Tissues Of Vital Organs Research Articles

New Approaches to Treating Cardiac Cachexia in the Older Patient.

Congestive heart failure (CHF) is a leading cause of morbidity and mortality in the elderly, accounting for more hospitalizations than any other condition. Advanced stages of congestive heart failure can be associated with serious complications such as cardiac cachexia (defined here as unintentional weight loss of more than 6% in 6 months). Cardiac cachexia and the associated progressive weight loss are sometimes overlooked by older patients, their families and care providers. A delay in the diagnosis can result in further loss of vital organ tissue, progressive weakness, fall-related injuries and even long-term care institutionalization and/or death. During the past several years, researchers have begun to broaden their understanding of this common, morbid and often fatal condition, and these findings will help to characterize the features that assist in its diagnosis, minimize its exacerbation, delay the progressive decline, and educate clinicians about the potential management options.

Intravenous perfluorocarbons for prevention of ventilator-associated ARDS

Emulsified perfluorocarbons (PFC) are synthetic hydrocarbons that can carry 50 times more oxygen than human plasma. Their properties may be advantageous in applications requiring preservation of tissue viability in oxygen-deprived states [1,2], making them a potential candidate for combat and civilian prehospital resuscitation. Our hypothesis is that an intravenous dose of PFC increases vital organ tissue oxygenation, improves survival after hemorrhagic shock (HS) and may reduce or prevent the development of ventilator-associated ARDS. Here we report data from the first part (HS only) of a multiphase swine study to study the benefits of PFC in treating HS and preventing ARDS. This initial study was designed to ensure safe use of PFC in traumatized animals.

Targeting the hypoxia-adenosinergic signaling pathway to improve the adoptive immunotherapy of cancer

The recent approval by the FDA of cancer vaccines and drugs that blockade immunological negative regulators has further enhanced interest in promising approaches of the immunotherapy of cancer. However, the disappointingly short life extension has also underscored the need to better understand the mechanisms that prevent tumor rejection and survival even after the blockade of immunological negative regulators. Here, we describe the implications of the "metabolism-based" immunosuppressive mechanism, where the local tissue hypoxia-driven accumulation of extracellular adenosine triggers suppression via A2 adenosine receptors on the surface of activated immune cells. This molecular pathway is of critical importance in mechanisms of immunosuppression in inflamed and cancerous tissue microenvironments. The protection of tumors by tumor-generated extracellular adenosine and A2 adenosine receptors could be the misguided application of the normal tissue-protecting mechanism that limits excessive collateral damage to vital organs during the anti-pathogen immune response. The overview of the current state of the art regarding the immunosuppressive effects of extracellular adenosine is followed by a historical perspective of studies focused on the elucidation of the physiological negative regulators that protect tissues of vital organs from excessive collateral damage, but, as a trade-off, may also weaken the anti-pathogen effector functions and negate the attempts of anti-tumor immune cells to destroy cancerous cells.

Antioxidant and Tissue-Protective Studies on Ajwa Extract: Dates from Al-Madinah Al-Monwarah, Saudia Arabia

The objective was to study the in-vivo protective effect of Al-Madinah Ajwa (name of the most famous date in Al-Madinah Al-Monwarah City) extract against lead acetate toxicity on the tissues of vital organs. Four rabbit groups were used as an animal model for this study. Ajwa extract treated group (300 mg/kg/day, for 14 days) were evaluated for lead acetate (500 ppm in drinking water for 14 days) intoxication compared to lead acetate alone-intoxicated group; Ajwa extract group and control group. This was done by assessment of liver and kidney functions, blood lead levels, levels of oxidants-antioxidants and histopathological changes in liver, kidney, heart and lung in different groups. The lead acetate intoxicated group showed significant elevation of serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin (TB), serum creatinine-urea (Cr-U), lipid hydroperoxide (LPO), protein carbonyl content (PCC), and depression of Superoxide dismutase (SOD) and Glutathione peroxidase (GPX) levels as compared to control. The Agwa extract showed tissue protective effect by significant restoration of (SGPT), (SGOT), (ALP), (TB), (Cr-U) (LPO), (PCC), (SOD) and (GPX) levels compared to the previous group. The histopathological evaluation showed marked vascular congestion, interstitial hemorrhage, cellular degeneration and necrosis in different organs of lead acetate intoxicated group, while Agwa extract treated group showed mild congestion and slight focal cellular degeneration. Therefore, outcome of the present study validates the ameliorative and protective effects of Al-Madinah Ajwa dates against the toxic effects of lead acetate poisoning.

Value of MR contrast media in image-guided body interventions

In the past few years, there have been multiple advances in magnetic resonance (MR) instrumentation, in vivo devices, real-time imaging sequences and interventional procedures with new therapies. More recently, interventionists have started to use minimally invasive image-guided procedures and local therapies, which reduce the pain from conventional surgery and increase drug effectiveness, respectively. Local therapy also reduces the systemic dose and eliminates the toxic side effects of some drugs to other organs. The success of MR-guided procedures depends on visualization of the targets in 3D and precise deployment of ablation catheters, local therapies and devices. MR contrast media provide a wealth of tissue contrast and allows 3D and 4D image acquisitions. After the development of fast imaging sequences, the clinical applications of MR contrast media have been substantially expanded to include pre- during- and post-interventions. Prior to intervention, MR contrast media have the potential to localize and delineate pathologic tissues of vital organs, such as the brain, heart, breast, kidney, prostate, liver and uterus. They also offer other options such as labeling therapeutic agents or cells. During intervention, these agents have the capability to map blood vessels and enhance the contrast between the endovascular guidewire/catheters/devices, blood and tissues as well as direct therapies to the target. Furthermore, labeling therapeutic agents or cells aids in visualizing their delivery sites and tracking their tissue distribution. After intervention, MR contrast media have been used for assessing the efficacy of ablation and therapies. It should be noted that most image-guided procedures are under preclinical research and development. It can be concluded that MR contrast media have great value in preclinical and some clinical interventional procedures. Future applications of MR contrast media in image-guided procedures depend on their safety, tolerability, tissue specificity and effectiveness in demonstrating success of the interventions and therapies.

Acute toxicity impacts of Euphorbia hirta L extract on behavior, organs body weight index and histopathology of organs of the mice and Artemia salina

Background:The methanol extract of Euphorbia hirta L (Euphorbiaceae), which is used in traditional medicines, was tested for in vivo toxicity.Materials and Methods:In vivo brine shrimp lethality assay and oral acute toxicity study at single high dose of 5000 mg/kg and observation for 14 days in mice were used to study the toxic effect of E. hirta.Results:Brine shrimp lethality assay was used to calculate the median lethal concentration (LC50) of E. hirta (for leaves, stems, flowers and roots) methanolic extracts at concentrations from 100 to 0.07 mg/ml. The LC50 values of 1.589, 1.420, 0.206 and 0.0827 mg/ml were obtained for stems, leaves, flowers and roots, respectively. Potassium dichromate (the positive control) had LC50 value of 0.00758 mg/ml. The acute oral toxicity study of the leaf extract resulted in one third mortality and mild behavioral changes among the treated mice. No significant statistical differences found between body weight, relative (%) and absolute (g) organ weights of treated and untreated groups (P> 0.05). Gross and microscopic examination of the vital organ tissues revealed no differences between control and treated mice. All the tissues appeared normal.Conclusions:E. hirta leaves methanol extract has exhibited mild toxic effects in mice.

Vital Organ Tissue Oxygenation After Serial Normovolemic Exchange Transfusion with HBOC-201 in Anesthetized Swine

This study determined the effects of serial, normovolemic, stepwise exchange transfusions with either 6% human serum albumin (HSA) or the hemoglobin-based oxygen carrier, HBOC-201, on tissue oxygenation of the heart, brain, and kidney in intact anaesthetized pigs. Exchange transfusions to 10%, 30%, and 50% of the pigs' total blood volume were completed at a withdrawal rate of 1.0 mL·kg(-1)·min(-1) followed by an infusion rate of 0.5 mL·kg(-1)·min(-1) of HBOC-201 or iso-oncotically matched 6% HSA. Measurements included invasive systemic hemodynamic (blood pressures, left ventricular end-diastolic pressure), hematolic (hemoglobin, hematocrit, methemoglobin), acid-base (pH, PCO2), and biochemistry (serum lactate) measurements. Brain and kidney tissue oxygenation (tPO2) was determined by electron paramagnetic resonance and heart tPO2 by O2 sensitive fiberoptic probe. The main results demonstrated that tPO2 after HBOC-201 remained stable despite significant decreases in hematocrit and changing hemodynamics. In vivo tPO2 measurements (heart tPO2 average ≥22 mmHg, brain tPO2 average ≥8 mmHg, and kidney tPO2 average ≥10 mmHg) were maintained in all groups at all times. Blood pressures were 20 to 30 mmHg higher after HBOC-201 compared with HSA controls. Heart rate and left ventricular end-diastolic pressure were not different among treatment groups. In conclusion, the administration of HBOC-201 maintained tPO2 in three vital organs after profound hemodilution.

Characterization of biological activity of Scatophagus argus venom

Scatophagus argus of the family Scatophagidae inflicts painful wounds in fishermen while handling it. The venom induces prominent local tissue damage characterized by pain, edema and necrosis. The pathogenesis of acute muscle damage in gastrocnemius muscle induced by S. argus venom was studied in mice. The inflammatory response induced by S. argus venom in the mice hind paw was studied measuring paw edema. Intramuscular injection of S. argus venom induced motoxicity. The effect of S. argus venom on the cellular components of inflammatory response was investigated. Venom from S. argus were quantitatively analyzed for enzymic and biochemical activity. The biochemical changes induced by the sublethal concentration of S. argus venom and histopathological studies of effect of venom on mice were carried out. Venom induced a rapid increment in serum creatine kinase (CK) and lactate dehydrogenase (LDH) showing the myotoxicity of venom. Concomitant with this a reduction of muscle CK and LDH activity was observed, where as no increment in muscle lactate was detected. Our findings showed that the edematic activity was dose dependent and remained significantly elevated over 48 h after injection. Administration of S. argus venom caused a significant cell accumulation of neutrophils in to peritoneal cavity as well as foot pad up to 24 h with maximal being at 4–6 h. The venom components analyzed showed the presence of phosphodiesterase, acid phosphatases, alkaline phosphatases, proteinase, and caseinolytic activity. SDS PAGE revealed the presence of major and minor protein bands between 6.5 and 68 kDa. The biochemical changes induced by the sublethal concentration of S. argus venom showed reversible changes in the hematological (blood cell count, hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin and platelet count) parameters which were significantly altered at 6 and 24 h (GLM repeated measures p < 0.05). Serum enzymes such as AST, ALT, ACP, ALP, LDH and urea were altered significantly which in turn confirmed the damage of vital organ tissue.

Clinico-toxinological characterization of the acute effects of the venom of the marine snail, Conus loroisii

The venom of the marine snail, Conus loroisii, was studied to assess its risk and lethal factors in regard of human welfare. The lethality of the crude venom (LD 50-5.0 mg/kg via i.p.) in mice was associated with reduced motor activity, asphyxiation, followed by respiratory failure. The effects on vital tissues revealed vascular congestion and inflammatory cell infiltration around the portal triad of the liver, spongiosis of the brain, hemorrhages/congested blood vessels in lung and endothelial cells of the renal tubule. Repeated measures of hematological profiles indicated that the venom significantly reduced erythrocytes ( P < 0.001, GLM repeated measures), followed associated with depletion of hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and platelet count. Serum enzymes such as, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase and alkaline and acid phosphatases were altered significantly ( P < 0.05, Friedman test), which in turn confirmed the damage of vital organ tissues. Dual effect of the venom on the activity of mouse brain acetylcholinesterase stand for concentration specific, whereas maximal inhibition (60.41%, P < 0.05, Wilcoxon signed rank test) in erythrocyte acetylcholinesterase did not show the dual activity observed in brain. The Ciphergen ProteinChip ® analysis of the envenomed serum further revealed that the venom causes changes in definite molecules involved in inflammatory process and ionic transport. In all, the venom of C. loroisii is potentially lethal to mammals, through its rapid action on the central and peripheral nervous systems by blocking neurotransmission with selective interference of ionic channels/receptors.

Anti-Tumor Activity of KOS-953, a Cremophor-Based Formulation of the hsp90 Inhibitor 17-AAG.

We have previously shown that inhibitors of the hsp90 molecular chaperone (including geldanamycin, 17-allylamino-17-demethoxy-geldanamycin (17-AAG) and other members of the ansamycin family) have in vitro and in vivo activity against MM cells (including drug-sensitive and -resistant cells) and confer sensitization to several other anti-tumor agents. An extensive program of phase I clinical trials in solid tumors has documented biological activity of 17-AAG with manageable hsp90 inhibitor-related toxicities and has identified maximum tolerated doses for further clinical development. These first trials involved an intravenous formulation of 17-AAG in DMSO and egg-phospholipids. As such, it is believed that the formulation may have contributed to some of the observed side effects of 17-AAG administration; and conversely, that alternative formulations of 17-AAG in clinically inert excipients might potentially allow for administration of higher doses of 17-AAG and more favorable clinical outcomes. In this study, we describe the in vitro and in vivo clinical profile of KOS-953, a cremophor-based 17-AAG formulation. In our in vitro studies, KOS-953 exhibits comparable anti-MM activity to DMSO-based 17-AAG, including activity against a broad spectrum of MM cell lines and primary cells which are both sensitive and resistant to cytotoxic chemotherapeutics, proteasome inhibitor bortezomib, thalidomide or its derivatives. Consistent with prior experience on DMSO-based formulations of 17-AAG, KOS-953 triggered intracellular depletion of several key kinases, including Akt, Raf, IKK-a; decreased the constitutive and cytokine-induced activity of NF-κB; and suppressed expression of diverse intracellular anti-apoptotic proteins (e.g. FLIP, XIAP, survivin); leading to tumor cell sensitization to other pro-apoptotic agents (e.g. cytotoxic chemotherapy, PS-341). Importantly, we evaluated the in vivo anti-tumor activity of KOS-953 in our SCID/NOD mouse model of diffuse MM bone lesions. In this model, mice with bioluminescence imaging-confirmed diffuse skeletal lesions were randomly assigned to receive either KOS-953 (50 mg/kg i.p., twice weekly) or equal volume of vehicle. Mice in both cohorts were followed-up serially by whole-body real-time fluorescence imaging and whole-body bioluminescence imaging, models previously validated in separate studies of our group. The primary endpoint of the study was the overall survival of mice, defined as time between injection of tumor cells and sacrifice for hind limb paralysis, moribund state, or death. KOS-953 treatment was associated with prolongation of overall survival of mice (p<0.05, log-rank test), and was well tolerated, without vital organ tissue damage in histopathologic analyses. These findings indicate that alternative 17-AAG formulations, such as cremophor-based ones, can deliver biologically-active doses of 17-AAG and achieve anti-tumor responses. Coupled with our accumulating experience on the role of hsp90 for MM cell proliferation, survival and drug-resistance, the current study therefore provides the preclinical framework for further clinical evaluation of hsp90 inhibitors, such as KOS-953, to improve treatment outcome in MM.

Pathomorphogenesis of tubercular histologic changes: mechanisms of granuloma formation, maintenance and necrosis

The histopathological hallmark of infections with Mycobacterium tuberculosis is the development of centrally necrotizing granulomatous lesions. Granulomas are focal accumulations of mononuclear cells in various states of differentiation, in which the local activation of mycobacteria-infected macrophages by specific T cells takes place. On the one hand, this assures efficient containment of mycobacterial growth and demarcation of the infectious focus. On the other hand this is associated with the displacement of and irreversible damage to functionally vital organ tissue (predominantly in the lungs). New insights, emerging from animal models of infection, into the dynamic mechanisms regulating the induction, maintenance and caseation of tuberculous granulomas explain why highly effective anti-inflammatory therapies, e. g. administration of anti-TNF monoclonal antibodies, may result in reactivation of tuberculosis.

Decompensation characterized by decreased perfusion of the heart and brain during hemorrhagic shock: role of endothelin-1.

Endothelin-1 (ET-1), a 21-amino-acid peptide produced by vascular endothelium, is a potent vasoconstrictor and a component of local regulation of vascular tone through its effect on underlying vascular smooth muscle. Hemorrhagic shock (HS) is characterized by compensatory regional vasoconstriction to decrease peripheral tissue perfusion and to maintain core organ perfusion. Decompensation occurs with prolonged duration of HS. In the present study, we hypothesized that systemic and vital organ tissue ET-1 concentrations would correlate with changes in systemic and vital organ perfusion associated with compensatory and decompensatory states of HS. After surgical instrumentation, HS was induced in male Sprague-Dawley rats by withdrawing blood via femoral artery to a mean arterial pressure of 35 to 40 mm Hg that was maintained for either 30 minutes or 90 minutes in separate groups of male Sprague-Dawley rats. Systemic hemodynamics and regional blood flow were measured using a radioactive microsphere technique. In separate groups of animals, sham, 30 minutes of HS, or 90 minutes of HS, plasma and tissue concentrations of ET-1 were determined using a radioimmunoassay technique. HS maintained for 90 minutes was associated with increased arterial base deficit from 3.6 +/- 0.53 mEq/L to 13 +/- 0.37 mEq/L, decreased cardiac output from 79 +/- 18 mL/min to 18 +/- 5 mL/min, and increased systemic vascular resistance from 1,004 +/- 102 mm Hg/L. min to 2,392 +/- 447 mm. Hg/L min as compared with baseline values. With 90 minutes of HS as compared with 30 minutes of HS, perfusion was significantly decreased in brain (72 +/- 11 vs. 29 +/- 6 mL/min. 100 g tissue) and heart (483 +/- 30 vs. 173 +/- 38 mL/min. 100 g tissue) and kidney perfusion was decreased (from 114 +/- 28 mL/min/100 g tissue to 29 +/- 2 mL/min. 100 g tissue), and ET-1 concentration was increased significantly in brain (cerebral cortex, 89 +/- 14 pg/100 g tissue to 144 +/- 19 pg/100 g tissue; midbrain, 172 +/- 15 pg/100 g tissue to 211 +/- 10 pg/100 g tissue), heart (left ventricle, 312 +/- 11 pg/100 g tissue to 360 +/- 14 pg/100 g tissue), kidney (medulla, 857 +/- 61 pg/100 g tissue to 1,277 +/- 41 pg/100 g tissue), and plasma (5.31 +/- 0.6 pg/100 g tissue to 21.26 +/- 2.9 pg/mL). Decreased vital organ and peripheral tissue perfusion, a primary decompensation effect of HS, was apparent with 90 minutes of HS but not with 30 minutes, and was associated with increased vital organ tissue and plasma ET-1 concentrations. These data suggest a role for ET-1 in control mechanisms of progressive vasoconstriction that occurs with prolonged duration of HS.

Elimination of paraquat.

There is a striking discrepancy between the efficacy of the kidneys, haemodialysis and haemoperfusion in removing paraquat from the body and the poor prognosis of paraquat poisoning even when the blood and urine concentrations (which are good indices of concentrations in lung and other tissues) are very low. Extracorporeal elimination techniques have been used world-wide in paraquat poisoning. Do they remove paraquat effectively? Certainly. Do they increase the survival rate? Probably not. The reason being that when these techniques of elimination are initiated, potentially lethal concentrations of paraquat have already been attained in the highly vascular tissues of vital organs and in pneumocytes. The data presented here suggest that the successful treatment of paraquat poisoning will not be achieved by modification of toxicokinetics.