[German Version of the Childbirth Self-Efficacy Inventory and its Short Form]. / Deutsche Version des Childbirth Self-Efficacy Inventory und dessen Kurzform - ein Fragebogen zur Selbstwirksamkeit.

BACKGROUND: The Childbirth Self-Efficacy Inventory (CBSEI) is an instrument that measures women's perceived self-efficacy towards labour. It is used in 9 countries, a 32-item short form (CBSEI-C32) in 4 countries. German versions of the CBSEI and the CBSEI-C32 have not been developed thus far. METHODS: A forward-backward translation was performed, followed by administration of both instruments to a sample of 155 participants of antenatal classes. Pregnant women answered questions regarding their medical history and user-friendliness of the instruments. 80 respondents completed the CBSEI, 75 the CBSEI-C32. Reliability via Cronbach alpha was calculated for the 4 subscales of the CBSEI and the 2 subscales of the short form. Validity was only assessed for the 2 scales of the CBSEI-C32 because all women (n=155) completed this instrument. RESULTS: 2 Cronbach alpha values were greater than 0.74 (adequate), the others greater than 0.80 (good). Most of the factors of the CBSEI-C32 (75%) were above ≥0.5. Calculation of the item-to-total-correlations revealed that the exclusion of 3 items might be indicated for the German version. The short form showed a significant association between level of education and perceived self-efficacy (p=0.01). RESULTS in the area of user-friendliness were more encouraging for the CBSEI-C32 than for the CBSEI. CONCLUSION: The German version of the CBSEI is a useful instrument which may improve advice and counselling during prenatal care in Germany.

Clinical trials with sigma ligands.

So far, sigma-ligands have been investigated for several indications in human studies in functional diarrhea as a model of somatoform disorder (igmesine), depression (igmesine, opipramol), anxiety (opipramol and--in animal models--siramisine), schizophrenia (panamasine, SL 82.0715, rimcazole, DuP 734, BMY 14 802), and somatoform disorders (opipramol). Results for schizophrenia failed to be clear cut and so investigations have apparently stopped for the time being. The Sigma-1-selective igmesine (200 mg) showed good results in a phase-1-model of functional diarrhea and some promising results in depressed patients. However, further development has been stopped due to marketing reasons, which is also true for siramasine, a selective sigma-2-ligand with anxiolytic properties. Opipramol, which, apart from a sigma-1- and 2-receptor liability, also possesses histamine-H(1)-antagonistic properties in connection with lower affinities for D(2) and 5-HT(2A) showed broad efficacy in generalized anxiety disorder and somatoform disorders. The receptor profile of opipramol and the results of studies of the selective sigma site ligands siramisine and igmesine suggest that opipramol acts pharmacologically and clinically via sigma receptors.

Recognition and invasion of human skin by Schistosoma mansoni cercariae: the key-role of L-arginine.

The attachment of Schistosoma mansoni cercariae to mammalian skin is specifically stimulated by L-arginine. As L-arginine is an unsuitable signal for a specific identification of mammalian skin we examined the following 5 hypotheses to explain the advantage of the cercarial sensitivity to L-arginine. (1) A Schistosoma infection lowered the arginine concentration in the serum of mice, and this could enable the cercariae to avoid attachments to already infected mice. However, the infection did not reduce the arginine concentration in the skin and the cercarial attachment responses to it. (2) Creeping cercariae showed chemotactic orientation specifically along increasing L-arginine gradients. L-arginine could act as a pheromone which could guide cercariae towards common penetration sites. However, the cercarial acetabular gland contents were not attractive and they did not (in contrast to previous reports) contain much arginine. (3) Schistosomula (transformed cercariae) could use L-arginine to produce nitric oxide (NO) for blood vessel dilation during their migration in the host. However, in vitro the transformed cercariae did not convert L-arginine into citrulline and NO. (4) Schistosomula could bind L-arginine from the surrounding tissues and so escape the cellular immune attack (which needs L-arginine as the precursor of NO). However, transformed cercariae bound no more L-arginine than L-serine and L-lysine. (5) Schistosomula, migrating parallel to the surface in the mammalian epidermis, are dependent on information on their position between the inner and the surface layers of the skin. In the mouse skin, they adjusted their body axis with the ventral side toward the deeper (arginine-residue rich) epidermis layers. When migrating in agar, they showed chemo-orientation toward serum, and D-glucose and L-arginine were the stimulating compounds therein. The burrowing schistosomula adjusted their body axis (as in the epidermis) with the ventral side toward the higher concentration of L-arginine and not of glucose. We argue that the sensitivity for L-arginine has its primary function in orientation within mammalian skin and in location of blood vessels.

Opipramol for the treatment of generalized anxiety disorder: a placebo-controlled trial including an alprazolam-treated group.

Opipramol, a drug widely prescribed in Germany, is a tricyclic compound with no reuptake-inhibiting properties. However, it has pronounced D2-, 5-HT2-, and H1-blocking potential and high affinity to sigma receptors (sigma-1 and sigma-2). In early controlled trials, anxiolytic effects were revealed. However, those studies were performed before the concept of generalized anxiety disorder (GAD) was established. Because of the interesting receptor-binding profile and promising results of the early clinical trials, the authors performed a state-of-the-art placebo-controlled trial using alprazolam as an active control. Three hundred seven outpatients with GAD were included. After a 7-day single-blind placebo washout, patients were randomly assigned to receive either opipramol (final dose, 200 mg/day), alprazolam (2 mg/day), or placebo and were treated for 28 days. The efficacy of both active compounds was higher than the effects with placebo treatment. There were statistically significant differences (p < 0.05, according to the analysis of covariance) in the main outcome criterion (baseline-adjusted final means of an intent-to-treat analysis of the total scores on the Hamilton Rating Scale for Anxiety) and in secondary efficacy parameters, with global improvement of 47% for placebo and significantly more for opipramol (63%) and alprazolam (64%). Regarding safety and tolerability, no substantial differences in the number of adverse events observed between treatment groups were obvious. Sedation seemed more pronounced with alprazolam treatment than with opipramol or placebo. In this trial, it was demonstrated for the first time that opipramol, a strong but nonselective sigma site ligand, possesses anxiolytic efficacy superior to placebo in the treatment of GAD.

Characterization of lineage-specific chimaerism in patients with acute leukaemia and myelodysplastic syndrome after allogeneic stem cell transplantation before and after relapse.

Recently, we have shown that patients with acute leukaemias and myelodysplastic syndromes (MDS), who showed increasing mixed chimaerism (MC) upon serial PCR analysis after transplant, have a significantly increased risk of relapse. To determine whether the increasing MC in these patients is caused by the reappearance of normal recipient haematopoiesis or by the reoccurrence of malignant cells, we purified different leucocyte subpopulations and analysed these subfractions with regard to their donor-recipient ratio by a PCR-based method for the analysis of minisatellite DNA regions. In 14 patients [eight acute lymphoblastic leukaemia (ALL), three acute myelogenous leukaemia (AML) and three MDS] subfractions were analysed when increasing MC was first noted upon serial analysis of the peripheral blood. In seven of these 14 patients (four ALL, two AML and one MDS), subfractions were characterized at the time of frank haematological relapse. In all 14 patients investigated with increasing MC, recipient cells were detected in different mononuclear cell subpopulations. In patients characterized during frank relapse, two distinct distribution patterns were found. Patients who relapsed before day +300 (one ALL, two AML and one MDS) showed recipient-derived (normal) cells in addition to blast populations in different mononuclear subsets as well as granulocytes. In patients with acute leukaemias who relapsed after day +300 (two ALL and one AML), only leukaemic cells were found that were of recipient origin, whereas all other haematopoietic cell lines were donor derived. These data show that persistent MC in the early post-transplant period is caused predominantly by normal recipient haematopoietic cells. This finding further supports the hypothesis that a state of mixed haematopoietic chimaerism may reduce the clinical graft-versus-leukaemia (GVL) effect of alloreactive donor-derived effector cells in patients with acute leukaemias and MDS, and thus facilitate the proliferation of residual malignant cells that may have survived the preparative regimen.

Opipramol for the treatment of somatoform disorders results from a placebo-controlled trial.

Although somatoform disorders are highly prevalent, so far there is no established pharmacological treatment. Opipramol is a psychopharmacon widely prescribed in Germany. Early trials with opipramol showed the drug's effectiveness in anxiety states coupled with somatic complaints. Therefore, the efficacy of opipramol in somatoform disorders was evaluated using adequate clinical trial methods. A multicentre, randomized, 6-week, placebo-controlled clinical trial was performed in a total of 200 patients suffering from somatoform disorders according to ICD-10. In the main outcome criterion, the somatic subscore of the Hamilton Anxiety Scale, and in nearly all other outcome criteria opipramol (200 mg/day) was statistically more effective than placebo. A similar number of adverse events was noted in both groups. The results of this first-placebo-controlled study in somatoform disorders suggest efficacy of opipramol in this indication but need replication.

Preparation of 4-(4'-Hydroxyanilino)-5-anilinophthalimide and 4,5-Bis-(4'-hydroxyanilino)-phthalimide by Microbial Hydroxylation.

A microbial screening indicated that two fungal strains, Beauveria bassiana DSM 1344=ATCC 7159 and Cunninghamella elegans DSM 1908=ATCC 9245, as well as four bacterial strains belonging to the genus Streptomyces were able to hydroxylate 4,5-dianilinophthalimide (DAPH, CGP52411) to 4-(4'-hydroxyanilino)-5-anilinophthalimide. Cunninghamella elegans DSM 1908 turned out to be the most active biocatalyst and was also able to form the dihydroxy derivative, 4,5-bis(4'-hydroxyanilino)phthalimide. The reaction for the monohydroxylated biotransformation product was carried out on a preparative scale, and the culture conditions for the formation of 4-(4'-hydroxy- anilino)-5-anilinophthalimide with this strain were op-timized.

New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development.

On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,8 aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.

Fourth-harmonic generation of a continuous-wave CO(2) laser by use of an AgGaSe(2)/ZnGeP(2) doubly resonant device.

We report a doubly resonant continuous-wave CO(2) laser frequency-quadrupling device that generates 200nW of 2.55-mum (4?) and as much as 2mW of 5.1-mum (2?) radiation out of 1.7-W fundamental radiation at 10.2 mum (?). The quadrupling process results from two resonant cascading second-harmonic generations by use of a walk-off-compensated twin AgGaSe(2) device (??2?) and a ZnGeP(2)nonlinear crystal (2??4?).

Phospholipase A2 activity in vitro cultured cells--influence of ascorbate supplementation.

Non-malignant LLCMK cells and malignant B16 cells were supplemented with ascorbate, over the concentration range 0-100 micrograms/ml ascorbate. The effects of ascorbate supplementation on cell growth and phospholipase A2 activity of the membrane fractions of the respective cell lines were determined. Increasing ascorbate supplementation had a significant inhibitory effect on the growth of the B16 cells. Phospholipase A2 activity in the control B16 cells was lower than that detected in the control LLCMK cells. Phospholipase A2 activity decreased significantly in the B16 cells upon increasing ascorbate supplementation, while the supplementation of ascorbate to the LLCMK cells did not have any significant effect on phospholipase A2 activity in these cells.

The use of plasma levels for FK 506 dosing in liver-grafted patients.

FK 506 plasma levels were analyzed in 89 liver-grafted patients under FK 506-based immunosuppression. Plasma levels were found to be influenced by the patients' liver function: compared to patients without major liver dysfunction, those with cholestasis had higher plasma levels and these plasma levels were able to differentiate between rejection and toxicity. In patients with stable liver function, no clear difference was observed with regard to the plasma levels detectable during toxicity or rejection. We conclude that plasma levels can be used to determine the FK 506 dose but only in patients with cholestasis (i.e., during the early post-transplant course, or in patients with cholestatic rejection). In patients with stable liver function, plasma levels are only of limited clinical relevance.

Comparison of different assays for the quantitation of FK 506 levels in blood or plasma.

In a prospective study, we evaluated the analytical performance of different assays for the quantitation of FK 506 in blood and plasma. The new whole blood IMX assay was compared with four modifications (liquid/liquid or solid/liquid extraction of blood or plasma respectively) of the standard enzyme-linked immunosorbent assay (ELISA). Both assays utilize the same monoclonal antibody for detection of FK 506. Using isolated FK 506 metabolites generated in vitro, this antibody was shown to recognize not only the unmodified parent drug but also FK 506 metabolites. In stable liver-grafted patients, sensitivity of both modifications of the whole blood ELISA was adequate. In contrast, in some stable patients, plasma ELISA was not able to detect FK 506; this was observed mainly after liquid/liquid extraction of FK 506. Sensitivity of the IMX assay was also low; in six of 10 stable liver-grafted patients, IMX levels were below the limit of detection. In all assays, FK 506 levels were found to be elevated during episodes of liver dysfunction; a possible explanation for this effect would be that of accumulation of cross-reacting FK 506 metabolites. As FK 506 metabolites are known to be less immunosuppressive than the parent drug, liver function should always be taken into account if IMX or ELISA levels are used for drug monitoring.

Interrelationship of ascorbate, arachidonic acid and prostaglandin E2 in B16 melanoma cells.

Previous studies have shown that ascorbate (Asc) supplementation affects arachidonic acid (AA) and prostaglandin E2 (PGE2) levels in B16 murine melanoma cells. In this study, non-malignant LLCMK cells and malignant B16 cells were respectively supplemented with 20 microCi 15-3H AA, to investigate whether these two cell types were able to take up AA from the media. Furthermore, these cells were also supplemented with Asc (0-100 micrograms/ml) to determine the effect of Asc supplementation on 15-3H AA uptake. Both cell types incorporated 15-3H AA, while Asc supplementation enhanced this 15-3H AA uptake. To determine the site of the AA incorporation, both cell types were supplemented with 2.5 microM AA and Asc (0-100 micrograms/ml). The % AA composition of the stroma fractions of both cell types was increased with 100 micrograms/ml Asc supplementation. Supplementation of these cells with AA (0-50 microM) resulted in an increase in PGE2 levels in the B16 cells. Since PGE2 has been shown, in turn, to stimulate adenylate cyclase (AC) activity, the LLCMK and B16 cells were supplemented with 0-100 microM PGE2. A 3-fold increase of AC activity in the B16 cells occurred as a result of this supplementation.

The effect of ascorbate on essential fatty acid composition in B16 melanoma cells.

Ascorbate has been shown to be involved in essential fatty acid (EFA) metabolism, resulting in the suggestion that the effect of ascorbate on cell growth may be mediated through an influence on the metabolism of these FAs. This study examined the effect of ascorbate, supplemented over the nutritional concentration range of 0-100 micrograms/ml, on the in vitro cell growth of non-malignant LLCMK (monkey kidney) cells and malignant B16 murine melanoma cells. The effect of ascorbate on EFA composition was also investigated, and involved the determination of the levels of linoleic acid (LA), gamma-linoleic acid (GLA), dihomogammalinolenic acid (DGLA) and arachidonic acid (AA) present in the stroma and membrane of the two cell types. Ascorbate had no significant inhibitory or stimulatory effect on the growth of either the LLCMK or B16 cells. EFA levels detected in the LLCMK cells were generally higher than those detected in the B16 cells. The % composition of the various EFAs in the stroma fractions of the two cell types were higher than the level of the corresponding EFAs in the membrane fractions. GLA levels were not detectable in the membrane fractions of the B16 cells. AA % composition determined in both cell types, was greater than that of any other EFA % composition.

The effect of ascorbic acid on arachidonic acid and prostaglandin E2 metabolism in B16 murine melanoma cells.

Ascorbic acid (Asc), arachidonic acid (AA) and prostaglandin E2 (PGE2) are reported to be important in maintaining the stability of the cell matrix. Asc has also been shown to influence fatty acid (FA) and PGE2 synthesis, with the result that effects of Asc on cell growth are suggested to be mediated through the metabolism of these two compounds. This study examined the effect of Asc, supplemented over the concentration range of 0-100 micrograms/ml, on the in vitro cell growth of non-malignant LLCMK (monkey kidney) cells and malignant B16 murine melanoma cells. The effects of Asc supplementation on AA and PGE2 levels in the cell stroma and membrane fractions of the two cell types was also determined. Asc had no significant inhibitory or stimulatory effect on the growth of either the B16 or LLCMK cells. The total percentage AA composition determined in the B16 control cells (combined stroma and membrane fractions), was similar to that determined in the LLCMK control cells. Asc supplementation of the B16 cells, resulted in an inverse relationship between B16 cell growth and total percentage AA composition. PGE2 concentration in the control B16 cells (combined stroma and membrane fractions) was significantly higher than that detected in the control LLCMK cells. No PGE2 was detected in the B16 stroma fraction, with all appearing to be located in the membrane fraction. However, upon the supplementation of the B16 cells with increasing Asc concentrations, PGE2 appeared to be mobilized from the membrane fraction, resulting in increasing PGE2 levels in the stroma fraction relative to the membrane fraction. This was accompanied by a significant decrease in PGE2 concentration, in the membrane fraction. B16 cell growth and total (stroma and membrane fractions) PGE2 concentration in these cells was inversely related, when cultures were supplemented with increasing levels of Asc. Asc supplementation of the LLCMK cells did not appear to have any significant effect on AA or PGE2 metabolism in these cells.

Oxcarbazepine does not affect the anticoagulant activity of warfarin.

The possible interaction of the antiepileptic drug oxcarbazepine (OCBZ) on the anticoagulant effect of warfarin was investigated in 10 healthy male volunteers. After reaching steady-state conditions by repeated administration of warfarin, the prothrombin time (Quick value) was assessed before and after single (600 mg) and multiple dosing (450 mg twice daily in 1 week) of OCBZ. In 7 of the 10 volunteers with evaluable data, the prothrombin time was not significantly different (paired t test) from baseline either after single (p = 0.299) or repeated dosing (p = 0.333), indicating that OCBZ does not interact to any relevant extent with the hypothrombinemic effect of warfarin.

Hyponatremic coma under oxcarbazepine therapy.

Oxcarbazepine (OXC) is considered to be a promising new antiepileptic drug with similar efficacy and better tolerability compared to carbamazepine (CBZ). However, hyponatremia is supposed to occur even more often than with CBZ. We report on a patient who developed hyponatremic coma under OXC with a serum sodium level of 115 mmol/l, the second published case of OXC-induced hyponatremia with serious clinical adverse effects.