snu-aidas/HVMap-dataset huggingface dataset:
Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.

OBJECTIVE To evaluate the safety, tolerability, and amyloid beta (Abeta) response to the gamma-secretase inhibitor LY450139 in Alzheimer disease. DESIGN Multicenter, randomized, double-blind, dose-escalation, placebo-controlled trial. SETTING Community-based clinical research centers. Patients Fifty-one individuals with mild to moderate Alzheimer disease were randomized to receive placebo (n=15) or LY450139 (100 mg [n=22] or 140 mg [n=14]), with 43 completing the treatment phase. Intervention The LY450139 groups received 60 mg/d for 2 weeks, then 100 mg/d for 6 weeks, and then either 100 or 140 mg/d for 6 additional weeks. MAIN OUTCOME MEASURES Primary outcome measures were adverse events, plasma and cerebrospinal fluid Abeta levels, vital signs, electrocardiographic data, and laboratory safety test results. Secondary outcome measures included the Alzheimer's Disease Assessment Scale cognitive subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living Scale. RESULTS Group differences were seen in skin and subcutaneous tissue concerns (P=.05), including 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse event-related discontinuations, including 1 transient bowel obstruction. The plasma Abeta(40) concentration was reduced by 58.2% for the 100-mg group and 64.6% for the 140-mg group (P<.001). No significant reduction was seen in cerebrospinal fluid Abeta levels. No group differences were seen in cognitive or functional measures. CONCLUSIONS LY450139 was generally well tolerated at doses of up to 140 mg/d for 14 weeks, with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Abeta concentrations were consistent with inhibition of gamma-secretase. Trial Registration clinicaltrials.gov Identifier: NCT00244322.
Reduction in skin grafting after the introduction of hydrofiber dressings in partial thickness burns: a comparison between a hydrofiber and silver sulphadiazine.

AIM/PURPOSE The aim of this study was to compare clinical outcome of children with scald burns treated with a hydrofiber dressing (Aquacel(®), Convatec Inc.) with the former standard of care with silver sulfadiazine (Flammazine(®); Solvay Pharmaceuticals), considering surgical intervention and length of stay (LOS). METHODS A retrospective study of all consecutive children from zero to four years with primary scald burns up to 10% admitted to the Burn Centre of the Maasstad Hospital Rotterdam between January 1987 and January 2010 were reviewed. For data collection a prospective computerized database was used. For comparison the study period was divided into two periods representing the period before and after the introduction of the hydrofiber dressing (HFD), respectively 1987-1999 (period 1) and 1999-2010 (period 2). RESULTS Over the whole study period 27.3% of 502 patients treated with silver sulfadiazine (Ag-SD) underwent surgery, while before the introduction of HFD 30.5% of 338 Ag-SD treated patients were operated upon. After the introduction of the HFD 20.7% of 164 patients treated with Ag-SD eventually underwent skin grafting, a significant difference with the 11.6% of 302 patients whose wounds were dressed with HFD (p<0.01). CONCLUSIONS Compared to silver sulfadiazine treatment a reduced number of surgical interventions was observed in mixed partial thickness scald burns up to 10% TBSA burned in children aged 0-4 years after the introduction of hydrofiber dressings. The mode of treatment with this wound dressing also limited hospital length of stay.
Techniques and probes for the study of Xenopus tropicalis development.

The frog Xenopus laevis has provided significant insights into developmental and cellular processes. However, X. laevis has an allotetraploid genome precluding its use in forward genetic analysis. Genetic analysis may be applicable to Xenopus (Silurana) tropicalis, which has a diploid genome and a shorter generation time. Here, we show that many tools for the study of X. laevis development can be applied to X. tropicalis. By using the developmental staging system of Nieuwkoop and Faber, we find that X. tropicalis embryos develop at similar rates to X. laevis, although they tolerate a narrower range of temperatures. We also show that many of the analytical reagents available for X. laevis can be effectively transferred to X. tropicalis. The X. laevis protocol for whole-mount in situ hybridization to mRNA transcripts can be successfully applied to X. tropicalis without alteration. Additionally, X. laevis probes often work in X. tropicalis--alleviating the immediate need to clone the X. tropicalis orthologs before initiating developmental studies. Antibodies that react against X. laevis proteins can effectively detect the X. tropicalis protein by using established immunohistochemistry procedures. Antisense morpholino oligonucleotides (MOs) offer a new alternative to study loss of gene activity during development. We show that MOs function in X. tropicalis. Finally, X. tropicalis offers the possibility for forward genetics and genomic analysis.
Effect of losartan on ambulatory short-term blood pressure variability and cardiovascular remodeling in hypertensive patients on hemodialysis.

OBJECTIVE Previous studies have shown increases in ambulatory short-term blood pressure (BP) variability to be related to cardiovascular disease. In this study, we examined whether an angiotensin II type 1 receptor blocker losartan would improve ambulatory short-term BP variability in hypertensive patients on hemodialysis. METHODS Forty hypertensive patients on hemodialysis therapy were randomly assigned to the losartan treatment group (n=20) or the control treatment group (n=20). At baseline and 6 and 12 months after the treatment, 24-h ambulatory BP monitoring was performed. Echocardiography and measurements of brachial-ankle pulse wave velocity (baPWV) and biochemical parameters were also performed before and after therapy. RESULTS After 6- and 12-months of treatment, nighttime short-term BP variability, assessed on the basis of the coefficient of variation of ambulatory BP, was significantly decreased in the losartan group, but remained unchanged in the control group. Compared with the control group, losartan significantly decreased left ventricular mass index (LVMI), baPWV, and the plasma levels of brain natriuretic peptide and advanced glycation end products (AGE). Furthermore, multiple regression analysis showed significant correlations between changes in LVMI and changes in nighttime short-term BP variability, as well as between changes in LVMI and changes in the plasma levels of AGE. CONCLUSION These results suggest that losartan is beneficial for the suppression of pathological cardiovascular remodeling though its inhibitory effect on ambulatory short-term BP variability during nighttime.
The cost of providing comprehensive HIV treatment in PEPFAR-supported programs.

BACKGROUND PEPFAR, national governments, and other stakeholders are investing unprecedented resources to provide HIV treatment in developing countries. This study reports empirical data on costs and cost trends in a large sample of HIV treatment sites. DESIGN In 2006-2007, we conducted cost analyses at 43 PEPFAR-supported outpatient clinics providing free comprehensive HIV treatment in Botswana, Ethiopia, Nigeria, Uganda, and Vietnam. METHODS We collected data on HIV treatment costs over consecutive 6-month periods starting from scale-up of dedicated HIV treatment services at each site. The study included all patients receiving HIV treatment and care at study sites [62,512 antiretroviral therapy (ART) and 44,394 pre-ART patients]. Outcomes were costs per patient and total program costs, subdivided by major cost categories. RESULTS Median annual economic costs were US$ 202 (2009 USD) for pre-ART patients and US$ 880 for ART patients. Excluding antiretrovirals, per patient ART costs were US$ 298. Care for newly initiated ART patients cost 15-20% more than for established patients. Per patient costs dropped rapidly as sites matured, with per patient ART costs dropping 46.8% between first and second 6-month periods after the beginning of scale-up, and an additional 29.5% the following year. PEPFAR provided 79.4% of funding for service delivery, and national governments provided 15.2%. CONCLUSION Treatment costs vary widely between sites, and high early costs drop rapidly as sites mature. Treatment costs vary between countries and respond to changes in antiretroviral regimen costs and the package of services. Whereas cost reductions may allow near-term program growth, programs need to weigh the trade-off between improving services for current patients and expanding coverage to new patients.
Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation.

Five strains of scrapie agent were used as intracerebral inocula for 2 inbred mouse strains, C57BL and VM, and their F1 cross. The degree of vacuolation in specified regions of the brain, and the relative distribution of this damage in 9 regions represented as a “lesion profile”, was different for each agent. Any of the 5 scrapie agents could be distinguished from the others with a very high degree of reliability solely on the basis of these histological parameters, using either strain of mouse. The lesion profile was unaffected by the dose of the agent, using doses of ME7 agent ranging over 6 orders of magnitude in C57BL mice. The genotype of mouse had a marked effect on the overall degree of vacuolation and on the shape of the lesion profile: these effects were more profound with some agents than others. In certain areas of the brain, depending upon the strain of agent used, the (C57BL × VM)F1 cross was found to have either significantly more or significantly less vacuolation than either parental genotype. The genetic control of the lesion profile was found to be too complex for more detailed analysis in these data.
Cyclin A2 is an RNA binding protein that controls Mre11 mRNA translation

Cyclin A2 activates the cyclin-dependent kinases Cdk1 and Cdk2 and is expressed at elevated levels from S phase until early mitosis. We found that mutant mice that cannot elevate cyclin A2 are chromosomally unstable and tumor-prone. Underlying the chromosomal instability is a failure to up-regulate the meiotic recombination 11 (Mre11) nuclease in S phase, which leads to impaired resolution of stalled replication forks, insufficient repair of double-stranded DNA breaks, and improper segregation of sister chromosomes. Unexpectedly, cyclin A2 controlled Mre11 abundance through a C-terminal RNA binding domain that selectively and directly binds Mre11 transcripts to mediate polysome loading and translation. These data reveal cyclin A2 as a mechanistically diverse regulator of DNA replication combining multifaceted kinase-dependent functions with a kinase-independent, RNA binding–dependent role that ensures adequate repair of common replication errors.
Cluster sampling to assess immunization coverage: a review of experience with a simplified sampling method.

The Expanded Program on Immunization (EPI) is using a simplified cluster sampling method, based on the random selection of 210 children in 30 clusters of 7 children each, to estimate immunization coverage levels. This article analyzes the results of this method in actual and computer simulated surveys. Results from 60 actual surveys conducted in 25 countries were available for analysis, for a total of 446 sample estimations of immunization coverage. 83% of the sample results had 95% confidence limits within + or - 10%, and none of the surveys had 95% confidence limits exceeding + or - 13%. In addition, 12 hypothetical population strata with immunization coverage rates ranging from 10%-99% were established for the purposes of computer simulation, and 10 hypothetical communities were established by allocating to them various proportions of each of the strata. These simulated surveys also supported the validity of the EPI method: over 95% of the results were less than + or - 10% from the actual population mean. The precision of this method, as estimated from the results of both actual and simulated surveys, is considered satisfactory for the requirements of the EPI. Among the actual surveys, the proportion of results whose confidence limits exceeded + or - 10% was greatest (50%) when immunization coverage in the sample was 45%-54%.
Materials and Methods Figs. S1 to S15 References Supporting Online Materials

Endosomal Toll-like receptors (TLRs) 7 and 9 recognize viral pathogens and induce signals leading to the activation of nuclear factor κB (NF-κB)-dependent proinflammatory cytokines and interferon regulatory factor 7 (IRF7)-dependent type I interferons (IFNs). Recognition of viral nucleic acids by TLR9 requires its cleavage in the endolysosomal compartment. Here, we show that TLR9 signals leading to the activation of type I IFN, but not proinflammatory cytokine genes, require TLR9 trafficking from endosomes to a specialized lysosome-related organelle. Furthermore, we identify adapter protein-3 as the protein complex responsible for the trafficking of TLR9 to this subcellular compartment. Our results reveal an intracellular mechanism for bifurcation of TLR9 signals by selective receptor trafficking within the endosomal system.
Structural trends in the aging femoral neck and proximal shaft: analysis of the Third National Health and Nutrition Examination Survey dual-energy X-ray absorptiometry data.

Hip scans of U.S. adults aged 20-99 years acquired in the Third National Health and Nutrition Examination Survey (NHANES III) using dual-energy X-ray absorptiometry (DXA) were analyzed with a structural analysis program. The program analyzes narrow (3 mm wide) regions at specific locations across the proximal femur to measure bone mineral density (BMD) as well as cross-sectional areas (CSAs), cross-sectional moments of inertia (CSMI), section moduli, subperiosteal widths, and estimated mean cortical thickness. Measurements are reported here on a non-Hispanic white subgroup of 2,719 men and 2,904 women for a cortical region across the proximal shaft 2 cm distal to the lesser trochanter and a mixed cortical/trabecular region across the narrowest point of the femoral neck. Apparent age trends in BMD and section modulus were studied for both regions by sex after correction for body weight. The BMD decline with age in the narrow neck was similar to that seen in the Hologic neck region; BMD in the shaft also declined, although at a slower rate. A different pattern was seen for section modulus; furthermore, this pattern depended on sex. Specifically, the section modulus at both the narrow neck and the shaft regions remains nearly constant until the fifth decade in females and then declined at a slower rate than BMD. In males, the narrow neck section modulus declined modestly until the fifth decade and then remained nearly constant whereas the shaft section modulus was static until the fifth decade and then increased steadily. The apparent mechanism for the discord between BMD and section modulus is a linear expansion in subperiosteal diameter in both sexes and in both regions, which tends to mechanically offset net loss of medullary bone mass. These results suggest that aging loss of bone mass in the hip does not necessarily mean reduced mechanical strength. Femoral neck section moduli in the elderly are on the average within 14% of young values in females and within 6% in males.
A negative staining method for high resolution electron microscopy of viruses.

Abstract A simple technique has been developed for the study of the external form and structure of virus particles. High contrast with good preservation is obtained by mixing virus preparations with 1% phosphotungstic acid adjusted to pH 7.5 and spraying directly onto electron microscope supporting films made from evaporated carbon. The application of the technique to tobacco mosaic virus and turnip yellow mosaic virus is described. Structural details suggested by X-ray diffraction methods have been resolved.
Long noncoding RNA as modular scaffold of histone modification complexes

Long intergenic noncoding RNAs (lincRNAs) regulate chromatin states and epigenetic inheritance. Here, we show that the lincRNA HOTAIR serves as a scaffold for at least two distinct histone modification complexes. A 5' domain of HOTAIR binds polycomb repressive complex 2 (PRC2), whereas a 3' domain of HOTAIR binds the LSD1/CoREST/REST complex. The ability to tether two distinct complexes enables RNA-mediated assembly of PRC2 and LSD1 and coordinates targeting of PRC2 and LSD1 to chromatin for coupled histone H3 lysine 27 methylation and lysine 4 demethylation. Our results suggest that lincRNAs may serve as scaffolds by providing binding surfaces to assemble select histone modification enzymes, thereby specifying the pattern of histone modifications on target genes.
Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.

BACKGROUND The amyloid fibril deposits that cause systemic amyloidosis always contain the nonfibrillar normal plasma protein, serum amyloid P component (SAP). The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) efficiently depletes SAP from the plasma but leaves some SAP in amyloid deposits that can be specifically targeted by therapeutic IgG anti-SAP antibodies. In murine amyloid A type amyloidosis, the binding of these antibodies to the residual SAP in amyloid deposits activates complement and triggers the rapid clearance of amyloid by macrophage-derived multinucleated giant cells. METHODS We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored. RESULTS There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed. CONCLUSIONS Treatment with CPHPC followed by an anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01777243.).
LPA Gene, Ethnicity, and Cardiovascular Events

Background: The relationship of LPA single nucleotide polymorphisms (SNPs), apolipoprotein(a) isoforms, and lipoprotein(a) [Lp(a)] levels with major adverse cardiovascular events (MACE) in different ethnic groups is not well known. Methods: LPA SNPs, apolipoprotein(a) isoforms, Lp(a), and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levels were measured in 1792 black, 1030 white, and 597 Hispanic subjects enrolled in the Dallas Heart Study. Their interdependent relationships and prospective association with MACE after median 9.5-year follow-up were determined. Results: LPA SNP rs3798220 was most prevalent in Hispanics (42.38%), rs10455872 in whites (14.27%), and rs9457951 in blacks (32.92%). The correlation of each of these SNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions among ethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed that quartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (95% confidence interval) for time to MACE of 2.35 (1.50–3.69, P<0.001) and 1.89 (1.26–2.84, P=0.003), respectively, versus quartile 1. Addition of the major apolipoprotein(a) isoform and the 3 LPA SNPs to these models attenuated the risk, but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating time to MACE in specific ethnic groups, Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform was an inverse predictor in blacks, the size of the major apolipoprotein(a) isoform was an inverse predictor in whites, and OxPL-apoB was a positive predictor in Hispanics. Conclusions: The prevalence and association of LPA SNPs with size of apolipoprotein(a) isoforms, Lp(a), and OxPL-apoB levels are highly variable and ethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoB levels, despite significant ethnic differences in LPA genetic markers.
The role of alcohol in the Russian mortality crisis.

AIMS Alcohol is believed to be an important factor behind the sharp rise in mortality during the period 1990-94 in Russia. However, the rise in the standard alcohol consumption proxy does not seem to be sufficient to explain all the increase in mortality. This study adopts a novel approach to exploring the role of the alcohol factor in the increased mortality by investigating whether the mismatch between trends in mortality and recorded alcohol consumption is due to an underestimation of the consumption increase. DESIGN AND MEASUREMENTS First, the alcohol effect on the male accident rate was estimated using data for the period 1959-89. Next, the estimated alcohol effect and the observed accident mortality rate for the period 1990-98 were used to backcast alcohol consumption during that period. Thirdly, the backcasted alcohol series was used to predict trajectories in alcohol poisoning mortality, the homicide rate and all-cause mortality during the period 1990-98. FINDINGS There was a markedly stronger increase in the backcasted consumption proxy than in the standard alcohol consumption proxy during the period 1990-98. There was a substantial gap between the observed mortality rates and the rates predicted from the standard alcohol consumption proxy, whereas the predictions from the backcasted alcohol proxy were much closer to the target. CONCLUSIONS Much of the rise in Russian mortality in 1990-94 appears to have been due to the increase in population drinking, but this increase is grossly underestimated by the commonly used consumption proxy combining alcohol sales, estimation of illicit alcohol production and proportion of alcohol-positive violent deaths.