Efficacy of resuscitative infusion with hemoglobin vesicles in rabbits with massive obstetric hemorrhage.

BACKGROUND: Hemoglobin vesicles have been developed as artificial oxygen carriers, and they have the potential to serve as a substitute for red blood cell transfusion. OBJECTIVE: This study aimed to evaluate the efficacy of hemoglobin vesicle infusion for the initial treatment instead of red blood cell transfusion in rabbits with massive obstetric hemorrhage. STUDY DESIGN: Pregnant New Zealand white rabbits (28th day of pregnancy; normal gestation period, 29-35 days) underwent uncontrolled hemorrhage to induce shock by transecting the right midartery and concomitant vein in the myometrium. Subsequently, rabbits received isovolemic fluid resuscitation through the femoral vein with an equivalent volume of hemorrhage every 5 minutes. Resuscitative infusion regimens included 5% human serum albumin (n=6), stored washed red blood cells with plasma (vol/vol=1:1; n=5), and hemoglobin vesicle with 5% human serum albumin (vol/vol=4:1; n=5). A total of 60 minutes after the start of bleeding, rabbits underwent surgical hemostasis by ligation of the bleeding vessels and then were monitored for survival within 24 hours. RESULTS: During fluid resuscitation, hemoglobin vesicle infusion and red blood cell transfusion maintained a mean arterial pressure of >50 mm Hg and a hemoglobin concentration of >9 g/dL and prevented the elevation of plasma lactate. In contrast, resuscitation with 5% human serum albumin alone could not prevent hemorrhagic shock as evidenced by a low mean arterial pressure (40 mm Hg), a low hemoglobin concentration (2 g/dL), and a marked elevation of plasma lactate. All animals in the red blood cell group and the hemoglobin vesicle group survived more than 8 hours, whereas all animals in the 5% human serum albumin group died within 8 hours. CONCLUSION: Hemoglobin vesicle infusion may be effective in the initial management of massive obstetric hemorrhage.

Protein nanoparticles in drug delivery: animal protein, plant proteins and protein cages, albumin nanoparticles.

In this article, we will describe the properties of albumin and its biological functions, types of sources that can be used to produce albumin nanoparticles, methods of producing albumin nanoparticles, its therapeutic applications and the importance of albumin nanoparticles in the production of pharmaceutical formulations. In view of the increasing use of Abraxane and its approval for use in the treatment of several types of cancer and during the final stages of clinical trials for other cancers, to evaluate it and compare its effectiveness with conventional non formulations of chemotherapy Paclitaxel is paid. In this article, we will examine the role and importance of animal proteins in Nano medicine and the various benefits of these biomolecules for the preparation of drug delivery carriers and the characteristics of plant protein Nano carriers and protein Nano cages and their potentials in diagnosis and treatment. Finally, the advantages and disadvantages of protein nanoparticles are mentioned, as well as the methods of production of albumin nanoparticles, its therapeutic applications and the importance of albumin nanoparticles in the production of pharmaceutical formulations.

High adherence to prophylaxis regimens in haemophilia B patients receiving rIX-FP: Evidence from clinical trials and real-world practice.

INTRODUCTION: Adherence to prophylaxis regimens is essential for bleed prevention in haemophilia but remains a challenge due to the need for frequent infusions. AIM: To evaluate patient adherence to prophylaxis regimens with a long-acting recombinant factor IX (rIX-FP; IDELVION® ) in clinical studies and real-world practice. METHODS: In two phase 3 clinical studies, patients with haemophilia B (FIX ≤2%) recorded their dose, dosing frequency and rIX-FP consumption in an e-diary. Adherence to prescribed prophylaxis regimens was assessed in all patients and to prescribed dose in patients ≥12 years only. Additionally, adherence to rIX-FP prophylaxis regimens in real-world practice was captured. RESULTS: In clinical studies, 94.9% (n = 56/59) of patients ≥12 years and 100% (n = 27) of paediatric patients received ≥80% of the expected number of infusions for their assigned prophylaxis schedule. Overall, mean adherence rate was 95.5% across all prophylaxis regimens in patients ≥12 years and 97.9% with a 7-day regimen in paediatric patients. In patients ≥12 years, 85.7% (n = 54/63) were dose adherent, defined as receiving within 10% of their prescribed dose ≥80% of the time. In real-world practice, adherence was observed in 100% (n = 14 and n = 15, respectively) of patients in two haemophilia treatment centres and 57.1% (n = 4/7) of patients in a third centre; non-adherence (n = 3/7) was linked to insurance-related and parental issues. CONCLUSION: In clinical studies, patients with haemophilia B had high adherence rates to rIX-FP prophylaxis regimens with a variety of dosing intervals, enabling them to achieve very low bleeding rates. High adherence may also be achievable in real-world practice.

Lactic acid suppresses IgE-mediated mast cell function in vitro and in vivo.

Mast cells have functional plasticity affected by their tissue microenvironment, which greatly impacts their inflammatory responses. Because lactic acid (LA) is abundant in inflamed tissues and tumors, we investigated how it affects mast cell function. Using IgE-mediated activation as a model system, we found that LA suppressed inflammatory cytokine production and degranulation in mouse peritoneal mast cells, data that were confirmed with human skin mast cells. In mouse peritoneal mast cells, LA-mediated cytokine suppression was dependent on pH- and monocarboxylic transporter-1 expression. Additionally, LA reduced IgE-induced Syk, Btk, and ERK phosphorylation, key signals eliciting inflammation. In vivo, LA injection reduced IgE-mediated hypothermia in mice undergoing passive systemic anaphylaxis. Our data suggest that LA may serve as a feedback inhibitor that limits mast cell-mediated inflammation.

Transcellular Pathways in Lymphatic Endothelial Cells Regulate Changes in Solute Transport by Fluid Stress.

RATIONALE: The transport of interstitial fluid and solutes into lymphatic vessels is important for maintaining interstitial homeostasis and delivering antigens and soluble factors to the lymph node for immune surveillance. Transendothelial transport across lymphatic endothelial cells (LECs) is commonly considered to occur paracellularly, or between cell-cell junctions, and driven by local pressure and concentration gradients. However, emerging evidence suggests that LECs also play active roles in regulating interstitial solute balance and can scavenge and store antigens, raising the possibility that vesicular or transcellular pathways may be important in lymphatic solute transport. OBJECTIVE: The aim of this study was to determine the relative importance of transcellular (vesicular) versus paracellular transport pathways by LECs and how mechanical stress (ie, fluid flow conditioning) alters either pathway. METHODS AND RESULTS: We demonstrate that transcellular transport mechanisms substantially contribute to lymphatic solute transport and that solute uptake occurs in both caveolae- and clathrin-coated vesicles. In vivo, intracelluar uptake of fluorescently labeled albumin after intradermal injection by LECs was similar to that of dermal dendritic cells. In vitro, we developed a method to differentially quantify intracellular solute uptake versus transendothelial transport by LECs. LECs preconditioned to 1 µm/s transmural flow demonstrated increased uptake and basal-to-apical solute transport, which could be substantially reversed by blocking dynamin-dependent vesicle formation. CONCLUSIONS: These findings reveal the importance of intracellular transport in steady-state lymph formation and suggest that LECs use transcellular mechanisms in parallel to the well-described paracellular route to modulate solute transport from the interstitium according to biomechanical cues.

Hepatic and Intrahepatic Targeting of Hydrogen Sulfide Prodrug by Bioconjugation.

Hydrogen sulfide (H2S) is an endogenous gaseous transmitter known to play an important role in biological functions. For the hepatic and intrahepatic targeting of H2S prodrug at the cellular level, we developed two types of sulfo-albumins, in which five sulfide groups (source of H2S) were covalently bound to succinylated (Suc) or galactosylated (Gal) bovine serum albumin (BSA). Sulfo-BSA-Suc and polyethylene glycol (PEG)-Sulfo-BSA-Gal, both released H2S in the 5 mM glutathione solution, but not in the plasma. Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal were taken up by RAW264.7 cells (mouse macrophage-like cells) and Hep G2 cells (human hepatocellular carcinoma cells), respectively, and H2S was released. These results indicate that Sulfo-BSA-Suc and PEG -Sulfo-BSA-Gal selectively released H2S intracellularly. In a biodistribution study, up to 80% of 111In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal rapidly accumulated in the liver, 30 min after intravenous injection in mice. Furthermore, 111In-labeled Sulfo-BSA-Suc and PEG-Sulfo-BSA-Gal predominantly accumulated in liver nonparenchymal (endothelial cells and Kupffer cells) and parenchymal cells (hepatocytes), respectively. These findings suggest that targeted delivery of H2S prodrug to a specific type of liver cells was successfully achieved by bioconjugation.

Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects.

Background and Purpose- A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms. Methods- Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells. Results- Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin. Conclusions- HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.

Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism.

Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice exposed to NO2 and that administration of uricase inhibited the development of OVA-driven allergic airway disease subsequent to OVA challenge, as well as the generation of OVA-specific Abs. However, uricase was itself immunogenic, inducing a uricase-specific adaptive immune response that occurred even when the enzymatic activity of uricase had been inactivated. Inhibition of the OVA-specific response was not due to the capacity of uricase to inhibit the early steps of OVA uptake or processing and presentation by dendritic cells, but occurred at a later step that blocked OVA-specific CD4(+) T cell proliferation and cytokine production. Although blocking uric acid formation by allopurinol did not affect outcomes, administration of ultra-clean human serum albumin at protein concentrations equivalent to that of uricase inhibited NO2-promoted allergic airway disease. These results indicate that, although uric acid levels are elevated in the airways of NO2-exposed mice, the powerful inhibitory effect of uricase administration on allergic sensitization is mediated more through Ag-specific immune deviation than via suppression of allergic sensitization, a mechanism to be considered in the interpretation of results from other experimental systems.

Predictive Value of Serum Albumin Level for the Prognosis of Severe Sepsis Without Exogenous Human Albumin Administration: A Prospective Cohort Study.

BACKGROUND:: The prognostic significance of serum albumin levels in patients with sepsis has previously been reported; however, these studies have not excluded the potential confounding effect of exogenous albumin administration. In this study, we investigate the predictive value of serum albumin for the prognosis of severe sepsis without the interference of exogenous albumin administration. METHODS:: A prospective cohort study was conducted from April to November 2014 in the internal and surgical intensive care units of a tertiary care hospital. During the study period, due to a supply shortage, patients were not treated with human albumin. Serum albumin levels were measured, and laboratory and clinical data were collected at the onset of severe sepsis. Prognostic factors were analyzed using receiver operating characteristic curve and multivariate Cox proportional hazard regression analysis. Survival was assessed by Kaplan-Meier method. RESULTS:: One hundred sixteen patients were included in the study. The overall 28-day mortality was 26.7%. The most common infection sources were lower respiratory tract, abdomen/pelvis, and bloodstream. Compared to patients who survived, those who died had lower serum albumin levels and higher Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Receiver operating characteristic curves demonstrate that albumin level is a strong predictor of 28-day mortality, and the optimal cutoff value maximizing sensitivity and specificity is 29.2 g/L. Through multivariate Cox regression analysis, low serum albumin levels (<29.2 g/L) and APACHE II scores are identified as independent risk factors for mortality. Patients with lower serum albumin levels more often had abdominal/pelvic sources of infection, acute kidney or liver injury, septic shock, and higher APACHE II and SOFA scores. The 28-day survival rate was lower for patients with serum albumin below 29.2 g/L than for patients with serum albumin at or above this level. CONCLUSION:: Having excluded potential confounding effect of exogenous albumin administration, low serum albumin levels are associated with an increased risk of death in patients with severe sepsis.

Transport of AOPP-Albumin into Human Alveolar Epithelial A549 Cell.

PURPOSE: Alveolar clearance of proteins, such as albumin, plays an essential role in recovery from lung injuries. Albumin is known to be oxidized by reactive oxygen species (ROS), leading to generation of advanced oxidation protein products (AOPP)-albumin in the alveolar lining fluid. In this study, we aimed to characterize the uptake of FITC-labeled AOPP-albumin (FITC-AOPP-albumin) into human alveolar epithelial cell line, A549. METHODS: FITC-AOPP-albumin uptake into A549 cells and its effect of ROS generation was evaluated using fluorescence spectrometer and flow cytometry, respectively. RESULTS: FITC-AOPP-albumin was taken up by A549 cells in a time- and temperature-dependent fashion, and showed saturation kinetics with a Km value of 0.37 mg/mL. The uptake of FITC-AOPP-albumin was suppressed by phenylarsine oxide, a clathrin-mediated endocytosis inhibitor, but not by indomethacin and nystatin, caveolae-mediated endocytosis inhibitors, or 5-(N-ethyl-N-isopropyl) amiloride, a macropinocytosis inhibitor. AOPP-albumin induced ROS generation in A549 cells, suggesting that alveolar clearance of AOPP-albumin should be important to prevent further ROS generation. CONCLUSION: AOPP-albumin is transported into alveolar epithelial cells through clathrin-mediated endocytosis, which may be important to prevent further ROS generation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Fluid therapy and shock: an integrative literature review.

BACKGROUND: shock refers to a physiological situation that puts life at risk. Its early identification and the timely institution of therapeutic measures can avoid death. Despite the frequent administration of fluid therapy as a treatment for shock, the type and dose of fluids to be delivered remain undetermined. AIM: to determine the type of fluids to be administered and the type of approach to be performed in the different types of shock. METHOD: integrative literature review. RESULTS: data about fluid therapy in hypovolaemic and distributive shock were obtained, specifically in the haemorrhagic and the septic types. None of the articles addressed cardiogenic shock. CONCLUSION: hypotensive resuscitation, with blood, is the most appropriate approach in haemorrhagic shock. There remains a question regarding the best approach in septic shock. However, conservative fluid therapy seems to be appropriate, with preference given to the administration of balanced crystalloids or albumin as an alternative.

Albumin-Based Nitric Oxide Traffic System for the Treatment of Intractable Cancers.

Biomacromolecules (>40 kDa) have been developed as drug delivery system (DDS) carriers of low-molecular weight drugs to promote these drugs' uptake by cancer tissues via enhanced permeability and retention (EPR) effects. Human serum albumin (HSA) has been found to accumulate in cancer tissues via this EPR effect. HSA is the most abundant protein in serum, which performs essential physiological functions such as the transportation of many endogenous and exogenous ligands. Nitric oxide (NO) is a very small ligand of HSA; it is a unique and diffusible molecular messenger that plays a central role in mammalian physiology. Although the in vivo half-life of NO is extremely short, HSA could prolong the half-life of NO via S-nitrosation at the position of Cys-34. S-Nitrosated HSA (mono-SNO-HSA) is called an 'Endogenous NO traffic protein,' due to the highly stable S-nitroso form in circulating blood, and to the efficiency of S-transnitrosation in cells that require NO. Mono-SNO-HSA possesses a very strong cytoprotective action via the induction of heme oxygenase-1. On the other hand, HSA reinforced with approximately seven NO molecules (poly-SNO-HSA), which we developed by means of chemical modification, possesses multiple anticancer activities. Our previous data clarified that the high expression of protein disulfide isomerase on the surface of cancer cells plays a very important role in the anticancer action of poly-SNO-HSA. In this review, we focus on the advantage of poly-SNO-HSA in treating intractable cancers from the viewpoint of drug delivery systems and drug resistance.

Volume of Plasma Expansion and Functional Outcomes in Stroke.

BACKGROUND: Plasma expansion in acute ischemic stroke has potential to improve cerebral perfusion, but the long-term effects on functional outcome are mixed in prior trials. The goal of this study was to evaluate how the magnitude of plasma expansion affects neurological recovery in acute stroke. METHODS: This was a secondary analysis of data from the Albumin in Acute Stroke Part 2 trial investigating the relationship between the magnitude of overall intravenous volume infusion (crystalloid and colloid) to clinical outcome. The data were inclusive of 841 patients with a mean age of 64 years and a median National Institutes of Health Stroke Scale (NIHSS) of 11. In a multivariable-adjusted logistic regression model, this analysis tested the volume of plasma expansion over the first 48 h of hospitalization as a predictor of favorable outcome, defined as either a modified Rankin Scale score of 0 or 1 or a NIHSS score of 0 or 1 at 90 days. This model included all study patients, irrespective of albumin or isotonic saline treatment. RESULTS: Patients that received higher volumes of plasma expansion more frequently had large vessel ischemic stroke and higher NIHSS scores. The multivariable-adjusted model revealed that there was decreased odds of a favorable outcome for every 250 ml additional volume plasma expansion over the first 48 h (OR 0.91, 95 % CI, 0.88-0.94). CONCLUSIONS: The present study demonstrates an association between greater volume of plasma expansion and worse neurological recovery.

Inducing Controlled Release and Increased Tumor-Targeted Delivery of Chlorambucil via Albumin/Liposome Hybrid Nanoparticles.

Liposomes possess good biocompatibility and excellent tumor-targeting capacity. However, the rapid premature release of lipophilic drugs from the lipid bilayer of liposomes has negative effect on the tumor-targeted drug delivery of liposomes. In this study, a lipophilic antitumor drug-chlorambucil (CHL)-was encapsulated into the aqueous interior of liposomes with the aid of albumin to obtain the CHL-loaded liposomes/albumin hybrid nanoparticles (CHL-Hybrids). The in vitro accumulative release rate of CHL from CHL-Hybrids was less than 50% within 48 h, while the accumulative CHL release was more than 80% for CHL-loaded liposomes (CHL-Lip). After intravenous injection into rats, the half-life (t 1/2ß = 5.68 h) and maximum blood concentration (C max = 4.58 µg/mL) of CHL-Hybrids were respectively 1.1 times and 3.5 times higher than that of CHL-Lip. In addition, CHL-Hybrids had better tumor-targeting capacity for it significantly increased the drug accumulation in B16F10 tumors, which contributed to the significantly control of tumor growth compared with CHL-Lip. Furthermore, CHL-Hybrid-treated B16F10 melanoma-bearing mice displayed the longest median survival time of 30.0 days among all the treated groups. Our results illustrated that the proposed hybrids drug delivery system would be a promising strategy to maintain the controlled release of lipophilic antitumor drugs from liposomes and simultaneously facilitate the tumor-targeted drug delivery.

A Phase III Study of Balugrastim Versus Pegfilgrastim in Breast Cancer Patients Receiving Chemotherapy With Doxorubicin and Docetaxel.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of once-per-cycle balugrastim versus pegfilgrastim for neutrophil support in breast cancer patients receiving myelosuppressive chemotherapy. METHODS: Breast cancer patients (n = 256) were randomized to 40 or 50 mg of subcutaneous balugrastim or 6 mg of pegfilgrastim ≈24 hours after chemotherapy (60 mg/m(2) doxorubicin and 75 mg/m(2) docetaxel, every 21 days for up to 4 cycles). The primary efficacy parameter was the duration of severe neutropenia (DSN) in cycle 1. Secondary parameters included DSN (cycles 2-4), absolute neutrophil count (ANC) nadir, febrile neutropenia rates, and time to ANC recovery (cycles 1-4). Safety, pharmacokinetics, and immunogenicity were assessed. RESULTS: Mean cycle 1 DSN was 1.0 day with 40 mg of balugrastim, 1.3 with 50 mg of balugrastim, and 1.2 with pegfilgrastim (upper limit of 95% confidence intervals for between-group DSN differences was <1.0 day for both balugrastim doses versus pegfilgrastim). Between-group efficacy parameters were comparable except for time to ANC recovery in cycle 1 (40 mg of balugrastim, 2.0 days; 50 mg of balugrastim, 2.1; pegfilgrastim, 2.6). Median terminal elimination half-life was ≈37 hours for 40 mg of balugrastim, ≈36 for 50 mg of balugrastim, and ≈45 for pegfilgrastim. Antibody response to balugrastim was low and transient, with no neutralizing effect. CONCLUSION: Once-per-cycle balugrastim is not inferior to pegfilgrastim in reducing cycle 1 DSN in breast cancer patients receiving chemotherapy; both drugs have comparable safety profiles. IMPLICATIONS FOR PRACTICE: This paper provides efficacy and safety data for a new, once-per-cycle granulocyte colony-stimulating factor, balugrastim, for the prevention of chemotherapy-induced neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. In this phase III trial, balugrastim was shown to be not inferior to pegfilgrastim in the duration of severe neutropenia in cycle 1 of doxorubicin/docetaxel chemotherapy, and the safety profiles of the two agents were similar. Once-per-cycle balugrastim is a safe and effective alternative to pegfilgrastim for hematopoietic support in patients with breast cancer receiving myelosuppressive chemotherapy associated with a greater than 20% risk of developing febrile neutropenia.

The low molecular weight fraction of human serum albumin upregulates production of 15d-PGJ2 in Peripheral Blood Mononuclear Cells.

Activation of the innate immune system involves a series of events designed to counteract the initial insult followed by the clearance of debris and promotion of healing. Aberrant regulation can lead to systemic inflammatory response syndrome, multiple organ failure, and chronic inflammation. A better understanding of the innate immune response may help manage complications while allowing for proper immune progression. In this study, the ability of several classes of anti-inflammatory drugs to affect LPS-induced cytokine and prostaglandin release from peripheral blood mononuclear cells (PBMC) was evaluated. PBMC were cultured in the presence of dexamethasone (DEX), ibuprofen (IBU), and the low molecular weight fraction of 5% albumin (LMWF5A) followed by stimulation with LPS. After 24 h, TNFα, PGE2, and 15d-PGJ2 release was determined by ELISA. Distinct immunomodulation patterns emerged following LPS stimulation of PBMC in the presence of said compounds. DEX, a steroid with strong immunosuppressive properties, reduced TNFα, PGE2, and 15d-PGJ2 release. IBU caused significant reduction in prostaglandin release while TNFα release was unchanged. An emerging biologic with known anti-inflammatory properties, LMWF5A, significantly reduced TNFα release while enhancing PGE2 and 15d-PGJ2 release. Incubating LMWF5A together with IBU negated this observed increased prostaglandin release without affecting the suppression of TNFα release. Additionally, LMWF5A caused an increase in COX-2 transcription and translation. LMWF5A exhibited a unique immune modulation pattern in PBMC, disparate from steroid or NSAID administration. This enhancement of prostaglandin release (specifically 15d-PGJ2), in conjunction with a decrease in TNFα release, suggests a switch that favors resolution and decreased inflammation.

Doxorubicin-Bound Albumin Nanoparticles Containing a TRAIL Protein for Targeted Treatment of Colon Cancer.

PURPOSE: We developed a new nanoparticle formulation comprised of human serum albumin (HSA) for co-delivery of doxorubicin (Dox) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with the goal of apoptotic synergy in the treatment of colon cancer. METHODS: TRAIL (0.2, 0.4, 1.0%)- and Dox-loaded HSA nanoparticles (TRAIL/Dox HSA NPs) were prepared by using the nab(TM) technology. Morphological and physicochemical characterizations were investigated by dynamic light scattering and transmission electron microscopy. Synergistic cytotoxicity, apoptotic activity, and potential penetration into mass tumor were determined in HCT116 cell-based systems. Furthermore, antitumor efficacy and tumor targeting were also investigated. RESULTS: TRAIL/Dox HSA NPs were uniformly spherical with sizes of 60 ~ 120 nm. The encapsulation efficacy of Dox and TRAIL was 68.9-77.2% and 80.4-86.0%, respectively. TRAIL 1.0%/Dox HSA NPs displayed the best inhibition of HCT116 colon cancer cells; inhibition was 6 times higher than achieved with Dox HSA NPs. The TRAIL 1.0%/Dox HSA NPs formulation was studied further. Flow cytometry analysis and TUNEL assay revealed that TRAIL 1.0%/Dox HSA NPs had markedly greater apoptotic activity than Dox HSA NPs. In HCT116 tumor-bearing BALB/c nu/nu mice, TRAIL 1.0%/Dox HSA NPs had significantly higher antitumor efficacy than Dox HSA NPs (tumor volume; 933.4 mm(3) vs. 3183.7 mm(3), respectively). TRAIL 1.0%/Dox HSA NPs penetrated deeply into tumor masses in a HCT116 spheroid model and localized in tumor sites after tail vein injection. CONCLUSIONS: Data indicate that TRAIL 1.0%/Dox HSA NPs offer advantages of co-delivery of Dox and TRAIL in tumors, with potential synergistic apoptosis-based anticancer therapy.

The correlation between preoperative levels of albumin and tlc and mortality in patients with femoral neck fracture.

A femoral neck fracture in an elderly patient often represents a major challenge for the orthopaedic surgeon who has to face not only the fracture, but also all the multiple issues related to age. Among others, malnutrition has been recognised as an important factor associated with severe aggravation in these patients. One-hundred-and-forty-seven patients were enrolled to investigate the use of two markers of patient nutritional status, i.e. serum albumin level and total leukocyte count (TLC), as predictors of mortality in the elderly patient suffering from proximal femur fracture. We found that low preoperative values of serum albumin and TLC proved to be directly related to worse outcomes. Therefore, these exams can be useful to identify patients with a femoral neck fracture that have higher risk of malnutrition and consequent higher mortality and that can benefit from some measures, such as albumin or protein nutritional supplement.

Volume expanders for the prevention of ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a serious and potentially fatal complication of ovarian stimulation which affects 1% to 14% of all in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles. A number of clinical studies with conflicting results have reported on the use of plasma expanders such as albumin, hydroxyethyl starch (HES), mannitol, polygeline and dextran as a possible intervention for the prevention of OHSS. Women with very high estradiol levels, high numbers of follicles or oocytes retrieved, and women with polycystic ovary syndrome (PCOS), are at particularly high risk of developing OHSS. Plasma expanders are not commonly used nowadays in ovarian hyperstimulation. This is mainly because clinical evidence on their effectiveness remains sparse, because of the low incidence of moderate and severe ovarian hyperstimulation syndrome (OHSS) and the simultaneous introduction of mild stimulation approaches, gonadotropin-releasing hormone (GnRH) antagonist protocols and the freeze-all strategy for the prevention of OHSS. OBJECTIVES: To review the effectiveness and safety of administration of volume expanders for the prevention of moderate and severe ovarian hyperstimulation syndrome (OHSS) in high-risk women undergoing IVF or ICSI treatment cycles. SEARCH METHODS: We searched databases including the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and trial registers to September 2015; no date restrictions were used as new comparators were included in this search. The references of relevant publications were also searched. We attempted to contact authors to provide or clarify data that were unclear from trial or abstract reports. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing volume expanders versus placebo or no treatment for the prevention of OHSS in high-risk women undergoing ovarian hyperstimulation as part of any assisted reproductive technique. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies, assessed risk of bias and extracted relevant data. The primary review outcome was moderate or severe OHSS. Other outcomes were live birth, pregnancy and adverse events. We combined data to calculate pooled Peto odds ratios (ORs) and 95% confidence intervals (CIs) for each intervention. Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for each comparison, using GRADE methods. MAIN RESULTS: We included nine RCTs (1867 women) comparing human albumin (seven RCTs) or HES (two RCTs) or mannitol (one RCT) versus placebo or no treatment for prevention of OHSS. The evidence was very low to moderate quality for all comparisons. The main limitations were imprecision, poor reporting of study methods, and failure to blind outcome assessment.There was evidence of a beneficial effect of intravenous albumin on OHSS, though heterogeneity was substantial (Peto OR 0.67 95% CI 0.47 to 0.95, seven studies, 1452 high risk women; I² = 69%, very low quality evidence) . This suggests that if the rate of moderate or severe OHSS with no treatment is 12%, it will be about 9% (6% to12%) with the use of intravenous albumin. However, there was evidence of a detrimental effect on pregnancy rates (Peto OR 0.72 95% CI 0.55 to 0.94, I² = 42%, seven studies 1069 high risk women, moderate quality evidence). This suggests that if the chance of pregnancy is 40% without treatment, it will be about 32% (27% to 38%) with the use of albumin.There was evidence of a beneficial effect of HES on OHSS (Peto OR 0.27 95% CI 0.12 to 0.59, I² = 0%, two studies, 272 women, very low quality evidence). This suggests that if the rate of moderate or severe OHSS with no treatment is 16%, it will be about 5% (2% to 10%) with the use of HES. There was no evidence of an effect on pregnancy rates (Peto OR 1.20 95% CI 0.49 to 2.93, one study, 168 women, very low quality evidence).There was evidence of a beneficial effect of mannitol on OHSS (Peto OR 0.38, 95% CI 0.22 to 0.64, one study, 226 women with PCOS, low quality evidence). This means that if the risk of moderate or severe OHSS with no treatment is 52%, it will be about 29% (19% to 41%) with mannitol. There was no evidence of an effect on pregnancy rates (Peto OR 0.85 95% CI 0.47 to 1.55; one study, 226 women, low quality evidence).Live birth rates were not reported in any of the studies. Adverse events appeared to be uncommon, but were too poorly reported to reach any firm conclusions. AUTHORS' CONCLUSIONS: Evidence suggests that the plasma expanders assessed in this review (human albumin, HES and mannitol) reduce rates of moderate and severe OHSS in women at high risk. Adverse events appear to be uncommon, but were too poorly reported to reach any firm conclusions, and there were no data on live birth. However, there was evidence that human albumin reduces pregnancy rates. While there was no evidence that HES, or mannitol had any influence on pregnancy rates, the evidence of effectiveness was based on very few trials which need to be confirmed in additional, larger randomised controlled trials (RCTs) before they should be considered for routine use in clinical practice.

Albumin dialysis with MARS for the treatment of anabolic steroid-induced cholestasis.

 Background and aims. Steroid-related hepatotoxicity has become one of the most relevant causes of drug induced liver cholestasis. Some patients do not improve after standard medical treatment (SMT) and may therefore require other approaches, like extracorporeal liver support. MATERIAL AND METHODS: We report four cases of patients with pruritus, abnormal liver function tests and biopsy-proven anabolic steroid-induced cholestasis who were unresponsive to SMT. They underwent treatment with albumin dialysis (Molecular Adsorbent Recirculating System -MARS®-). A minimum of two MARS sessions were performed. RESULTS: After MARS® procedure, patients' symptoms improved, as well as liver function tests, thus avoiding liver transplantation. CONCLUSION: Albumin dialysis appears as a valuable therapeutic option for the management of anabolic steroid-induced cholestasis in patients that are unresponsive to SMT.