A comparison of ceftazidime and aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn

We report a prospective, non-blind, randomised, multicentre, parallel group, multinational investigation to compare ceftazidime to aminoglycoside based regimens as empirical treatment in 1316 cases of suspected sepsis in the newborn. In each of the 15 study centres either ceftazidime alone (CAZ) or ceftazidime + ampicillin (CAZ+AMP) was compared to an aminoglyocoside/ampicillin combination (AG+AMP). In all cases treatment was based on an intention to treat. Bacteria considered to be pathogenic were isolated from 176/1316 (13.4%) patients. The incidence of proven infection varied from 39% in a Yugoslav centre to 6% in a British centre; a further 489/1316 (37.1%) patients fulfilled the criteria for clinically suspected sepsis. A total of 210 bacterial isolates from 197 infection sites in 176 patients were considered to be clinically significant. The cure rate for evaluable patients with proven infection who were treated with CAZ+AMP (97%, 30/31) was significantly higher than that for the corresponding patients treated with AG+AMP (66%, 26/39), (P<0.002). The difference in cure rate between CAZ monotherapy (79%, 34/43) and AG+AMP (86%, 32/37) was not significant. Treatment failed in 28/150 (18.7%) evaluable patients. There were significantly fewer failures (P<0.001) with CAZ+AMP than with AG+AMP therapy. There were 55 staphylococcal infections. Treatment was successful in 16/19 evaluable patients treated with CAZ or CAZ+AMP and in 16/29 evaluable patients treated with AG+AMP. None of the study centres encountered problems with ceftazidime resistant bacteria. The cure rate for patients with only clinical and radiological evidence of sepsis was greater than 94% in all treatment groups. Of the study population 65 (4.9%) died, 15 deaths were attributed to infection, pathogenic bacteria were only isolated from 10. The mortality rate for infected babies was 5.7% compared to 4.8% for those without confirmed infection. All the deaths associated with infection were due to Gram-positive bacteria. This study suggests that the practice of continuing antibiotic therapy once pretreatment cultures are known to be negative should be seriously reconsidered. It is concluded that CAZ+AMP is superior to either AG+AMP or ceftazidime monotherapy for the treatment of infection in the newborn. Further studies are required to confirm these observations in neonates with proven infection.The ESPID Neonatal Sepsis Study Group: Recruitment >=50 patients included Prof. R. Dagan, Soroka Medical Centre, Beer-Sheva, Israel; Dr. I. Tessin, Hospital of Molndal, Molndal, Sweden; Dr. D. Harvey and Dr. J. de Louvois, Queen Charlotte's and Chelsea Hospital, London, UK; Dr. B. Trollfors and Dr. K. Thiringer, Ostra Sjukuset, Goteborg, Sweden; Dr. A. Valido, Maternidade, Dr. Alfredo Costa, Lisbon, Portugal; Dr. H. Baumer, Freedom Fields Hospital, Plymouth, UK: Prof. J. Brines and Dr. Diez, University of Valencia, Valencia, Spain; Dr. L. Benic, Dr. J. Kajfes Hospital, Zagreb, Yugoslavia; and Prof. J. Badoual, Hopital St. Vincent de Paul, Paris, France.Recruitment <50 patients included Prof. L. Corbeel, UZ Gasthuisberg, Leuven, Belgium; Prof. R. Roos, Univ.-Kinderklinik, Munich, FRG; Dr. D. Kafetzisa, University of Athens, Athens, Greece; Dr. S. Pedersen, Kolding Sykehus, Kolding, Denmark; and Prof. A. Columbo, Ospedali Riunuti di Bergamo, Bergamo, Italy.     

The 24-Hour Sleep Propensity Function: Experimental Bases for Somnotypology

The present study investigated the temporal structure of sleep propensity during 48 hours using an ultrashort 7-min sleep/13-min wake cycle. Eight subjects were tested under two experimental conditions of either attempting sleep, or resisting sleep after a monitored night in the laboratory. Electrophysiological recordings were carried out during the 7-min trials. The temporal structure and the overall level of sleepiness of the 48-hour sleep propensity functions calculated from the amount of total sleep in each trial revealed a high within-subjects stability. This was found both across the two days of the study within conditions, and across conditions. Also, diurnal levels of sleepiness were systematically related to nocturnal sleep parameters. Subjects having short nocturnal sleep latencies and higher sleep efficiencies slept more during the day. It is proposed that the structure and level of the sleep propensity function can be used to characterize individuals along two dimensions of somnotypology: "morningness-eveningness" and "sleepy-alert."     

Relative pharmacokinetics of three amikacin brands in onco-hemotologic pediatric patients experiencing febrile neutropeina.

Three commercially available brands of amikacin were investigated in a parallel study design for the assessment of comparative pharmacokinetics in pediatric oncology patients with chemotherapy-induced neutropenic febrile episode. Amikacin concentration in serum samples was determined by fluorescence polarization immunoassay method using Abbott TDx system. Computer software, PK II was used for computation of pharmacokinetic parameters of amikacin. The serum concentration of all brands nonsignificantly (p > 0.05) varied at all time points, except at 1 and 2 hrs post dosing. At 1 hr post dosing, the serum concentration of brand II varied from rest of two brands. Whereas at 2 hr following I/V infusion, brands II and I were statistically different. Highest serum concentration of 38.69 +/- 1.45 microg/ml was observed in case of brand III while brands I and II showed lower but not significantly different serum concentration values, i.e., 36.30 +/- 1.65 and 37.89 +/- 1.32 microg/ml, respectively when compared with brand I. The other pharmacokinetic parameters of 3 brands found to have non-significant difference (P < 0.05) except, t(1/2)alpha and Cl of brands I and II that deviated statistically significant (p < 0.01). The relative bioavailability of brand II and III as compared with brand I, considered as standard 86.17 and 96.86%, respectively falls within the accepted limits of +/- 20% required for the bioequivalence of any two brands. Based upon findings of the present study, all these brands may be used interchangeably in oncology patients. Further studies, however are needed to determine whether the statistically elevated Cl value in brand II is of any clinical significance.     

Exposure of melanoma cells to dacarbazine results in enhanced tumor growth and metastasis in vivo.

PURPOSE: In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo. MATERIALS AND METHODS: The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice. RESULTS: The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF. CONCLUSION: Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.     

Epidermal growth factor receptor tyrosine kinase inhibitor does not improve paclitaxel effect in an orthotopic mouse model of lung cancer.

PURPOSE: The purpose is to evaluate whether inhibition of epidermal growth factor receptor (EGFR) activation by PKI166, an EGFR-tyrosine kinase inhibitor, affects growth of human lung cancer implanted orthotopically into the lungs of nude mice. EXPERIMENTAL DESIGN: Lungs of mice were injected with NCI-H358 human bronchioloalveolar cancer cells. In three experiments, groups of mice (n = 10 per group) were randomized 7 days after tumor implantation to receive one of the following treatments: i.p. paclitaxel 100 or 200 microg (4 or 8 mg/kg) once per week, oral PKI166 100 or 200 mg/kg three times per week, paclitaxel plus PKI166, or i.p. saline and oral PKI166-vehicle (control) for 5 weeks. Mice were killed 6.5 to 8 weeks after tumor implantation. The experiments were repeated with PC14PE6 human lung adenocarcinoma cells to assess effect on survival. RESULTS: Immunohistochemical analyses revealed the expression and phosphorylation of EGFR in the growing tumors. Treatment with PKI166 alone or in combination with paclitaxel diminished activation of EGFR on tumor cells, yet maximal therapeutic effect was observed in mice treated with paclitaxel alone. Activated mitogen-activated protein kinase and basic fibroblast growth factor expression were similar in all treatment groups. Survival in mice treated with the combination of paclitaxel and PKI166 was shorter than in those treated with paclitaxel alone. CONCLUSIONS: Our results suggest that concurrent administration of EGFR-tyrosine kinase inhibitor and chemotherapy is equivalent and may indeed be inferior to chemotherapy alone, even if EGFR is functional and its phosphorylation effectively inhibited. Our data show that the interaction of EGFR-TKIs and chemotherapy is complex and suggest that other growth factors may activate the downstream signaling events.     

The effect of intensive care on in-hospital survival

Intensive Care Units (ICU) are one of the most powerful and expensive technologies within inpatient care. However, its effect on survival is still an issue under discussion. The objective of this paper is to assess the effect of General ICU on in-hospital survival. We assessed the effect of ICU on survival using Linear and Probit regressions. Since admission to IC is not random and depends on unobserved (to the researcher) heterogeneity, we reassessed the IC effect by Instrumental Variables (IV) and Bivariate Probit techniques, using crowding in the IC unit as an instrument. The results show that a simple Probit of the IC effect on survival is 7–10 percentage-points (pts). The IV estimate of the IC effect on survival is 21–34 pts, and the Bivariate Probit estimate is 17–21 pts. We conclude that although admitted patients are at lower risk of death, as determined by their observable (to the researcher) characteristics, controlling for observable differences, those with a higher unobserved risk of mortality are more likely to be admitted. The implications for an optimal admission policy are discussed.     

Synergistic integration of metal nanoclusters and biomolecules as hybrid systems for therapeutic applications

Therapeutic nanoparticles are designed to enhance efficacy, real-time monitoring, targeting accuracy, biocompatibility, biodegradability, safety, and the synergy of diagnosis and treatment of diseases by leveraging the unique physicochemical and biological properties of well-developed bio-nanomaterials. Recently, bio-inspired metal nanoclusters (NCs) consisting of several to roughly dozens of atoms (<2 nm) have attracted increasing research interest, owing to their ultrafine size, tunable fluorescent capability, good biocompatibility, variable metallic composition, and extensive surface bio-functionalization. Hybrid core–shell nanostructures that effectively incorporate unique fluorescent inorganic moieties with various biomolecules, such as proteins (enzymes, antigens, and antibodies), DNA, and specific cells, create fluorescently visualized molecular nanoparticle. The resultant nanoparticles possess combinatorial properties and synergistic efficacy, such as simplicity, active bio-responsiveness, improved applicability, and low cost, for combination therapy, such as accurate targeting, bioimaging, and enhanced therapeutic and biocatalytic effects. In contrast to larger nanoparticles, bio-inspired metal NCs allow rapid renal clearance and better pharmacokinetics in biological systems. Notably, advances in nanoscience, interfacial chemistry, and biotechnologies have further spurred researchers to explore bio-inspired metal NCs for therapeutic purposes. The current review presents a comprehensive and timely overview of various metal NCs for various therapeutic applications, with a special emphasis on the design rationale behind the use of biomolecules/cells as the main scaffolds. In the different hybrid platform, we summarize the current challenges and emerging perspectives, which are expected to offer in-depth insight into the rational design of bio-inspired metal NCs for personalized treatment and clinical translation.Key words: Metal nanoclusters, Biomolecule, Nanoparticles, Hybrid system, Synergistic properties, Fluorescence, Bioprobe, Therapy     

Potentiation of tumor response to radiation or chemoradiation by selective cyclooxygenase-2 enzyme inhibitors

Cyclooxygenase-2 (COX-2) is an enzyme expressed primarily in pathologic states, such as inflammatory disorders and cancer, where it mediates prostaglandin production. Its overexpression is associated with more aggressive biologic tumor behavior and adverse patient outcome. Increasing evidence shows that agents that selectively inhibit COX-2 enhance tumor response to radiation or chemotherapeutic agents. This article gives an overview of some of this evidence. In addition, we describe new results showing that celecoxib, a selective COX-2 inhibitor, enhanced response of A431 human tumor xenografts in nude mice to radiation by an enhancement factor (EF) of 1.43 and to the chemotherapeutic agent docetaxel by an EF of 2.07. Celecoxib also enhanced tumor response when added to the combined docetaxel plus radiation treatment (EF = 2.13). Further experiments showed that selective COX-2 inhibitors enhanced tumor cell sensitivity to ionizing radiation, involving inhibition of cellular repair from radiation damage and cell cycle redistribution as mechanisms for some cell types. The results show that selective COX-2 inhibitors have the potential to improve tumor radiotherapy or radiochemotherapy, and this therapeutic strategy is currently under clinical testing.