Disability in Parkinson's disease (PD) is measured by standardised scales including the MDS-UPDRS, which are subject to high inter and intra-rater variability and fail to capture subtle motor ...impairment. The BRadykinesia Akinesia INcoordination (BRAIN) test is a validated keyboard tapping test, evaluating proximal upper-limb motor impairment. Here, a new Distal Finger Tapping (DFT) test was developed to assess distal upper-limb function. Kinetic parameters of the test include kinesia score (KS20, key taps over 20 s), akinesia time (AT20, mean dwell-time on each key) and incoordination score (IS20, variance of travelling time between key taps). To develop and evaluate a new keyboard-tapping test for objective and remote distal motor function in PD patients. The DFT and BRAIN tests were assessed in 55 PD patients and 65 controls. Test scores were compared between groups and correlated with the MDS-UPDRS-III finger tapping sub-scores. Nine additional PD patients were recruited for monitoring motor fluctuations. All three parameters discriminated effectively between PD patients and controls, with KS20 performing best, yielding 79% sensitivity for 85% specificity; area under the receiver operating characteristic curve (AUC) = 0.90. A combination of DFT and BRAIN tests improved discrimination (AUC = 0.95). Among three parameters, KS20 showed a moderate correlation with the MDS-UPDRS finger-tapping sub-score (Pearson's r = - 0.40, p = 0.002). Further, the DFT test detected subtle changes in motor fluctuation states which were not reflected clearly by the MDS-UPDRS-III finger tapping sub-scores. The DFT test is an online tool for assessing distal movements in PD, with future scope for longitudinal monitoring of motor complications.
Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired ...inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined. Approach and Results: Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3-, CD19-, Ly6G-) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow-derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL interleukin-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow-derived macrophages and wound macrophages. This demonstrated decreased expression of
, an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow-derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in
compared with nonseptic controls.
These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1-mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
Aggregation is a common problem affecting biopharmaceutical development that can have a significant effect on the quality of the product, as well as the safety to patients, particularly because of ...the increased risk of immune reactions. Here, we describe a new high-throughput screening algorithm developed to classify antibody molecules based on their propensity to aggregate. The tool, constructed and validated on experimental aggregation data for over 500 antibodies, is able to discern molecules with a high aggregation propensity as defined by experimental criteria relevant to bioprocessing and manufacturing of these molecules. Furthermore, we show how this tool can be combined with other computational approaches during early drug development to select molecules with reduced risk of aggregation and optimal developability properties.
In this report we describe experiments to investigate a simple virulence model in which Pseudomonas aeruginosa PAO1 rapidly paralyzes and kills the nematode Caenorhabditis elegans. Our results imply ...that hydrogen cyanide is the sole or primary toxic factor produced by P. aeruginosa that is responsible for killing of the nematode. Four lines of evidence support this conclusion. First, a transposon insertion mutation in a gene encoding a subunit of hydrogen cyanide synthase (hcnC) eliminated nematode killing. Second, the 17 avirulent mutants examined all exhibited reduced cyanide synthesis, and the residual production levels correlated with killing efficiency. Third, exposure to exogenous cyanide alone at levels comparable to the level produced by PAO1 killed nematodes with kinetics similar to those observed with bacteria. The killing was not enhanced if hcnC mutant bacteria were present during cyanide exposure. And fourth, a nematode mutant (egl-9) resistant to P. aeruginosa was also resistant to killing by exogenous cyanide in the absence of bacteria. A model for nematode killing based on inhibition of mitochondrial cytochrome oxidase is presented. The action of cyanide helps account for the unusually broad host range of virulence of P. aeruginosa and may contribute to the pathogenesis in opportunistic human infections due to the bacterium.
BackgroundSerotype 19A invasive pneumococcal disease (IPD) increased annually in the United States after the introduction of the 7-valent conjugate vaccine (PCV7). To understand this increase, we ...characterized serotype 19A isolates recovered during 2005 MethodsIPD cases during 1998–2005 were identified through population-based surveillance. We performed susceptibility testing and multilocus sequence typing on 528 (95%) of 554 serotype 19A isolates reported in 2005 ResultsThe incidence of IPD due to serotype 19A increased from 0.8 to 2.5 cases per 100,000 population between 1998 and 2005 (P<.05), whereas the overall incidence of IPD decreased from 24.4 to 13.8 cases per 100,000 population (P<.05). Simultaneously, the incidence of IPD due to penicillin-resistant 19A isolates increased from 6.7% to 35% (P<.0001). Of 151 penicillin-resistant 19A isolates, 111 (73.5%) belonged to the rapidly emerging clonal complex 320, which is related to multidrug-resistant Taiwan19F-14. The remaining penicillin-resistant strains were highly related to other clones of PCV7 serotypes or to isolates within major 19A clonal complex 199 (CC199). In 1999, only CC199 and 3 minor clones were apparent among serotype 19A isolates. During 2005, 11 multiple-isolate clonal sets were detected, including capsular switch variants of a serotype 4 clone ConclusionsPCV7 ineffectiveness against serotype 19A, antibiotic resistance, clonal expansion and emergence, and capsular switching have contributed to the genetic diversity of 19A and to its emergence as the predominant invasive pneumococcal serotype in the United States
Practice guidelines recommend long-term stroke prophylaxis in patients with chronic atrial fibrillation (cAF).
To examine treatment initiation and persistence and factors that influence the choice of ...cAF treatment.
This study used the General Practice Research Database, including computerized medical records of general practitioners in the UK. Patients aged 40+ years with cAF after 1 January 2000 were included. Cox proportional hazards regression models evaluated initiation and treatment continuation over time of warfarin and aspirin. Treatment discontinuation was defined as no repeat prescription within a three-month period after the expected end of the treatment course.
The study population included 41 910 cAF patients. Elderly patients (aged 85+) were less likely to start warfarin relative rate (RR) = 0.16, 95% confidence interval (CI) 0.15-0.18 and more likely to start aspirin (RR = 1.66, 95% CI 1.47-1.88) than patients aged 40-64 years. A history of dementia (RR = 0.28, 95% CI 0.17-0.44) and falls (RR = 0.76, 95% CI 0.70-0.83) also reduced the likelihood of warfarin initiation. Adjusting for age and gender, higher stroke risk (CHADS2 score) was not found to be associated with initiation of warfarin or aspirin contrary to current guidelines recommendations. One-year persistence was 70% for warfarin and 50% for aspirin. Treatment persistence was higher in elderly patients using warfarin and aspirin. A higher CHADS(2) score was associated with improved persistence only with warfarin.
The low likelihood of patients with cAF in general practice remaining on treatment long-term indicates that not all benefits as observed in clinical trials may be achieved in usual clinical practice.
Magnetic resonance fingerprinting (MRF) is highly promising as a quantitative MRI technique due to its accuracy, robustness, and efficiency. Previous studies have found high repeatability and ...reproducibility of 2D MRF acquisitions in the brain. Here, we have extended our investigations to 3D MRF acquisitions covering the whole brain using spiral projection k-space trajectories.
Our travelling head study acquired test/retest data from the brains of 12 healthy volunteers and 8 MRI systems (3 systems at 3 T and 5 at 1.5 T, all from a single vendor), using a study design not requiring all subjects to be scanned at all sites. The pulse sequence and reconstruction algorithm were the same for all acquisitions.
After registration of the MRF-derived PD T1 and T2 maps to an anatomical atlas, coefficients of variation (CVs) were computed to assess test/retest repeatability and inter-site reproducibility in each voxel, while a General Linear Model (GLM) was used to determine the voxel-wise variability between all confounders, which included test/retest, subject, field strength and site.
Our analysis demonstrated a high repeatability (CVs 0.7–1.3% for T1, 2.0–7.8% for T2, 1.4–2.5% for normalized PD) and reproducibility (CVs of 2.0–5.8% for T1, 7.4–10.2% for T2, 5.2–9.2% for normalized PD) in gray and white matter.
Both repeatability and reproducibility improved when compared to similar experiments using 2D acquisitions. Three-dimensional MRF obtains highly repeatable and reproducible estimations of T1 and T2, supporting the translation of MRF-based fast quantitative imaging into clinical applications.
A long sought after goal using chemical abundance patterns derived from metal-poor stars is to understand the chemical evolution of the Galaxy and to pin down the nature of the first stars (Pop III). ...Metal-poor, old, unevolved stars are excellent tracers as they preserve the abundance pattern of the gas from which they were born, and hence they are frequently targeted in chemical tagging studies. Here, we use a sample of 14 metal-poor stars observed with the high-resolution spectrograph called the Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) to derive abundances of 32 elements (34 including upper limits). We present well-sampled abundance patterns for all stars obtained using local thermodynamic equilibrium (LTE) radiative transfer codes and one-dimensional (1D) hydrostatic model atmospheres. However, it is currently well-known that the assumptions of 1D and LTE may hide several issues, thereby introducing biases in our interpretation as to the nature of the first stars and the chemical evolution of the Galaxy. Hence, we use non-LTE (NLTE) and correct the abundances using three-dimensional model atmospheres to present a physically more reliable pattern. In order to infer the nature of the first stars, we compare unevolved, cool stars, which have been enriched by a single event (“mono-enriched”), with a set of yield predictions to pin down the mass and energy of the Pop III progenitor. To date, only few bona fide second generation stars that are mono-enriched are known. A simple
χ
2
-fit may bias our inferred mass and energy just as much as the simple 1D LTE abundance pattern, and we therefore carried out our study with an improved fitting technique considering dilution and mixing. Our sample presents Carbon Enhanced Metal-Poor (CEMP) stars, some of which are promising bona fide second generation (mono-enriched) stars. The unevolved, dwarf BD+09_2190 shows a mono-enriched signature which, combined with kinematical data, indicates that it moves in the outer halo and likely has been accreted onto the Milky Way early on. The Pop III progenitor was likely of 25.5
M
⊙
and 0.6 foe (0.6 10
51
erg) in LTE and 19.2
M
⊙
and 1.5 foe in NLTE, respectively. Finally, we explore the predominant donor and formation site of the rapid and slow neutron-capture elements. In BD-10_3742, we find an almost clean r-process trace, as is represented in the star HD20, which is a “metal-poor Sun benchmark” for the r-process, while TYC5481-00786-1 is a promising CEMP-r/-s candidate that may be enriched by an asymptotic giant branch star of an intermediate mass and metallicity.
In this essential contribution to twentieth-century political history, Julie A. Gallagher documents six decades of politically active black women in New York City who waged struggles for justice, ...rights, and equality not through grassroots activism but through formal politics._x000B__x000B_In tracing the paths of black women activists from women's clubs and civic organizations to national politics--including appointments to presidential commissions, congressional offices, and even a presidential candidacy--Gallagher also articulates the vision of politics the women developed and its influence on the Democratic party and its policies. Deftly examining how race, gender, and the structure of the state itself shape outcomes, she exposes the layers of power and discrimination at work in all sectors of U.S. society. _x000B__x000B_Taking a long historical view across the twentieth century, Black Women and Politics in New York City is arranged chronologically, beginning with the fight for suffrage and rights in the first two decades of the century and moving through strides made and political opportunities seized during the Great Depression, the World War II era, resistance in the 1950s, and feminism and civil rights in the 1960s and 1970s. Gallagher examines the career of political trailblazer Shirley Chisholm, the first black woman elected to Congress and the first to run for president on a national party ticket, with extensive attention to the efforts of generations of politically active black women who came before her._x000B__x000B_Gallagher's study of African American women in New York City politics adds to the growing body of scholarship on the civil rights struggle and revises twentieth-century women's history, particularly feminist activism, to include African American women who hitherto have been excluded from the narrative. Sensitively and insightfully offering revision and expansion of the accepted interpretations of black feminism to include liberal reformers, Gallagher draws on an impressive array of sources to highlight the struggles black women waged through formal politics for themselves, their communities, and broader ideals of equality.
The exact pathogenesis of visual hallucinations in Parkinson's disease is not known but an integrated model has been proposed that includes impaired visual input and central visual processing, ...impaired brainstem regulation of sleep-wake cycle with fluctuating vigilance, intrusion of rapid eye movement dream imagery into wakefulness and emergence of internally generated imagery, cognitive dysfunction and influence of dopaminergic drugs. In a clinical study, we assessed motor and non-motor function, including sleep, mood, autonomic and global, frontal and visuoperceptive cognitive function in patients with and without visual hallucinations. A subgroup of patients underwent detailed ophthalmological assessment. In a separate pathological study, histological specimens were obtained from cases of pathologically proven Parkinson's disease and a retrospective case notes review was made for reporting of persistent formed visual hallucinations. An assessment of Lewy body and Lewy neurite pathology was carried out in five cortical regions as recommended by diagnostic criteria for dementia with Lewy Bodies and in brainstem nuclei. Ninety-four patients (mean age 67.5 ± 9.5 years) participated in the clinical study of whom 32% experienced visual hallucinations. When corrected for multiple comparisons, patients with visual hallucinations had significantly greater disease duration, treatment duration, motor severity and complications, sleep disturbances, in particular excessive daytime somnolence and rapid eye movement sleep behavioural disorder, disorders of mood, autonomic dysfunction and global, frontal and visuoperceptive cognitive dysfunction. Of the 94 patients, 50 (53%) underwent ophthalmological assessment. There were no differences in ocular pathology between the visual hallucination and non-visual hallucination groups. In a logistic regression model the four independent determinants of visual hallucinations were rapid eye movement sleep behavioural disorder (P = 0.026), autonomic function (P = 0.004), frontal cognitive function (P = 0.020) and a test of visuoperceptive function (object decision; P = 0.031). In a separate study, post-mortem analysis was performed in 91 subjects (mean age at death 75.5 ± 8.0 years) and persistent visual hallucinations were documented in 63%. Patients in the visual hallucinations group had similar disease duration but had significantly higher Lewy body densities in the middle frontal (P = 0.002) and middle temporal gyri (P = 0.033) and transentorhinal (P = 0.005) and anterior cingulate (P = 0.020) cortices but not parietal cortex (P = 0.22). Using a comprehensive assessment of the clinical, demographic and ophthalmological correlates of visual hallucinations in Parkinson's disease, the combined data support the hypothesized model of impaired visual processing, sleep-wake dysregulation and brainstem dysfunction, and cognitive, particularly frontal, impairment all independently contributing to the pathogenesis of visual hallucinations in Parkinson's disease. These clinical data are supported by the pathological study, in which higher overall cortical Lewy body counts, and in particular areas implicated in visuoperception and executive function, were associated with visual hallucinations.
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