1/19. Can early postnatal closed head injury induce cortical dysplasia.PURPOSE: Increased availability of surgically resected epileptogenic tissues reveals often unsuspected cortical dysplasia (CD). There is some controversy about the ontogenic stages in which these occur. Although most take place during neuroblast proliferation and migration, there is some evidence for some CD occurring during postmigrational intrinsic cortical organization. It has been shown that various kinds of focal cortical manipulations in rats, if performed within 3-4 postnatal days, lead to the genesis of various cortical malformations including a four-layered microgyrus or an unlayered CD. It is not known whether such events also might occur in the human brain. methods: Two children sustained minor head trauma within 4 postnatal days and later developed intractable epilepsy, which was relieved by surgery. Neuropathologic analysis of the resected tissues revealed an unsuspected microdysplastic cortex immediately adjacent to a focal, modest meningeal fibrosis, presumably secondary to the old closed head trauma. RESULTS: The main histologic features were a disorganized, unlayered cortex; abnormal clusters of neurons, often with complex, randomly oriented proximal dendritic patterns with absent apical orientation; the presence of a number of heterotopic small and large neurons in the white matter; absence of inflammatory infiltrates, of hemosiderine, of reactive gliosis, or of an excessive number of blood vessels. The morphologic features in these surgical specimens suggest that these focal malformations occur because of a regional disorder of postmigrational intrinsic cortical remodeling. CONCLUSIONS: The clinical histories and the pathologic findings lend some support to the hypothesis that minor morbid events occuring in the immediate postnatal period may lead to microdysplasia in the human similar to those induced in rat pups. The animal model could be helpful to clarify the genesis of some cases of CD and of the epileptogenicity often manifesting later in life.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
2/19. Human equivalent of the mouse Nude/SCID phenotype: long-term evaluation of immunologic reconstitution after bone marrow transplantation.Human Nude/SCID (severe combined immunodeficiency) is the first severe combined immunodeficiency caused by mutation of the winged-helix-nude (WHN) gene, which is expressed in the thymus but not in the hematopoietic lineage. The disease is characterized by a T-cell defect, congenital alopecia, and nail dystrophy. A Nude/SCID patient who underwent bone marrow transplantation from the human leukocyte antigen-identical heterozygote brother was studied to investigate, in this unique model, the role of the thymus in immunologic reconstitution. Despite an increase in CD3( ), CD4( ), and CD8( ) cells, CD4( ) CD45 RA naive lymphocytes were not regenerated. Conversely, naive CD8( ) cells were normal. After an initial recovery, lymphocyte proliferation to mitogens progressively declined compared with controls and genotypically identical donor cells grown in the WHN( /-) environment. Analysis of the T-cell receptor (TCR) repertoire of CD4( ) cells revealed that only 3 of 18 Vbeta families had an altered CDR3 heterogeneity length profile. Conversely, CD8( ) lymphocytes showed an abnormal distribution in most Vbeta families. These data indicate that the thymus is differentially required in the reconstitution of CD4( ) and CD8( ) naive subsets and in the maintenance of their TCR repertoire complexity. Taken together, these findings suggest that bone marrow transplantation is ineffective in the long-term cure of this form of SCID.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
3/19. A neuroendocrine/small cell prostate carcinoma xenograft-LuCaP 49.The late stages of progression of prostate carcinoma are typically characterized by an androgen-insensitive, rapidly proliferative state. Some late-stage tumors are composed predominantly of neuroendocrine cells. Virtually no animal models of a neuroendocrine/small cell variant of prostate carcinoma are available for experimental studies. We report a human neuroendocrine/small cell prostate carcinoma xenograft that was developed from a nodal metastasis of a human prostate carcinoma and that has been propagated as serial subcutaneous implants in severe combined immunodeficient mice for >4 years. Designated LuCaP 49, all tumor passages exhibit a neuroendocrine/small cell carcinoma phenotype-insensitivity to androgen deprivation, expression of neuroendocrine proteins, lack of expression of prostate-specific antigen or androgen receptor, and an unusually rapid growth (a doubling time of 6.5 days) for prostate cancer xenografts. Genetically this tumor exhibits loss of heterozygosity for the short arm of chromosome 8 and has a complex karyotype. This xenograft should prove to be useful in the investigation of mechanisms underlying the androgen-insensitive state of progressive prostate carcinoma.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
4/19. Rituximab, cyclophosphamide, dexamethasone (RCD) regimen induces cure in WSU-WM xenograft model and a partial remission in previously treated Waldenstrom's macroglobulinemia patient.Waldenstrom's macroglobulinemia (WM) is an uncommon lymphoproliferative disease which remains incurable with current treatment protocols. We have previously established a permanent WM cell line, WSU-WM, which grows as a xenograft in severe combined immune deficient (SCID) mice. In this study, we investigated the antitumor effects of Rituximab (RTX), cyclophosphamide (CTX), dexamethasone (DEX) [RCD]-Regimen in vivo WSU-WM SCID xenograft and in a patient with WM. For the pre-clinical efficacy study, WSU-WM-bearing SCID mice were randomly assigned to receive RTX (150 mg/kg/inj, i.v., QDX5), CTX (90 mg/kg/inj, s.c. QDX5) as single agents or diluent. The combination group received RTX at 150 mg/kg/inj, QDX5; CTX at 150 mg/kg/inj, QODX3 and DEX at 1.0 mg/kg/inj, i.v., QDX5. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log10 kill (net) for RTX and CTX were 24.5%, 37 days, 5.52 and 88%, 0.0 days, 0.0log10 kill, respectively. No cures were observed with either agent; however, all mice (6/6, with bilateral tumors) were cured when treated with RCD-regimen. A 57-year-old patient with relapsed WM was treated with the RCD-regimen and showed an excellent partial remission for seven months. The patient tolerated the treatment very well, the hemoglobin improved dramatically, platelets remained stable, the IgM level normalized and there was only minimal involvement of bone marrow. Based on these results, the RCD regimen is effective against WM and its activity should be further evaluated in clinical trials.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
5/19. Iron-mobilizing properties of the gadolinium-DTPA complex: clinical and experimental observations.BACKGROUND: gadolinium (Gd) magnetic resonance imaging (MRI) contrast agents are considered to be safe in patients with impaired renal function. Our study investigates a mechanism of severe iron intoxication with life-threatening serum iron levels in a haemodialysis patient following MRI with Gd-diethylenetriaminepentaacetic acid (Gd-DTPA) administration. His previous history was remarkable for multiple blood transfusions and biochemical evidence of iron overload. We hypothesized that Gd-DTPA may have an iron-mobilizing effect in specific conditions of iron overload combined with prolonged exposure to the agent. methods: For the in vitro study, Gd-DTPA was added to mice liver homogenate and iron metabolism parameters were measured after incubation in comparison with the same samples incubated with saline only. For the in vivo study, an experimental model of acute renal failure in iron-overloaded rats was designed. Previously iron-overloaded and normally fed rats underwent bilateral nephrectomy by renal pedicle ligation, followed by Gd-DTPA or saline injection. Iron and iron saturation levels were checked before and 24 h after Gd-DTPA or vehicle administration. RESULTS: Significant mobilization of iron from mice liver tissue homogenate in mixtures with Gd in vitro was seen in the control (saline) and in the experimental (Gd) groups (513 /-99.1 vs 1117.8 /-360.8 microg/dl, respectively; P<0.05). Administration of Gd-DTPA to iron-overloaded rats after renal pedicle ligation caused marked elevation of serum iron from baseline 143 /-3.4 to 570 /-8 microg/dl (P<0.0001). There were no changes of the named parameter, either in iron-overloaded anuric rats after saline injection or in normal diet uraemic animals, following Gd-DTPA administration. CONCLUSIONS: The combination of iron overload and lack of adequate clearance of Gd chelates may cause massive liberation of iron with dangerous elevation of free serum iron. It is highly recommended that after Gd contrast study, end-stage renal disease patients with probable iron overload should undergo prompt and intensive haemodialysis for prevention of this serious complication.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
6/19. The effect of repeated phlebotomy on bilirubin turnover, bilirubin clearance and unconjugated hyperbilirubinaemia in the crigler-najjar syndrome and the jaundiced Gunn rat: application of computers to experimental design.1. A multicompartmental model of erythrokinetics and bilirubin production has been developed to predict the consequences of chronic phlebotomy on daily bilirubin turnover. 2. Control values for four physiological variables including bilirubin turnover were determined in a 20-year-old woman with type I congenital nonhaemolytic jaundice (crigler-najjar syndrome). With these base-line data, the model predicted the following changes during phlebotomy: a 34% fall in bilirubin turnover; a 240% increase in the haemoglobin content of bone-marrow erythroid precursors; a 25% fall in the half-life of 51Cr-labelled erythrocytes; a characteristic alteration of the erythrocyte survival curve after labelling with [2-14C]glycine. 3. On the assumption, previously validated in normal volunteer subjects and patients with Gilbert's syndrome, that hepatic bilirubin clearance was independent of turnover and would therefore remain unchanged, a fall in plasma unconjugated bilirubin concentration during phlebotomy from 436 to 282 mumol/1 was expected. 4. Accordingly, the patient underwent phlebotomy 350 ml/week for 2 months, and 500 ml/week during an additional 3 months. Appropriate studies during phlebotomy confirmed each of the predictions in paragraph 2 above. In particular, turnover fell by 31%. Unexpectedly, plasma unconjugated bilirubin remained essentially unchanged. Analogous results were observed in phlebotomized jaundiced Gunn rats. 5. Kinetic studies in both the patient and the rats demonstrated that the failure of plasma unconjugated bilirubin to fall in parallel with bilirubin turnover resulted from a prolongation of the terminal half-life of radioactively labelled bilirubin and a fall in bilirubin clearance in every instance. 6. These studies indicate that (a) in congenital non-haemolytic jaundice, bilirubin clearance is uniquely influenced by bilirubin turnover and (b) compartmental modelling and kinetic studies are useful for predicting and interpreting the results of both physiological experiments and experimental therapeutic regimens.- - - - - - - - - - ranking = 1keywords = life (Clic here for more details about this article) |
7/19. erythropoietin has an anti-myeloma effect - a hypothesis based on a clinical observation supported by animal studies.Recombinant human erythropoietin (rHuEpo) was introduced into clinical practice more than a decade ago, and has been found to be effective in the treatment of several types of anemia, including anemia of end-stage renal failure and cancer-related anemia. No study has suggested that Epo might have an effect on the biology of the disease, nor any survival advantage to cancer patients treated with Epo for anemia has been reported. Here we report six patients with advanced multiple myeloma (MM) with very poor prognostic features, whose expected survival was <6 months. All six patients were treated with rHuEpo for their anemia, either without any chemotherapy or very mild chemotherapy for a short time. Yet, surprisingly they lived for 45-133 months totally from MM diagnosis and 38-94 months with rHuEpo (with a good quality of life). In fact, one patient, is still alive and well, more than 8 yr after chemotherapy was discontinued because of a resistant aggressive disease. The course in these six MM patients led us to hypothesize that Epo might have an antineoplastic or antimyeloma effect. We proceeded and tested that hypothesis in mouse models of myeloma (Mittelman M et al., Proc Natl Acad Sci USA 98:5181,2001). In these models we confirmed that rHuEpo induced tumor regression in about 50% of the BALB/c mice inoculated with MOPC-315 myeloma cells. We then presented evidence that the mechanism is a new immune-mediated phenomenon, via activation of CD8 T cells. Furthermore, evidence from the literature supports the antineoplastic effect of Epo. Epo might be used as an adjunct immune treatment in various malignant diseases, in addition to the current regimens and chemotherapeutic protocols. Future trials should determine the role of Epo in myeloma and cancer treatment, besides clarifying concerns about the presence of Epo receptors on some tumor cells.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
8/19. PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder.Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-fibroblast growth factor receptor (FGFR) 1 fusion tyrosine kinase. Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this disease. We hypothesized that small-molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo. Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLC-gamma, STAT5, and phosphatidylinositol 3-kinase/AKT, required the proline-rich domains, but not the ZNF domains, of ZNF198. A small-molecule tyrosine kinase inhibitor, PKC412 (N-benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1-induced MPD. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disorder with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome.- - - - - - - - - - ranking = 4keywords = life (Clic here for more details about this article) |
9/19. Current trends in managing oral mucositis.Oral mucositis is an inflammatory and ulcerative process of the oral cavity that results from an assault on the epithelial mucous membrane tissue and most commonly is associated with the administration of radiotherapy and chemotherapy. The incidence of oral mucositis ranges from 15%-40% in patients receiving stomatotoxic chemotherapy or radiotherapy and 70%-90% in bone marrow recipients. knowledge regarding the pathophysiology of oral mucositis has evolved and now guides practice. Assessment tools to measure the level of mucositis provide valuable data concerning the status of the oral cavity. No single oral assessment tool has been found to be appropriate in all clinical settings. mucositis has a significant impact on patients' quality of life and treatment plan. Management of oral mucositis is aimed at minimizing this side effect and its subsequent sequelae. The strategies of care are geared toward early intervention and supportive care for patients at risk for developing mucositis and include specific targeted therapies for the management of debilitating side effects. This article provides an overview of the risk factors, pathophysiology, incidence, impact, clinical presentation, oral assessment tools, management strategies, and nursing implications related to oral mucositis.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
10/19. ECMO without heparin: laboratory and clinical experience.To evaluate the feasibility of long-term extracorporeal membrane oxygenation (ECMO) without heparin, we placed six lambs on standard venoarterial ECMO for 71 to 96 hours. Group 1 (3 animals) was given doses of heparin to maintain activated clotting times (ACT) greater than 400 seconds. No form of anticoagulant was used for the three animals in group 2. Blood flow was maintained at 60 mL/kg/min. No histological evidence of thrombosis was noted at necropsy. ACT, prothrombin time, and partial thromboplastin time were higher in group 1, and much lower, although still above normal in group 2. fibrinogen was significantly lower in group 2 (75 /- 35 v 219 /- 64 mg/dL group 1), and, although the platelet count was lower in group 2 (142 /- 76 x 10(3)/mm3 v 225 /- 167 x 10(3)/mm3), it was clinically acceptable. These results encouraged us to discontinue heparin when faced with severe hemorrhage in four patients on ECMO, rather than withdraw support at a time when there was little chance of survival. heparin was discontinued for 10.5 /- 6 hours. The mean ACT was reduced from 220 /- 23 seconds to 144 /- 22 seconds. One patient, who required repair of gastric necrosis while on ECMO following repair of a congenital diaphragmatic hernia, survived and had a decrease in blood loss from 2 to 0 mL/kg/h after the heparin was discontinued. One of the three patients who died had an autopsy with no evidence of thrombosis. We conclude that it may be reasonable to discontinue heparin in the face of life-threatening hemorrhage while on ECMO.- - - - - - - - - - ranking = 0.5keywords = life (Clic here for more details about this article) |
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