4-Epidoxycycline: an alternative to doxycycline to control gene expression in conditional mouse models.

Since the pioneering work by Gossen and Bujard in 1992 demonstrating the usefulness of the Escherichia coli derived tet resistance operon for regulating gene expression a large collection of doxycycline-controlled transgenic mice has been established. Gene switching in eukaryotic tissue culture cells or mice requires administration of tetracycline, anhydrotetracycline or doxycycline to efficiently inactivate the transactivator protein tTA (TET-OFF system) or alternatively to activate the reverse transactivator protein rtTA (TET-ON system). However, the antibiotic activity of doxycycline can create an imbalance of the intestinal flora, resulting in diarrhoea and in a smaller number of animals in colitis. Previous studies reported that 4-epidoxycycline (4-ED), a hepatic metabolite of doxycycline, does not function as an antibiotic in mice. This gave us the idea that 4-ED might be useful for controlling gene expression in mice without the unwanted antibiotic side effect. To study the applicability of 4-ED for control of gene expression we used cell lines expressing the oncogene HER2 under control of tTA (TET-OFF) as well as rtTA (TET-ON). 4-ED and doxycycline were similarly efficient in switching on or -off HER2 expression. In vivo we used a conditional mouse model that allows switching off HER2 in tumor tissue. We show that (i) doxycycline, 7.5mg/ml in drinking water (used as a positive control), (ii) 4-ED, 7.5mg/ml in drinking water, (iii) 4-ED, 10mg/kg body weight, s.c., and (iv) anhydrotetracycline, 10mg/kg, s.c. (used as a second positive control), were similarly efficient. Using mice with tumor volumes of 1.6cm(3) all four schedules led to a tumor remission of more than 95% within 7 days. In conclusion, 4-ED is similarly efficient as doxycycline to control gene expression in vitro and in mice. Since 4-ED lacks the antibiotic activity of doxycycline it may help to avoid adverse side effects and selection of resistant bacteria.

Dopamine-antagonistic, anticholinergic, and GABAergic effects on declarative and procedural memory functions.

Declarative and procedural memory functions are related to dissociable neuroanatomic substrates. In the present study differential effects of pharmacologically induced changes in dopaminergic, GABAergic, and cholinergic activity in the brain on declarative (object and face recognition, immediate and delayed word recall) and procedural memory processes (compensatory tracking) were investigated. In a double-blind design, either 3 mg of haloperidol, 11 mg of midazolam, 1 mg of scopolamine, or placebo were administered to 80 healthy volunteers randomly assigned to one of the four drug conditions. Although all three drugs produced a detrimental effect on immediate and delayed word recall, recall performance was substantially more impaired by the benzodiazepine midazolam than by either haloperidol or scopolamine. While recognition of faces was affected by neither of the drugs, performance on object recognition was significantly decreased by midazolam as compared to placebo. Procedural learning was markedly impaired by all drugs but, again, the observed effect was most pronounced with midazolam. Additional analyses of measures of subjective activation, cortical arousal, and psychomotor performance argued against the assumption that the observed memory-impairing effects were secondary to drug-induced sedation. The overall pattern of results revealed that memory processes are much more susceptible to changes in GABAergic than in dopaminergic or cholinergic neurotransmitter activity. Furthermore, the present findings point to the conclusion that the modulating effects of dopaminergic, GABAergic, and cholinergic neurotransmitter systems on declarative and procedural memory functions are less specific than suggested by neuropsychological studies in patients.

[The hormone profile in the blood plasma of heifers after cycle synchronization with prostaglandin F2alpha]. / Untersuchungen zum Hormonprofil im Blutplasma von Färsen nach Zyklussynchronisation mit Prostaglandin F2alpha.

Highly sensitive radio-immuno assay (RIA) was used for 21 days to study the curves of several steroid hormones, progesterone (P), oestradiol 17 beta (E2), and testosterone (T), as well as of luteinizing hormone (LH) in peripheral blood of six heifers to which oestrus had been induced by prostaglandin F2 alpha. The validity of the authors' RIA for P, E2, and T determination in blood plasma was positively verified by two reliability criteria, correctness and accuracy, as well as by comparative determinations, using reference methods. Only four of the six heifers returned to oestrus, within 21 days from first oestrus induction. A typical cycle-related curve of the P concentration in peripheral blood with peak values between the 13th and 17th days of cycle (15-26 nmol/l) was recorded from four animals. The peak values of pre-ovulatory E2 and LH were between 33.0 and 53.2 pmol/l or between 19.5 and 52.5 micrograms/l. Some of the T rises in peripheral blood were in parallel to E2 concentrations. All hormone curves are presented in detail and are discussed in relation to clinico-physiological findings.

Computer-assisted instruction in radiology.

We developed an interactive computer system to support various educational uses. The system allowed numerous instructors to create lessons or tests in a flexible, personalized fashion. As a pilot project, the system was used to develop and administer a computer-driven final examination in a didactic radiology course for second-year medical students. It was our objective to change the examination into an enjoyable experience that would also bring about long-term learning gains. The computer added immediate feedback to the testing situation.

Plain radiography with a rare-earth screen: comparison with calcium tungstate screen.

Plain radiographic examinations were performed on 388 patients (adult and pediatric) using either a calcium tungstate or rare-earth screen. Radiographs were compared for overall image quality, mottle, contrast, density, and detail. The rare-earth screen produced radiographs with significantly more mottle than did the standard screen. However, this was almost never of diagnostic importance. A small but significant decrease in overall image quality also was found with the rare-earth screen. This was the result of minor differences between the grading of optimal and good. A major advantage of rare-earth screens is a 50% or more reduction in radiation exposure. The results here show that rare-earth screens may be used in plain radiographic examinations without a clinically important decrease in image quality.

A computer system to monitor radiology department activity: a management tool to improve patient care.

A microcomputer system has been developed and installed at the Mallinckrodt Institute of Radiology to monitor the moment-to-moment activity in a radiology department. Data about department performances are collected, summarized, and displayed in graphs and tables on terminals at stations throughout the department. The system is currently used to monitor a wide variety of functions including patient waiting time, report production time, film-library operations, equipment maintenance, and room use. Since the displays are updated in real-time, it is possible to identify and address problems as they occur, thereby providing a method of evaluation that leads to improved performance as related to patient care.