Sequence fidelity of a template-directed PNA-ligation reaction.

The ligation method and an appended duplex-stabilizing dye affect both yield and sequence selectivity of a template-controlled PNA-ligation. The highest selectivity was obtained with a peptide condensation that formed an abasic site.

Effects of enalaprilat on circadian profiles in blood pressure and heart rate of spontaneously and transgenic hypertensive rats.

We investigated the dose-dependent cardiovascular effects of enalaprilat at different dosing times in two animal models of hypertension. Blood pressure (BP) and heart rate (HR) were measured telemetrically in 5 spontaneously hypertensive rats (SHR) and in 5 transgenic hypertensive rats (TGR) after intraperitoneal (i.p.) injection of enalaprilat either at 700 h or at 1900 h. In SHR, dosing of enalaprilat at the beginning of the resting period, i.e., at 700 h, significantly reduced BP but did not influence HR. After dosing at 1900 h, BP was unchanged, whereas HR increased, which might have resulted from reflexly increased sympathetic tone. In TGR, enalaprilat at either dosing time decreased BP dose dependently and to a higher extent than in SHR, but the effects were more pronounced after morning than after evening dosing. These findings demonstrate that in two animal models of hypertension the antihypertensive effects of enalaprilat depended on the time of drug dosing.

Correlative circadian rhythms of cholecystokinin and dopamine content in nucleus accumbens and striatum of rat brain.

Due to contrary results concerning the interaction of cholecystokinin and dopamine (CCK/DA) circadian variations in CCK/DA concentration were investigated in forebrain nuclei of rats (Nc. accumbens, striatum) in order to assess the influence of time of day on neurotransmission. CCK was determined by a radioimmunoassay, DA was measured by electrochemical detection after HPLC separation. A distinct circadian rhythm, superimposed by harmonics (12 h, 6 h) was found in the content of both DA and CCK. A trough was shown for CCK during the light phase and a crest during the late afternoon and the dark phase, respectively. For DA the opposite was found. Caused by a phase-shift of about 3-4 h, the CCK/DA rhythms are negatively correlated. The differences are significant at 11.00 h, 13.00 h, 21.00 h, and 03.00 h. The results indicate that circadian processes are involved in neuronal transmission of CCK and DA.

Circadian blood pressure variation in transgenic hypertensive rats.

Automatic, around-the-clock blood pressure measurements have increased our understanding of hypertension in humans. Patients with essential hypertension display patterns similar to those observed in normotensive subjects, whereas those with secondary hypertension frequently show abnormal circadian rhythms characterized by a failure to reduce blood pressure at night. We have modeled this situation in rats. Normotensive Wistar-Kyoto and Sprague-Dawley rats, spontaneously hypertensive rats, and rats made hypertensive by transgenic implantation of the mouse salivary gland renin gene (TGR[mRen-2]27) underwent chronic implantation of a device that telemetrically monitored their blood pressures, heart rates, and motor activities. In either normotensive or hypertensive rats, motor activity peaked during the dark phase, indicating that animals from all strains were nocturnal. In both normotensive and spontaneously hypertensive rats, the 24-hour blood pressure and heart rate profiles showed peak values during the rats' active phase at night, ie, between midnight and 3 AM. In the transgenic rats, on the other hand, blood pressure values were at maximum during the day around noon, when the rats were in their resting phase. The heart rate of the transgenic rats nevertheless still peaked around midnight. These data suggest that normotensive rats and those with primary and secondary hypertension display circadian rhythms of blood pressure and heart rate analogous to those observed in normotensive and primary or secondary hypertensive humans, respectively. The TGR(mRen-2)27 strain may be a useful model with which to investigate the mechanisms responsible for alterations in circadian rhythms of blood pressure and heart rate in forms of secondary hypertension.

[PHARMFIT--a program for the evaluation of digitally collected cardiovascular parameters]. / PHARMFIT--ein Programm zur Auswertung digital erfasster kardiovaskulärer Messdaten.

The PHARMFIT program allows the non-linear fit of simple and combined cosine functions to data from long-term monitoring of cardiovascular parameters and the statistical evaluation of the quality of fit. With the SYNOPS utility a statistical comparison of different fit models can be achieved. As an example, the systolic blood-pressure data obtained in a hypertensive subject by ambulatory blood-pressure monitoring (ABPM) over a period of 36 h is used. The program demonstrates that the fit of a combined cosine function including a 24-h and a 12-h period describes the data better than a simple 24-h cosine function. The quality of fit is significantly improved by inclusion of the first harmonics. The PHARMFIT program can help to get a better analysis of ABPM data.

PHARMFIT--a nonlinear fitting program for pharmacology.

A new program is presented for nonlinear fitting of data from pharmacological and chronobiological investigations. It contains functions for calculating data from ligand-binding studies and competition experiments, for the analysis of dose-response curves, for pharmacokinetic calculations, and for cosine analysis of harmonic and overlapping rhythms. In addition, it is possible to implement general equations by the user. The program allows data exchange with most spreadsheet, database, and graphics presentation programs, and accepts data from two widely used ambulatory 24-h blood-pressure monitoring systems. The fitting procedure uses the Marquardt-Levenberg algorithm. It calculates the weighted or the unweighted fit together with a great variety of statistics for estimation of goodness of fit. A graphics module permits graphical presentation of the fitted curve. Moreover, fitting of data to different models can be compared for the most likely fit and model discrimination statistics for improvement of further experiments are provided. To demonstrate the chronobiological application of the fitting program PHARMFIT, the analysis of telemetric heart rate data from rats is presented.

Effects of amlodipine on circadian rhythms in blood pressure, heart rate, and motility: a telemetric study in rats.

In male Wistar rats [light(L): 07:00-19:00 h, dark(D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED50 values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.

The potency of interferon-alpha 2 and interferon-gamma in a combination therapy of dendritic keratitis. A controlled clinical study.

Forty-five patients with virologically confirmed dendritic keratitis were treated in a randomized, double-blind controlled study with a basic therapy of trifluorothymidine (TFT) eye drops. In addition they received different human recombinant interferon (rHu IFN) eye drops. The following results were obtained for average healing times: TFT plus one drop daily of rHu IFN-alpha 2 arg (30 million iu/ml): 3.3 days, TFT plus rHu IFN-gamma (30 million iu/ml): 3.9 days, TFT plus a mixture of alpha plus gamma (0.3 million iu/ml each): 6.1 days, TFT plus a mixture of alpha plus gamma (1.5 million iu/ml each): 3.3 days. High-titer gamma interferon did not significantly differ from high-titer alpha interferon in the combination therapy of dendritic keratitis. A mixture of alpha plus gamma at a moderate titer (1.5 million iu/ml each) was as effective as a high-titer mono-preparation. Adding a low-titer interferon mixture gave no better therapeutic results than antiviral monotherapy. Thus it seems possible to save about 90% of interferon commonly used in the combination therapy of dendritic keratitis by applying a mixture of different suitable interferons instead of interferon monospecies.

State-dependent learning in hyperactive children receiving methylphenidate.

State-dependent learning refers to a failure of learning mastered under one drug condition to be remembered when tested under another drug condition. Previous studies of state-dependent learning in hyperactive children receiving stimulants have yielded conflicting results. The authors systematically evaluated learning and transfer of learning in children who were or were not receiving methylphenidate and included several design features intended to optimize the likelihood of demonstrating state-dependent learning. They found no evidence of state-dependent learning. These results diminish concern regarding state-dependent effects in hyperactive children who are positive drug responders and who are clinically administered methylphenidate to control their hyperactivity.

Combination therapy for dendritic keratitis. High-titer alpha-interferon and trifluridine.

Previous studies showed that the combination of trifluridine with human leukocyte interferon in the treatment of dendritic keratitis is effective, and that the best results were obtained with the highest titer then available (30 X 10(6) IU/mL). The present study was undertaken to see if an even higher titer (100 X 10(6) IU/mL) would be more effective. A statistically significant greater effectiveness of the higher titer could not be verified.

[Chlamydial disease of the eye: a report on 27 cases. Clinical picture, differential diagnosis, treatment (author's transl)]. / Chlamydienerkrankungen des Auges. Bericht über 27 Patienten, Klinik- Differentialdiagnose-Therapie.

During the past five years a presumptive diagnosis of ocular chlamydial disease has been made in 90 patients consulting the outpatient department of Freiburg University Eye Clinic. The diagnosis was confirmed by different methods (giemsa stains, chlamydia cultures and serology, electron microscopy and histology) in 27 cases. The clinical spectrum included inclusion blennorrhea in newborns as well as inclusion conjunctivitis, TRIC keratoconjunctivitis and sporadic trachoma in adults. Presumably the incidence of the disease is much higher than indicated by our figures. We suspect a very high number of undiagnosed cases. These patients usually do not receive proper therapy (tetracyclin or erythromycin for at least three weeks) and their disease may run a protracted course with the risk of permanent eye damage.