community-acquired infection with healthcare-associated methicillin-resistant Staphylococcus aureus: the role of home nursing care.

OBJECTIVE: To better understand the role of indirect transmission in community-acquired infection with methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: Prospective case-control study. SETTING: A French teaching hospital. PATIENTS: A total of 198 case patients and 198 control patients with MRSA or methicillin-susceptible S. aureus infection diagnosed between April 2002 and July 2003. RESULTS: Multivariate analysis showed a highly significant independent link between MRSA infection at admission and prior receipt of home nursing care (odds ratio [OR], 3.7; P<.001). Other independent risk factors were prior hospitalization (OR, 3.8; P<.001), transfer from another institution (OR, 2.3; P=.008), and age older than 65 years (OR, 1.6; P=.04). Prior home nursing care showed a frequency dose-response relationship. Eleven MRSA-infected patients had had home nursing procedures but no hospital stay in the previous 3 years. These patients' MRSA strains were related to the prevalent MRSA clone currently spreading in French hospitals. CONCLUSION: Home nursing care appears to be an independent risk factor for MRSA acquisition in the community. The reservoir probably consists of MRSA carriers discharged from the hospital. Community nurses seem to be a potential vector.     

Synergistic antitumor activity of capecitabine in combination with irinotecan

5-Fluorouracil (5-FU) and capecitabine alone and in combination with irinotecan/oxaliplatin are clinically active in the treatment of colorectal and other solid tumors. Studies of the antitumor activity and toxicity of capecitabine or irinotecan alone and in combination with each other, were compared with 5-FU and raltitrexed in human tumor xenografts of colorectal and squamous cell carcinoma of the head and neck using clinically relevant schedules. Antitumor activity and toxicity were evaluated in nude mice bearing human colon carcinomas of HCT-8 and HT-29 and in head and neck squamous cell carcinomas of A253 and FaDu xenografts using the maximum tolerable dose of single-agent capecitabine, 5-FU, or raltitrexed, or each of the drugs in combination with irinotecan. Mice were treated with capecitabine and irinotecan alone or in combination using 2 different schedules: (1) capecitabine orally once a day for 7 days and a single dose of irinotecan (50 mg/kg intravenously [I.V.]), with each drug alone or in combination, and (2) capecitabine orally 5 days a week for 3 weeks and irinotecan 50 mg/kg (I.V. injection) once a week for 3 weeks, with each drug alone or in combination. For comparative purposes, the antitumor activity of single-agent capecitabine, 5-FU, or raltitrexed, or each drug in combination with irinotecan was carried out at its maximum tolerated dose (MTD) using a 3-week schedule. Results indicated that HT-29 and A253 xenografts were de novo resistant (no cure) to capecitabine and irinotecan alone at the MTD, whereas HCT-8 and FaDu xenografts were relatively more sensitive, yielding 10%-20% cures. The combination of irinotecan/capecitabine was much more active than either drug alone against all 4 tumor models. The cure rates were increased from 0 to 20% in A253 and HT-29 xenografts and from 10%-20% to 80%-100% in HCT-8 and FaDu tumor xenografts, respectively. Irinotecan/capecitabine had clear advantage over irinotecan/5-FU and irinotecan/raltitrexed in efficacy and selectivity in that they were more active and less toxic. The extent of synergy with irinotecan/capecitabine appears to be tumor-dependent and independent of the status of p53 expression. The potential impact of the preclinical results on clinical practice for the use of these drugs in combination needs clinical validation.     

Acute leukemia during pregnancy: a report on 37 patients and a review of the literature

BACKGROUND: Acute leukemia (AL) requiring cytotoxic treatment occurring during pregnancy poses a very difficult therapeutic dilemma. METHODS: By means of a mail questionnaire, information on a series of 37 patients with a diagnosis of AL during pregnancy was collected from 13 French centers between December, 1988 and November, 2003. RESULTS: Thirty-one patients had acute myeloid leukemia (AML), and 6 patients had acute lymphoblastic leukemia (ALL). Nine patients were diagnosed during the first trimester, 10 patients were diagnosed during the second trimester, and 18 patients were diagnosed during the third trimester. Fifteen pregnancies ended with therapeutic or spontaneous abortion. There were 13 normal deliveries, including 1 gemellary pregnancy, and 9 Cesarean sections. Twenty-three healthy babies survived from the 37 pregnancies, of whom 15 babies had been exposed to chemotherapeutic agents. A complete remission was achieved in 34 patients. Eleven women had severe extrahematologic complications during the induction remission course. The median disease-free survival (DFS) was not reached, with a 5-year DFS of 54%. Ten patients developed recurrent disease. Overall, 12 of 37 pregnant women died from leukemia. CONCLUSIONS: Pregnancy does not affect the course of AL. In the first trimester, termination of pregnancy should be discussed because of the potential fetal consequences of chemotherapy. Chemotherapy treatment during the second or third trimester may not require termination of pregnancy, because as remission of AL and delivery of a normal infant are likely to be obtained.     

Enhanced 7-ethyl-10-hydroxycamptothecin (SN-38) lethality by methylselenocysteine is associated with Chk2 phosphorylation at threonine-68 and down-regulation of Cdc6 expression

Methylselenocysteine (MSC) is an organic selenium compound in preventative clinical trials involving prostate, lung, and colon carcinoma. We found that methioninase-activated MSC potentiates 7-ethyl-10-hydroxycamptothecin (SN-38)-induced cell lethality in vitro in the p53-defective human head and neck carcinoma A253 cells. Activated MSC increases chk2 phosphorylation at threonine-68 induced by SN-38, with no significant effect on chk1 phosphorylation. Cell cycle arrest induced by SN-38, however, was not abrogated or potentiated by MSC. These results suggest that the enhanced cellular lethality of SN-38 by MSC was not associated with cell cycle regulation pathways. Because chk2, in addition to its role in cell cycle arrest, can induce apoptosis by phosphorylation/activation, we examined whether increased chk2 phosphorylation could induce preapoptotic DNA fragmentation. DNA damage analysis showed that megabase DNA fragmentation is decreased, accompanied by the increased 30 to 300 kilobase pairs of DNA fragmentation after exposure to SN-38 with MSC, compared with SN-38 alone. No significant changes in the amount of DNA fragments were observed in cells treated with SN-38 or MSC alone. Moreover, proteolytic destruction of DNA replication-associated proteins cdc6, MCM2, and cdc25A may induce a DNA damage checkpoint response. The observed down-regulation of DNA replication proteins cdc6, MCM2, and cdc25A after exposure to SN-38 with MSC further indicates a relationship between drug response and DNA damage. Exposure to SN-38 with MSC resulted in a significant increase of poly(ADP-ribose) polymerasecleavage and caspase 3 activation. All together, the data support the hypothesis that enhanced lethality of this combination is associated with increased chk2 phosphorylation at Thr68 and down-regulation of specific DNA replication-associated proteins, which result in poly(ADP-ribose) polymerase cleavage, caspase 3 activation, and the induction of 30 to 300 kilobase pairs of DNA fragmentation.     

System performance of a prototype flat-panel imager operated under mammographic conditions

The results of an empirical and theoretical investigation of the performance of a high-resolution, active matrix flat-panel imager performed under mammographic conditions are reported. The imager is based upon a prototype, indirect detection active matrix array incorporating a discrete photodiode in each pixel and a pixel-to-pixel pitch of 97 microm. The investigation involved three imager configurations corresponding to the use of three different x-ray converters with the array. The converters were a conventional Gd2O2S-based mammographic phosphor screen (Min-R) and two structured CsI:Tl scintillators: one optimized for high spatial resolution (FOS-HR) and the other for high light output (FOS-HL). Detective quantum efficiency for mammographic exposures ranging from approximately 2 to approximately 40 mR at 26 kVp were determined for each imager configuration through measurements of x-ray sensitivity, modulation transfer function (MTF), and noise power spectrum (NPS). All configurations were found to provide significant presampling MTF at frequencies beyond the Nyquist frequency of the array, approximately 5.2 mm(-1) , consistent with the high spatial resolution of the converters. In addition, the effect of additive electronic noise on the NPS was found to be significantly larger for the configuration with lower system gain (FOS-HR) than for the configurations with higher gain (Min-R, FOS-HL). The maximum DQE values obtained with the CsI:Tl scintillators were considerably greater than those obtained with the Min-R screen due to the significantly lower Swank noise of the scintillators. Moreover, DQE performance was found to degrade with decreasing exposure, although this exposure-dependence was considerably reduced for the higher gain configurations. Theoretical calculations based on the cascaded systems model were found to be in generally good agreement with these empirically determined NPS and DQE values. In this study, we provide an example of how cascaded systems modeling can be used to identify factors limiting system performance and to examine trade-offs between factors toward the goal of maximizing performance.     

Thymidine and hypoxanthine protection patterns of the folic acid-enhanced synergies for combinations of trimetrexate plus a polyglutamylatable inhibitor of purine or thymidylate synthesis against human ileocecal HCT-8 cells

In order to examine the intracellular locus of the folic acid (PteGlu)-enhanced synergies of trimetrexate (TMQ) plus the thymidylate synthase (TS) inhibitor, raltitrexed (RTX), and TMQ plus the glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, AG2034, comprehensive protection studies with thymidine (dThd) and hypoxanthine (HX) were conducted in a 96-well plate cell growth inhibition (sulforhodamine B) assay. Current modeling techniques were extended to characterize these protection patterns involving multiple-agent interaction. Wild-type human ileocecal HCT-8 cells and DW2, a subline deficient in folylpoly-gamma-glutamate synthetase (FPGS) were individually treated for 96 h with TMQ, AG2034 and a 1:1 mixture of TMQ:AG2034 or with TMQ, RTX, and a 1:1 mixture of TMQ:RTX in the presence of PteGlu (2.3 or 40 micro M) and the protection agents (10 micro M dThd and/or 100 micro M HX). Drug treatments were randomly assigned to wells. Both isobols and 3-dimensional concentration-effect surfaces were used to assess the nature and the intensity of drug interactions. The structural Hill model was fitted to data with weighted non-linear regression for most cases. A so-called 'double Hill' model was sometimes more appropriate when a plateau in the middle of the concentration-effect curve was found. In HCT-8 and DW2 cells at 2.3 and 40 micro M PteGlu, inhibition of DHFR by TMQ induced antithymidylate and antipurine effects; AG2034 and RTX selectively inhibited de novo purine or thymidine synthesis, respectively. dThd protection increased the PteGlu-enhancement of the TMQ + AG2034 synergy, whereas HX protection increased the PteGlu-enhancement of the TMQ + RTX synergy. The PteGlu-enhanced synergies of TMQ + AG2034 and TMQ + RTX occur primarily through inhibition of purine synthesis and inhibition of thymidylate synthesis, respectively. These results further substantiate the hypothesis that the nonpolyglutamylatable DHFR inhibitor, TMQ, acts as a modulator by decreasing the protection by PteGlu of cells against the polyglutamylatable AG2034 and RTX.     

Targeting Molecular Signals in Chk1 Pathways as a New Approach for Overcoming Drug Resistance

The common clinical problem in the successful treatment of cancer is the resistance of cancer cells to chemotherapeutic drugs. Chemotherapy kills drug-sensitive cells, but leaves behind a higher proportion of drug-resistant cells. The resistance can be due to altered drug accumulation, retention, metabolism and distribution, or to reduced drug–target interaction. More recently, cell cycle progression, DNA mismatch repair (MMR) and cell death have been shown to play an important role in the regulation of cell resistance to anticancer drugs. Chk1 regulation pathways, DNA MMR and p73, as well as altered apoptotic cell death involved in the cell resistance toward DNA damaging agents will be reviewed in this article.     

Preclinical Development of Eniluracil: Enhancing the Therapeutic Index and Dosing Convenience of 5-Fluorouracil

Eniluracil (5-ethynyluracil, GW 776, 776C85) isbeing developed as a novel modulator of 5-fluorouracil (5-FU) forthe treatment of cancer. Eniluracil is an effective mechanism-based inactivator of dihydropyrimidine dehydrogenase (DPD), thefirst enzyme in the catabolic pathway of 5-FU. By temporarilyeliminating this prevalent enzyme, eniluracil providespredictable dosing of 5-FU and enables oral administration of5-FU to replace intravenous bolus and continuously infuseddosing. New DPD is synthesized with a half-life of 2.6 days. Italso eliminates the formation of problematic 5-FU catabolites.Most importantly, in laboratory animals, eniluracil increases thetherapeutic index and absolute efficacy of 5-FU. Accompanyingreports in this journal indicate that eniluracil has promisingclinical potential.     

Low-dose megavoltage cone-beam CT imaging using thick, segmented scintillators

Megavoltage, cone-beam computed tomography (MV CBCT) employing an electronic portal imaging device (EPID) is a highly promising technique for providing soft-tissue visualization in image-guided radiotherapy. However, current EPIDs based on active matrix flat-panel imagers (AMFPIs), which are regarded as the gold standard for portal imaging and referred to as conventional MV AMFPIs, require high radiation doses to achieve this goal due to poor x-ray detection efficiency (～2% at 6 MV). To overcome this limitation, the incorporation of thick, segmented, crystalline scintillators, as a replacement for the phosphor screens used in these AMFPIs, has been shown to significantly improve the detective quantum efficiency (DQE) performance, leading to improved image quality for projection imaging at low dose. Toward the realization of practical AMFPIs capable of low dose, soft-tissue visualization using MV CBCT imaging, two prototype AMFPIs incorporating segmented scintillators with ～11 mm thick CsI:Tl and Bi(4)Ge(3)O(12) (BGO) crystals were evaluated. Each scintillator consists of 120 × 60 crystalline elements separated by reflective septal walls, with an element-to-element pitch of 1.016 mm. The prototypes were evaluated using a bench-top CBCT system, allowing the acquisition of 180 projection, 360° tomographic scans with a 6 MV radiotherapy photon beam. Reconstructed images of a spatial resolution phantom, as well as of a water-equivalent phantom, embedded with tissue equivalent objects having electron densities (relative to water) varying from ～0.28 to ～1.70, were obtained down to one beam pulse per projection image, corresponding to a scan dose of ～4 cGy--a dose similar to that required for a single portal image obtained from a conventional MV AMFPI. By virtue of their significantly improved DQE, the prototypes provided low contrast visualization, allowing clear delineation of an object with an electron density difference of ～2.76%. Results of contrast, noise and contrast-to-noise ratio are presented as a function of dose and compared to those from a conventional MV AMFPI.     

Comparative study of the pollen protein contents in two major varieties of Cupressus arizonica planted in Tehran

During past few years, the Cupressus arizonica has been abundantly planted in Tehran, causing a significant increase of allergic diseases from the middle of winter to the beginning of spring. The aim of this study was the comparison of pollen protein content in two major varieties of C. arizonica planted in Tehran, including C. arizonica var. arizonica and C. arizonica var. glabra, in order to determine pollen's specificity of each variety and also to find out whether environmental conditions can influence pollen protein contents and its allergenic components. Pollen grains were directly collected from mature male cones of trees planted in different areas of the city. Pollen's proteins were extracted, and were analyzed by SDS PAGE. Total protein content of pollen extracts was measured by Bradford assay. Our investigations revealed noticeable differences in protein content of each variety. Bradford protein assay showed a higher total protein content in C. arizonica var. arizonica pollen extracts. A new major protein, with an approximate molecular weight of about 35 kDa was detected in both varieties. Immunoblotting using the serum of a cypress allergic subject showed that the protein with 35 kDa was also the major allergen of both varieties in pollen extracts. These results showed that there are some intraspecie specificities in Arizona cypress pollens. The major allergen of Cupresuss arizonica pollen, Cup a 1 (45 kDa), has been reported as the most representative protein in pollen extracts of Mediterranean countries, but in our autochthon extracts of both varieties, a protein band at 35 kDa was more representative. These observations seem to indicate that C. arizonica pollen protein content may be influenced by environmental conditions. Moreover, Immunoblot results provided a reliable indication on the allergenic activity of this new major protein band at 35 kDa. The confirmation of these aspects would facilitate the preparation of an effective extract, improving the diagnosis of the allergy to the Cupressus arizonica pollen.