Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012739 (disseminated intravascular coagulation)
 8,673 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhabdomyolysis is a severe clinical symptom of variable etiology. Acquired factors of exogenous origin such as traumata and endogenous metabolic disturbances have to be separated from hereditary disease as causative mechanism. Most frequently, exertional stress during hyperthermia, traumatic damage or ethanol abuse are observed. Almost independent of the diverse initial events, the pathogenesis follows a common final pathway with intracellular calcium accumulation and ATP depletion. Clinical symptoms vary. Seldom, the classical triad of muscle pain, weakness, and dark urine is observed. Recurrent episodes should raise suspicion of an inherited disorder. Severe complications are hypovolemia, electrolyte disorders with hyperkalemia and hypocalcemia resulting in life threatening arrhythmias, a compartment syndrome, disseminated intravascular coagulation and acute renal failure, which is frequently oligo-anuric. In combination with often severe underlying disease, renal failure causes death in 1/5 of the patients. The diagnosis is made with the determination of serum creatine kinase and the myoglobin levels in plasma and urine. Therapeutic options are to correct the hypovolemia with sufficient fluid supply, the prevention of oliguria using loop diuretics, alkalinization of the urine, normalization of serum electrolytes with reduction of hyperkaemia, and decompression of compartment syndromes. An underlying disease should be evaluated to initiate specific therapeutical and preventative steps. Avoiding pre-disposing factors by identifying the mechanisms of disease will reduce the occurrence of rhabdomyolysis with its still high mortality.
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PMID:[Rhabdomyolysis]. 1295 32

Some organelles responsible for contraction consist of bundles of 2-4 nm filaments called nanofilaments. Such organelles are present in the longitudinal flagellum of Ceratium (Dinoflagellate): the R-fibre is the motor system for contraction and parallels the axoneme, which is responsible for wave generation. We used a highly sensitive polarization microscope developed by one of the authors to measure the birefringence of these nanofilament bundles during contraction in vivo. Our results show that the R-fibre gives a highly birefringent signal, retarding the polarization to much the same extent irrespective of the direction of polarization. By rotating the axis of the microscope compensator we confirmed that the birefringence is positive, suggesting that the bundles run parallel to the longitudinal axis of the flagellum. Conversely, when the compensator was rotated contrary to the direction of retardation, the bundle appeared dark (except when the organelle was in a fully contracted state). Experiments performed on detergent-treated and ATP-reactivated flagella show that a portion of the flagella regained activity with the addition of ATP in the presence of low Ca(2+) concentrations. This demonstrates the ability to reactivate flagellar motility after permeabilization and that axonemal microtubules were not responsible for the strong flagellar birefringence. Combined with complementary data from DIC microscopy of demembranated flagella and electron microscopy, these findings have led to the development of a model of the R-fibre and a comparison with other types of birefringent nanofilament bundles, such as the myoneme of Acantharia.
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PMID:Analysis of the contraction of an organelle using its birefringency: the R-fibre of the Ceratium (Dinoflagellate) flagellum. 1519 82

Rhabdomyolysis is defined as a syndrome resulting from skeletal muscle injury with release of muscle cell contents into the plasma. One of the main causes of rhabdomyolysis is eccentric exercise against high resistance. There are mechanical as well as metabolic causes in exercise induced rhabdomyolysis. The mechanical aspect includes high physical tension on the muscle fiber and the metabolic causes include lack of available ATP and disturbance in intracellular electrolyte balance, especially calcium. The clinical picture of rhabdomyolysis may include muscle soreness, reduction of the range of motion, decreased muscle strength, black urine and, in severe cases, acute renal failure. Laboratory results may include delayed high levels of muscle enzymes in the plasma, myoglobinemia and myoglobinuria, disturbance in blood electrolyte balance, and in severe cases, disturbance in coagulatory function and DIC. Compartment syndrome may also be part of severe rhabdomyolyis. The main treatment for rhabdomyolysis is fluids administration and maintaining urination, in order to preserve renal function. In severe compartment syndrome fasciotomy may be necessary. There is a wide variability in the severity of rhabdomyolysis. This variability is not completely understood but may be related to the level of physical fitness, morphometrical characteristics and gender. In order to prevent exercise induced rhabdomyolysis, a gradual training program should be maintained providing enough recovery time, preserving fluid balance, and avoiding extreme eccentric exercise and exercise in high heat load.
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PMID:[Exercise induced rhabdomyolysis--characteristics, mechanisms and treatment]. 1571 20

In the previous paper [Gligorijevic, B., et al. (2006) Biochemistry 45, pp 12400-12410], we reported on a customized Nipkow spinning disk confocal microscopy (SDCM) system and its initial application to DIC imaging of hemozoin within live, synchronized, intraerythrocytic Plasmodium falciparum malarial parasites. In this paper, we probe the biogenesis as well as the volume and pH regulation of the parasite digestive vacuole (DV), using the fluorescence imaging capabilities of the system. Several previous reports have suggested that mutant PfCRT protein, which causes chloroquine resistance (CQR) in P. falciparum, also causes increased acidification of the DV. Since pH and volume regulation are often linked, we wondered whether DV volume differences might be associated with CQR. Using fast acquisition of SDCM z stacks for synchronized parasites with OGd internalized into the DV, followed by iterative deconvolution using experimental point spread functions, we quantify the volume of the DV for live, intraerythrocytic HB3 (CQS), Dd2 (CQR via drug selection), GCO3 (CQS), and GCO3/C3(Dd2) (CQR via transfection with mutant pfcrt) malarial parasites as they develop within the human red blood cell. We find that relative to both CQS strains, both CQR strains show significantly increased DV volume as the organelle forms upon entry into the trophozoite stage of development and that this persists until the trophozoite-schizont boundary. A more acidic DV pH is found for CQR parasites as soon as the organelle forms and persists throughout the trophozoite stage. We probe DV volume and pH changes upon ATP depletion, hypo- and hypertonic shock, and rapid withdrawal of perfusate chloride. Taken together, these data suggest that the PfCRT mutations that cause CQR also lead to altered DV volume regulation.
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PMID:Spinning disk confocal microscopy of live, intraerythrocytic malarial parasites. 2. Altered vacuolar volume regulation in drug resistant malaria. 1702 97

Airway submucosal glands are sites of high expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel and contribute to fluid homeostasis in the lung. However, the molecular mechanisms of gland ion and fluid transport are poorly defined. Here, submucosal gland serous acinar cells were isolated from murine airway, identified by immunofluorescence and gene expression profiling, and used in physiological studies. Stimulation of isolated acinar cells with carbachol (CCh), histamine or ATP was associated with marked decreases in cell volume (20 +/- 2% within 62 +/- 5 s) that were tightly correlated with increases in cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) as revealed by simultaneous DIC and fluorescent indicator dye microscopy. Simultaneous imaging of cell volume and the Cl(-)-sensitive fluorophore SPQ indicated that the 20% shrinkage was associated with a fall of [Cl(-)](i) from 65 mm to 28 mm, reflecting loss of 67% of cell Cl(-) content, accompanied by parallel efflux of K(+). Upon agonist removal, [Ca(2+)](i) relaxed and the cells swelled back to resting volume via a bumetanide-sensitive Cl(-) influx pathway, likely to be NKCC1. Accordingly, agonist-induced serous acinar cell shrinkage and swelling are caused by activation of solute efflux and influx pathways, respectively, and cell volume reflects the secretory state of these cells. In contrast, elevation of cAMP failed to elicit detectible volume responses, or enhance those induced by submaximal [CCh], because the magnitude of the changes were likely to be below the threshold of detection using optical imaging. Finally, when stimulated with cholinergic or cAMP agonists, cells from mice that lacked CFTR, as well as wild-type cells treated with a CFTR inhibitor, exhibited identical rates and magnitudes of shrinkage and Cl(-) efflux compared with control cells. These results provide insights into the molecular mechanisms of salt and water secretion by lung submucosal glands, and they suggest that while murine submucosal gland fluid secretion in response to cholinergic stimulation can originate from CFTR-expressing serous acinar cells, it is not dependent upon CFTR function.
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PMID:Optical imaging of Ca2+-evoked fluid secretion by murine nasal submucosal gland serous acinar cells. 1752 16

Glutathione (GSH) is transported into renal mitochondria by the dicarboxylate (DIC; Slc25a10) and 2-oxoglutarate carriers (OGC; Slc25a11). To determine whether these carriers function similarly in liver mitochondria, we assessed the effect of competition with specific substrates or inhibitors on GSH uptake in isolated rat liver mitochondria. GSH uptake was uniphasic, independent of ATP hydrolysis, and exhibited K(m) and V(max) values of 4.08 mM and 3.06 nmol/min per mg protein, respectively. Incubation with butylmalonate and phenylsuccinate inhibited GSH uptake by 45-50%, although the individual inhibitors had no effect, suggesting in rat liver mitochondria, the DIC and OGC are only partially responsible for GSH uptake. H4IIE cells, a rat hepatoma cell line, were stably transfected with the cDNA for the OGC, and exhibited increased uptake of GSH and 2-oxoglutarate and were protected from cytotoxicity induced by H(2)O(2), methyl vinyl ketone, or cisplatin, demonstrating the protective function of increased mitochondrial GSH transport in the liver.
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PMID:Hepatic mitochondrial transport of glutathione: studies in isolated rat liver mitochondria and H4IIE rat hepatoma cells. 1837 55

Deficiency of the Caenorhabditis elegans protein, DIC-1, located in the inner membrane of mitochondria produces an abnormal mitochondrial morphology. The mechanism by which DIC-1 controls the topology of the inner membrane was investigated by transiently over-expressing DIC-1 in C. elegans. Cryo-electron microscopy showed that DIC-1 over-expression greatly increased the number and fractional area of mitochondrial cristae, suggesting that DIC-1 actively participates in cristae formation. These morphological changes were accompanied by increases in the oxygen consumption rate and ATP content of C. elegans worms, and decreases in reactive oxygen species (ROS) and sensitivity to paraquat. DIC-1 knockdown induced the opposite changes in ATP, ROS and paraquat-sensitivity. The ability of DIC-1 to increase cristae formation and secondarily, oxidative phosphorylation, suggests a potential use of this factor to control mitochondrial activity.
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PMID:DIC-1 over-expression enhances respiratory activity in Caenorhabditis elegans by promoting mitochondrial cristae formation. 1921 May 47

The serous acini of airway submucosal glands are important for fluid secretion in the lung. Serous cells are also sites of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. However, the mechanisms of serous cell fluid secretion remain poorly defined. In this study, serous acinar cells were isolated from porcine bronchi and studied using optical techniques previously used to examine fluid secretion in rat parotid and murine nasal acinar cells. When stimulated with the cholinergic agonist carbachol, porcine serous cells shrank by approximately 20% (observed via DIC microscopy) after a profound elevation of intracellular [Ca(2+)] ([Ca(2+)](i); measured by simultaneous fura 2 fluorescence imaging). Upon removal of agonist and relaxation of [Ca(2+)](i) to resting levels, cells swelled back to resting volume. Similar results were observed during stimulation with histamine and ATP, and elevation of [Ca(2+)](i) was found to be necessary and sufficient to activate shrinkage. Cell volume changes were associated with changes in [Cl(-)](i) (measured using SPQ fluorescence), suggesting that shrinkage and swelling are caused by loss and gain of intracellular solute content, respectively, likely reflecting changes in the secretory state of the cells. Shrinkage was inhibited by niflumic acid but not by GlyH-101, suggesting Ca(2+)-activated secretion is mediated by alternative non-CFTR Cl(-) channels, possibly including Ano1 (TMEM16A), expressed on the apical membrane of porcine serous cells. Optimal cell swelling/solute uptake required activity of the Na(+)K(+)2Cl(-) cotransporter and Na(+)/H(+) exchanger, both of which are expressed on the basolateral membrane of serous acini and likely contribute to sustaining transepithelial secretion.
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PMID:Mechanisms of Ca2+-stimulated fluid secretion by porcine bronchial submucosal gland serous acinar cells. 1996 83

Nucleotides, including ADP, ATP and uridine triphosphate (UTP), are discharged profusely in the circulation during many pathological conditions including sepsis. Sepsis can cause hypotension and systemic activation of the coagulation and fibrinolytic systems in humans, which may cause disseminated intravascular coagulation. We investigated whether nucleotide-induced cardiovascular collapse as provoked by systemic infusion of adenosine, ADP, ATP, UTP and nitric oxide affected the haemostatic system as assessed by whole blood thromboelastography (TEG) analysis. Ten pigs received a randomized infusion of adenosine, ADP, ATP, UTP or nitric oxide until mean arterial pressure was reduced to approximately 40% of baseline simulating sepsis-induced hypotension. The effect of the infusions on the haemostatic system was evaluated by TEG, and endothelial release of tissue plasminogen activator and plasminogen activator inhibitor-1 was measured. In contrast to the other infused substrates, ADP caused a reduction in maximum amplitude (71.4 to 64.2; P < 0.05), and reduced the angle, representing the thrombus formation (75.6 to 66.4; P < 0.05), indicating hypocoagulation. Despite increases in t-PA release (2.1 to 2.7 ng/ml; P < 0.05) and reductions in plasminogen activator inhibitor (33.9 +/- 10.9-17.8 +/- 4.4 ng/ml; P < 0.05) no increased fibrinolysis was found when whole blood was evaluated by TEG. Circulating ADP induces hypocoagulation without signs of increased fibrinolysis as evaluated by TEG. The potential clinical significance of these findings should be investigated further because ADP discharged systemically may possibly contribute to the coagulopathy observed in severe sepsis.
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PMID:Effects of nucleotides and nucleosides on coagulation. 2038 37

ATP is the universal energy currency but mysteriously its cellular concentration is much higher than that needed for providing energy. Recently ATP was decoded to act as a hydrotrope to dissolve liquid-liquid phase separation (LLPS) of FUS whose aggregation leads to ALS/FTD. By DIC microscopy and NMR, here we characterized the effect of ATP on LLPS of FUS and its N-/C-terminal domains. Very unexpectedly, we found that like nucleic acids, ATP enhances LLPS of FUS at low but dissolves at high concentrations. Intriguingly, ATP monotonically dissolves LLPS of NTD, while it induces LLPS of CTD at low but dissolves at high concentrations. Our study reveals for the first time that ATP can enhance LLPS most likely by behaving as a bivalent binder. Most importantly, our results imply that age-dependent reduction of ATP concentrations may not only result in decreasing its capacity in preventing protein aggregation, but also in enhancing aggregation.
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PMID:ATP enhances at low concentrations but dissolves at high concentrations liquid-liquid phase separation (LLPS) of ALS/FTD-causing FUS. 3020 60


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