Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae

Cyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane.     

Diabetes and work at sea: has everything been already settled? Article for discussion

Along with increased worldwide incidence of diabetes, the frequency of its occurrence among persons employed on seagoing vessels has also grown (12). According to the current regulations, persons treated with insulin are not admitted to work at sea, and those treated with oral drugs have a markedly limited access to such a work. This may lead to concealing the fact of being a diabetic, thus enhancing the existing hazards. Current improved methods of glycemia self-control and treatment of diabetes have radically improved vital abilities of diabetics. Having this in mind, a question arises whether the binding regulations on the fitness of diabetics for work at sea should be verified.     

The visual acuity impairment as the only sign of cerebral aneurysms--case report

Cerebral aneurysms are the most common reason of subarachnoid haemorrhage at the age of 50-60. Though the results of such haemorrhage are severe (high morbidity and mortality), it is quite often, the first noticeable sign of the problem. Previous symptoms i. e. headache, ophthalmic disturbances, temporary neurological symptoms are often passed over. The authors present the case of a young woman with cerebral aneurysms, in which the visual acuity impairment was the only symptom of the disease.     

Why human pemphigoid autoantibodies do not trigger disease by the passive transfer into mice?

The recapitulation of disease features in animals by the transfer of patient autoantibodies has been used to demonstrate the autoimmune nature of several diseases. Failure of disease induction by the passive transfer of autoantibodies has been assigned to a limited cross-reactivity of the autoantibodies with the murine tissue. However, the possibility that the passively transferred "inflammatory" patient autoantibodies may not be able to unfold their pathogenic potential due to restricted Fc-dependent effector functions has not yet been systematically explored. In this study we analyze the interaction of patients' autoantibodies with murine complement and granulocytes. Bullous pemphigoid is a blistering disease associated with autoantibodies, which are thought to induce subepidermal blistering by activating complement and granulocytes. The passive transfer of patients autoantibodies failed to induce skin blistering in wild type mice. The cross-reactivity of pemphigoid autoantibodies with murine antigens was analyzed in silico, ex vivo and by the passive transfer of IgG in vivo. Complement-fixing ability of patients' autoantibodies was evaluated by complement-binding test. Granulocyte activation was assessed by reactive oxygen species production assay and the cryosection model. We have found that although pemphigoid autoantibodies bound to murine skin in vitro and in vivo, they showed a lower capacity to fix murine complement and a reduced ability to activate murine granulocytes when compared with human complement and cells, respectively. These results indicate that for disease models using the passive transfer of patient autoantibodies, their interaction with the innate factors of the host should be optimized to match the human situation.     

The effects of orexins on monoaminerg-induced changes in vasopressin level in rat neurohypophyseal cell cultures

The effects of orexin–monoaminergic compound interactions on vasopressin release were studied in 14-day neurohypophyseal cell cultures from adult rats, prepared by an enzymatic dissociation technique. The vasopressin contents of the supernatants were determined by radioimmunoassay. Following administration of either orexin-A or orexin-B in increasing doses, significant changes were not observed in the vasopressin levels of the supernatant media. The vasopressin level substantially increased after epinephrine, norepinephrine, serotonin, histamine, dopamine or K⁺ treatment. Preincubation with either orexin-A or orexin-B reduced the epinephrine-, histamine- or serotonin-induced increases in vasopressin level, but the vasopressin concentrations of the supernatant media remained above the control level. There was no significant difference in decreasing effect between orexin-A and orexin-B. Neither orexin-A nor orexin-B induced changes in vasopressin release following monoaminergic compound treatment. The results indicate that the changes in vasopressin secretion induced by the monoaminergic system can be directly influenced by orexin system. It may be presumed that the orexins can play a physiological role in the regulation of the water metabolism by reducing the effect of increased vasopressin release caused by monoaminergic compounds. The interactions between the monoaminergic and orexin systems regarding vasopressin secretion occur at both the hypothalamic and the neurohypophyseal level.     

Preliminary experience using oncoplastic techniques of reduction mammaplasty and intraoperative radiotherapy: report of 2 cases

Background  

Since 2004 in the Department of Oncological Integrated Surgery at the National Institute for Cancer Research of Genoa, we have applied different techniques of reduction mammaplasty for a subgroup of 26 patients with medium- to large-sized and ptotic breasts who are candidates for conservative surgery.     

Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle‐derived stem cells expressing bone morphogenetic protein 4 and soluble flt‐1

Objective

The control of angiogenesis during chondrogenic differentiation is an important issue affecting the use of stem cells in cartilage repair, especially with regard to the persistence of regenerated cartilage. This study was undertaken to investigate the effect of vascular endothelial growth factor (VEGF) stimulation and the blocking of VEGF with its antagonist, soluble Flt‐1 (sFlt‐1), on the chondrogenesis of skeletal muscle‐derived stem cells (MDSCs) in a rat model of osteoarthritis (OA).

Methods

We investigated the effect of VEGF on cartilage repair in an immunodeficiency rat model of OA after intraarticular injection of murine MDSCs expressing bone morphogenetic protein 4 (BMP‐4) in combination with MDSCs expressing VEGF or sFlt‐1.

Results

In vivo, a combination of sFlt‐1– and BMP‐4–transduced MDSCs demonstrated better repair without osteophyte formation macroscopically and histologically following OA induction, when compared with the other groups. Higher differentiation/proliferation and lower levels of chondrocyte apoptosis were also observed in sFlt‐1– and BMP‐4–transduced MDSCs compared with a combination of VEGF‐ and BMP‐4–transduced MDSCs or with BMP‐4–transduced MDSCs alone. In vitro experiments with mixed pellet coculture of MDSCs and OA chondrocytes revealed that BMP‐4–transduced MDSCs produced the largest pellets, which had the highest gene expression of not only type II collagen and SOX9 but also type X collagen, suggesting formation of hypertrophic chondrocytes.

Conclusion

Our results demonstrate that MDSC‐based therapy involving sFlt‐1 and BMP‐4 repairs articular cartilage in OA mainly by having a beneficial effect on chondrogenesis by the donor and host cells as well as by preventing angiogenesis, which eventually prevents cartilage resorption, resulting in persistent cartilage regeneration and repair.

     

The role of the oral flora in the pathogenesis of aspiration pneumonia

The bacterial pneumonia is one of the most frequent complications leading to death among hospitalized patients. The morbidity and mortality of pneumonia is extremely high in the intensive care units and in chronic nursing stations, especially in institutes dealing with old patients. The most common form of lung infection is the aspiration pneumonia. Periodontal diseases play an evident role in the etiology of aspiration pneumonia due to their effect to alter the oral bacterial flora. Authors review the significance of pathogen microorganisms originating from the oral cavity in the development of bacterial pneumonia. The extent of the affected population is discussed and the importance of their oral hygiene and bacterial flora is also specified. The bacterial, enzymatic and molecular pathomechanisms leading to aspiration pneumonia are described, and high risk populations and treatment types are determined. The possibilities of prevention methods for aspiration pneumonia are fully explained and recent directions of actual researches and proposals to minimize the incidence of this disease are summarized.     

Iron sucrose induced morphological and functional changes in the rat kidney

Treatment of anemia in uremic patients requires simultaneous supplementation of erythropoietin and iron. Because of the impaired iron absorption from the gastrointestinal tract in conditions of renal insufficiency, intravenous supplementation is a treatment of choice in such conditions. Iron compounds used for intravenous supplementation induce several systemic side effects, and therefore, we studied the effect of chronic exposure to iron sucrose in rats on renal function. Experiments were performed on male Wistar rats, which were infused intraperitoneally every 4 days, for 28 days with iron sucrose in a dose 1 mg/kg bw or 10 mg/kg bw diluted in 20 mL of the dialysis fluid. Control animals were infused with plain dialysis fluid. Renal function was evaluated at the beginning and at the end of the study. Additionally morphology of the kidneys was evaluated in all animals after 28 days of the study. Chronic exposure of rats to iron sucrose resulted in increased accumulation of PAS-positive material in their glomeruli: + 38% at Fe 1 mg/kg bw P < 0.05 and + 42% at Fe 10 mg/kg/bw P < 0.01 and collagen in the peritubular area: + 40% at Fe 1 mg/kg bw P < 0.005 and + 77% at Fe 10 mg/kg/bw P < 0.001. Only renal clearance of urea was decreased by 53%, P < 0.01 in rats exposed to iron sucrose at a dose of 10 mg/kg bw. Chronic exposure of rats to iron sucrose results in morphologic changes of the kidney; however, mild impairment in renal function was observed only at the highest (10 mg Fe/kg bw) concentration of iron sucrose.