Comparative in vitro and in vivo activities of six new monofluoroquinolone and difluoroquinolone 3-carboxylic acids with a 7-azetidin ring substituent.

E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 are new monofluorinated or difluorinated quinolone agents that are chemically characterized by the presence of an azetidin ring, with different C'-3 substituents, at position 7 of the molecular structure. The MICs of the difluorinated compounds E-4501, E-4474, and E-4441 for 90% of isolates were 0.06 to 1, 0.06 to 1, and 0.12 to 1 microgram/ml, respectively, against gram-positive organisms (staphylococci, streptococci, and Enterococcus faecalis); 0.0015 to 0.12, 0.015 to 0.12, and 0.03 to 0.12 microgram/ml, respectively, against members of the family Enterobacteriaceae except Providencia spp.; and 1, 1, and 2 micrograms/ml, respectively, against Pseudomonas aeruginosa. E-4501, E-4474, and E-4441 inhibited all anaerobic bacteria at concentrations of 1, 2, and 4 micrograms/ml, respectively. Difluorinated compounds were significantly more active than the corresponding monofluorinated analogs E-4502, E-4500, and E-4480 against aerobic and facultatively anaerobic organisms, as well as against anaerobes. Considering monofluorinated and difluorinated compounds, activity in moderate ascending order was observed in quinolones containing an amine and a methyl group (E-4441 and E-4480), an amine group (E-4474 and E-4500), and a methylamine group (E-4501 and E-4502) in the C'-3 position of the azetidin ring. E-4501, E-4474, and E-4441 were more active than norfloxacin and DR-3355 [S-(-)-ofloxacin], had activities comparable to or slightly lower than that of ciprofloxacin against gram-negative bacteria, and were more active than all the reference quinolones against gram-positive organisms and anaerobes. E-4502 and E-4501, which were used to determine the effect of pH, were less active in acidic medium. In general, E-4502, E-4501, E-4500, E-4480, E-4474, and E-4441 activities were not affected or increased in medium containing serum but decreased in the presence of 10 mM Mg2+ or in human urine at pH 5.5. The protective effect of E-4501, E-4474, and E-4441 after oral administration against systemic infections with Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa in mice was greater than that of ciprofloxacin.     

Descenso de la edad al diagnóstico en el cáncer de mama

Introduction

Increasingly younger women are apparently diagnosed with breast cancer. The aim of this study was to determine whether age at diagnosis of this disease is declining.

Material and methods

We calculated incidence rates for breast cancer in Zaragoza (Spain) by age groups. The median age at diagnosis over a 20-year period was calculated. A Joinpoint regression was subsequently performed to determine the trend.

Results

The median showed a downward trend with an annual percentage change of -0.3% (95% CI -0.6, -0.1) over the 20-year period. The crude incidence rates for age groups showed that the positive trend was highest among women aged more than 85 years, PAC = 14% (95% CI 4.03; 25.9), followed by the group aged 40-44 years with a PAC of 10% (95% CI 3.4, 17.1).

Conclusions

The median age at diagnosis of breast cancer has declined over the past 20 years.     

Effects of human chorionic gonadotrophin administration on day 5 after oestrus on corpus luteum characteristics, circulating progesterone and conceptus elongation in cattle

The aim of the present study was to test the hypothesis that elevated concentrations of progesterone (P4) resulting from the induction of an accessory corpus luteum (CL) by human chorionic gonadotrophin (hCG) administration on day 5 after oestrus would lead to advanced conceptus elongation on day 14 following embryo transfer on day 7. The oestrous cycles of cross-bred beef heifers were synchronised and animals were randomly assigned to receive either of two treatments: (1) intramuscular injection of 3000 IU hCG on day 5 after oestrus (n=14); or (2) intramuscular injection of saline on day 5 after oestrus (n=13). Ovaries were scanned daily by transrectal ultrasonography to assess CL development. Serum concentrations of P4 were determined from daily blood samples collected from the jugular vein. In vitro-produced bovine blastocysts were transferred to synchronised recipients on day 7 after oestrus (n=15 blastocysts per recipient). Heifers were killed on day 14 after oestrus and the uterus was flushed to recover the embryos. Injection of hCG on day 5 induced ovulation of the dominant follicle in all treated heifers and increased the total area of luteal tissue on the ovary, which was associated with a significant increase (P<0.001) in serum concentrations of P4 from day 7 to day 14. Positive associations were detected between circulating P4 with CL area (within-day correlations ranging from r=0.45 to r=0.67) and total area of luteal tissue (within-day correlations ranging from r=0.65 to r=0.86) Administration of hCG did not affect the proportion of day 14 conceptuses recovered. However, compared with the control group, hCG-treated heifers had increased conceptus length (3.91±1.23 vs. 5.57±1.02 mm, respectively; P=0.06), width (1.00±0.06 vs. 1.45±0.05 mm, respectively; P=0.002) and area (5.71±0.97 vs. 8.31±0.83, respectively; P=0.02). Although numerically greater, mean interferon-τ (IFNT) production in vitro did not differ significantly (P=0.54) between embryos recovered from hCG-treated and control heifers. In contrast, there was a strong positive correlation between individual embryo length (r=0.76; P<0.001) and individual embryo area (r=0.72; P<0.001) and IFNT production. In conclusion, administration of hCG on day 5 after oestrus resulted in the formation of an accessory CL and hypertrophy of the original CL, the result of which was an increase in P4 concentrations from day 7 onwards. These elevated P4 concentrations were associated with an increased conceptus area. Furthermore, conceptus size was highly correlated with IFNT secretion in vitro.     

Effectiveness of interventions designed to modify and maintain perceptual abilities in people with Alzheimer's disease and related dementias

An evidence-based review was undertaken to answer the question, "What is the evidence for the effect of interventions designed to modify and maintain perceptual abilities on the occupational performance of people with Alzheimer's disease and related dementias?" A systematic search of electronic databases and application of inclusion and exclusion criteria guided the selection of 31 articles. Each article was critically appraised, and the evidence was synthesized. Some interventions use remaining perceptual abilities to enable people to find their way in a facility and decrease attempts at exiting. Preliminary evidence has supported use of visual stimulation and barriers. We found some evidence for the use of auditory stimuli and group therapy that aim to change perceptual abilities. Research with high-level evidence is required to validate these findings. Evidence on the benefits of Snoezelen is not conclusive for occupational performance outcomes; further research to justify its use as an occupational therapy intervention may be warranted.     

Influence of the SURLAS applicator on radiation dose distributions during simultaneous thermoradiotherapy with helical tomotherapy

Simultaneous thermoradiotherapy has been shown to maximize the effect of hyperthermia as a radiation sensitizer in cancer treatment. Here we follow our previous work on feasibility of thermoradiotherapy with the scanning ultrasound reflector linear array system (SURLAS) and TomoTherapy HiArt treatment system, and investigate the influence of the SURLAS hyperthermia applicator on delivered radiation dose with the TomoTherapy. A radiation treatment plan was calculated and the treatment was delivered to a phantom with SURLAS on top simulating the likely clinical setup. Proper positioning of the SURLAS was assisted with a magnetic position-and-orientation tracking device (POTD) and was verified with megavoltage-computed tomography. The delivered dose was measured with an ionization chamber (point measurement) and a radiographic film (2D dose distributions). The planned and delivered point dose data agreed within 0.61% +/- 0.63%. Planar dose data agreed within a dose difference of < or =3% of the maximum dose, and a distance-to-dose-agreement of < or =1 mm. The susceptibility of the delivered radiation dose on correct SURLAS positioning was studied as well. The largest dose discrepancy was measured for a position for which a maximum number of radiation beams intersected the incorrectly positioned SURLAS within one TomoTherapy gantry rotation. The point dose disagreed by 6.14% +/- 0.52%, and 2.25% of pixels of the 2D dose distribution did not pass the 3% dose difference/1 mm distance-to-dose-agreement criteria. Our study showed that correct positioning of the SURLAS applicator had an influence on the delivered radiation dose. Delivered and planned dose distributions were in an excellent agreement when SURLAS was positioned according to the treatment plan. Moving the applicator from its planned position was found to cause a modification of delivered dose distributions. A precise and reproducible positioning of the applicator was assured with a POTD.