Link among apolipoprotein E E4, gait, and cognition in neurodegenerative diseases: ONDRI study.

INTRODUCTION: Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases. METHODS: Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance. RESULTS: APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non-APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain-specific poorer cognitive performances, mediated by smaller gray matter volume. DISCUSSION: Gait slowness in APOE E4 carriers with neurodegenerative diseases may indicate extensive gray matter changes associated with poor cognition. HIGHLIGHTS: APOE E4 and slow gait are risk factors for cognitive decline in neurodegenerative diseases. Slow gait and smaller gray matter volumes are associated, independently of APOE E4. Worse cognition in APOE E4 carriers with slow gait is explained by smaller GM volume. Gait slowness in APOE E4 carriers indicates poorer cognition-related brain changes.

Purple urine in a patient with UTI and constipation.

Purple urine bag syndrome (PUBS) is a visually striking and a rare side effect in a patient with urinary tract infection where urine in the catheter bags and tubing turn purple. The urine in PUBS gets its color from the combination of two pigments, indirubin and indigo, which are breakdown products of tryptophan. The most important risk factors include long-term catheterization, female gender, chronic constipation, old age and being bed bound. Here, we present a case of PUBS in an elderly female with a history of bladder cancer that needed catheterization along with constipation.

Use of Hepatic Artery Infusion Pumps in the Treatment of Hepatic Metastases.

The first trials of hepatic artery infusion pump (HAIP) chemotherapy occurred in the 1990s. The high percentage of recurrent disease after curative resection of colon cancer and perioperative systemic chemotherapy has renewed.

Multiomics Analysis Provides Insight into the Laboratory Evolution of Escherichia coli toward the Metabolic Usage of Fluorinated Indoles.

Organofluorine compounds are known to be toxic to a broad variety of living beings in different habitats, and chemical fluorination has been historically exploited by mankind for the development of therapeutic drugs or agricultural pesticides. On the other hand, several studies so far have demonstrated that, under appropriate conditions, living systems (in particular bacteria) can tolerate the presence of fluorinated molecules (e.g., amino acids analogues) within their metabolism and even repurpose them as alternative building blocks for the synthesis of cellular macromolecules such as proteins. Understanding the molecular mechanism behind these phenomena would greatly advance approaches to the biotechnological synthesis of recombinant proteins and peptide drugs. However, information about the metabolic effects of long-term exposure of living cells to fluorinated amino acids remains scarce. Hereby, we report the long-term propagation of Escherichia coli (E. coli) in an artificially fluorinated habitat that yielded two strains naturally adapted to live on fluorinated amino acids. In particular, we applied selective pressure to force a tryptophan (Trp)-auxotrophic strain to use either 4- or 5-fluoroindole as essential precursors for the in situ synthesis of Trp analogues, followed by their incorporation in the cellular proteome. We found that full adaptation to both fluorinated Trp analogues requires a low number of genetic mutations but is accompanied by large rearrangements in regulatory networks, membrane integrity, and quality control of protein folding. These findings highlight the cellular mechanisms behind the adaptation to unnatural amino acids and provide the molecular foundation for bioengineering of novel microbial strains for synthetic biology and biotechnology.

Clinical characteristics and outcomes after bowel surgery and ostomy formation at the time of debulking surgery for advanced-stage epithelial ovarian carcinoma.

OBJECTIVE: There are limited data on clinical outcomes of patients with advanced-stage epithelial ovarian cancer who require ostomy formation at the time of either primary cytoreductive surgery or interval cytoreductive surgery. The objective of this study was to evaluate patients undergoing bowel surgery and ostomy formation after primary or interval surgery. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIC-IV epithelial ovarian cancer who underwent cytoreductive surgery between January 2010 and December 2014 were identified retrospectively. Patients with non-epithelial histology, low-grade serous histology or incomplete medical records were excluded. Demographic and clinical data were collected and analyzed. Age, stage, co-morbidity index, pre-operative CA125, pre-operative albumin, and Aletti surgical complexity score were included in a multivariable logistic regression model to assess independent associations with ostomy formation. RESULTS: A total of 554 patients were included in the study. Of these, 261 (47%) underwent primary cytoreduction and 293 (53%) underwent interval cytoreduction. Patients undergoing primary surgery were more likely to undergo bowel resection, compared with interval surgery patients (37.2% vs 14%, p<0.001). Of the 139 (25.1%) patients who underwent bowel surgery, 25 (18%) underwent ostomy formation (11 ileostomies and 14 colostomies). Rates of ostomy formation were similar between the groups (6.1% primary vs 3.1% interval, p=0.10). Patients undergoing ostomy formation were more likely to have longer mean operative time (335 vs 229 min, p<0.001) and undergo small and large bowel resections at the time of cytoreductive surgery (44% vs 14%, p<0.001). Multivariate analysis revealed that a high surgical complexity score was associated with ostomy formation. Of the patients who underwent ostomy formation, 13 (43.3%) underwent stoma reversal including 11 ileostomies and two colostomies. Median time to ostomy reversal was 7 months. CONCLUSION: Bowel surgery is more common among patients undergoing primary surgery as compared with interval surgery, but this does not result in an increased risk of ostomy formation.

Deciphering the Fluorine Code-The Many Hats Fluorine Wears in a Protein Environment.

Deciphering the fluorine code is how we describe not only the focus of this Account, but also the systematic approach to studying the impact of fluorine's incorporation on the properties of peptides and proteins used by our groups and others. The introduction of fluorine has been shown to impart favorable, but seldom predictable, properties to peptides and proteins, but up until about two decades ago the outcomes of fluorine modification of peptides and proteins were largely left to chance. Driven by the motivation to extend the application of the unique properties of the element fluorine from medicinal and agro chemistry to peptide and protein engineering we have established extensive research programs that enable the systematic investigation of effects that accompany the introduction of fluorine into this class of biopolymers. The introduction of fluorine into amino acids offers a universe of options for modifications with regard to number and position of fluorine substituents in the amino acid side chain. Moreover, it is important to emphasize that the consequences of incorporating the C-F bond into a biopolymer can be attributed to two distinct yet related phenomena: (i) the fluorine substituent can directly engage in intermolecular interactions with its environment and/or (ii) the other functional groups present in the molecule can be influenced by the electron withdrawing nature of this element (intramolecular) and in turn interact differently with their immediate environment (intermolecular). Based on our studies, we have shown that a change in number and/or position of as subtle as one single fluorine substituent has the power to considerably modify key properties of amino acids such as hydrophobicity, polarity, and secondary structure propensity. These properties are crucial factors in peptide and protein engineering, and thus, fluorinated amino acids can be applied to fine-tune properties such as protein folding, proteolytic stability, and protein-protein interactions provided we understand and become able to predict the outcome of a fluorine substitution in this context. With this Account, we attempt to analyze information we gained from our recent projects on how the nature of the fluorine atom and C-F bond influence four key properties of peptides and proteins: peptide folding, protein-protein interactions, ribosomal translation, and protease stability. These results impressively show why the introduction of fluorine creates a new class of amino acids with a repertoire of functionalities that is unique to the world of proteins and in some cases orthogonal to the set of canonical and natural amino acids. Our concluding statements aim to offer a few conserved design principles that have emerged from systematic studies over the last two decades; in this way, we hope to advance the field of peptide and protein engineering based on the judicious introduction of fluorinated building blocks.

Clinical Presentation of Complete Hydatidiform Mole and Partial Hydatidiform Mole at a Regional Trophoblastic Disease Center in the United States Over the Past 2 Decades.

OBJECTIVE: The aim of this study was to compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among cases of complete mole (CM) and partial mole (PM) from 1994 to 2013. METHODS: This study included all cases of patients with CM and PM from our trophoblastic disease center between 1994 and 2013. Their clinical and pathologic reports were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin levels, and the rate of progression to GTN were compared. RESULTS: The median gestational age at evacuation was 9 weeks for CM and 12 weeks for PM (P < 0.001). Patients with PM had lower pre-evacuation serum human chorionic gonadotropin levels (P < 0.001), and they were also less likely to present with vaginal bleeding (P < 0.001), biochemical hyperthyroidism (P < 0.001), anemia (P < 0.001), uterine size greater than dates (P < 0.001), and hyperemesis (P = 0.002). Consequently, patients with PM were less likely to have been clinically diagnosed as moles compared with CM prior to uterine evacuation (P < 0.001). The development of GTN occurred in 17.7% (33/186) and 4.1% (7/169) of patients with CM and PM, respectively (P < 0.001). CONCLUSIONS: This study indicates that, at our center over the past 20 years, both CM and PM were usually evacuated in the first trimester of pregnancy. Because CM more commonly presents with the signs and symptoms of molar disease than PM, CM is more commonly diagnosed prior to evacuation.

Fluorine teams up with water to restore inhibitor activity to mutant BPTI.

Introducing fluorine into molecules has a wide range of effects on their physicochemical properties, often desirable but in most cases unpredictable. The fluorine atom imparts the C-F bond with low polarizability and high polarity, and significantly affects the behavior of neighboring functional groups, in a covalent or noncovalent manner. Here, we report that fluorine, present in the form of a single fluoroalkyl amino acid side chain in the P1 position of the well-characterized serine-protease inhibitor BPTI, can fully restore inhibitor activity to a mutant that contains the corresponding hydrocarbon side chain at the same site. High resolution crystal structures were obtained for four BPTI variants in complex with bovine ß-trypsin, revealing changes in the stoichiometry and dynamics of water molecules in the S1 subsite. These results demonstrate that the introduction of fluorine into a protein environment can result in "chemical complementation" that has a significantly favorable impact on protein-protein interactions.

A computerized treatment algorithm trial to optimize mineral metabolism in ESRD.

BACKGROUND AND OBJECTIVES: Achievement of mineral targets in patients receiving dialysis remains challenging. This study sought to evaluate outcomes for phosphorus, calcium, and parathyroid hormone when a dialysis population was switched from a predominantly active vitamin D analogue treatment regimen to a computerized algorithm incorporating both cinacalcet and active vitamin D as potential first-line therapies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This longitudinal prospective trial enrolled 92 patients undergoing maintenance hemodialysis. Baseline measures (the average of the 3 months before computerized algorithm implementation) were compared with the proportion of patients achieving the prespecified targets at 6 and 12 months. RESULTS: After 6 months there was a statistically significant improvement in the percentage of patients achieving the primary and secondary phosphorus targets (primary: phosphorus ≤ 5.5 mg/dl, increase from 41% to 75%, P<0.001; secondary: phosphorus 3.0-4.6 mg/dl, increase from 16% to 38%; P=0.005). These improvements were sustained at 12 months. There was a statistically significant improvement in the percentage of patients achieving all three prespecified secondary endpoints (an increase from 12.8% to 25.6% at 12 months; P=0.04); however, this was mainly driven by improved phosphorus control. The proportion of patients achieving the primary or secondary parathyroid hormone targets did not improve. CONCLUSIONS: A greater proportion of dialysis patients achieved improved phosphorus but not parathyroid hormone control by switching from a predominantly active vitamin D analogue-based treatment regimen for mineral and bone disorder to a computer-driven algorithm that incorporated cinacalcet and low-dose active vitamin D analogues as first-line therapy.

The relative importance of provider, program, school, and community predictors of the implementation quality of school-based prevention programs.

Previous research has demonstrated the importance of a variety of factors on the implementation of school-based prevention programs, specifically characteristics of program providers, program structure, school climate, and school and community structure. The current study expands this research by examining the potential relationships between all of these factors and implementation quality in a series of multilevel models. Using data from a nationally representative sample of 3,730 program providers surveyed in 544 schools, it was found that program structure characteristics were of greater importance in the prediction of high quality implementation than were characteristics of the program providers, school climate, and school and community structure. Implications of these findings are discussed.

Do predictors of the implementation quality of school-based prevention programs differ by program type?

Research has indicated that the effectiveness of school-based prevention programs is affected by the implementation quality of these programs. As the importance of implementation has become clear, researchers have identified factors that appear to be related to implementation quality, including local program selection and training, integration into school operations, organizational capacity, principal support, and program standardization; however, it is unknown whether the impact of these factors differs by program type. Data from a nationally representative sample of 544 schools are used to create structural equation models representing hypothesized relationships among school and program factors and implementation quality, controlling for exogenous community factors. The relative importance of these factors for individual-level programs, such as behavior modification and counseling programs, versus environmental-level programs, such as improvements to classroom management or school planning and climate change programs, is the focus of this study. Implications for the implementation of school-based prevention program are discussed.

School predictors of the intensity of implementation of school-based prevention programs: results from a national study.

Research has indicated that the effectiveness of school-based prevention programs is affected by the implementation quality of these programs. As the importance of implementation has become clearer, researchers have begun to examine factors that appear to be related to implementation quality. Data from a nationally representative sample of 544 schools were used to examine structural equation models representing hypothesized relationships among school and program factors and implementation intensity, controlling for exogenous community factors. Significant relationships were found between implementation intensity and several school and program factors, including local program development process, integration into school operations, organizational capacity, principal support, and standardization. Implications of these findings are discussed.

Implementation issues for consumer-directed programs: comparing views of policy experts, consumers, and representatives.

An increasing number of aging community providers and consumers support consumer-direction (CD) in long-term care services. In regard to devolution, consumer-direction goes beyond the usual approach of shifting responsibilities from the federal government to state governments to bring programs "closer to the people." Consumer-direction goes even further by placing resources directly in the hands of consumers. Yet, many questions remain unanswered regarding how to implement CD personal assistance services in general, and especially for older persons. This article describes the importance of examining views from multiple key stakeholders involved in implementing CD programs. We report on three background studies that have informed the Cash and Counseling Demonstration and Evaluation (CCDE) design and implementation-policy expert interviews as well as surveys and focus groups with consumers and representatives. As a fourth data source, we drew upon experiences in designing the CCDE and initial results from the first year of implementation. Each of the three studies on its own provided essential information for planning the CCDE. However, when we examined the studies together, and added CCDE design and implementation experiences, views expressed by the different stakeholders formed a type of multi-perspective "dialogue" that expanded our knowledge about implementing CD services. We hope this increased knowledge will help expand the availability of such services for consumers of any age who want to direct their own care.