Top PDF A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis.

A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis.

A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis.

Neutrophils play a central role in eliminating bacterial pathogens, but may also contribute to end-organ damage in sepsis. Interleukin-8 (IL-8), a key modulator of neutrophil function, signals through neutrophil specific surface receptors CXCR-1 and CXCR-2. In this study a mechanistic computational model was used to evaluate and deploy an extracorporeal sep- sis treatment which modulates CXCR-1/2 levels. First, a simplified mechanistic computa- tional model of IL-8 mediated activation of CXCR-1/2 receptors was developed, containing 16 ODEs and 43 parameters. Receptor level dynamics and systemic parameters were cou- pled with multiple neutrophil phenotypes to generate dynamic populations of activated neu- trophils which reduce pathogen load, and/or primed neutrophils which cause adverse tissue damage when misdirected. The mathematical model was calibrated using experimental data from baboons administered a two-hour infusion of E coli and followed for a maximum of 28 days. Ensembles of parameters were generated using a Bayesian parallel tempering approach to produce model fits that could recreate experimental outcomes. Stepwise logis- tic regression identified seven model parameters as key determinants of mortality. Sensitiv- ity analysis showed that parameters controlling the level of killer cell neutrophils affected the overall systemic damage of individuals. To evaluate rescue strategies and provide prob- abilistic predictions of their impact on mortality, time of onset, duration, and capture efficacy of an extracorporeal device that modulated neutrophil phenotype were explored. Our find- ings suggest that interventions aiming to modulate phenotypic composition are time sensi- tive. When introduced between 3–6 hours of infection for a 72 hour duration, the survivor population increased from 31% to 40–80%. Treatment efficacy quickly diminishes if not introduced within 15 hours of infection. Significant harm is possible with treatment durations ranging from 5–24 hours, which may reduce survival to 13%. In severe sepsis, an extracor- poreal treatment which modulates CXCR-1/2 levels has therapeutic potential, but also potential for harm. Further development of the computational model will help guide optimal
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Spontaneous neutrophil migration patterns during sepsis after major burns.

Spontaneous neutrophil migration patterns during sepsis after major burns.

Neutrophil migration phenotype in patients with major burns We measured eighteen independent parameters of neutrophil migration in 74 samples from 13 patients with major burns, during treatment at Massachusetts General Hospital (Table 1) and 3 healthy volunteers. We validated first the device and compared it with previous studies [32], by measuring neutrophil migration in three healthy volunteers. The measured differences in migration speed between patients with major burns and healthy subjects are in agreement with previous observations [16, 32–39]. We also measured differences in the parameters of directionality and persistence between the neutrophils from patients with major burns and healthy controls. These differences between neutrophils from burn patients and healthy controls are summarized in Table 2 and a heat map (Fig. 2B). Neutrophils from patients with major burns migrate in smaller numbers (MC), at slower average velocity (v), and are less directional (D). Fewer neutrophils reach the end of the channels in response to the two chemoattractants tested (T, TL). For the majority of samples, these parameters were on average at least two standard deviations below healthy donors.
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Modulation and Apoptosis of Neutrophil Granulocytes by Extracorporeal Photopheresis in the Treatment of Chronic Graft-Versus-Host Disease.

Modulation and Apoptosis of Neutrophil Granulocytes by Extracorporeal Photopheresis in the Treatment of Chronic Graft-Versus-Host Disease.

It has been reported that ECP induces rapid maturation of monocytes to dendritic cells [40, 41] and increased apoptosis of alloreactive T lymphocytes. However, direct effects by induction of apoptosis in alloreactive T lymphocytes affect only a minority of alloreactive T cells, since only 5–10% of all leukocytes [20, 21] are exposed to chemoirradiation ex vivo of which only a small fraction consists of alloreactive cells. Indirect mechanisms like modulation of dendritic cells and monocytes [42] are alternative mechanisms to explain the immunomodulatory effects caused by ECP. Dendritic cells which are co-incubated with apoptotic T-lymphocytes have been shown to acquire a tolerogenic phenotype and to induce Tregs [43]. Our data suggest, that neutrophil granulocytes might also contribute to the anti-inflammatory properties of ECP. Because of the large number of treated cells, neutrophil granulocytes that are treated by ECP can contribute significantly to the large pool of apoptotic cells, which can lead to the induction of indirect tolerogenic effects on antigen-presenting cells. The results we show also indicate, that ECP decreases the inflammatory activity of neutrophils and induces arginase-1 release from apoptotic neutrophils. Recently, it was shown in a murine model, that neutrophil-derived ROS contributed to the severity of GVHD [36]. Therefore, a decreased ability to release respira- tory oxygen and nitrogen species-found in our in vitro and ex vivo experiments- might lead to reduced tissue damage. Further functional studies showed a reduced secretion of the pro- inflammatory cytokines CXCL8 and CCL4 by neutrophil granulocytes after ECP treatment. Since accumulation of CXCL8 is a feature of steroid-refractory GVHD [44] and CCL4 contrib- utes to accumulation of alloreactive T cells in GVHD, a reduction of CXCL8 and CCL4 secre- tion from neutrophils might also contribute to the efficacy of ECP. Comparative analysis of blood samples drawn from peripheral veins of patients before and after ECP contain a mix of a small number of ECP-treated and a larger number of non-treated leukocytes. Nevertheless analysis of apoptosis rate and function of neutrophil granulocytes isolated from these samples confirm the findings of our in vitro studies. Based on these findings, it can be concluded that during ECP-treatment a large number of so-called “pre-apoptotic” neutrophils is infused into
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Arq. Bras. Cardiol.  vol.85 número2

Arq. Bras. Cardiol. vol.85 número2

suture. The distal part of the tube was led to the abdomen as reported in the first case, and the anastomosis was performed close to the bifurcation with a continuous 4-0 Prolene suture. When the correction of the aorta was finished, the patient was put in the Trendelemburg position, and the surgical table was rotated to the right side. In that position and with the aid of a suction tissue stabilizer (Octopuss – Medtronic), myocardial re- vascularization was performed with saphenous vein bypass graft to the marginal branch of the circumflex artery and saphenous vein bypass graft to the anterior descending branch. Because the aorta was extremely thick, the proximal anastomoses were per- formed in the Dacron tube in its origin from the ascending aorta. The postoperative period was uneventful, and the patient stayed 2 days in the ICU and 8 more days at the hospital. On hospital discharge, the electrocardiogram showed an improvement in is- chemia as compared with that in the preoperative period. As in the first patient, this surgery was performed without extracorpo- real circulation. Both patients underwent anticoagulation before hospital discharge.
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Model for Quantitative Evaluation of Enzyme Replacement Treatment

Model for Quantitative Evaluation of Enzyme Replacement Treatment

With methods for investigation on time series, the model applies the Origin 6 [5] and Statistika 6 [4] software programs with their input being the individual data of children with Gaucher disease for quantitative evaluation the individual tendency in the development of the disease of each child and its correlation. On the basis of these results, we were able to recommend suitable changes in ERT.

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Prognostic role of NLR in urinary cancers: a meta-analysis.

Prognostic role of NLR in urinary cancers: a meta-analysis.

Increasing evidence showed the association of inflammation and cancer [30] and was helpful in the prevention and treatment of cancer, such as the anti-inflammation therapy of bladder cancer [31,32]. An enhanced neutrophil response and/or suppression of lymphocyte leading to a high NLR might promote carcinogenesis and inhibit antitumor immune response [33,34]. Molecular signaling and pathway triggered by inflammatory mediators could promote cancer cell proliferation angiogenesis and metastasis, thus impacting the tumor response to therapies [35]. Additionally, some studies showed that elevated NLR indicate an increased risk of ischemic cardiovascular diseases [36], high mortality in patients with bacteraemia [37] and raised gastrointestinal morbidity and mortality [38,39] which may underlie the poor prognosis of patients with an increased NLR. Nowadays, tumor stage and other clinical parameters such as PSA and Gleason grade were applied to obtain prognostic information and be helpful in choice of appropriate treatment strategies for patients with urinary cancers. Peripheral blood tests before treatment or at the time of diagnosis may reflect inflammatory conditions within the tumor. NLR calculated from the convenient and cheap test could provide appropriate prognostic information for the patients in the treatment of urinary cancers.
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Efeito terapêutico de células-tronco mesenquimais no tratamento da sepse experimental

Efeito terapêutico de células-tronco mesenquimais no tratamento da sepse experimental

Sepsis, a medical condition that affects 18 million people per year worldwide, is characterized by a generalized inflammatory state caused by infection. The widespread activation of coagulation pathways and inflammation progresses to multiple organ failure, the collapse of the circulatory system (septic shock) and death. Despite decades of research and numerous clinical trials, little progress has been made in developing new treatments and mortality rates are virtually the same in the last 20 to 30 years. As such, sepsis remains a difficult opponent for surgeons and their patients, so the search for new therapeutic alternatives becomes strictly essential. Recently stem cells have emerged as a promising therapy for a variety of diseases, including cardiovascular diseases, neurodegenerative disorders, peripheral vascular disease, renal disease, and several others. Its beneficial effects are due mainly to their ability to connect to injury and inflammation, to attenuate the inflammatory response, and accelerate tissue healing and neoangiogenesis due to noxious stimuli. Considering this therapeutic potential, this study aimed to evaluate whether these cells could lead to immune response back into balance, reducing the pathophysiology of sepsis and thereby increase the survival time in mice using an experimental model of sepsis. Our results demonstrated that treatment with mesenchymal stem cells was able to increase survival time of the animals that were tested. This effect is due to the ability of these cells to modulate the immune response providing a smaller reduction in tissue injury and apoptotic cells. These findings demonstrate that mesenchymal stem cells have therapeutic potential and can function as a possible future treatment for sepsis.
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Clinics  vol.72 número11

Clinics vol.72 número11

The early identification, accurate diagnosis and prognostic evaluation of ACLF can provide a guiding basis for active and effective treatment. Therefore, a better understanding of prognostic factors and more precise prognostic evaluation systems for ACLF are in urgent need. A variety of factors can affect the progression and prognosis of ACLF. Many prognostic scoring systems are available for predicting the outcomes of ACLF, including the Child-Turcotte-Pugh (CTP) system, the model for end-stage liver disease (MELD) and the MELD-sodium (MELD-Na). Each scoring system has certain limitations given that not all of the influencing factors can be included in the individual assessment. The integrated MELD (iMELD) is a new scoring system that features the addition of two independent ACLF prognostic risk factors, age and serum Na levels, to the MELD scoring system (8). In addition, the albumin-bilirubin (ALBI) grading system is a recently developed scoring system to assess liver function (9). Several studies have compared the predictive ability of dif- ferent scoring systems in ACLF (10-12). Comparisons of the predictive abilities of the CTP, MELD, MELD-Na, iMELD and ALBI scoring systems for the prognosis of HBV-ACLF are rarely reported. Attempts to analyze the impact of clinical parameters and the combined prognostic abilities of these parameters on ACLF prognosis have provided inconsistent results due to differences in study subjects, study phases and follow-up periods (13-15). The integration of general information, clinical indicators and a prognostic scoring system may better predict the short-term outcomes of patients with HBV-ACLF.
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Application of time-series analysis for prediction of molding sand properties in production cycle

Application of time-series analysis for prediction of molding sand properties in production cycle

For all hourly based data sets the information content in re- sidual data was equal 1. It means that both statistical tests explic- itly indicated that the residual data may include important infor- mation and therefore it is advisable to apply a regression model for finding desired predictions. By contrast, for most of the daily based data sets the information content in residual data was below 0,5, (in almost half of the cases it was equal to zero). Taking into account that the residual data are important fraction of the whole variability in those sets (an example is shown in Fig. 1), these results indicate that the time-series analysis can give prediction results with relatively large errors.
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J. bras. pneumol.  vol.37 número6 en v37n6a16

J. bras. pneumol. vol.37 número6 en v37n6a16

Another point that has recently been discussed was the duration of the maintenance phase, which until then had been established at 1 year. Since the risk of AAV recurrence can be as high as 4.3% per month, and since recurrence implies the reinstitution of cyclophosphamide (with its possible severe adverse events), some authors suggest the use of azathioprine for 2 years, for 3 years, or even indefinitely. The factors associated with AAV recurrence include PR3-ANCA positivity, upper airway injury, pulmonary involvement, and a history of AAV recurrence. A greater number of risk factors translate to a greater propensity to use azathioprine for an indefinite length of time, as follows: 2 mg • kg −1 • day −1 in the first year;
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Paraquat-induced reactive oxygen species inhibit neutrophil apoptosis via a p38 MAPK/NF-κB-IL-6/TNF-α positive-feedback circuit.

Paraquat-induced reactive oxygen species inhibit neutrophil apoptosis via a p38 MAPK/NF-κB-IL-6/TNF-α positive-feedback circuit.

The nonselective contact herbicide paraquat (PQ) is a strong pneumotoxicant; it accumulates in the lung through a polyamine uptake system and can induce redox cycling, leading to oxidative stress-related damage [1,2]. Evidence has shown that reactive oxygen species (ROS) occupy a central role in PQ-induced acute lung injury (ALI). ROS production impairs tissue and cell function by inducing lipid peroxidation, protein damage, and DNA breakage [3]. In addition to direct ROS-induced pathology, the inflammation response that is secondary to PQ poisoning is also involved in disease pathogenesis. As intrinsic signal transduction molecules, ROS are important components in the complex modulation of neutrophil apoptosis [4,5]. Under normal circum- stances, rapid apoptosis is a neutrophilic characteristic. The average life span of neutrophil is 8-20 h in circulation [6]. Control of neutrophil apoptosis is essential to rapidly resolve inflammatory reactions [7]. Recent studies have shown that apoptosis contrib- utes to ALI pathogenesis, and neutrophil apoptosis in particular exacerbates the condition [8–11].
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Int. braz j urol.  vol.31 número2

Int. braz j urol. vol.31 número2

We present a case of retrocaval ureter featuring laparoscopic technique treatment using extraperitoneal access and extracorporeal suture of the ureteral stumps. Surgical time was 130 min- utes, and the anastomosis was performed in 40 minutes. There were no intra- or postoperative compli- cations, and the patient was discharged from hospital on the second postoperative day. The medium- term outcome featured similar results to pure laparoscopic technique.

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Neutrophil function and metabolism in individuals with diabetes mellitus

Neutrophil function and metabolism in individuals with diabetes mellitus

Neutrophils act as first-line-of-defense cells and the reduction of their functional activity contributes to the high susceptibility to and severity of infections in diabetes mellitus. Clinical investigations in diabetic patients and experimental studies in diabetic rats and mice clearly demonstrated consistent defects of neutrophil chemotactic, phagocyt- ic and microbicidal activities. Other alterations that have been re- ported to occur during inflammation in diabetes mellitus include: decreased microvascular responses to inflammatory mediators such as histamine and bradykinin, reduced protein leakage and edema forma- tion, reduced mast cell degranulation, impairment of neutrophil adhe- sion to the endothelium and migration to the site of inflammation, production of reactive oxygen species and reduced release of cyto- kines and prostaglandin by neutrophils, increased leukocyte apopto- sis, and reduction in lymph node retention capacity. Since neutrophil function requires energy, metabolic changes (i.e., glycolytic and glutaminolytic pathways) may be involved in the reduction of neutro- phil function observed in diabetic states. Metabolic routes by which hyperglycemia is linked to neutrophil dysfunction include the ad- vanced protein glycosylation reaction, the polyol pathway, oxygen- free radical formation, the nitric oxide-cyclic guanosine-3'-5’mono- phosphate pathway, and the glycolytic and glutaminolytic pathways. Lowering of blood glucose levels by insulin treatment of diabetic patients or experimental animals has been reported to have significant correlation with improvement of neutrophil functional activity. There- fore, changes might be primarily linked to a continuing insulin deficiency or to secondary hyperglycemia occurring in the diabetic individual. Accordingly, effective control with insulin treatment is likely to be relevant during infection in diabetic patients.
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Um sistema eletrônico de alerta ajuda a reduzir o tempo para diagnóstico de sepse

Um sistema eletrônico de alerta ajuda a reduzir o tempo para diagnóstico de sepse

It is difficult to determine if the electronic identification tool changed outcomes, considering that multiple changes in patient care occurred during the observation period. However, a role for early recognition in mortality reduction cannot be ruled out since the time to screening was the same in survivors and non-survivors. Both the time required from triage-to-diagnosis and triage-to-antibiotics as well as different aspects of early treatment of sepsis were similar between survivors and non-survivors. Considering that the efficiency of the care process offered to these two groups of patients was similar and that variables such as age, APACHE II and occurrence of septic shock were higher among non-survivors (Table 4), the intrinsic conditions of severely ill patients may carry more weight in the risk of death associated with sepsis and septic shock. The mortality rates higher than 30% observed in the first years are comparable to those found in Brazilian adult ICUs by the BASES Study and SPREAD Study. (1,51)
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The Economics of Sub-optimal Policies for Traffic Congestion

The Economics of Sub-optimal Policies for Traffic Congestion

Closer to this paper is the work of Gallego, Montero, and Salas [2013]. These authors analyze two policies, in Mexico City and Santiago (Chile), aimed at reducing congestion and pollution. They find the policies that impose driving restrictions may lead to a higher number of cars on the city. Our results point on the same direction. Batarce and Ivaldi [2014] estimate the demand for transportation mode taking into account traffic congestion in an equilibrium setup. In their work, traffic congestion is the equilibrium of a game with a continuum of drivers. De Borger and Proost [2012] theoretically analyze the political economy aspects of congestion pricing. Their results corroborate the emprical observation that road pricing is politically difficult to implement. We analyze the same problem empirically.
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Long-term ethanol intoxication reduces inflammatory responses in rats

Long-term ethanol intoxication reduces inflammatory responses in rats

A subcutaneous 6-day-old air pouch was produced as described by Edwards et al. (19). Briefly, on the 4th day of ethanol inha- lation, the dorsal region of the rats was shaved and 20 ml of sterile air was injected subcuta- neously. Three days later, 10 ml of sterile air was again injected into the air pouch to maintain the patency of the cavity. On the 10th day of ethanol inhalation (6 days after the initial injection of air), 500 µg/ml carra- geenan was injected into the pouch 6 h be- fore removal from the chamber (treated group). In the withdrawal group, 500 µg/ml carrageenan was injected into the pouch 1 h after removal from the chamber. The ani- mals were sacrificed 6 h after the carrageen- an injection. Control animals did not inhale ethanol and had saline or carrageenan in- jected into the air pouch. The pouch was washed with 5 ml phosphate-buffered saline (PBS) containing heparin (5 IU/ml) and 3% bovine serum albumin (BSA). The washout fluid was collected and total and differential leukocyte counts were performed by the method of Ribeiro et al. (20).
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High-energy extracorporeal shockwave therapy in a patellar tendon animal model: a vascularizationfocused study

High-energy extracorporeal shockwave therapy in a patellar tendon animal model: a vascularizationfocused study

study indicated that ESW appeared to induce the early release of vascular growth factors from the tendon. These growth factors induced angiogenesis, which led to increased blood supply to the tendon, which in turn supported tissue regeneration. 18 Hsu et al. studied the effects of ESW in a rabbit model of patellar tendinitis induced by the injection of collagenase and found an increase in vascularization at 16 weeks. 31 It is noteworthy that while all three of these studies showed an increase in tendon vascularization after ESW treatment, our results did not demonstrate such an increase. It should also be noted that only one of these three studies is comparable to our study in terms of the methodology used. Each type of tissue has a particular impedance value. The impedance of bone is much greater than that of water, and therefore, bone absorbs large amounts of energy from shockwaves. However, the impedance of a healthy tendon is very similar to that of water, and thus, a tendon absorbs less energy than bone. However, a calcified tendon has a higher level of impedance because of the presence of calcium crystals. This could explain why HEST is more effective in cases of chronic enthesopathies because the tendons in these cases tend to be tougher and more calcified than in acute enthesopathies. 6
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Rev. Bras. Reumatol.  vol.56 número6

Rev. Bras. Reumatol. vol.56 número6

Women referred by the public health system to the Out- patient Rheumatology Service of the Federal University of Triângulo Mineiro (UFTM) were prospectively diagnosed with SLE according to guidelines established by the American Col- lege of Rheumatology and enrolled in the study. Patients had different times of SLE onset and were being treated with corticoids and/or hydroxychloroquine and/or azathioprine. Disease severity was established using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score system. Healthy female volunteers served as controls. The study pro- tocol was approved by the UFTM Committee on the Use of Human Subjects, and written informed consent was obtained from all patients and controls.
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Neutrophil Responses to Sterile Implant Materials.

Neutrophil Responses to Sterile Implant Materials.

Retrieved microcapsules were washed with Krebs-Henseleit solution prior to phase contrast imaging, or were fixed in 2% paraformaldehyde (in PBS) for 4 hours. Following multiple washing steps (washing buffer–PBS containing 1% BSA), microcapsules were suspended in staining solu- tion (same as in flow cytometry) in 1.5 ml micro-centrifuge tubes. Primary antibodies against, Ly6G-Alexa-Fluor-647 (1A8, Biolegend; 1:50 dilution), DNA/Histone H1 (MAB3864, Millipore; 1:200 dilution), neutrophil elastase (ab21595, Abcam; 1:200 dilution), Histone-H1 (ab61177, Abcam; 1:250 dilution), citrulline Histone-H3 (ab5103, Abcam; 1:100 dilution), and/or myelo- peroxidase (ab90810, Abcam; 1:50 dilution) were added and left on a gentle rocker for 1 hour at 4°C. Following multiple washes, secondary antibodies were added at 1:1000 dilution and left on a gentle rocker for 1 hour at 4C. Again, after multiple washes, microcapsules were suspended in PBS and 500nM DAPI and/or Sytox red (Life Technologies) added for 15 min at room tempera- ture. Following 3 washes using PBS, microcapsules were suspended in 50:50 glycerol:PBS solu- tion and saved at 4°C for imaging. None of the steps involved addition of tween or other detergents for cell permeabilization. Immunofluorescence imaging was performed using a Zeiss LSM-700. Laser power and gain settings were adjusted using control samples that were stained with secondary antibodies only, and kept constant while imaging all the samples. Z-stacks of individual capsules (50–100 μm depth) were collected with a 4–5 μm section interval, and a 3-D stack (represented as a 2-D image) was generated using 3D reviewer on the Zeiss Zen software. Three post image acquisition processing steps were performed on FIJI: (i) adjustment of bright- ness and contrast to the entire image (including control samples), (ii) cropping images to limit the region of interest to individual capsules and (iii) the addition of a scale-bar.
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Um sistema eletrônico de alerta ajuda a reduzir o tempo para diagnóstico de sepse

Um sistema eletrônico de alerta ajuda a reduzir o tempo para diagnóstico de sepse

(C) Indirect electronic alert to telephonist: after an interruption of data collection and case management in 2008 and 2009, an electronic alert system based on MEWS was implemented to identify patients at risk. During 2010, the alert was sent by e-mail to the hospital telephone service, which informed the nurses responsible for each ward. In-house computer technicians developed an algorithm to automatically calculate the MEWS score at each ordinary insertion of vital signs in the electronic health record. Due to technical limitations, the insertion of SODs was not mandatory in this phase. A score ≥ 3 constituted an alert in the wards and allowed for the early identification of at-risk patients.
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