Search

Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major genetic cause of parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor, and the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we investigated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells. Restoration of parkin expression promoted G1 phase cell-cycle arrest and mitigated the proliferation rate of glioma cells in vitro and in vivo. Notably, parkin-expressing glioma cells showed a reduction in levels of cyclin D1, but not cyclin E, and a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. In accordance, cells derived from a parkin-null mouse model exhibited increased levels of cyclin D1, VEGF receptor, and Akt phosphorylation, and divided significantly faster when compared with wild-type cells, with suppression of these changes following parkin reintroduction. Clinically, analysis of parkin pathway activation was predictive for the survival outcome of patients with glioma. Taken together, our study provides mechanistic insight into the tumor suppressor function of parkin in brain tumors and suggests that measurement of parkin pathway activation may be used clinically as a prognostic tool in patients with brain tumor. Cancer Res; 72(10); 2543–53. ©2012 AACR.

PDF file - 64K

PDF file - 130K

PDF file - 508K

Objectives To evaluate the utility of the splenial angle (SA), an axial angular index of lateral ventriculomegaly measured on diffusion tensor MRI color fractional anisotropy maps, in differentiating NPH from Alzheimer’s disease (AD), Parkinson’s disease (PD), and healthy controls (HC), and post-shunt changes in NPH, compared to Evans’ index and callosal angle. Methods Evans’ index, callosal angle, and SA were measured on brain MRI of 76 subjects comprising equal numbers of age- and sex-matched subjects from each cohort of NPH, AD, PD, and HC by two raters. Receiver operating characteristics (ROC) and multivariable analysis were used to assess the screening performance of each measure in differentiating and predicting NPH from non-NPH groups respectively. Temporal changes in the measures on 1-year follow-up MRI in 11 NPH patients (with or without ventriculoperitoneal shunting) were also assessed. Results Inter-rater and intra-rater reliability were excellent for all measurements (intraclass correlation coefficients > 0.9). Pairwise comparison showed that SA was statistically different between NPH and AD/PD/HC subjects (p < 0.0001). SA performed the best in predicting NPH, with an area under the ROC curve of > 0.98, and was the only measure left in the final model of the multivariable analysis. Significant (p < 0.01) change in SA was seen at follow-up MRI of NPH patients who were shunted compared to those who were not. Conclusions The SA is readily measured on axial DTI color FA maps compared to the callosal angle and shows superior performance differentiating NPH from neurodegenerative disorders and sensitivity to ventricular changes in NPH after surgical intervention. Key Points • The splenial angle is a novel simple angular radiological index proposed for idiopathic normal pressure hydrocephalus, measured in the ubiquitous axial plane on DTI color fractional anisotropy maps. • The splenial angle quantitates the compression and stretching of the posterior callosal commissural fibers alongside the distended lateral ventricles in idiopathic normal pressure hydrocephalus (NPH) using tools readily accessible in clinical practice and shows excellent test-retest reliability. • Splenial angle outperforms Evans’ index and callosal angle in predicting NPH from healthy, Parkinson’s disease, and Alzheimer’s disease subjects on ROC analysis with an area under the curve of > 0.98 and is sensitive to morphological ventricular changes in NPH patients after ventricular shunting.

Chathuri Yatawara,1 Fatin Zahra Zailan,1 Esther Vanessa Chua,1 Linda Lay Hoon Lim,1 Eveline Silva,1 Joanna Sihan Wang,1 Adeline Ng,1 Kok Pin Ng,1 Nagaendran Kandiah1– 3 1Department of Neurology, National Neuroscience Institute, Singapore, Singapore; 2Duke-NUS Medical School, Singapore, Singapore; 3Lee Kong Chian School of Medicine-Imperial College London, Nanyang Technological University, Singapore, SingaporeCorrespondence: Nagaendran KandiahNational Neuroscience Institute, Level 3, Clinical Staff Office, 11 Jalan Tan Tock Seng, Singapore, 308433, SingaporeTel +65 6357 7171Fax +65 6357 7137Email Nagaendran.Kandiah@singhealth.com.sgBackground: Rivastigmine is used to treat cognitive impairment in Alzheimer’s disease (AD); however, the efficacy of Rivastigmine in patients with AD and concomitant small vessel cerebrovascular disease (svCVD) remains unclear. We investigated the effectiveness of Rivastigmine Patch in patients with AD and svCVD.Methods: In this open-label study, 100 patients with AD and MRI confirmed svCVD received 9.5mg/24 hours Rivastigmine transdermal treatment for 24 weeks. The primary outcome was global cognition indexed using the ADAS-Cog. Secondary outcomes included clinical-rated impression of change (indexed using (ADCS‐CGIC), activities of daily living (indexed using ADCS-ADL) and side effects.Results: Overall, performance on the ADAS-Cog after 24 weeks deteriorated by 1.78 (SD = 5.29) points. Fifty-two percent of the sample demonstrated improvement or remained stable, while 48% demonstrated worsening of ADAS-Cog scores. Of the 52%, significant improvement (2 or more-point decline) on the ADAS-Cog was observed in 25% of the sample, with a mean change of − 5.08 (SD = 3.11). A decline on the ADAS-Cog was observed in 48% of the sample, with a mean change of 6 (SD = 2.98) points. Cognitive outcome did not interact with severity of svCVD. ADCS-ADL scores remained stable from baseline to week 24 and ADCS‐CGIC reports indicated that 81% of the patients remained stable after treatment. Side effects were reported by 16% of the patients, with contact dermatitis being the most common.Conclusion: Our findings suggest that Rivastigmine may have a role in the management of patients having AD and concomitant mild-severe svCVD, with minimal side effects.Keywords: rivastigmine, Alzheimer’s disease, small vessel cerebrovascular disease, treatment

Adult-onset diffuse leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare progressive degenerative white matter disease caused by mutations in the colony-stimulating factor-1 receptor gene. Patients commonly present in the 4th or 5th decade with variable clinical presentations including behavioral changes, dementia, parkinsonism, and motor dysfunctions, eventually leading to death within a few years. Although the disease is typically hereditary, sporadic cases are known to occur. The classic MRI features of ALSP include T2 hyperintensities in the frontal and parietal white matter, scattered foci of restricted diffusion in the white matter, age-advanced cerebral involutional changes, thinning and signal changes in the corpus callosum, absence of infratentorial involvement and lack of enhancement. CT commonly shows tiny calcifications in the corpus callosum and deep white matter. We report a unique case of sporadic ALSP that initially presented as young stroke with acute onset of left-sided hemiparesis and no preceding history of cognitive decline. However, subsequent cognitive and behavioral changes lead to the consideration of an alternative diagnosis. Stroke-like symptoms is a very rare primary presentation of this disease entity. We have highlighted the classic MRI and CT features that helped to guide its diagnosis in our patient and prompted early corroborative genetic testing.

Background: micro-RNAs (miRNAs) are stable, small, non-coding RNAs enriched in exosomes. Their variation in levels according to different disease etiologies have made them a promising diagnostic biomarker for neurodegenerative diseases such as Alzheimer’s disease (AD). Altered expression of miR-320a, miR-328-3p, and miR-204-5p have been reported in AD and frontotemporal dementia (FTD). Objective: To determine their reliability, we aimed to examine the expression of three exosomal miRNAs isolated from cerebrospinal fluid (CSF) of patients with young-onset AD and FTD (

Background and purpose Although COVID‐19 predominantly affects the respiratory system, recent studies have reported the occurrence of neurological disorders such as stroke in relation to COVID‐19 infection. Encephalitis is an inflammatory condition of the brain that has been described as a severe neurological complication of COVID‐19. Despite a growing number of reported cases, encephalitis related to COVID‐19 infection has not been adequately characterised. To address this gap, this systematic review and meta‐analysis aims to describe the incidence, clinical course, and outcomes of patients who suffer from encephalitis as a complication of COVID‐19. Methods All studies published between 1 November 2019 and 24 October 2020 that reported on patients who developed encephalitis as a complication of COVID‐19 were included. Only cases with radiological and/or biochemical evidence of encephalitis were included. Results In this study, 610 studies were screened and 23 studies reporting findings from 129,008 patients, including 138 with encephalitis, were included. The average time from diagnosis of COVID‐19 to onset of encephalitis was 14.5 days (range = 10.8–18.2 days). The average incidence of encephalitis as a complication of COVID‐19 was 0.215% (95% confidence interval [CI] = 0.056%–0.441%). The average mortality rate of encephalitis in COVID‐19 patients was 13.4% (95% CI = 3.8%–25.9%). These patients also had deranged clinical parameters, including raised serum inflammatory markers and cerebrospinal fluid pleocytosis. Conclusions Although encephalitis is an uncommon complication of COVID‐19, when present, it results in significant morbidity and mortality. Severely ill COVID‐19 patients are at higher risk of suffering from encephalitis as a complication of the infection.

Introduction COVID-19 is a multi-system infection which predominantly affects the respiratory system, but also causes systemic inflammation, endothelialitis and thrombosis. The consequences of this include renal dysfunction, hepatitis and stroke. In this systematic review, we aimed to evaluate the epidemiology, clinical course, and outcomes of patients who suffer from stroke as a complication of COVID-19. Methods We conducted a systematic review of all studies published between November 1, 2019 and July 8, 2020 which reported on patients who suffered from stroke as a complication of COVID-19. Results 326 studies were screened, and 30 studies reporting findings from 55,176 patients including 899 with stroke were included. The average age of patients who suffered from stroke as a complication of COVID-19 was 65.5 (Range: 40.4–76.4 years). The average incidence of stroke as a complication of COVID-19 was 1.74% (95% CI: 1.09% to 2.51%). The average mortality of stroke in COVID-19 patients was 31.76% (95% CI: 17.77% to 47.31%). These patients also had deranged clinical parameters including deranged coagulation profiles, liver function tests, and full blood counts. Conclusion Although stroke is an uncommon complication of COVID-19, when present, it often results in significant morbidity and mortality. In COVID-19 patients, stroke was associated with older age, comorbidities, and severe illness.

IMPORTANCE: The presence of Notch homolog 2 N-terminal-like C (NOTCH2NLC) repeat expansions are associated with neuronal intranuclear inclusion body disease (NIID), with varied neurological signs, including neuropathy, ataxia, parkinsonism, and tremor. To date, genetic screening of NOTCH2NLC GGC repeats in a cohort with typical Parkinson disease (PD) appears not to have been reported. OBJECTIVE: To investigate if NOTCH2NLC GGC expansions are present in a cohort of patients with PD and controls. DESIGN, SETTING, AND PARTICIPANTS: This case-control study was conducted in 2 tertiary movement disorder centers in Singapore. Participants were recruited and followed up from January 2005 to January 2020. The presence of NOTCH2NLC GGC expansion repeats was screened using polymerase chain reaction tests, and representative samples were verified with long-read genome sequencing. MAIN OUTCOMES AND MEASURES: Qualitative and quantitative comparisons between participants with sporadic PD, healthy control participants, and individuals with NIID. RESULTS: A total of 2076 participants, including 1000 with sporadic PD (600 men [60.0%]; mean age at onset, 62.6 [7.7] years) and 1076 healthy controls (581 men [54.0%]; mean age at study recruitment, 54.9 [9.4] years) were recruited. A total of 13 patients with PD and no healthy control participants were identified as carrying NOTCH2NLC GGC repeat expansions of more than 40 units; the frequency of more than 40 repeat expansions was higher in participants with PD than controls (P

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5'-untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long-read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92-138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26-380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID. National Medical Research Council (NMRC) This study was funded by Singapore's National Medical Research Council (ASLN by the Transition Award (MOH-TA18may-0003); ZC by the NMRC Centre Grant Seed Funding Programme-Pilot Grant (IRNMR17CPG02); CTL by the NNI Research Endowment Fund (NNI-HREF NRH16/001).

The COVID‐19 pandemic has caused tremendous suffering for patients with dementia and their caregivers. We conducted a survey to study the impact of the pandemic on patients with mild frontotemporal dementia (FTD). Our preliminary findings demonstrate that patients with FTD have significant worsening in behavior and social cognition, as well as suffer greater negative consequences from disruption to health‐care services compared to patients with AD. The reduced ability to cope with sudden changes to social environments places patients with FTD at increased vulnerability to COVID‐19 infection as well as to poorer clinical and social outcomes. Caregivers of FTD patients also demonstrate high burden during crisis situations. A proportion of patients with FTD benefitted from use of web‐based interactive platforms. In this article, we outline the priority areas for research as well as a roadmap for future collaborative research to ensure greatest benefit for patients with FTD and their caregivers.

BackgroundTertiary Lymphoid Structures (TLS) are highly organized ectopic lymphoid structures found in inflamed or tumor tissues, acting as sites of lymphoid recruitment and immune activation. A high TLS density within the tumor is commonly associated with an increased prognostic effect of TILs and with an improved disease free survival and overall survival for patients.1 However, the existence of conflicting studies suggest that multiple TLS features should be taken into account when assessing their prognostic value, such as their location, cellular composition, maturation stage and spatial organisation, as those may affect their functionalities.2MethodsWith the aim of gaining insights into TLS biology and evaluating the prognostic role of TLS in Non-Small Cell Lung Carcinoma according to their multiple features, we developed a TLS multiplex immunofluorescent (mIF) panel that includes T cells (CD3, CD8), B cells (CD20), Follicular Dendritic cells (CD21, CD23) and mature dendritic cells (DC-LAMP) markers. We deployed this panel across a cohort of primary tumors from NSCLC patients (n=408) and established a mIF image analysis workstream to assess the status and spatial location of each cell within the tissue. A H&E staining of the same tissue section was performed to evaluate mIF spatial data in relation to the tumor context. Additional multi-omics assessments were conducted across the same cohort including; whole exome sequencing, NanoString transcriptomics, and immunohistochemistry (e.g. PD-L1, FOXP3, NKp46, LKB1, CTLA4). We have leveraged clinical metadata, including demographics (e.g. age, sex, smoking status) and clinical risk factors (e.g. stage, grade, Standard of Care treatment) with clinical follow up (e.g. OS, PFS) for prevalence analysis, novel biomarker identification, and survival association.ResultsAssessment of the prevalence of each cell phenotype within the tumor tissue and TLS, the cell-cell interactions, the distance between each cell type, and the distance of non-TLS immune cells to the closest TLS will be described, demonstrating the different types of lymphoid aggregates and TLS and their functional status. An integrative analysis combining spatial biology data with multi-omics and clinical data will be presented evaluating the prognostic value of TLS composition, maturation status and spatial organization, in correlation with additional biomarkers and clinical characteristics.ConclusionsThis exploratory study using cutting-edge technologies enables us to better understand how TLS orchestrate an organised anti-tumour response, defining TLS spatial biomarker signatures, TLS gene signatures, and TLS features associated with patient outcomes to evaluate in the clinic.ReferencesMarie-Caroline Dieu-Nosjean, Jérémy Goc, Nicolas A Giraldo, Catherine Sautès-Fridman, Wolf Herman Fridman. Tertiary lymphoid structures in cancer and beyond. Trends Immunol 2014;35(11):571–580.Catherine Sautès-Fridman, Florent Petitprez, Julien Calderaro, Wolf Herman Fridman. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 2019;19(6):307–325.Ethics ApprovalThe study was approved by AstraZeneca.

A 48-year-old woman presented with asymptomatic painless optic disc swelling, seizures, cognitive decline, and weakness over 3 months. She had an upper motor neuron pattern of grade 4/5 weakness in all 4 limbs. Brain MRI revealed striking linear radial perivascular enhancement in the deep white matter1,2 (figure, A and B); MRI spine revealed longitudinally extensive C3-to-conus cord T2 hyperintensity and T1 enhancement2 (figure, C and D). CSF demonstrated glial fibrillary acidic protein (GFAP) pattern by indirect immunofluorescence with GFAPα specificity confirmed by cell-based assay. The patient improved clinically (figure, E and F) with steroid treatment. Linear/radial perivascular enhancement in the deep white matter prompts consideration of a corticosteroid-responsive meningoencephalomyelitis termed autoimmune GFAP astrocytopathy.1

C9orf72 repeat expansions is a major cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. Sizes of

We utilized ultrasensitive single molecule technology to measure plasma alpha‐synuclein in 221 subjects (51 controls, 170 PD). Plasma alpha‐synuclein levels were significantly higher in PD than controls (15506.3 vs. 13057.0 pg/mL, P = 0.037), adjusting for age and gender. In PD, alpha‐synuclein levels did not vary by H&Y stage or UPDRS motor scores but were significantly higher in PD patients with poorer cognition (MMSE ≤ 25) than controls (P = 0.016, Bonferroni corrected P = 0.047). Alpha‐synuclein levels quantified using ultrasensitive single molecule technology discriminate PD from controls and correlate with cognitive severity. These preliminary findings require independent validation to determine the utility of this assay.

Individuals with mild cognitive impairment (MCI) exhibit varying serial position effect (SPE) performances. The relationship between SPE performance in word list recall and clinical, genetic, and neuroimaging features of MCI requires elucidation. 119 MCI and 68 cognitively normal (CN) participants underwent cognitive assessment, apolipoprotein E (ApoE) genotyping, and volumetric MRI brain scans processed via voxel-based morphometry. A 10-word recall task was used to assess SPE performance in relation to recency and primacy recall. MCI participants were classified as having Good SPE performance (high primacy and recency, Good SPE) or Poor SPE performance (low primacy only, LP-SPE; low recency only, LR-SPE; or both low, Low SPE). Poor SPE participants had reduced grey matter (GM) volumes and increased white matter hyperintensities (WMH) volumes. Participants with LP-SPE demonstrated reduced hippocampal GM volumes and were more likely to be ApoE e4 carriers. LR-SPE was associated with higher WMH volumes. Presence of both greater WMH volumes and ApoE e4 resulted in Low SPE. LP-SPE MCI participants had features typical of Alzheimer's disease. LR-SPE MCI was associated with increased WMH volumes, likely representing vascular pathology. SPE profiles are associated with distinct clinical patterns of MCI pathophysiology and could have potential as a clinical marker.

Co-existence of Parkinson’s disease (PD) and essential tremor (ET) may reflect overlapping pathophysiology underlying both conditions. Furthermore, PD patients with leucine-rich repeat kinase-2 (LRRK2) mutations may present with ET-like features, suggesting the possibility of common genetic underpinnings. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple PD cohorts. We hypothesized that R1398H and N551K may show a similar effect in ET. In a case-control study involving 3198 subjects (2680 controls and 518 ET cases), R1398H was detected in 16.6% of ET cases compared to 18.0% in controls (OR = 0.91, 95% CI = 0.71–1.17, p = 0.46); while N551K was detected in 16.5% of ET cases compared to 18.0% of controls (OR = 0.89, 95% CI = 0.69–1.15, p = 0.37). While these results suggest that LRRK2 R1398H or N551K do not appear to modulate the risk of ET, it remains possible that a protective trend for both variants may be present in ET and a much larger sample size is required to identify this.

Microtubule‐associated protein tau mutations result in 10–20% of cases of genetic frontotemporal lobar degeneration. Tau mutation carriers typically develop behavioral variant frontotemporal dementia with or without parkinsonism. Unlike most frontotemporal dementia gene mutations, heterozygous R406W tau mutation carriers most often develop clinical Alzheimer's disease. We report a homozygous tau R406W mutation carrier with behavioral variant frontotemporal dementia who developed symptoms 20 years before mean family symptom onset. Voxel‐based morphometry showed frontoinsular, frontal, and mesial temporal cortical atrophy. Homozygous tau R406W mutations appear to accelerate symptom onset and drive a behavioral variant frontotemporal dementia syndrome.

Background Immunosuppression is effective in the secondary prevention of neuromyelitis optica spectrum disorder (NMOSD) relapse. However, some of the newer immunosuppressive agents are costly or unavailable in resource-poor countries; older immunosuppressive agents might be just as effective. We aimed to evaluate the efficacy and tolerability of methotrexate in treating NMOSD in an Asian cohort. Methods We retrospectively reviewed all patients with NMOSD treated with methotrexate at the National Neuroscience Institute, Singapore, between 1992 and September 2012. We compared the annualized relapse rates and disability as measured by the Expanded Disability Status Scale before and after methotrexate treatment. Results Eight of 180 patients with central nervous system demyelinating diseases fulfilled the inclusion criteria. At median follow up of 53 months (range 42–70 months), the median post-treatment annualized relapse rate was significantly lower than the pretreatment rate (0.00 [range 0.00–3.09] vs 0.97 [range 0.08–10.14] relapses). The median Expanded Disability Status Scale remained stable (pretreatment 6.5 [range 3.0–8.0] vs post-treatment 6.0 [range 2.0–8.0], P = 0.238); 75% of our cohort remained relapse-free on treatment. None of our patients were intolerant of methotrexate. Conclusions Methotrexate is well-tolerated in our NMOSD patients, and appears to be effective in decreasing relapse rates and preventing disability progression. It is widely available and less costly than newer immunomodulatory agents. As such, it can be recommended as a therapeutic option for NMOSD in patients who fail first-line therapy.

Reading disorder is a recognized feature in primary progressive aphasia (PPA). Surface dyslexia, characterized by regularization errors, is typically seen in the English-speaking semantic variant of PPA (svPPA). However, dyslexic characteristics of other languages, particularly logographical languages such as Chinese, remain sparse in the literature. This study aims to characterize and describe the dyslexic pattern in this group of patients by comparing an English-speaking svPPA group with a Chinese-speaking svPPA group. The authors hypothesized that Chinese-speaking individuals with svPPA would likely commit fewer surface dyslexic errors. By accessing the database of Singapore's National Neuroscience Institute and the National Alzheimer's Coordinating Center of the United States, the authors identified three Chinese-speaking and 18 English-speaking patients with svPPA, respectively, for comparison. The results suggest that, instead of surface dyslexia, svPPA in Chinese-speaking individuals is characterized by a profound deep dyslexic error. Based on current evidence suggesting the role of the temporal pole as a semantic convergence center, the authors conclude that this region also mediates and converges lexical-semantic significance in logographical languages.

The concept that frontotemporal dementia (FTD) is a purely cortical dementia has largely been refuted by the recognition of its close association with motor neuron disease, and the identification of transactive response DNA-binding protein 43 (TDP-43) as a major pathological substrate underlying both diseases. Genetic findings have transformed this field and revealed connections between disorders that were previous thought clinically unrelated. The discovery that the C9ORF72 locus is responsible for the majority of hereditary FTD, amyotrophic lateral sclerosis (ALS), and FTD-ALS cases and the understanding that repeat-containing RNA plays a crucial role in pathogenesis of both disorders has paved the way for the development of potential biomarkers and therapeutic targets for these devastating diseases. In this review, we summarize the historical aspects leading up to our current understanding of the genetic, clinical, and neuropathological overlap between FTD and ALS, and include brief discussions on chronic traumatic encephalopathy (CTE), given its association with TDP-43 pathology, its associated increased dementia risk, and reports of ALS in CTE patients. In addition, we describe other genetic associations between dementia and neuromuscular disease, such as inclusion body myositis with Paget's disease and FTD.

Machining of hardened steel and other difficult-to-cut materials requires instant heat transfer from the cutting edge of the tool to improve tool life. Supply of high-volume and high-pressure coolant often provides the best answer. This paper deals with an experimental investigation on the effect of high-pressure coolant on workpiece hardness, comparing it with dry cut and conventional coolant. The effectiveness of high-pressure coolant is evaluated in terms of improvement of surface finish, reduction in tool wear and cutting forces, and control of chip shape. It is found that the cutting force is reduced, surface finish improved, and chip width is reduced with the use of high-pressure coolant.

Expanding the bandwidth of surface seismic data, particularly towards low frequencies, is essential for many exploration and production objectives. Broader band signals, both in land and marine environments have marked benefits for imaging deeper targets, imaging through absorptive overburdens, and especially inversion for rock properties. Various methods have been proposed and implemented to expand seismic bandwidth; these include both acquisition and signal processing methods. A question that is often asked is how much difference does changing the acquisition geometry make? In this paper, we present a case study of a consistent, experimental offshore dataset in Southeast Asia. This data consists of a single boat pass of different cable depth configurations. These data were then processed with their appropriate deghosting methods and results compared. In addition, we examine methods for evaluating the success of these methods and their potential pitfalls. The key determinant of the eventual bandwidth of surface seismic data is the convolution of the source, near surface effects (free surface ghosts in the marine situation), the overall earth attenuation, and the level of additive environmental noise. Some of these effects can be modified by changes in the field acquisition geometry or at least, deterministically compensated for. The noise level may constrain or limit the capacity of signal processing tools to compensate for the “field” effects. When evaluating the raw and processed data it is wise to use various types of analysis and displays. Simple seismic amplitude stack sections and associated spectra can be misleading. Spectral “split” plots and inversion of the seismic data is often more indicative of success. In marine seismic acquisition, the free-surface ghost effect is one factor that can strongly impact the data bandwidth characteristics according to streamer and source depth. It is also a factor that could easily be adjusted in the survey design. Shallow towing favors the higher frequency response at the expense of low frequencies, whilst deeper towing favors the lower frequencies, at the expense of higher frequencies. Moreover, a deeper tow typically has lower levels of swell noise. At very low frequencies, the critical two octaves between two to eight Hertz, the level of ambient towing noise rises, the “DC notch” strengthens, and the power output of airgun sources declines. This combination provides both the biggest challenge and the opportunity of bandwidth expansion.

Background and Purpose— Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare congenital disorder caused by mutation in the ROBO3 gene. It is characterized by absent horizontal eye movements with progressive scoliosis developing in childhood and adolescence. To our knowledge, both diffusion tensor imaging evaluation in HGPPS patients who present with stroke and truncating stop codon mutation in the ROBO3 gene have yet to be reported. Summary of Case— We present a man with HGPPS who experienced a left pure motor stroke as a result of a left corona radiata infarct on diffusion-weighted imaging. Diffusion tensor imaging tractography confirmed the presence of uncrossed corticospinal tracts, accounting for the ipsilateral deficit. He was also found to possess a novel ROBO3 stop codon mutation on genetic testing. Conclusions— Patients with HGPPS may present with stroke symptoms on the ipsilateral side of the infarct in view of uncrossed corticospinal tracts. Truncating mutation in ROBO3 may provide additional pathophysiologic insights.

Aim: For chemotherapy regimens with intermediate FN risk (10–20%), physicians should assess patient risk factors to determine whether overall risk is >20% and G-CSF PP is indicated1. This study described factors considered important by physicians when assessing FN risk and deciding to use G-CSF PP in pts receiving intermediate-FN-risk chemotherapy. Methods: This prospective observational study (NCT01813721) was conducted in Europe, Australia and Canada. Before pt enrolment, investigators reported their own FN risk threshold at which they usually give G-CSF PP, and selected and ranked factors they considered important when assessing overall FN risk and deciding to give G-CSF PP (investigator baseline assessment). For each enrolled pt, their overall FN risk score and the same factors were assessed before starting chemotherapy (patient assessment), and whether G-CSF PP was planned was reported. Results: The final analysis included 165 investigators (67% medical oncologists) and 944 pts (median age 61 years, range 20–94) with breast cancer (42%), lung cancer (39%) or NHL (19%). Stage IV disease was reported in 34% of pts; 1% had a history of FN. Table 1 lists factors most often ranked for FN risk assessment and G-CSF PP decision. The median investigator-reported FN risk threshold was 20% and the pt median overall FN risk score was 18%. G-CSF PP was planned in 82% pts with an overall FN risk score≥the investigator's threshold and in 19% pts with an overall risk score Top 5 most frequently listed factors deemed important by investigators in the overall FN risk assessment and the G-CSF PP decision, at baseline and for each individual patient Factors considered in overall FN risk assessment, % (95% CI) Factors considered in G-CSF PP decision, % (95% CI) Investigator assessment (n = 165) Patient assessment (n = 944) Investigator assessment (n = 165) Patient assessment (n = 944) Chemotherapy agents in the backbone 88 (82–93) Chemotherapy agents in the backbone 93 (88–96) Outcome of FN risk assessment 89 (83–93) Outcome of FN risk assessment 79 (71–84) Prior history of FN 83 (76–89) Tumour type 72 (61–82) Age 80 (71–87) Guidelines 67 (53–79) Baseline laboratory values 76 (68–83) Guidelines 62 (48–74) Baseline laboratory values 74 (64–82) Treatment intent 67 (59–74) Age 73 (64–81) Tumour stage 43 (34–53) Guidelines 71 (61–78) Age 51 (43–60) Prior chemotherapy 71 (62–78) Age 39 (32–48) Treatment intent 69 (61–77) ECOG/Karnofsky performance status 36 (28–45) CI, confidence interval; ECOG, Eastern Cooperative Oncology Group. Conclusions: The most frequently considered factors were chemotherapy regimen for assessing FN risk and FN risk assessment outcome for decision to initiate G-CSF PP. Other factors were selected less consistently at the investigator and pt level. A standardised approach to risk factor assessment may improve guideline adherence and G-CSF use. 1Aapro et al. (2011) Eur J Cancer;47:8–32 Disclosure: G. Freyer: Consultant for Amgen France; E. Kalinka-Warzocha: Received honoraria from Amgen for clinical trials. Given lectures for Amgen; M. Marinca: Has spoken in speaker bureaus for Amgen Romania; L. Decosta: Employed by Amgen and holds stock; Z. Szabo: Employed by Amgen and holds stock. All other authors have declared no conflicts of interest.

Blur images are often subjected to the loss of high frequency content during acquisition, compression and multimedia transmission. Hence, objective blur assessment is implemented to identify and quantify image quality degradation by blurriness artifact in order to maintain and control the quality of the images. In this paper, objective full-reference and no-reference blur assessments using edge information are presented with the aim to provide computational models that can automatically measure the amount of blurriness artifact such as Gaussian blur on the images. The amount of Gaussian blur on an image, also known as the final blur measurement is determined by averaging the sum of edge width over all detected edges which satisfy the edge criteria. The final blur measurement for all test images based on full-reference and no-reference implementations are also validated with subjective results. The validation results show that the objective full-reference and no-reference blur assessments correlate closely to perceptual image quality.