In vitro activity of E-4868, a new trifluoroquinolone,compared to six similar compounds

The compound E-4868 (Laboratorios Dr. Esteve) is a trifluoro, 7-azetidinyl quinolone with properties resembling those of other fluoroquinolones. Its activity in vitro was compared to that of six other similar drugs against more than 700 nosocomial isolates using standard methods. The MIC50s of E-4868 for enteric bacilli ranged from 0.015 to 0.25 µg/ml, being highest forProvidencia spp.Pseudomonas aeruginosa strains were two-fold more susceptible to E-4868 than to ofloxacin. MICs of E-4868 forHaemophilus influenzae, Moraxella catarrhalis and pathogenicNeisseria spp. were all 0.12 µg/ml. E-4868 was equal in activity to or eight-fold more active than ciprofloxacin against gram-positive cocci. The MICs of E-4868 for pneumococci were all 0.5 µg/ml but anaerobes such asBacteroides fragilis were generally less susceptible (MIC90, 4 µg/ml). There was almost complete cross-resistance to several other fluoroquinolones. Resistant mutants were selected by a multiple passage technique but the rate of mutation to resistance was very low (< 10^–8) at an 8 x MIC.     

Studies on the mammary tumor-inhibiting effects of diethylstilbestrol and its mono- and diphosphate

Summary Diethylstilbestrol (DES), diethylstilbestrol monophosphate (DES-MP) and diethylstilbestrol diphosphate (DES-DP) were tested for their estrogen receptor affinity, estrogenic potency and mammary tumor-inhibiting activity in vitro and in vivo. DES had a much higher receptor binding affinity than its mono-or diphosphate. All three compounds inhibited the growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB 231 breast cancer line only at relatively high concentrations. The estrogenic potency in the immature mouse uterine weight test decreased in the order DES>DES-MPDES-DP. The hormone-dependent MXT mammary tumor of the mouse was inhibited by all three compounds at a dosage of 1.0 mg/kg per week. At a dose of 0.01 mg/kg, DES, DES-MP, and DES-DP stimulated the tumor growth. Thus, for the first time, a biphasic effect on tumor growth was demonstrated in intact mature animals. As the effects of all three compounds were similar in this assay, a cleavage of the phosphate groups is likely. A decrease in estrogenic potency concomitant with a retained antitumor effect of DES-MP and DES-DP compared to DES was not demonstrable in the mature mouse using the MXT assay, only in the uterotrophic test in the immature mouse.Dedicated to Professor Dietrich Schmähl on occasion of his 60th birthdaySupported by the Deutsche Forschungsgemeinschaft and by the Verband der Chemischen Industrie, Fonds der Chemischen Industrie. The authors thank Dr. Weigert, Asta-Werke AG, Degussa Pharma Gruppe, Bielefeld, FRG, for the analysis of DES-MP and DP     

Practice patterns of Doctor of Pharmacy graduates: educational implications

The purpose of this study was to evaluate the appropriateness of the predominantly clinical PharmD curriculum in light of actual employment patterns of PharmD graduates. Data were gathered via a survey of PharmD graduates from the seven post-baccalaureate programs active since 1972. Respondents were asked about their employment patterns and characteristics; about their formal education in the areas of management, statistics, and research methods; and to indicate whether they had completed residencies or fellowships. The results indicate that many PharmD graduates are employed in positions requiring considerable nonclinical skills, especially management skills. The results further indicate that few respondents have completed formal education, residencies, or fellowships which would prepare them for management or other nonclinical positions. Consequently, it appears that PharmD programs should require considerably more management training and education in order to adequately prepare their graduates for the positions open to them.     

Improved Maternal and Infant Outcomes with Serial,Self-Reported Early Prenatal Substance Use Screening

Maternal and Child Health Journal - Most screening tools identifying women with substance use are not validated, used once in pregnancy, and are not reflective of continued substance use. We...     

Short- and long-term impact of neutropenia within the first year after kidney transplantation

The aim of this retrospective single-center study was to investigate the short- and long-term impact of neutropenia occurring within the first year after kidney transplantation, with a special emphasis on different neutropenia grades. In this unselected cohort, 225/721 patients (31%) developed 357 neutropenic episodes within the first year post-transplant. Based on the nadir neutrophil count, patients were grouped as neutropenia grade 2 (<1.5–1.0*10⁹/l; n = 105), grade 3 (<1.0–0.5*10⁹/l; n = 65), and grade 4 (<0.5*10⁹/l; n = 55). Most neutropenia episodes were presumably drug-related (71%) and managed by reduction/discontinuation of potentially responsible drugs (mycophenolic acid [MPA] 51%, valganciclovir 25%, trimethoprim/sulfamethoxazole 19%). Steroids were added/increased as replacement for reduced/discontinued MPA. Granulocyte colony-stimulating factor was only used in 2/357 neutropenia episodes (0.6%). One-year incidence of (sub)clinical rejection, one-year mortality, and long-term patient and graft survival were not different among patients without neutropenia and neutropenia grade 2/3/4. However, the incidence of infections was about 3-times higher during neutropenia grade 3 and 4, but not increased during grade 2. In conclusion, neutropenia within the first year after kidney transplantation represents no increased risk for rejection and has no negative impact on long-term patient and graft survival. Adding/increasing steroids as replacement for reduced/discontinued MPA might supplement management of neutropenia.     

Randomized controlled trial comparing magnetic marker localization (MaMaLoc) with wire-guided localization in the treatment of early-stage breast cancer

Wire-guided localization (WGL) is the standard of care in the surgical treatment of nonpalpable breast tumors. In this study, we compare the use of a new magnetic marker localization (MaMaLoc) technique to WGL in the treatment of early-stage breast cancer patients. Open-label, single-center, randomized controlled trial comparing MaMaLoc (intervention) to WGL (control) in women with early-stage breast cancer. Primary outcome was surgical usability measured using the System Usability Scale (SUS, 0–100 score). Secondary outcomes were patient reported, clinical, and pathological outcomes such as retrieval rate, operative time, resected specimen weight, margin status, and reoperation rate. Thirty-two patients were analyzed in the MaMaLoc group and 35 in the WGL group. Patient and tumor characteristics were comparable between groups. No in situ complications occurred. Retrieval rate was 100% in both groups. Surgical usability was higher for MaMaLoc: 70.2 ± 8.9 vs. 58.1 ± 9.1, p < 0.001. Patients reported higher overall satisfaction with MaMaLoc (median score 5/5) versus WGL (score 4/5), p < 0.001. The use of magnetic marker localization (MaMaLoc) for early-stage breast cancer is effective and has higher surgical usability than standard WGL.     

Stretch activation and myogenic oscillation of isolated contractile structures of heart muscle

Summary Glycerinated or freeze-dryed fibre bundles of heart muscles (papillary and trabecular muscles of rabbit or guinea pig) show in ATP-salt solution with about 10^–6M Ca²⁺ an active, delayed tension increment after quick or sinusoidal stretching. The active tension increase is completely different from the passive tension increment caused by stretching of the elastic structures of the muscle; this well known length dependence of tension is also in phase with the length changes (or the tension-phase preceeds the length-phase in visco-elastic bodies). On the other hand, the active tension increase is delayed with respect to the length change; this can be observed very well after rectangular changes in length. The delayed activation of the contractile bonds at stretch and the delayed deactivation at shortening induce the muscle-during sinusoidal length changes in a characteristic frequency range-to produce power output. The frequency range corresponds to the heart beat frequency of the living muscle. Temperature rise and inorganic phosphate accelerate, Mg-ions and ADP retard the contraction speed. Ca-ions influence only the amount of the isometric tension, but not the contractile velocity.Supported by the Deutsche Forschungsgemeinschaft (Grant RU 154/3).     

Aging does not affect the sleep endocrine response to total sleep deprivation in humans

Aging is associated with decreased sleep continuity, slow wave sleep (SWS), growth hormone (GH) release and an increased hypothalamo-pituitary-adrenocortical (HPA) system activity. Total sleep deprivation (TSD) is a strong stimulus for sleep. To determine if aging affects the response to TSD, for the first time the combined effects of TSD on conventional and spectral sleep electroencephalographic (EEG) parameters and GH, cortisol and prolactin secretion were compared in elderly (60–80 years; n = 7) vs. younger subjects (20–30 years; n = 7). MANOVA revealed a reduction of SWS in the elderly. TSD led to an increase in SWS, a decrease in sleep onset latency, rapid eye movement (REM) density and by trend REM-latency without a global group difference. GH was reduced, whereas prolactin was enhanced in the elderly. After TSD GH was unchanged and prolactin secretion was enhanced without group difference. Thus, the plasticity of the sleep-endocrine system in response to TSD is sustained during aging. The possible involvement of the GABAergic system, that seems not to be severely impaired with age, is proposed.     

Cavernous Haemangiomas of the Spinal Cord. A Review of 117 Cases

 The data of 48 studies (published between 1903 and 1996), presenting information of all together 107 patients (108 lesions) regarding pre-treatment clinical and radiological factors, treatment strategies, and the outcome, plus our own experience of nine patients were retrospectively re-analyzed. The prognostic influence of pre-treatment factors was estimated with the chi-square statistics. Clinical evaluation before/after treatment was performed using the Frankel scale. The average bleeding rate was obtained from the ratio of percentage of first bleeding events in the population to the mean age of the population.  There were 47 males and 69 females (aged from twelve to 88 years). Thirty nine percent of the lesions were found in the cervical, 54% in the thoracic (30% upper, 24% lower) and 7% in the lumbar cord. The peak age of presentation was in the fourth decade, the median duration of symptoms was 32 months. Clinical symptoms before treatment were progressive in all cases. Three patterns of clinical presentation could be identified: a) episodes of stepwise clinical deterioration (30%), b) slow progression of neurological decline (41%), c) acute onset with rapid or gradual decline over weeks or months (26%). 58% of the lesions showed clinical or radiological signs of haemorrhage. In 66% of surgical patients (91 efficiently documented cases), clinical improvement was achieved, 28% remained unchanged and 6% deteriorated. Whereas age, sex and lesion location had no influence on the results, duration of symptoms (<three years) correlated significantly to a better outcome (p<0.02).  Surgical management in symptomatic patients is recommended. Once clinical signs caused by the malformation have appeared, the patients tend to experience progressive neurological deterioration.