer’s and CBS-non-Alzheimer’s groups. MAIN OUTCOME MEASURES: Baseline group comparisons were conducted using: 1) Clinical trajectory; 2) Cognitive screening scales; 3) Serum neurofilament light chain (NF-L); 4) TRIM11, ApoE and MAPT genotypes; 5) Volumetric MRI. RESULTS: 222 APS cases (101 PSP, 55 MSA, 40 CBS and 26 indeterminate) were recruited (58% male; mean age at recruitment, 68.3 years). Age-matched controls (n=76) and PD cases (n=1967) were also included. Concordance between the ante-mortem clinical diagnosis and pathological diagnosis was achieved in 12/13 (92%) of PSP and CBS cases coming to post-mortem. Applying the MDS PSP diagnostic criteria almost doubled the number of patients diagnosed with PSP. 49/101 (49%) of reclassified PSP patients did not have classical PSP-Richardson syndrome. PSP-subcortical patients had a longer diagnostic latency and a more benign clinical trajectory than PSP-Richardson syndrome and PSP-cortical (p<0.05). PSP-subcortical was distinguished from PSP-cortical and PSP-Richardson syndrome by cortical volumetric MRI measures (AUC 0.84-0.89), cognitive profile (AUC 0.80-0.83), serum NF-L (AUC 0.75-0.83) and TRIM11 rs564309 genotype. Midbrain atrophy was a common feature of all PSP subtypes. 8/17 (47%) of CBS patients with CSF analysis were identified as having CBS-Alzheimer’s. CBS-Alzheimer’s patients had a longer diagnostic latency, relatively benign clinical trajectory, greater cognitive impairment and higher APOE-ε4 allele frequency than CBS-non-Alzheimer’s (p<0.05, AUC 0.80-0.87). Serum NF-L levels distinguished PD from PSP and CBS (p<0.05, AUC 0.80). CONCLUSIONS AND RELEVANCE: Clinical, therapeutic and epidemiological studies focusing on PSP-Richardson syndrome are likely to miss a large number of patients with underlying PSP-tau pathology. CSF analysis defines a distinct CBS-Alzheimer’s subgroup. PSP and CBS subtypes have distinct characteristics that may enhance their early diagnosis

Electrical Stimulation Influences Satellite Cell Proliferation and Apoptosis in Unloading-Induced Muscle Atrophy in Mice

Muscle atrophy caused by disuse is accompanied by adverse physiological and functional consequences. Satellite cells are the primary source of skeletal muscle regeneration. Satellite cell dysfunction, as a result of impaired proliferative potential and/or increased apoptosis, is thought to be one of the causes contributing to the decreased muscle regeneration capacity in atrophy. We have previously shown that electrical stimulation improved satellite cell dysfunction. Here we test whether electrical stimulation can also enhance satellite cell proliferative potential as well as suppress apoptotic cell death in disuse-induced muscle atrophy. Eight-week-old male BALB/c mice were subjected to a 14-day hindlimb unloading procedure. During that period, one limb (HU-ES) received electrical stimulation (frequency: 20 Hz; duration: 3 h, twice daily) while the contralateral limb served as control (HU). Immunohistochemistry and western blotting techniques were used to characterize specific proteins in cell proliferation and apoptosis. The HU-ES soleus muscles showed significant improvement in muscle mass, cross-sectional area, and peak tetanic force relative to the HU limb (p<0.05). The satellite cell proliferative activity as detected within the BrdU+/Pax7+ population was significantly higher (p<0.05). The apoptotic myonuclei (detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) and the apoptotic satellite cells (detected by cleaved Poly [ADP-ribose] polymerase co-labeled with Pax7) were reduced (p<0.05) in the HU-ES limb. Furthermore the apoptosis-inducing factor and cleaved caspase-3 were down-regulated while the anti-apoptotic Bcl-2 protein was up-regulated (p<0.05), in the HU-ES limb. These findings suggest that the electrical stimulation paradigm provides an effective stimulus to rescue the loss of myonuclei and satellite cells in disuse muscle atrophy, thus maintaining a viable satellite cell pool for subsequent muscle regeneration. Optimization of stimulation parameters may enhance the outcome of the intervention

Structural Characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei Bound to the Antifungal Drugs Posaconazole and Fluconazole

Chagas Disease is caused by kinetoplastid protozoa Trypanosoma cruzi, whose sterols resemble those of fungi, in both composition and biosynthetic pathway. Azole inhibitors of sterol 14α-demethylase (CYP51), such as fluconazole, itraconazole, voriconazole, and posaconazole, successfully treat fungal infections in humans. Efforts have been made to translate anti-fungal azoles into a second-use application for Chagas Disease. Ravuconazole and posaconazole have been recently proposed as candidates for clinical trials with Chagas Disease patients. However, the widespread use of posaconazole for long-term treatment of chronic infections may be limited by hepatic and renal toxicity, a requirement for simultaneous intake of a fatty meal or nutritional supplement to enhance absorption, and cost. To aid our search for structurally and synthetically simple CYP51 inhibitors, we have determined the crystal structures of the CYP51 targets in T. cruzi and T. brucei, both bound to the anti-fungal drugs fluconazole or posaconazole. The structures provide a basis for a design of new drugs targeting Chagas Disease, and also make it possible to model the active site characteristics of the highly homologous Leishmania CYP51. This work provides a foundation for rational synthesis of new therapeutic agents targeting the three kinetoplastid parasites

Pathogenesis, diagnosis and management of pneumorrhachis

Pneumorrhachis (PR), the presence of intraspinal air, is an exceptional but eminent radiographic finding, accompanied by different aetiologies and possible pathways of air entry into the spinal canal. By reviewing the literature and analysing a personal case of traumatic cervical PR after head injury, we present current data regarding the pathoanatomy, clinical and radiological presentation, diagnosis and differential diagnosis and treatment modalities of patients with PR and associated pathologies to highlight this uncommon phenomenon and outline aetiology-based guidelines for the practical management of PR. Air within the spinal canal can be divided into primary and secondary PR, descriptively classified into extra- or intradural PR and aetiologically subsumed into iatrogenic, traumatic and nontraumatic PR. Intraspinal air is usually found isolated not only in the cervical, thoracic and, less frequently, the lumbosacral regions but can also be located in the entire spinal canal. PR is almost exceptional associated with further air distributions in the body. The pathogenesis and aetiologies of PR are multifold and can be a diagnostic challenge. The diagnostic procedure should include spinal CT, the imaging tool of choice. PR has to be differentiated from free intraspinal gas collections and the coexistence of air and gas within the spinal canal has to be considered differential diagnostically. PR usually represents an asymptomatic epiphenomenon but can also be symptomatic by itself as well as by its underlying pathology. The latter, although often severe, might be concealed and has to be examined carefully to enable adequate patient treatment. The management of PR has to be individualized and frequently requires a multidisciplinary regime