Can sequential administration minimise the cost of high dose chemotherapy? An economic assessment in inflammatory breast cancer

OBJECTIVE: To evaluate the potential cost savings of using sequential high dose chemotherapy (HDC), with granulocyte colony-stimulating factor (filgrastim) and stem cell support, rather than single course administration of HDC with bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). PERSPECTIVE: French public hospital perspective. METHODS: Direct medical costs of sequential treatment, estimated on the basis of physical quantities of resources consumed by 95 patients with inflammatory breast cancer (IBC) included in a French pilot multicentric trial (PEGASE 02), were compared with those of historical control groups of patients treated with single course HDC, either with BMT (n = 27) or PBSCT (n = 14). Costs were evaluated in 1998 French francs (1 Euro = 6.55957 French francs). RESULTS: The total cost of sequential HDC was significantly lower than that for single course HDC both with BMT (-29%; 22,755 Euros vs 32,284 Euros; p < 0.001) or PBSCT (-16%; 22,755 Euros vs 27,209 Euros; p = 0.026). This was mainly due to a reduction in the length of hospitalisation in transplantation units. CONCLUSION: According to our results, economic arguments cannot be used against the widespread use of sequential HDC for patients with IBC. However, further economic evaluations based on overall and disease-free survivals alongside a randomised clinical trial are still needed to definitively establish the cost effectiveness of sequential administration of HDC.     

Tumor cell hypoxia and the hypoxia-response signaling system as a target for prostate cancer therapy

The accumulation of cancerous cells within a growing prostate tumor can deprive them of adequate vascular support. Without this support, the affected tumor cells become hypoxic, a condition that is usually unfavorable for the further growth and survival of eukaryotic cells. Mammalian cells, however, have the ability of responding to a hypoxic environment by activating a "hypoxia-response" signaling system. Ultimately, this signaling system upregulates the expression of a network of gene products that increase the propensity of the cell to survive even in this adverse environment. With increasing evidence that hypoxia and an activated hypoxia-response signaling system can influence progression (via increased angiogenic propensity and apoptotic resistance) and the therapeutic responsiveness of prostate cancer cells, this review will examine the concept of targeting hypoxia or the hypoxia-response system of prostate tumor cells as a means to suppress prostate tumor progression and metastasis or perhaps even as a means for eliminating prostate tumors in advanced prostate cancer patients.     

The association of autosomal dominant optic atrophy and moderate deafness may be due to the R445H mutation in the OPA1 gene

PURPOSE: To examine the involvement of the optic atrophy 1 (OPA1) gene in optic atrophy associated with moderate deafness. DESIGN: Observational case report.The entire coding sequence of the OPA1 gene was directly sequenced in the case of a patient suffering from optic atrophy associated with moderate deafness. RESULTS: A de novo heterozygous mutation R445H in the OPA1 gene was found. No similar mutation was detected in either of the patient's parents or in the 100 chromosome controls. CONCLUSION: The R445H mutation in OPA1 might be the cause of the association between dominant optic atrophy and moderate deafness, a phenotype that may be currently underdiagnosed.     

Candida parapsilosis keratitis

PURPOSE: To present clinical, microbiologic, and histopathologic features of keratitis due to Candida parapsilosis. METHODS: Clinicomicrobiologic evaluation of four patients (four eyes) with culture-proven C. parapsilosis keratitis. The patients were evaluated for symptoms, visual acuity, clinical observations, microbiologic examination of corneal scrapings, and pathologic examination of corneal buttons. RESULTS: Three cases were observed after penetrating keratoplasty, and one case occurred after inhalation of corticosteroids. Clinical presentation of C. parapsilosis keratitis showed a great diversity. There was one case of crystalline keratopathy and three cases of suppurative corneal infiltrate. Histopathology of corneal buttons showed interlamellar accumulations of yeast. Medical treatment included topical amphotericin B and systemic triazoles. Penetrating keratoplasty was required in three patients. CONCLUSION: Risk factors for C. parapsilosis keratitis may include corticosteroid use and prior corneal transplantation. The prognosis of C. parapsilosis keratitis with antifungal and surgical therapy may vary from good visual outcome to intraocular extension with phthisis bulbi.     

Placental growth factor,a member of the VEGF family,contributes to the development of choroidal neovascularization

PURPOSE: VEGF has been shown to be necessary, but not sufficient alone, for the development of subretinal pathologic angiogenesis. In the current study, the influence of placental growth factor (PlGF), a member of the VEGF family, in human and experimental choroidal neovascularization (CNV) was investigated. METHODS: The presence of VEGF family member mRNA was evaluated by RT-PCR in neovascular membranes extracted during surgery. The spatial and temporal pattern of VEGF isoforms and PlGF mRNA expression were explored by using the laser capture catapulting technique and RT-PCR in a murine laser-induced model and in vitro. PlGF expression was also studied in human donor eyes. The influence of endogenous PlGF was evaluated in deficient mice (PlGF(-/-)) and by antibody-mediated neutralization of the PlGF receptor. RESULTS: Human neovascular membranes consistently expressed VEGF-A, -B, and -C; PlGF; and VEGFR-1 and -2. The VEGF(120) isoform mRNA was primarily induced in early stages of angiogenesis in vivo and in vitro. PlGF mRNA expression was present in the intact choroid and significantly upregulated during the course of experimental CNV. Both deficient PlGF expression in PlGF(-/-) mice and PlGF receptor neutralization in wild-type mice prevented the development of choroidal neovascularization induced by laser. CONCLUSIONS: These observations demonstrate the participation of PlGF in experimental CNV. They identify therefore PlGF as an additional promising target for ocular antiangiogenic strategies.     

Influence of L-nitro-arginine methyl ester,acetylcholine, and adenosine on mean blood pressure,pulse pressure,and pulse pressure amplification in rats

The blood pressure pattern in spontaneously hypertensive rats (SHRs) involves three main characteristics: increase in mean blood pressure (MBP); increase in thoracic aorta (proximal) and iliac (distal) pulse pressure (PP); disappearance of the normal PP amplification between the proximal and the distal arteries. Whether pharmacologic agents may reduce MBP with different or even opposite effects regarding PP and PP amplification has been poorly investigated. In SHRs and Wistar-Kyoto (WKY) anesthetized rats, the NO inhibitor l-nitro-arginine methyl ester (l-NAME) was infused at the dosage of 1 mg/kg for 30 min. Before and after infusion, 7 microg/kg/min acetylcholine (Ach) and 200 mg/kg adenosine (Ado) were perfused for 4 min. Proximal and distal intra-arterial BP was monitored throughout the procedure. In both WKYs and SHRs, l-NAME increased proximal and distal systolic (SBP), diastolic (DBP), and MBP but not PP. Before l-NAME, SBP, DBP, and MBP were significantly reduced by Ado and Ach. After l-NAME, such blood pressure reductions were abolished with Ach but not Ado. In both strains, the proximal and distal PP, when expressed in percent reduction of MBP, were significantly higher under Ado than under Ach. The Ado but not Ach changed PP amplification, causing a reduction in WKYs and an increase in SHRs independent of l-NAME. Vasodilating agents may reduce MBP with significantly different effects on PP. The Ado alters PP amplification, an effect not obtained with the nitric oxide endothelium-dependent vasorelaxing agent Ach. Tail SBP measurements cannot predict such dissociated changes.     

Implication of raft microdomains in drug induced apoptosis

DNA damaging agents such as 1-beta-D-arabinofuranosylcytosine (Ara-C) and daunorubicin (DNR) are widely used in the treatment of acute nonlymphocytic leukemia. These drugs have, of course, been the objects of intense basic research, as well as preclinical and clinical study. Although specific biochemical lesions (DNA damage) have been associated with Ara-C- and DNR-mediated cytotoxicity, the pathways leading to the induction of apoptosis remain ill defined. This standpoint has forced investigators to explore a new concept in cell response to cytotoxic stress: apoptosis signaling. The recent identification of a ceramide (CER) mediated apoptotic signaling pathway triggered by antitumor agents offers a new perspective for the treatment of neoplastic cells. Indeed, these agents have been shown to induce apoptosis through the activation of a sphingomyelinase (SMase) responsible for the hydrolysis of sphingomyelin (SM) and the generation of CER. The latter acts as a potent apoptosis mediator, triggering several downstream signaling pathways among which the stress-activated protein kinase cascade (MEKK1-SEK1-SAP/JNK) plays a critical role in apoptosis induction. However, the spacio-temporal organization of the key early signaling events is unclear. The present review delineates what appears to be a critical factor in apoptosis signaling: sphingomyelin enriched plasma membrane rafts. The apparent topological partitioning between DNA damage and apoptosis signaling (integrated into specialized plasma membrane domains) is discussed.     

DNA vaccination of neonate piglets in the face of maternal immunity induces humoral memory and protection against a virulent pseudorabies virus challenge

DNA vaccination represents a unique opportunity to overcome the limitations of conventional vaccine strategy in early life in the face of maternal-derived immunity. We used the model of pseudorabies virus (PRV) infection in pigs to further explore the potential of DNA vaccination in piglets born to sows repeatedly vaccinated with a PRV inactivated vaccine. A single immunisation of 8-week-old piglets with a DNA vaccine expressing secreted forms of PRV gB, gC, and gD, triggered an active serological response, confirming that DNA vaccination can over-ride significant residual maternal-derived immunity. A clear anamnestic response was evidenced when a secondary DNA vaccination was performed at 11 weeks of age, suggesting that DNA vaccination, performed in the face of passive immunity, elicited a strong humoral memory. We subsequently explored the potential of DNA vaccination in neonate piglets (5-6 days of age) in the face of very high titres of maternal antibodies and demonstrated that very high titres of passive antibodies selectively inhibited serological responses but not the establishment of potent memory responses. Finally, we demonstrated that DNA vaccination provided protection against an infectious PRV challenge at the end of the fattening period (i.e. at approximately 5 months of age). Collectively, our results pave the way for a new flexible vaccination program, which could ensure uninterrupted protection of fattening pigs over their entire economical life under field conditions.     

Alcohol use and intoxication in sport university students

AIMS: To investigate patterns of alcohol consumption and intoxication in French sport science students. METHODS: Second- and third-year sport university students (n = 677) completed an anonymous self-report questionnaire. RESULTS AND CONCLUSIONS: 20.4% reported more than six episodes of intoxication during the previous year. Male students drank more frequently and were more frequently intoxicated than were female students. Compared to their peers in the general population, sport students drank less frequently, but reported more episodes of intoxication. There were no differences in frequency of intoxication according to competitive level.