Multiple Organ Dysfunction in Older Major Trauma Critical Care Patients: A Multicenter Prospective Observational Study.

The objective was to explore the characteristics and outcomes of multiple organ dysfunction syndrome (MODS) in older trauma patients. Background: Severely injured older people present an increasing challenge for trauma systems. Recovery for those who require critical care may be complicated by MODS. In older trauma patients, MODS may not be predictable based on chronological age alone and factors associated with its development and resolution are unclear. Methods: Consecutive adult patients (aged ≥16 years) admitted to 4 level 1 major trauma center critical care units were enrolled and reviewed daily until discharge or death. MODS was defined by a daily total sequential organ failure assessment score of >5. Results: One thousand three hundred sixteen patients were enrolled over 18 months and one-third (434) were aged ≥65 years. Incidence of MODS was high for both age groups (<65 years: 64%, ≥65 years: 70%). There were few differences in severity, patterns, and duration of MODS between cohorts, except for older traumatic brain injury (TBI) patients who experienced a prolonged course of MODS recovery (TBI: 9 days vs no TBI: 5 days, P < 0.01). Frailty rather than chronological age had a strong association with MODS development (odds ratio [OR], 6.9; 95% confidence intervals [CI], 3.0-12.4; P < 0.001) and MODS mortality (OR, 2.1; 95% CI, 1.31-3.38; P = 0.02). Critical care resource utilization was not increased in older patients, but MODS had a substantial impact on mortality (<65 years: 17%; ≥65 years: 28%). The majority of older patients who did not develop MODS survived and had favorable discharge outcomes (home discharge ≥65 years NoMODS: 50% vs MODS: 15%; P < 0.01). Conclusions: Frailty rather than chronological age appears to drive MODS development, recovery, and outcome in older cohorts. Early identification of frailty after trauma may help to predict MODS and plan care in older trauma.

Effect of captopril on post-infarction remodelling visualized by light sheet microscopy and echocardiography.

Angiotensin converting enzyme inhibitors, among them captopril, improve survival following myocardial infarction (MI). The mechanisms of captopril action remain inadequately understood due to its diverse effects on multiple signalling pathways at different time periods following MI. Here we aimed to establish the role of captopril in late-stage post-MI remodelling. Left anterior descending artery (LAD) ligation or sham surgery was carried out in male C57BL/6J mice. Seven days post-surgery LAD ligated mice were allocated to daily vehicle or captopril treatment continued over four weeks. To provide comprehensive characterization of the changes in mouse heart following MI a 3D light sheet imaging method was established together with automated image analysis workflow. The combination of echocardiography and light sheet imaging enabled to assess cardiac function and the underlying morphological changes. We show that delayed captopril treatment does not affect infarct size but prevents left ventricle dilation and hypertrophy, resulting in improved ejection fraction. Quantification of lectin perfused blood vessels showed improved vascular density in the infarct border zone in captopril treated mice in comparison to vehicle dosed control mice. These results validate the applicability of combined echocardiographic and light sheet assessment of drug mode of action in preclinical cardiovascular research.

Graft survival of fourth-time renal transplant recipients is similar to third-time recipients: A SRTR database analysis.

BACKGROUND: Candidates for repeat kidney transplant (KT) have increased. While graft and patient survival are inferior to primary KT, second and third KTs improve patient survival over dialysis. Little is known about the outcomes after fourth KTs. METHODS: We retrospectively compared characteristics of third and fourth KTs in the SRTR. Factors associated with graft survival in third vs fourth KT and patient survival of fourth KT vs patients waitlisted for a 4th KT were assessed by Cox regression and multivariable linear regression analysis. RESULTS: There were 3055 third- and fourth-time KTs performed in the United States. Fourth-time graft survival was not significantly different from third-time transplants (HR 1.06, P = .653). Patients who received a fourth KT have a significant survival advantage compared with patients who remained on the waitlist for a fourth KT (HR = 0.53, P = .006). CONCLUSIONS: Graft and patient survival of fourth KTs are comparable to third KTs, but inferior to first and second KTs in terms of graft and patient survival. Recipients of fourth KT have had an increased life expectancy compared with patients waitlisted for a fourth KT.

A combination of transanal minimally invasive surgery and transanal technique to facilitate suturing during transanal minimally invasive surgery.

Transanal minimally invasive surgery (TAMIS) is an effective option for the local excision of benign, non-invasive rectal lesions, or selected early stage rectal cancers. However, the suturing encountered in TAMIS remains technically challenging. A combination of TAMIS and transanal approach to suturing is demonstrated to address this challenge. A 64-year-old female with a T1N0 adenocarcinoma located in the anterior mid-rectum underwent TAMIS for resection of the lesion. Total operative time was 91 minutes. Free peritoneal defect was closed in two layers. The patient was discharged on postoperative day 1. Final pathology revealed a 0.7 cm T1 well-differentiated adenocarcinoma 0.8 cm from the closest resection margin. The patient remains free of systemic or local recurrence at 24 months. TAMIS is a safe and effective option for removal of benign rectal lesions or selected low grade T1 adenocarcinomas of the rectum. A hybrid TAMIS and transanal approach to suturing may often easily address the technical challenge of pure laparoscopic suturing in TAMIS.

Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm.

Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.

Large-corpus phoneme and word recognition and the generality of lexical context in CVC word perception.

PURPOSE: Speech recognition may be analyzed in terms of recognition probabilities for perceptual wholes (e.g., words) and parts (e.g., phonemes), where j or the j-factor reveals the number of independent perceptual units required for recognition of the whole (Boothroyd, 1968b; Boothroyd & Nittrouer, 1988; Nittrouer & Boothroyd, 1990). For consonant-vowel-consonant (CVC) nonsense syllables, j ∼ 3 because all 3 phonemes are needed to identify the syllable, but j ∼ 2.5 for real-word CVCs (revealing ∼2.5 independent perceptual units) because higher level contributions such as lexical knowledge enable word recognition even if less than 3 phonemes are accurately received. These findings were almost exclusively determined with the 120-word corpus of the isophonemic word lists (Boothroyd, 1968a; Boothroyd & Nittrouer, 1988), presented one word at a time. It is therefore possible that its generality or applicability may be limited. This study thus determined j by using a much larger and less restricted corpus of real-word CVCs presented in 3-word groups as well as whether j is influenced by test size. METHOD: The j-factor for real-word CVCs was derived from the recognition performance of 223 individuals with a broad range of hearing sensitivity by using the Tri-Word Test (Gelfand, 1998), which involves 50 three-word presentations and a corpus of 450 words. The influence of test size was determined from a subsample of 96 participants with separate scores for the first 10, 20, and 25 (and all 50) presentation sets of the full test. RESULTS: The mean value of j was 2.48 with a 95% confidence interval of 2.44-2.53, which is in good agreement with values obtained with isophonemic word lists, although its value varies among individuals. A significant correlation was found between percent-correct scores and j, but it was small and accounted for only 12.4% of the variance in j for phoneme scores ≥60%. Mean j-factors for the 10-, 20-, 25-, and 50-set test sizes were between 2.49 and 2.53 and were not significantly different from one another. CONCLUSIONS: The j-factor based on a 450-word corpus and tri-word testing confirms and expands on findings from single-word presentations of isophonemic lists and a 120-word corpus. This enhances the generality (external validity) of the notions that j ∼ 2.5 for real-word CVCs, and lexical knowledge enables CVC word recognition based on ∼2.5 independent perceptual units. The robust nature of isophonemic word test outcomes is confirmed by close agreement with those provided by the high-reliability Tri-Word Test. Percent-correct performance was correlated with j but appeared to account for less than 13% of j-factor variance for most scores likely to be encountered in practice. Variability in the size of j suggests individual differences in the ability to take advantage of lexical knowledge in word recognition. The j-factor may be useful to inform rehabilitation needs, intervention content, and outcome assessment, as well as for other clinical applications.

Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE-/- mice.

The family of secretory phospholipase A2 (sPLA2) enzymes has been associated with inflammatory diseases and tissue injury including atherosclerosis. A-001 is a novel inhibitor of sPLA2 enzymes discovered by structure-based drug design, and A-002 is the orally bioavailable prodrug currently in clinical development. A-001 inhibited human and mouse sPLA2 group IIA, V, and X enzymes with IC50 values in the low nM range. A-002 (1 mg/kg) led to high serum levels of A-001 and inhibited PLA2 activity in transgenic mice overexpressing human sPLA2 group IIA in C57BL/6J background. In addition, the effects of A-002 on atherosclerosis in 2 ApoE mouse models were evaluated using en face analysis. (1) In a high-fat diet model, A-002 (30 and 90 mg/kg twice a day for 16 weeks) reduced aortic atherosclerosis by 50% (P < 0.05). Plasma total cholesterol was decreased (P < 0.05) by 1 month and remained lowered throughout the study. (2) In an accelerated atherosclerosis model, with angiotensin II-induced aortic lesions and aneurysms, A-002 (30 mg/kg twice a day) reduced aortic atherosclerosis by approximately 40% (P < 0.05) and attenuated aneurysm formation (P = 0.0096). Thus, A-002 was effective at significantly decreasing total cholesterol, atherogenesis, and aneurysm formation in these 2 ApoE mouse models.

Therapeutic positioning of the multiply-injured trauma patient in ICU.

Critically-ill patients who have sustained multiple traumatic injuries have complex, and often conflicting, physiological needs. These have profound implications on the way in which nursing staff approach the physical positioning of these patients to minimize the risks of further physiological injury and damage, maintain homeostasis and promote optimum recovery. This article reviews and discusses the evidence base underpinning therapeutic positioning of the multiply-injured trauma patient within the intensive-care unit (ICU), focusing on patients with a known or suspected unstable spinal injury, pelvic injury, traumatic brain injury, chest injury, or multiple limb fractures. Included are guidelines on the therapeutic positioning of the multiply-injured trauma patient within the ICU, based on the current available evidence and also drawn from practical experience within the author's own place of work. There is also a brief discussion of how such guidelines may be introduced into clinical practice.

Chemical analysis of atherosclerotic plaque cholesterol combined with histology of the same tissue.

Sensitive method for chemical analysis of free cholesterol (FC) and cholesterol esters (CE) was developed. Mouse arteries were dissected and placed in chloroform-methanol without tissue grinding. Extracts underwent hydrolysis of cholesteryl esters and derivatization of cholesterol followed by liquid chromatography/mass spectrometry (LC/MS/MS) analysis. We demonstrated that FC and CE could be quantitatively extracted without tissue grinding and that lipid extraction simultaneously worked for tissue fixation. Delipidated tissues can be embedded in paraffin, sectioned, and stained. Microscopic images obtained from delipidated arteries have not revealed any structural alterations. Delipidation was associated with excellent antigen preservation compatible with traditional immunohistochemical procedures. In ApoE(-/-) mice, LC/MS/MS revealed early antiatherosclerotic effects of dual PPARalpha,gamma agonist LY465606 in brachiocephalic arteries of mice treated for 4 weeks and in ligated carotid arteries of animals treated for 2 weeks. Reduction in CE and FC accumulation in atherosclerotic lesions was associated with the reduction of lesion size. Thus, a combination of LC/MS/MS measurements of CE and FC followed by histology and immunohistochemistry of the same tissue provides novel methodology for sensitive and comprehensive analysis of experimental atherosclerotic lesions.

Reactive azo dye reduction by Shewanella strain J18 143.

A bacterial isolate designated strain J18 143, originally isolated from soil contaminated with textile wastewater, was shown to reduce intensely coloured solutions of the reactive azo dye, Remazol Black B to colourless solutions. Phylogenetic placement based on 16S rRNA gene sequence homology identified the bacterium as a Shewanella species. Based on results from analyses of the end products of dye decoloration of Remazol Black B and the simpler molecule, Acid Orange 7, using capillary electrophoresis, UV-visible spectrophotometry and liquid chromatography-mass spectrometry, we suggest that colour removal by this organism was a result of microbially mediated reduction of the chromophore in the dye molecules. Anaerobic dye reduction by Shewanella strain J18 143 was 30 times more efficient than the reduction carried out by aerated cultures. Whole cells used a range of electron donors for dye reduction, including acetate, formate, lactate, and nicotinamide adenine dinucleotide (NADH), with formate being the optimal electron donor. The impact of a range of process variables was assessed (including nitrate, pH, temperature, substrate concentration, presence of an extracellular mediator) and results suggest that whole cells of Shewanella J18 143 offer several advantages over other biocatalysts with the potential to treat azo dyes.

Variant acute promyelocytic leukemia translocation (15;17) originating from two subsequent balanced translocations involving the same chromosomes 15 and 17 while preserving the PML/RARA fusion.

Fluorescence in situ hybridization (FISH) analysis of the bone marrow of a 24-year-old man diagnosed with acute promyelocytic leukemia (APL) revealed a variant pattern with one fusion signal instead of the typical two fusions expected with the probe set used. The combined FISH and conventional chromosome analyses suggested that two subsequent translocations had occurred in this patient involving the same chromosomes 15 and 17. As the prognostic outcome in APL is strictly associated with the presence of a PML/RARA fusion, it is useful and necessary to perform both cytogenetic and FISH analyses of a variant t(15;17) to determine the status of the PML/RARA fusion.

C.I. Pigment red 266.

C.I. Pigment Red 266, or 4-[[4-(aminocarbonyl)phenyl]hydrazono]-N-(2-methoxyphenyl)-3-oxo-3,4-dihydronaphthalene-2-carboxamide, C(25)H(20)N(4)O(4), adopts the keto-hydrazone tautomeric form with significant intramolecular hydrogen bonding. The molecules pack to form layers involving an extensive network of intermolecular hydrogen bonds, in which the primary amide group plays a prominent role. The good technical performance of this pigment in application may be attributed principally to the pattern of intra- and intermolecular hydrogen bonding.

Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure.

Young mice tolerate myocardial loss after coronary artery ligation (CAL) without congestive heart failure (CHF) signs or mortality. We predicted a CHF phenotype after CAL in aged mice. Left coronary artery ligation produced permanent myocardial infarcts (MI). Mortality was higher in male 14-mo-old C57BL/6N mice (Older mice) than in 2-mo-old mice (Young mice) (16 of 25 Older mice died vs. 0 of 10 Young mice, P < 0.02). After 8 wk, rales, weight loss, and lethargy preceded deaths. Captopril (50 mg x kg(-1) x day(-1)) increased Older mouse survival (6 of 22 died, P < 0.02). Captopril improved systolic function (peak aortic blood velocity) from 76 +/- 6% of baseline in untreated Older mice to 93 +/- 8% (P < 0.036). At 24 h, MI comprised 28 +/- 4% of the left ventricle in Young mice, surprisingly larger than that in Older mice (18 +/- 2%, P < 0.011). Endocardial area underlying the infarct scar was significantly larger in Older mice than in Young mice. Captopril did not reduce expansion but markedly reduced septal hypertrophy. Aging reduces compensatory ability in mice despite smaller acute infarcts. Less effective myocardial repair, greater infarct expansion, and septal hypertrophy are seen with aging. Aging is a more relevant murine model of post-MI heart failure in patients.