Safety and efficacy of pimecrolimus cream 1% in the daily practice: Results of a patient self‐observation study in patients with atopic dermatitis

Background: Pimecrolimus cream 1% has proven to be well‐tolerated and effective in controlled clinical studies in patients with atopic dermatitis (AD). In a 15‐week patient self‐observation study, safety and efficacy was investigated in the daily practice. Patients and methods: 3502 patients with AD (mean age 26.2 ± 18 years, 62% female) received pimecrolimus cream 1% from 810 physicians in the German Federal Republic.The severity of the disease was assessed at baseline, two times during the 15‐week observation period and at the end of treatment.Patients recorded daily the degree of erythema and pruritus. At the end of treatment, safety and efficacy were assessed by the physician based on patient's daily records and by the patient. Results: The percentage of patients with severe or massive AD decreased from 25% to 7%, whereas the percentage of patients without or with mild symptoms increased from 9% to 55%.The efficacy of treatment was rated by physicians as good or very good in 83.5% of cases and by 79% of patients.At baseline 35% of the patients were free of flares as compared to 75% at the end of therapy. Disease control was better in patients who followed the recommended treatment algorithm for pimecrolimus cream.Tolerability was mostly rated as good or very good. Conclusion: Treatment with pimecrolimus cream 1% for patients with AD is well‐tolerated and effective in daily practice.     

Orthodontic fine adjustment after vertical callus distraction of an ankylosed incisor using the floating bone concept.

The outcome of vertical callus distraction of a segment of tooth-supporting alveolar process might be functionally and esthetically unsatisfactory because of the unidirectional impact of intraoral distraction devices. In this case report, we describe how, with a shortened consolidation phase and application of the floating bone effect, the tooth-supporting osteotomy segment can be successfully aligned 3 dimensionally. We applied orthodontic force systems that went beyond the unidirectional vector preset by the mechanical properties of the distraction device.     

Depletion of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine in three-dimensional collagen cultures of normal human breast epithelial cells.

O6-Alkylguanine--DNA alkyltransferase (AGT) is a protein which removes the promutagenic O6-alkylguanine lesion induced in DNA by alkylating agents. Our results demonstrate that freshly isolated organoids from reduction mammoplasty specimens contain significant levels of AGT activity. AGT activity in breast epithelial cells shows interindividual variation. Constitutive levels of AGT activity remain unchanged during short-term serum-free culture of breast epithelial cells inside three-dimensional rat-tail collagen gel matrix. In the present study, we optimized conditions for depleting AGT activity in human breast epithelial cells cultured in three-dimensional collagen gel matrix using O6-methylguanine and O6-benzylguanine which are substrates for AGT. AGT activity was efficiently inactivated by exposure of cells to O6-methylguanine or O6-benzylguanine. Inactivation with O6-benzylguanine was more rapid, of greater magnitude and consistency and occurred at lower concentrations than with O6-methylguanine. Near-complete inactivation (> 99.5%) of AGT activity was reproducibly achieved with 50 microM O6-benzylguanine. In contrast, 500 microM O6-methylguanine was needed to obtain a maximal effect and this reduced AGT activity by only 53-93% of control. Within 30 min of adding the free base, 50 microM O6-benzylguanine depleted 95% of the levels of AGT compared to 30% inhibition with 500 microM O6-methylguanine. The profile for restoration of AGT activity was different following a 24 h incubation and subsequent removal of each of the guanine derivatives. AGT activity levels remained undetectable for at least 2 days after removal of 50 microM O6-benzylguanine from the medium and recovered to only 53% of control values after an additional 3 days. AGT activity levels remained undetectable for at least 2 days after removal of 50 microM O6-benzylguanine from the medium and recovered to only 53% of control values after an additional 3 days. In contrast, following removal of 500 microM O6-methylguanine, the activity was restored from its nadir of 16% of control values reaching pretreatment levels after 5 days. These results suggest that treatment with O6-benzylguanine may be used to modulate the incidence of transforming mutations in cultured human breast epithelial cells treated with chemical carcinogens which give rise to O6-alkylguanine adducts.     

Preexposure to a nonaggressive opponent prevents low-intensity, social-conflict analgesia in mice

In a first experiment, exposure of DBA/2 mice to a small number of attack bites by a C57BL/6 mouse resulted in low-intensity analgesia as assessed by the tail-flick test. The analgesia dissipated within 10 min and was insensitive to naloxone (10 mg/kg, sc) but was antagonized by the irreversible opioid antagonist beta-chlornaltrexamine (5 mg/kg, sc). In a second experiment, preexposure to a nonaggressive C57BL/6 opponent prevented low-intensity analgesia induced by a small number of attack bites 24 hr later. The preexposure effect was abolished by naloxone (10 mg/kg, sc) given before the nonaggressive confrontation. This suggests that the release of endogenous opioids during preexposure interferes with the subsequent activation of endogenous opioid-mediated pain control mechanisms.     

Stereochemie substituierter Glutarsäuren, 2. Mitt. Synthese kernfluorierter,mehrfach substituierter Glutarsäuren

Stereochemistry of Substituted Glutaric Acids, II: Syntheses of Substituted 3-(4-Fluorophenyl)-glutaric Acids The stereoselective syntheses of (±)erythro- and (±) threo-3-(4-fluorophenyl)-2-methyl-glutaric acids (9), (10) by Michael addition of dimethyl malonate (2) to methyl E-2-methyl-4′-fluorocinnamate (1) via the subst. trimethylbutanetricarboxylates 3,4 and the subst. butanetricarboxylic acids 7,8 are described. 3 and 4 have been alkylated with methyl bromoacetate to the subst. tetramethylpentanetetracarboxylates 5 and 6 . Attempts towards saponification of 5 and 6 are reported.     

Stimulation of thrombopoiesis in mice bearing experimental tumors

Significant increase (p less than 0.05) in circulating platelet counts was observed in a wide spectrum of experimental tumors in mice. The mechanism of this abnormality was investigated in strain A mice bearing a transplantable ascites tumor, Sarcoma 180 (S 180). Thrombocytosis observed in the tumor hosts was not due to prolonged platelet surviva], as 51Cr platelet half-life was normal. On the other hand, stimulation of thrombopoiesis, expressed in terms of platelet 75Selenomethionine (75SeM) incorporation, appeared to be the primary reason for elevated platelet counts in the tumor-bearers. Evaluation of thrombopoietic activity in the femoral marrow and spleen by measuring organ uptake of 75SeM and megakaryocyte counts indicated that tumor-induced stimulation in thrombopoiesis may be attributed to enhancement in splenic activity. Pretreatment of normal mice with tumor ascites or tumor cell-conditioned medium resulted in enhancement in thrombopoiesis. The findings suggest the production of some factor(s) by the tumor cells which probably mediate the stimulation of platelet production in tumor hosts.     

Post-operative progress of dystonia patients following globus pallidus internus deep brain stimulation

In the current era of functional surgery for movement disorders, deep brain stimulation (DBS) of the globus pallidus internus (GPi) is emerging as the favoured intervention for patients with dystonia. Here we report our results in 20 patients with medically intractable dystonia treated with GPi stimulation. The series comprised 14 patients with generalized dystonia and six with spasmodic torticollis. Although comparisons were limited by differences in their respective neurological rating scales, chronic DBS clearly benefited both patient groups. Data conveying the rate of change in neurological function following intervention are also presented, demonstrating the gradual but progressive and sustained nature of improvement following stimulation of the GPi in dystonic patients.     

Killing of alpha-haemolytic and non-haemolytic Escherichia coli strains in human serum and polymorphonuclear leucocytes.

The role of alpha-haemolysin (AH) in the resistance of Escherichia coli strains, isolated from patients with extra-intestinal diseases or diarrhoea, to the bactericidal activity of human serum and intracellular killing in polymorphonuclear leucocytes (PMNL) was investigated in vitro. Sets of alpha-haemolytic and non-haemolytic E. coli strains and sets of isogenic E. coli strains, which included wild-type alpha-haemolytic strains and derived strains with a reduced production of AH, were used. Compared with non-haemolytic strains, alpha-haemolytic strains were significantly more resistant to the bactericidal activity of 10% and 100% human serum and to intracellular killing in PMNL. Higher resistance to serum killing and to intracellular killing in PMNL was also found in wild-type alpha-haemolytic E. coli than in isogenic bacteria with reduced production of AH. These results provide evidence that production of AH in E. coli strains counteracts both the bactericidal activity of serum and intracellular killing in PMNL.