Although more than half of the Earth’s population live in urban areas, we know remarkably little about most cities and what we do know is incomplete (lack of coverage) and inconsistent (varying ...definitions and scale). While there have been considerable advances in the derivation of a global urban mask using satellite information, the complexity of urban structures, the heterogeneity of materials, and the multiplicity of spectral properties have impeded the derivation of universal urban structural types (UST). Further, the variety of UST typologies severely limits the comparability of such studies and although a common and generic description of urban structures is an essential requirement for the universal mapping of urban structures, such a standard scheme is still lacking. More recently, there have been two developments in urban mapping that have the potential for providing a standard approach: the Local Climate Zone (LCZ) scheme (used by the World Urban Database and Access Portal Tools project) and the Global Human Settlement Layer (GHSL) methodology by JRC. In this paper the LCZ scheme and the GHSL LABEL product were compared for selected cities. The comparison between both datasets revealed a good agreement at city and coarse scale, while the contingency at pixel scale was limited due to the mismatch in grid resolution and typology. At a 1 km scale, built-up as well as open and compact classes showed very good agreement in terms of correlation coefficient and mean absolute distance, spatial pattern, and radial distribution as a function of distance from town, which indicates that a decomposition relevant for modelling applications could be derived from both. On the other hand, specific problems were found for both datasets, which are discussed along with their general advantages and disadvantages as a standard for UST classification in urban remote sensing.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset Parkinson's disease (PD). Emerging evidence suggests a role for LRRK2 in the endocytic pathway. Here, we show that LRRK2 is ...released in extracellular microvesicles (i.e. exosomes) from cells that natively express LRRK2. LRRK2 localizes to collecting duct epithelial cells in the kidney that actively secrete exosomes into urine. Purified urinary exosomes contain LRRK2 protein that is both dimerized and phosphorylated. We provide a quantitative proteomic profile of 1673 proteins in urinary exosomes and find that known LRRK2 interactors including 14-3-3 are some of the most abundant exosome proteins. Disruption of the 14-3-3 LRRK2 interaction with a 14-3-3 inhibitor or through acute LRRK2 kinase inhibition potently blocks LRRK2 release in exosomes, but familial mutations in LRRK2 had no effect on secretion. LRRK2 levels were overall comparable but highly variable in urinary exosomes derived from PD cases and age-matched controls, although very high LRRK2 levels were detected in some PD affected cases. We further characterized LRRK2 exosome release in neurons and macrophages in culture, and found that LRRK2-positive exosomes circulate in cerebral spinal fluid (CSF). Together, these results define a pathway for LRRK2 extracellular release, clarify one function of the LRRK2 14-3-3 interaction and provide a foundation for utilization of LRRK2 as a biomarker in clinical trials.
In patients with coronary heart disease (CHD), atrial fibrillation (AF) is associated with increased morbidity and mortality. We investigated the associations between clinical risk factors and ...biomarkers with incident AF in patients with CHD.
Around 13,153 patients with optimally treated CHD included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial with plasma samples obtained at randomization. Mean follow-up time was 3.5 years. The association between clinical risk factors and biomarkers with incident AF was estimated with Cox-regression models. Validation was performed in 1,894 patients with non-ST-elevation acute coronary syndrome included in the FRISC-II trial.
The median (min-max) age was 64 years (range 26-92) and 2,514 (19.1%) were women. A total of 541 patients, annual incidence rate of 1.2%, developed AF during follow-up. In multivariable models, older age, higher levels of NT-proBNP, higher body mass index (BMI), male sex, geographic regions, low physical activity, and heart failure were independently associated with increased risk of incident AF with hazard ratios ranging from 1.04 to 1.79 (P ≤ .05). NT-proBNP improved the C-index from 0.70 to 0.71. In the validation cohort, age, BMI, and NT-proBNP were associated with increased risk of incident AF with similar hazard ratios.
In patients with optimally treated CHD, the incidence of new AF was 1.2% per year. Age, NT-proBNP as a marker of impaired cardiac function, and BMI were the strongest factors, independently and consistently associated with incident AF. Male sex and low physical activity may also contribute to the risk of AF in patients with CHD.
Inhibition of inducible nitric oxide synthase reduces renal ischemia/reperfusion injury.
Nitric oxide (NO), produced via inducible nitric oxide synthase (iNOS), is implicated in the pathophysiology ...of renal ischemia/reperfusion (I/R) injury. The aim of this study was to investigate the effects of the iNOS inhibitors L-N6-(1-iminoethyl)lysine (L-NIL) and aminoethyl-isothiourea (AE-ITU) on (a) renal dysfunction and injury mediated by bilateral I/R of rat kidneys in vivo and (b) cytokine-stimulated NO production by primary cultures of rat proximal tubule (PT) cells.
Male Wistar rats subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h). Rats were administered either L-NIL (3 mg/kg IV bolus 15min prior to I/R followed by 1 mg/kg/h throughout I/R) or AE-ITU (1 mg/kg IV bolus 15min prior to I/R followed by 1 mg/kg/h throughout I/R). Serum and urinary biochemical indicators of renal dysfunction and injury were measured; serum creatinine (SCr, glomerular dysfunction), fractional excretion of Na+ (FENa, tubular dysfunction), serum aspartate aminotransferase (sAST, I/R injury) and urinary N-acetyl-˂-D-glucosaminidase (uNAG, tubular injury). Additionally, renal sections were used for histological grading of renal injury and for immunological evidence of nitrotyrosine formation. Nitrate/nitrate levels in plasma were measured using the Griess assay and used as an indicator of NO production. Primary cultures of rat PT cells were incubated with interferon-γ (IFN-γ, 100 IU/mL) and lipopolysaccharide (LPS, 10 μg/mL) for 24 h, either in the absence or presence of increasing concentrations of L-NIL or AE-ITU (0.001 to 1 mmol/L) after which nitrite/nitrate levels were measured using the Griess assay.
L-NIL and AE-ITU significantly reduced the I/R-mediated increases in SCr, FENa, sAST and uNAG, indicating attenuation of I/R-mediated renal dysfunction and injury. Specifically, L-NIL and AE-ITU reduced the I/R-mediated glomerular and tubular dysfunction and biochemical and histological evidence of tubular injury. Both L-NIL and AE-ITU attenuated the plasma levels of nitrate (indicating reduced NO production) and the immunohistochemical evidence of the formation of nitrotyrosine. In vitro, L-NIL and AE-ITU both significantly reduced cytokine-stimulated NO production by primary cultures of rat PT cells in a dose-dependent manner.
These results suggest that L-NIL and AE-ITU reduce the renal dysfunction and injury associated with I/R of the kidney, via inhibition of iNOS activity and subsequent reduction of NO (and peroxynitrite) generation. We propose that selective and specific inhibitors of iNOS activity may be useful against the NO-mediated renal dysfunction and injury associated with I/R of the kidney.
Because physical fitness and health are related to physical activity, it is important to gain an insight into the physical activity levels of persons with profound intellectual and multiple ...disabilities (PIMD). The purpose of this study was to examine heart rate patterns to measure the activity levels of persons with PIMD and to analyze these heart rate patterns according to participant characteristics, observed level of activity, days, and time of day. The heart rate patterns of 24 participants with PIMD were measured continuously using a heart rate monitor for 8 h · d for a period of 6 days. Physical activity levels were measured with questionnaires. Data were analyzed using multilevel analysis. The results indicate that the participants use only 32% of their heart rate reserve over 6 days. The intensity of heart rate reserve ranged from 1 to 62%. On a given day, wide ranges in heart rates between participants and within persons were observed. Between days, only small ranges in the heart rate were found. The participants could be grouped into 4 classes according to their heart rate. In addition, factors such as time of day, physical activity, and age are significantly related to heart rate patterns. In conclusion, this study is an important first step in exploring activity patterns based on heart rate patterns in persons with PIMD. The participants used relatively small fractions of their heart rate reserves. Time of day and age appear to have a considerable influence on heart rate patterns. The observed classes in heart rate patterns suggest that other probably more personal and psychosocial factors have significant influences on heart rate patterns, as well.
Chronic GVHD (cGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT). As preemptive therapy might be efficacious if administered early post transplant, we set out ...to determine whether cGVHD can be predicted from the serum level of a biomarker on day 7 or 28. In a discovery cohort of 153 HCT recipients conditioned with BU, fludarabine and rabbit antithymocyte globulin (ATG), we determined serum levels of B-cell-activating factor, vascular endothelial growth factor, soluble TNF-α receptor 1, soluble IL2 receptor α, IL5, IL6, IL7, IL15, γ-glutamyl transpeptidase, cholinesterase, total protein, urea and ATG. Patients with low levels of IL15 (<30.6 ng/L) on day 7 had 2.7-fold higher likelihood of developing significant cGVHD (needing systemic immunosuppressive therapy) than patients with higher IL15 levels (P<0.001). This was validated in a validation cohort of 105 similarly-treated patients; those with low IL15 levels had 3.7-fold higher likelihood of developing significant cGVHD (P=0.001). Low IL15 was not associated with relapse; it trended to be associated with acute GVHD and was associated with low infection rates. In conclusion, low IL15 levels on day 7 are predictive of cGVHD, and thus could be useful in guiding preemptive therapy.
The Cancer and Leukemia Group B (CALGB) has been conducting a prospective cytogenetic companion study (CALGB 8461) to all CALGB treatment protocols for newly diagnosed adults with acute lymphoblastic ...leukemia (ALL). These protocols underwent a significant change in 1988 when a new intensive chemotherapy program was introduced (CALGB 8811). We asked whether karyotype continued to represent a significant prognostic factor in adult ALL patients after the change. A total of 256 patients had adequate pretreatment cytogenetic analyses: 67 before 1988 and 189 subsequently. The complete remission (CR) rate for the whole group was 80%. Patients with t(9;22), t(4;11), −7, or +8 had significantly lower probabilities of continuous CR and survival at 5 years (.11 and .12) than patients with a normal karyotype (.38 and .37) and patients with miscellaneous cytogenetic abnormalities (.52 and .49;P < .001 for each comparison). When analyzed by treatment period, the CR rate before CALGB 8811 was 63%; subsequently, it was 86% (P < .001). Patients with cytogenetic abnormalities other than t(9;22), t(4;11), −7, or +8 had better CR rates, disease-free survival (DFS), and survivals (P = .001,P = .04, and P = .004, respectively) after the change to the more intensive chemotherapy regimens. Patients with normal cytogenetics had improved CR rate but no improved DFS or survival, whereas no significant benefit for patients with t(9;22), t(4;11), −7, or +8 was seen. In a multivariate analysis, karyotype retained its prognostic significance for DFS but not for survival; it remained the most important factor for DFS. We conclude that cytogenetic analysis at diagnosis should be used to guide treatment decisions in adults with ALL.
Introduction
The objective of this pilot study was to determine the preliminary efficacy of a novel ophthalmic suspension containing povidone-iodine 0.4% and dexamethasone 0.1% in the treatment of ...adenoviral conjunctivitis.
Methods
A prospective, open-label, single-armed, phase II clinical trial in humans. Eligible patients with the clinical signs and symptoms of acute conjunctivitis who tested positive for adenoviral antigen by Rapid Pathogen Screening (RPS) Adeno Detector™ were enrolled in a single treatment arm consisting of a combination povidone-iodine 0.4%/dexamethasone 0.1% sterile ophthalmic suspension given four times daily for a minimum of 5 days. RPS Adeno Detector testing was performed at baseline and at each follow-up visit along with ocular fluid sampling by conjunctival swabs. Subsequent analysis performed on all swabs included both adenoviral titer by quantitative polymerase chain reaction (qPCR) and cell culture with confirmatory immunofluorescence (CC-IFA). The primary endpoint was clinical resolution of conjunctival injection and discharge. Secondary measures included reduction of qPCR titers and eradication of infectious virus as determined by CC-IFA.
Results
A total of nine eyes of six patients with clinical signs and symptoms of acute viral conjunctivitis and a positive RPS Adeno Detector test result were enrolled in the study. In eight/nine eyes enrolled in the study, clinical resolution was observed by day 3 or day 4. In six/six eyes with detectable adenovirus by qPCR, significant reduction in viral titer was seen by day 3, day 4, or day 5. In five/six eyes with infectious virus confirmed by CC-IFA at enrollment, elimination of infectivity was achieved by day 4 or day 5. One patient was lost to follow-up.
Conclusions
An ophthalmic suspension containing povidone-iodine 0.4% and dexamethasone 0.1% may be a useful agent in the treatment of acute RPS Adeno Detector-positive conjunctivitis. A further placebo-controlled study with a larger number of patients is warranted.
Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with ...increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.
We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses.
A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval CI, 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed.
Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)
PDF
