Comparison of the acute renal and peripheral vascular responses to frusemide and bumetanide at low and high dose

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter-treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin-angiotensin-prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.

Resource utilisation, length of hospital stay, and pattern of investigation during acute medical hospital admission

To describe the patient demographic characteristics and organisational factors that influence length of stay (LOS) among emergency medical admissions. Also, to describe differences in investigation practice among consultant physicians and to examine the impact of these on LOS.

Isolation of a bone marrow-derived stem cell line with high proliferation potential and its application for preventing acute fatal liver failure

Transplantation of hepatocytes or hepatocyte-like cells of extrahepatic origin is a promising strategy for treatment of acute and chronic liver failure. We examined possible utility of hepatocyte-like cells induced from bone marrow cells for such a purpose. Clonal cell lines were established from the bone marrow of two different rat strains. One of these cell lines, rBM25/S3 cells, grew rapidly (doubling time, approximately 24 hours) without any appreciable changes in cell properties for at least 300 population doubling levels over a period of 300 days, keeping normal diploid karyotype. The cells expressed CD29, CD44, CD49b, CD90, vimentin, and fibronectin but not CD45, indicating that they are of mesenchymal cell origin. When plated on Matrigel with hepatocyte growth factor and fibroblast growth factor-4, the cells efficiently differentiated into hepatocyte-like cells that expressed albumin, cytochrome P450 (CYP) 1A1, CYP1A2, glucose 6-phosphatase, tryptophane-2,3-dioxygenase, tyrosine aminotransferase, hepatocyte nuclear factor (HNF)1 alpha, and HNF4alpha. Intrasplenic transplantation of the differentiated cells prevented fatal liver failure in 90%-hepatectomized rats. In conclusion, a clonal stem cell line derived from adult rat bone marrow could differentiate into hepatocyte-like cells, and transplantation of the differentiated cells could prevent fatal liver failure in 90%-hepatectomized rats. The present results indicate a promising strategy for treating human fatal liver diseases.

Proteolytic cleavage of elafin by 20S proteasome may contribute to inflammation in acute lung injury

RATIONALE:
We hypothesise that elafin levels in acute lung injury (ALI) decrease over time due, in part, to proteolytic degradation as observed in other lung diseases.
OBJECTIVES:
The aim of this study was to characterise temporal changes in elafin concentration in patients with ALI and to evaluate whether a decrease in elafin levels is due to elevated protease activity.
METHODS:
Bronchoalveolar lavage fluid (BALF) was obtained from patients with ALI within 48 h of onset of ALI (day 0), at day 3 and at day 7. Elafin levels were quantified by ELISA. Elafin susceptibility to proteolytic cleavage by ALI BALF was assessed by Western blot and by high-performance liquid chromatography-mass spectrometry.
MEASUREMENTS AND MAIN RESULTS:
Elafin levels were found to be significantly increased at the onset of ALI compared with healthy volunteers and fell significantly by day 7 compared with day 0. In contrast, levels of secretory leukocyte protease inhibitor did not decrease over time. This decrease in elafin was due to cleavage by the 20S proteasome which was significantly increased in ALI BALF. Incubation of ALI BALF with the proteasome inhibitor epoxomicin confirmed that 20S proteasome protease activity was responsible for proteolytic cleavage of elafin, resulting in diminished anti-elastase activity. In addition, free neutrophil elastase activity significantly increased in ALI BALF from day 0 to day 7.
CONCLUSIONS:
Elafin concentrations fall within the pulmonary compartment over the course of ALI as a result of proteolytic degradation. This loss of elafin may predispose people, in part, to excessive inflammation in ALI.

The effect of radiation technique and bladder filling on the acute toxicity of pelvic radiotherapy for localized high risk prostate cancer

Purpose: The goal of this project was to see if using IMRT to deliver elective pelvic nodal irradiation (EPNI) for prostate cancer reduced acute treatment toxicity.

Methods: Two hundred and thirty patients were enrolled into prospective trials delivering EPNI with a concomitant hypofractionated IMRT boost to the prostate. During accrual, the method of EPNI delivery changed as new literature emerged. Three methods were used (1) 4FB, (2) IMRT with 2 cm CTV margins around the pelvic vessels as suggested by Shih et al. (2005) [7] (IMRT-Shih), and (3) IMRT with nodal volumes suggested by the RTOG (IMRT-RTOG). Initially patients were treated with an empty bladder, with the remainder treated with bladder full.

Results: Patients in the 4FB group had higher rates of grade 2 acute GI toxicities compared to the IMRT-Shih and IMRT-RTOG groups (31.9% vs 20.8% vs 7.2%, p = 0.0009). Patients in the 4FB group had higher rates of grade 3 urinary frequency compared to the two IMRT groups (8.5% vs 0% vs 0%, p = 0.027). However, multivariate analysis suggested the factor that most influenced toxicity was bladder filling followed by IMRT.

Conclusions: Bladder filling appeared to be the dominant factor which predicted for acute toxicity, followed by the use of IMRT.

Score for neonatal acute physiology-II and neonatal pain predict corticospinal tract development in premature newborns

Premature infants are at risk for adverse motor outcomes, including cerebral palsy and developmental coordination disorder. The purpose of this study was to examine the relationship of antenatal, perinatal, and postnatal risk factors for abnormal development of the corticospinal tract, the major voluntary motor pathway, during the neonatal period. In a prospective cohort study, 126 premature neonates (24-32 weeks' gestational age) underwent serial brain imaging near birth and at term-equivalent age. With diffusion tensor tractography, mean diffusivity and fractional anisotropy of the corticospinal tract were measured to reflect microstructural development. Generalized estimating equation models examined associations of risk factors on corticospinal tract development. The perinatal risk factor of greater early illness severity (as measured by the Score for Neonatal Acute Physiology-II [SNAP-II]) was associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.02), even after correcting for gestational age at birth and postnatal risk factors (P = 0.009). Consistent with previous findings, neonatal pain adjusted for morphine and postnatal infection were also associated with a slower rise in fractional anisotropy of the corticospinal tract (P = 0.03 and 0.02, respectively). Lessening illness severity in the first hours of life might offer potential to improve motor pathway development in premature newborns.

Specific Newborn Individualized Developmental Care and Assessment Program movements are associated with acute pain in preterm infants in the neonatal intensive care unit

The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) is widely used in neonatal intensive care units and comprises 85 discrete infant behaviors, some of which may communicate infant distress. The objective of this study was to identify developmentally relevant movements indicative of pain in preterm infants.

Relations between behavioral and cardiac autonomic reactivity to acute pain in preterm neonates

The purpose of this study was to assess relations and concordance between behavioral and physiologic reactivity to pain in preterm neonates at 32 weeks postconceptional age as a function of gestational age at birth.

The developmental character of cardiac autonomic responses to an acute noxious event in 4- and 8-month-old healthy infants

Heart rate (HR) has been widely studied as a measure of an individual's response to painful stimuli. It remains unclear whether changes in mean HR or the variability of HR are specifically related to the noxious stimulus (i.e. pain). Neither is it well understood how such changes reflect underlying neurologic control mechanisms that produce these responses, or how these mechanisms change during the first year of life. To study the changes in cardiac autonomic modulation that occur with acute pain and with age during early infancy, the relationship between respiratory activity and short-term variations of HR (i.e. respiratory sinus arrhythmia) was quantified in a longitudinal study of term born healthy infants who underwent a finger lance blood collection at 4 months of age (n = 24) and again at 8 months of age (n = 20). Quantitative respiratory activity and HR were obtained during baseline, lance, and recovery periods. Time and frequency domain analyses from 2.2-min epochs of data yielded mean values, spectral measures of low (0.04-0.15 Hz) and high (0.15-0.80 Hz) frequency power (LF and HF), and the LF/HF ratio. To determine sympathetic and parasympathetic cardiac activity, the transfer relation between respiration and HR was used. At both 4 and 8 months, mean HR increased significantly with the noxious event (p > 0.01). There were age-related differences in the pattern of LF, HF, and LF/HF ratio changes. Although these parameters all decreased (p > 0.01) at 4 months, LF and LF/HF increased at 8 months and at 8 months HF remained stable in response to the noxious stimulus. Transfer gain changes with the lance demonstrated a change from predominant vagal baseline to a sympathetic condition at both ages. The primary finding of this study is that a response to an acute noxious stimulus appears to produce an increase in respiratory-related sympathetic HR control and a significant decrease in respiratory-related parasympathetic control at both 4 and 8 months. Furthermore, with increasing age, the sympathetic and parasympathetic changes appear to be less intense, but more sustained.

Concise Review: Mesenchymal Stem Cells for Acute Lung Injury: Role of Paracrine Soluble Factor

Morbidity and mortality have declined only modestly in patients with clinical acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), despite extensive research into the pathophysiology. Current treatment remains primarily supportive with lung-protective ventilation and a fluid conservative strategy. Pharmacologic therapies that reduce the severity of lung injury in preclinical models have not yet been translated to effective clinical treatment options. Consequently, further research in translational therapies is needed. Cell-based therapy with mesenchymal stem cells (MSCs) is one attractive new therapeutic approach. MSCs have the capacity to secrete multiple paracrine factors that can regulate endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. This review will focus on recent studies, which support the potential therapeutic use of MSCs in ALI/ARDS, with an emphasis on the role of paracrine soluble factors.

Adherence to hand hygiene and risk factors for poor adherence in 13 Ontario acute care hospitals

Multicenter studies assessing hand hygiene adherence and risk factors for poor performance are scarce. In an observational study involving 13 hospitals across Ontario, Canada, we found a mean adherence rate of 31.2%, and that adherence was positively associated with nurses, single rooms, contact precautions, and the availability of alcohol hand rub dispensers. Copyright © 2011 by the Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Molecular similarity between myelodysplastic form of chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts

Chronic myelomonocytic leukemia is similar to but a separate entity from both myeloproliferative neoplasms and myelodysplastic syndromes, and shows either myeloproliferative or myelodysplastic features. We ask whether this distinction may have a molecular basis. We established the gene expression profiles of 39 samples of chronic myelomonocytic leukemia (including 12 CD34-positive) and 32 CD34-positive samples of myelodysplastic syndromes by using Affymetrix microarrays, and studied the status of 18 genes by Sanger sequencing and array-comparative genomic hybridization in 53 samples. Analysis of 12 mRNAS from chronic myelomonocytic leukemia established a gene expression signature of 122 probe sets differentially expressed between proliferative and dysplastic cases of chronic myelomonocytic leukemia. As compared to proliferative cases, dysplastic cases over-expressed genes involved in red blood cell biology. When applied to 32 myelodysplastic syndromes, this gene expression signature was able to discriminate refractory anemias with ring sideroblasts from refractory anemias with excess of blasts. By comparing mRNAS from these two forms of myelodysplastic syndromes we derived a second gene expression signature. This signature separated the myelodysplastic and myeloproliferative forms of chronic myelomonocytic leukemias. These results were validated using two independent gene expression data sets. We found that myelodysplastic chronic myelomonocytic leukemias are characterized by mutations in transcription/epigenetic regulators (ASXL1, RUNX1, TET2) and splicing genes (SRSF2) and the absence of mutations in signaling genes. Myelodysplastic chronic myelomonocytic leukemias and refractory anemias with ring sideroblasts share a common expression program suggesting they are part of a continuum, which is not totally explained by their similar but not, however, identical mutation spectrum. © 2013 Ferrata Storti Foundation.

Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia

Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (CFLAR(L) and CFLAR(S) , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression. In cell line studies, simultaneous down-regulation of c-FLIP(L) and c-FLIP(S) proteins using siRNA induced apoptosis in U937 and NB-4 AML cells, but not K562 or OCI-AML3 cells. However, dual c-FLIP(L/S) downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor-related apoptosis-inducing ligand (rTRAIL). Moreover, specific downregulation of c-FLIP(L) was found to recapitulate the phenotypic effects of dual c-FLIP(L/S) downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down-regulate c-FLIP(L) expression by transcriptional and post-transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c-FLIP(L) down-regulation. These results suggest that c-FLIP(L) may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.