Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular ...filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics.
This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m
, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m
/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period.
Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA
was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m
, and historical eGFR slope -3.5 mL/min/1.73 m
/year. Compared with participants with albuminuria (
= 419), those with NDKF (
= 94) were significantly older (56 vs. 52 years), had lower HbA
(7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m
) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m
/year). These differences persisted when comparing groups with similar rates of historical eGFR loss.
PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.
Background Neutrophils are thought to play pivotal roles in eliminating pathogens, and they have also been implicated in end organ dysfunction associated with systemic inflammatory response syndrome ...(SIRS). Because modulating neutrophil survival and function has been proposed as a therapy for sepsis, it remains critical to determine under which circumstances modulating neutrophil function is efficacious. The aim of this study was to investigate whether sustaining the presence of neutrophils activated by hemorrhagic shock (HEM) would be disadvantageous during subsequent sepsis, ie, inflammation plus infection, or systemic inflammation without infection. Study Design Transgenic mice, overexpressing the antiapoptotic protein Bcl-2 in a myeloid restricted fashion (Bcl-2my ), and controls (C57) were subjected to HEM, followed 24 hours thereafter either by cecal ligation and puncture to induce sepsis, or by intraperitoneal injection of lipopolysaccharide to induce SIRS. Lung injury was assessed by bronchoalveolar lavage fluid protein and histology. Lung, plasma, and liver cytokines were quantified through CBA or ELISA. Results In sepsis, Bcl-2my had increased lung neutrophil and lower lung bacteria counts compared with C57. This translated into a marked early survival benefit for Bcl-2my . There were no differences between Bcl-2my and C57 with respect to the degree of lung injury or lung and plasma cytokines. In contrast, in SIRS, Bcl-2my exhibited markedly increased acute lung injury and lung and plasma cytokines when compared with C57. Bcl-2my also had a profound survival disadvantage. Conclusions Whether effects of prolonged survival of hemorrhage-primed neutrophils are beneficial or detrimental is determined by the nature of the second insult. During sepsis, prolonging neutrophil survival is beneficial, enhancing antimicrobial activity. Alternatively, during inflammation without infection, increased organ damage by long-lived neutrophils is detrimental.
The severe cognitive impairment that affects many of the elderly schizophrenic patients could represent the outcome of schizophrenia in old age for the very severe and chronically ill patients or may ...be the result of lengthy institutionalization and somatic treatment. Alternatively, it could be due to the presence of concurrent dementing disorders, such as Alzheimer's disease (AD) or multi-infarct dementia. Using an identical neuropathological protocol, brain specimens from schizophrenic patients who showed evidence of severe cognitive impairment were compared with 12 age-matched control cases and the same number of age-matched cases of neuropathologically confirmed patients with AD. Despite their relatively advanced age (mean age 77.1 years +/- 2.8), none of the schizophrenia cases showed sufficient degree of senile plaques and neurofibrillary tangle formations to confirm a diagnosis of AD. Other neurodegenerative disorders associated with dementia were also not identified. These studies suggest that alternative explanations need to be sought for the severe cognitive impairment commonly encountered in elderly schizophrenic patients.
Genetic heterogeneity contributes to clinical outcome and progression of most tumors, but little is known about allelic diversity for epigenetic compartments, and almost no data exist for acute ...myeloid leukemia (AML). We examined epigenetic heterogeneity as assessed by cytosine methylation within defined genomic loci with four CpGs (epialleles), somatic mutations, and transcriptomes of AML patient samples at serial time points. We observed that epigenetic allele burden is linked to inferior outcome and varies considerably during disease progression. Epigenetic and genetic allelic burden and patterning followed different patterns and kinetics during disease progression. We observed a subset of AMLs with high epiallele and low somatic mutation burden at diagnosis, a subset with high somatic mutation and lower epiallele burdens at diagnosis, and a subset with a mixed profile, suggesting distinct modes of tumor heterogeneity. Genes linked to promoter-associated epiallele shifts during tumor progression showed increased single-cell transcriptional variance and differential expression, suggesting functional impact on gene regulation. Thus, genetic and epigenetic heterogeneity can occur with distinct kinetics likely to affect the biological and clinical features of tumors.
The Unified Medical Language System (UMLS) combines many well-established authoritative medical informatics terminologies in one knowledge representation system. Such a resource is very valuable to ...the health care community and industry. However, the UMLS is very large and complex and poses serious comprehension problems for users and maintenance personnel. The authors present a representation to support the user's comprehension and navigation of the UMLS.
An object-oriented database (OODB) representation is used to represent the two major components of the UMLS-the Metathesaurus and the Semantic Network-as a unified system. The semantic types of the Semantic Network are modeled as semantic type classes. Intersection classes are defined to model concepts of multiple semantic types, which are removed from the semantic type classes.
The authors provide examples of how the intersection classes help expose omissions of concepts, highlight errors of semantic type classification, and uncover ambiguities of concepts in the UMLS. The resulting UMLS OODB schema is deeper and more refined than the Semantic Network, since intersection classes are introduced. The Metathesaurus is classified into more mutually exclusive, uniform sets of concepts. The schema improves the user's comprehension and navigation of the Metathesaurus.
The UMLS OODB schema supports the user's comprehension and navigation of the Metathesaurus. It also helps expose and resolve modeling problems in the UMLS.
This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal ...tandem duplication (ITD)–mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD–mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.
•Quizartinib at 60 mg/day (vs 30 mg/day) was associated with higher overall response, survival, and bridge to transplant.•The benefit-risk profile of quizartinib in relapsed or refractory FLT3-ITD–mutated AML warrants further evaluation of 60-mg once-daily dose.
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We measure CP-violating asymmetries of neutral charmed mesons in the modes D0 --> K- K+ and D0 --> pi- pi+ with the highest precision to date by using D0 --> K- pi+ decays to correct detector ...asymmetries. An analysis of 385.8 fb-1 of data collected with the BaBar detector yields values of aCP(KK) = (0.00 +/- 0.34 (stat.) +/- 0.13 (syst.))% and aCP(pipi) = (-0.24 +/- 0.52 (stat.) +/- 0.22 (syst.))%, which agree with Standard Model predictions.
Health care-associated infections (HAIs) result in increased patient morbidity and utilization of health care resources. Rates of HAI are increasing despite advances in health care technology. ...Limited antimicrobial agents and a dry drug pipeline make novel prevention efforts critical. Chlorhexidine, an antiseptic solution that has been used worldwide since the 1950s, is a safe and effective product with broad antiseptic activity. Novel uses of chlorhexidine-containing products are being implemented to promote antisepsis and prevent bacterial colonization and infection. We review some of the many infection control applications of chlorhexidine in the battle against HAI, such as general skin cleansing, skin decolonization, preoperative showering and bathing, vascular catheter site preparation, impregnated catheter site dressings, impregnated catheters, and oral decontamination. As mandatory public reporting and pay for performance force infection control issues to the forefront, chlorhexidine-containing products may provide a vast armamentarium for the control and prevention of HAI.
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