No abstract

Caspase-8 has been implicated in signaling for apoptotic cell death and for certain nonapoptotic functions. However, knowledge of actual physiological or pathophysiological processes to which this enzyme contributes is lacking. Using a mouse model and employing the conditional knockout approach to delete the caspase-8 gene specifically in the liver, we found that caspase-8 deficiency in hepatocytes facilitates infection of the liver by Listeria monocytogenes, attenuates the hepatocyte proliferation wave during the first 48 hours after partial hepatectomy and, depending on the genetic background of the mice, prompts a chronic inflammatory response to the hepatectomy, as a result of which the proliferation of hepatocytes, although initially suppressed, might later be persistently enhanced, resulting in significant hepatomegaly. Conclusion: These findings indicate that caspase-8 participates in regulation of the cellular response to infection and injury and that it does so by affecting various cellular functions, including cell death, cell proliferation, and induction of inflammation. (HEPATOLOGY 2007;45:1014-1024

In the liver, the magnitude of the percentage change in SI induced by hypercapnia and hyperoxia reflects changes in total blood volume; whereas percentage change in SI values induced by hypercapnia from a negative to a positive value reflects relative changes in portal-to-arterial blood flow ratio.

In the yeast Sacchromyces cerevisiae, addition of glucose to starved cells triggers a transient rise in the intracellular level of cyclic AMP that induces a protein phosphorylation cascade. The glucose signal is processed by the Cdc25/Ras/adenylyl cyclase pathway, where the role of Cdc25 is to catalyse the GDP-GTP exchange on Ras. The molecular mechanisms involved in the regulation of the activity of Cdc25 are unknown. We report here the use of highly selective anti-Cdc25 antibodies to demonstrate that Cdc25 is a phospho protein and that in response to glucose it is hyperphosphorylated, within seconds, by the cyclic AMP-dependent protein kinase. It is also demonstrated that, concomitantly with hyperphosphorylation, Cdc25 partially relocalizes to the cytoplasm, reducing its accessibility to membrane-bound Ras. These results are of general significance because of the highly conserved sequence of Ras-guanyl nucleotide exchange factors from yeasts to mammals.

ABSTRACT. Deep vein thrombophlebitis (DVT) and septic pulmonary emboli (PE) are rare in children. The association of DVT and acute disseminated staphylococcal disease (DSD) during childhood has not been previously reported. We report 3 children who developed a triad of DVT, septic PE, and acute osteomyelitis with Staphylococcus aureus cultured from blood and bone. One child succumbed, while 2 survived following prolonged, morbid hospitalizations. The rapid clinical deterioration observed in these patients might be caused by the aggressiveness of staphylococcal infection combined with an ongoing showering of septic emboli from the ileo-femoral DVT. We suggest that infected DVT with septic PE had a pivotal role in the development of DSD in these children. The presence of this triad should prompt aggressive treatment with the appropriate antibiotics, anticoagulation, surgical drainage, and assisted ventilation when indicated. Pediatrics 2000;106(6). URL: http://www.pediatrics.org/cgi/content/full/106/6/e87; deep vein thrombophlebitis, disseminated staphylococcal disease, osteomyelitis, pediatric, septic pulmonary emboli.ABBREVIATIONS. DVT, deep vein thrombophlebitis; PE, pulmonary emboli; DSD, disseminated staphylococcal disease; WBC, white blood cell count. D eep vein thrombophlebitis (DVT) and septic pulmonary emboli (PE) rarely occur in children. The triad of DVT, septic pulmonary embolism, and acute osteomyelitis in children has not been emphasized in the literature or in any report of acute disseminated staphylococcal disease (DSD) in childhood. [1][2][3][4][5][6] The present report describes 3 children with this triad, 1 of whom died, while 2 survived after prolonged, complicated hospitalizations. Theories regarding the role of DVT in the development of DSD, diagnostic modalities, and appropriate therapies are discussed. CASE REPORTS Patient 1An 11-year-old previously healthy boy presented with left hip pain, fever (approaching 39.7°C), recurrent vomiting, and a generalized erythematous rash of 2 days duration. Physical examination showed an alert child: temperature, 39°C; heart rate, 188 beats/minute; respiratory rate, 32 breaths/minute; and blood pressure, 75/50 mm Hg. A diffuse erythematous rash was present over the extremities. Chest examination revealed crepitations over the left side. The left hip joint was tender with no evidence of local infection.Initial laboratory results included: hemoglobin, 12.6 g/dL; white blood cell count (WBC), 28 000/mm 3 with 80% polymorphonuclears; platelet count, 168 000/mm 3 ; prothrombin time, 24% (international normalized ratio: 2.2); and partial thromboplastin time, 42.8 seconds. The chest radiograph showed bilateral diffuse infiltrates (Fig 1). Ultrasonography of the left hip joint demonstrated intraarticular fluid and thickening of the joint capsule. A bone scan was consistent with osteomyelitis of the left proximal femur. Doppler ultrasound revealed thrombosis with partial occlusion of the left femoral vein (Fig 2). Blood cultures were drawn and intravenous administ...

An increasing number of surface proteins are found anchored at the plasma membrane of various tissues and cell types by virtue of a glycosyl-phosphatidylinositol (GPI) structure instead of a transmembrane protein domain. This kind of membrane anchor typically contains, in addition to the myoinositol-harboring phospholipid, a carbohydrate core consisting of one nonacetylated glucosamine and three mannose residues in characteristic linkage. The latter may be branched and carry additional mannose, galactose, and/or phosphoethanolamine moieties. The preformed anchor structure is linked by a phosphodiester and an ethanolamine bridge to the carboxy terminus of the respective protein, thereby replacing a proteinaceous transmembrane domain present in the newly synthesized protein precursor (for reviews, see references 14, 17, 31, 52, and 56). The physiological significance of membrane anchorage by a glycolipidic structure has remained greatly obscure. Since GPI-anchored proteins have been detected recently also in lower eucaryotes, including the yeast Saccharomyces cerevisiae (9,35,43,54), the evolutionary conservation from S. cerevisiae to humans of the GPI anchor argues that it confers properties on the respective proteins that are not achieved by a proteinaceous transmembrane domain.It has been proposed that the spatial requirements, clustering behavior, and diffusion properties of GPI-anchored proteins in the outer leaflet of plasma membranes are the parameters critical for the use of either a transmembrane domain or a GPI moiety for membrane anchorage of a protein (7,13,61,62). In addition, it has been proposed, on the basis that, in situ, GPI anchors may be cleaved upon activation of endogenous (glycosyl)-phosphatidylinositol-specific phospholipases ([G]PIPLs), that GPI anchorage plays a role in regulating the concentration of certain proteins at the cell surface or in controlling protein localization and topology: in HeLa cells and in cultured bone marrow stromal cells, GPI-anchored decay-accelerating factor and heparan sulfate proteoglycan, respectively, are apparently removed constitutively from the plasma membrane and released into the culture medium by the action of an endogenous of type D (G)PI-PL ([G]PI-PLD) (32). In the yeast S. cerevisiae, expression of ␣-agglutinin at the cell wall depends on its synthesis as a GPI-anchored protein and occurs via an intermediate which lacks the myo-inositol moiety of the GPI anchor glycan (28, 59). However, other than (G)PI-PLs, which leave the myo-inositol residue attached to the glycan structure, processing enzymes of GPI anchors have not been identified. In addition to these cases of constitutive GPI anchor processing, in some vertebrate cells certain external signals, provided by serum factors like insulin and growth factors or by drugs, have been found to activate phospholipases which are capable of cleaving GPI anchors (20,26,40,48). In the case of the insulin-or sulfonylurea-induced lipolytic cleavage of the GPI anchors of lipoprotein lipase, 5Ј-nucleotidase, and ...

Current therapy of childhood cancer makes long-term survival a realistic outcome for most patients. However, some treatment regimens entail a significant risk of infertility. No established method for preservation of female fertility is currently available. Ovarian cryopreservation is an experimental technology that is being offered with increasing frequency to women undergoing cancer therapy. It has not yet been reported in children and adolescent girls. The aim of this review is to stimulate discussion on the possibility of performing ovarian cryopreservation in pre-menarcheal girls in advance of therapies that may induce ovarian failure. We present a multi-disciplinary discussion of the risks and benefits associated with the procedure and propose guidelines for its implementation. We propose that all girls about to receive treatment that has a high risk for infertility be offered consultation about the possibility of ovarian cryopreservation.

In various liver pathologies, fMRI response to hypercapnia and hyperoxia is sensitive to changes in liver hemodynamic status involved in hepatic damage or recovery; thus, this technique may offer an additional noninvasive diagnostic tool for evaluation and follow-up of liver diseases by means of examining perfusion-related alterations.