Clinical efficacy of a dry extract of five herbal drugs in acute viral rhinosinusitis.

OBJECTIVE: A herbal drug combination (Dry Extract BNO 1016) has been assessed for efficacy and tolerability in patients with acute viral rhinosinusitis. METHODOLOGY: In this randomised, controlled trial patients with symptom duration of up to 3 days, mild to moderate facial pain and a Major Symptom Score (MSS) between 8 and 12 were treated for 15 days with BNO 1016 or placebo (coated tablets administered orally). Primary efficacy endpoint was mean MSS at end of treatment. Secondary outcome measures included treatment response and changes in paranasal sinuses assessed by ultrasonography. RESULTS: Treatment resulted in clinically relevant, significant differences in mean MSS for BNO 1016 versus placebo. BNO 1016 provided symptom relief two days earlier than placebo. The number needed to treat for healing is 8. BNO 1016 was superior regarding responder rates at Day 10 and Day 14 and percentage of patients without signs of acute viral rhinosinusitis assessed by ultrasonography at end of treatment. BNO 1016 was well tolerated; no serious adverse events were reported. CONCLUSION: The herbal dry extract BNO 1016 is efficacious and well tolerated in patients with acute viral rhinosinusitis. TRIAL REGISTRATION: ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01146860; EudraCT: 2009-016682-28).

Validation of a German version of the P-QOL Questionnaire.

OBJECTIVE: The objective of this study was to validate the German version of the prolapse quality-of-life questionnaire (P-QOL). METHODS: The P-QOL questionnaire was translated into German and administered to women recruited from two gynecological outpatient clinics and seven gynecological practices. All women were examined in supine position using the Pelvic Organ Prolapse Quantification System of the International Continence Society. The validity was assessed by comparing symptom scores and quality-of-life scores between symptomatic and asymptomatic women. RESULTS: According to the English study, 140 symptomatic and 75 asymptomatic women were included. The total scores for each P-QOL domain were significantly different between symptomatic and asymptomatic women (p < 0.001). Seven symptom regarding questions showed significant differences (p < 0.05). CONCLUSION: The German version of P-QOL is a valid, reliable, and easily comprehensible instrument to assess quality of life and symptoms in German-speaking patients with urogenital prolapse.

A pharmacokinetic study of two modified-release methylphenidate formulations under different food conditions in healthy volunteers.

OBJECTIVES: Primary objective was to investigate bioequivalence of Ritalin LA(R); 40 mg compared to Medikinet retard 40 mg in healthy male volunteers under fasted and fed conditions. Secondary objectives included assessment of tolerability and determination of further pharmacokinetic parameters. The difference between the kinetic profiles of Ritalin LA(R) and Medikinet retard with respect to breakfast intake was additionally explored. METHODS: 28 subjects were randomized in this open-label, four-treatment, cross-over-design study. Pharmacokinetic evaluations included AUC(0-inf), Cmax, tmax, elimination half life (t1/2) and mean residence time MRT(0-inf)). The relative bioavailability of Ritalin LA(R) and Medikinet retard and the food effect were assessed using a 90% confidence interval (CI) based on the lower and upper endpoints of the CI for the ratios of the geometric means being within the 80 - 125% equivalence criterion. RESULTS: 25 volunteers completed all treatment arms. Frequency of adverse events were comparable for all treatments. Under fasted condition Ritalin LA(R) showed a consistent bimodal concentration time profile with two tmax peaks. Medikinet retard showed a steady absorption with a single tmax peak. The point estimators for AUC(0-inf) and Cmax were found to be 99.7% and 85.9%, respectively. Under fed condition both Ritalin LA(R) and Medikinet retard showed a bimodal concentration time profile with two tmax peaks. The point estimators for AUC(0-inf) and Cmax were estimated as 89.8% and 68.6%, respectively. CONCLUSIONS: Both methylphenidate formulations were safe and well tolerated. Ritalin LA and Medikinet retard were bioequivalent in fasted state but not in fed state. Only Ritalin LA had a biphasic kinetic profile under both fasted and fed conditions. This difference in the kinetic profiles might be of clinical relevance and might offer a potential advantage of Ritalin LA.

Rosiglitazone is effective and well-tolerated in a range of therapeutic regimens during daily practice in patients with type 2 diabetes.

Subjects (N = 22,808) with inadequately controlled type 2 diabetes mellitus (T2DM) were included in a large 6-month observational study in Germany. Rosiglitazone (RSG) was added to existing therapy in line with daily practice, with 19,962 subjects evaluated for efficacy by treatment group: RSG monotherapy (n = 1017), RSG plus metformin (MET) (n = 7160), RSG plus sulphonylurea (n = 5033), triple oral therapy (n = 4247), and the remaining subject population (n = 2505). Overall, RSG significantly reduced median HbA(1c) and fasting blood glucose by 1.3% and 50 mg/dl over 6 months (p < 0.001 for both). The proportion of subjects achieving glycaemic goals of

Complications, co-morbidity, and blood glucose control in type 2 diabetes mellitus patients in Germany--results from the CODE-2 study.

In this study, prevalence and incidence of complications as well as co-morbidity in type 2 diabetes patients in Germany were evaluated as part of a cost-of-illness study (CODE-2(TM), Costs of Diabetes in Europe - Type 2)In a pre-study, 197 general practitioners and diabetes specialists all over Germany provided data on the complication status of 2701 randomly selected patients with type 2 diabetes. The patients were grouped into five mutually exclusive strata. This pre-study was performed to generate a general overview on complication status to select proper patients for the main study. The main study was performed on stratified samples derived from the pre-study. Irrespective of the real prevalence of the five strata, an equal number of 160 were randomly selected from each stratum. Thus, rare complications were also covered in the study. Data from 809 patients were collected retrospectively on the basis of medical files during interviews with the physician. To achieve representative estimates of absolute prevalence and incidence of diabetes-related complications in Germany, results were weighted using frequencies of the strata. Severe complications were diagnosed in 50% of these patients. Prevalences were: 10.56% myocardial infarction, 6.66% stroke, 3.97% foot ulcer, 2.30% amputations and 1.34% blindness. Overall incidences in the diabetes population were estimated at 0.78% myocardial infarction, 1.28% stroke and 0.80% amputations. 23% of the diabetes patients suffered from 2 or more complications. The complication status became considerably worse with increasing time since the diagnosis of diabetes. The mean HbA1c level was 7.51% (i.e. 122% of the upper limit of the respective normal ranges). The presence of complications and co-morbidity in type 2 diabetes patients was a frequent finding. This underlines the importance of complications in diabetes patients and the necessity to increase any means of prevention in order to relieve the personal and economic burden of type 2 diabetes.

Psychosocial characteristics of infertile couples: a study by the 'Heidelberg Fertility Consultation Service'.

BACKGROUND: The aim of the study was to identify differences in psychological characteristics between couples with fertility disorders, especially idiopathic infertility, and a representative sample. MATERIAL AND METHODS: A total of 564 couples was examined using psychological questionnaires pertaining to sociodemographic factors, motives for wanting a child, dimensions of life satisfaction and couple relationships, physical and psychic complaints, and a personality inventory. RESULTS: Specific to our sample was the high educational level of the couples, and the large number with idiopathic infertility (27% of all diagnoses). There were no remarkable differences in psychological variables between the infertile couples and a representative sample, except that the infertile women showed higher scores on the depression and anxiety scales. Couples with idiopathic infertility showed no remarkable differences in the questionnaire variables compared with couples with other medical diagnoses of infertility. CONCLUSIONS: A typical psychological profile for infertile couples could not be identified using standardized psychometric rating methods. This may be an effect of the specific characteristics of our sample. For some couples, the infertility crisis can be seen as a cumulative trauma, which indicates that these couples have a marked need for infertility counselling.

Intracellular location and nuclear targeting of the Spi-1, Spi-2 and Spi-3 gene-derived serine protease inhibitors in non-secretory cells.

Proteases and their inhibitors are indispensable for the regulated activation and/or degradation of structural and functional proteins involved in basic cellular processes, e.g. in cell cycle control, cell growth, differentiation and apoptosis. In this context the serine protease inhibitors derived from the murine Spi-1, Spi-2 and Spi-3 genes, and their human homologs, deserve reconsideration. Microsequencing data indicate that a fraction of the three serpins has the capability to constitute a well characterized proteinase K, high salt and SDS-stable complex which coisolates with DNA under salting out conditions from various cell and tissue types. This tight association with DNA isolated under conditions designed to deproteinize DNA efficiently points to an in situ preformed chromatin complex. Accordingly, in addition to their well known functions as 'serum protease inhibitors' the Spi-1 and Spi-2 gene-derived proteins appear to have intracellular functions as well. The involvement of the three serpins in chromatin complexes requires their nuclear translocation. Application of (enhanced) green fluorescent protein technology and optical section microscopy reveals that truncation of the N-terminal signal sequences of the Spi-1 and Spi-2 gene-encoded proteins is a prerequisite for their nuclear translocation while non-truncated fusion proteins are enriched at the nuclear indentation which is the site of the Golgi apparatus and the centrosome. The identification of new species of intracellular serpins is of potential interest with respect to accumulating evidence for serine protease inhibitor-dependent inhibition or prevention of apoptosis.

Promoter of the gene encoding the 16 kDa DNA-binding and apoptosis-inducing C1D protein.

The 5' region of the gene encoding the human 16 kDa DNA-binding and apoptosis-inducing C1D protein was analysed for promoter activity. Sections of this region were cloned into a promoterless vector containing the enhanced green fluorescent protein (EGFP) as reporter gene. Expressed EGFP was estimated in transfected cells by quantitative fluorescence microscopy. The sequence between mRNA positions ATG -868 and ATG -12 results in relatively highest EGFP expression in transiently transfected human and murine cells. The upstream segment immediately adjacent to the 5' end of the most active fragment was identified as an inverted LINE-1 repeat element. Transient transfection experiments point to the presence of cis-acting repressing sequences on this LINE-1 element which reduce the transcriptional activity of the basal C1D promoter in human and murine cells by more than 95%. This result supports previous evidence suggesting that LINE-1 sequences may function as regulatory elements to control the expression of nearby genes.

Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group.

BACKGROUND: The consequences of infection with Staphylococcus aureus can be severe, so strategies for prevention are important. We examined S. aureus isolates from blood and from nasal specimens to determine whether the organisms in the bloodstream originated from the patient's own flora. METHODS: In a multicenter study, swabs for culture were obtained from the anterior nares of 219 patients with S. aureus bacteremia. A total of 723 isolates were collected and genotyped. In a second study, 1640 S. aureus isolates from nasal swabs were collected over a period of five years and then compared with isolates from the blood of patients who subsequently had S. aureus bacteremia. RESULTS: In the multicenter study of S. aureus bacteremia, the blood isolates were identical to those from the anterior nares in 180 of 219 patients (82.2 percent). In the second study, 14 of 1278 patients who had nasal colonization with S. aureus subsequently had S. aureus bacteremia. In 12 of these 14 patients (86 percent), the isolates obtained from the nares were clonally identical to the isolates obtained from blood 1 day to 14 months later. CONCLUSIONS: A substantial proportion of cases of S. aureus bacteremia appear to be of endogenous origin since they originate from colonies in the nasal mucosa. These results provide support for strategies to prevent systemic S. aureus infections by eliminating nasal carriage of S. aureus.

Sensitivity of repeated interdigital web pinching to detect antinociceptive effects of ibuprofen.

AIMS: The aim of the current study was to assess the viability of the interdigital web pinch model as a test for analgesic activity in volunteer-based early phase drug development. METHODS: Pain thresholds and sensitization to a series of four sessions of interdigital web pinching (12 Newtons force) were measured in 26 male volunteers before and 1 and 3 h after oral dosing with ibuprofen (800 mg) or placebo to ibuprofen. Within each time point, the pain thresholds were measured by calculating the average visual analogue scores (VAS) for the first session of pinching (VAS-1). Sensitization to pinching was assessed by calculating the average changes in these scores for the three subsequent sessions of pinching (VAS-2). Moreover, the difference between the VAS score after the first session of pinching and that obtained at the end of the fourth session of pinching was calculated as a secondary endpoint (VAS-3). RESULTS: Treatment with ibuprofen had no significant effect on VAS-1 at either 1 or 3 h after dosing. However, the mean values of VAS-2 and VAS-3, were significantly reduced (P < 0.05) following treatment with ibuprofen. CONCLUSIONS: This model has been able to detect an antinociceptive effect with ibuprofen. However, large numbers of subjects were required in order to demonstrate this effect and this feature would restrict the model's utility in early phase clinical trials where small numbers of subjects are normally employed.

One single mRNA encodes the centrosomal protein CCD41 and the endothelial cell protein C receptor (EPCR).

The cDNA encoding the centrosomal protein CCD41 is identical with the cDNA for the endothelial cell protein C receptor. This finding is not due to an artefact, e.g. caused by selection of false positive clones. The segment of the CCD41 cDNA encoding the protein originally termed CCD41 and deletion mutants of it were fused with the nucleotide sequence encoding the enhanced green fluorescent protein (EGFP). Transfection and expression of the full length construct produces a fusion protein mainly located in cell membranes reflecting the receptor-type protein. Deletion mutants, e.g. those where the signal sequence is deleted, result in fusion proteins which are exclusively incorporated into a small perinuclear structure which is the site of the centrosome. This result suggests that post-translational modification, namely deletion of the signal sequence, is decisive for the centrosomal location of the resulting centrosomal protein while the unprocessed protein is incorporated into cell membranes.

Induction of apoptosis by overexpression of the DNA-binding and DNA-PK-activating protein C1D.

Apoptosis is induced in various tumor cell lines by vector-dependent overexpression of the conserved gene C1D that encodes a DNA-binding and DNA-PK-activating protein. C1D is physiologically expressed in 50 human tissues tested, which points to its basic cellular function. The expression of this gene must be tightly regulated because elevated levels of C1D protein, e.g. those induced by transient vector-dependent expression, result in apoptotic cell death. Cells transfected with C1D-expressing constructs show terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling of DNA ends. Transfections with constructs in which C1D is expressed in fusion with the (enhanced) green fluorescent protein from A. victoria (EGFP) allow the transfected cells to be identified and the morphological changes induced to be traced. Starting from intense nuclear spots, green fluorescence reflecting C1D expression increases dramatically at 12-24 hours post-transfection. Expression of C1D-EGFP protein is accompanied by morphological changes typical of apoptotic cell death, e.g. cytoplasmic vacuolation, membrane blebbing and nuclear disintegration. Cell shrinkage and detachment from extracellular matrix are observed in monolayer cultures while suspension cells become progressively flattened. The facility to differentiate between transfected and non-transfected cells reveals that non-transfected cells co-cultured with transfected cells also show the morphological changes of apoptosis, which points to a bystander effect. C1D-dependent apoptosis is not induced in cells with non-functional p53. Accordingly, C1D-induced apoptosis is discussed in relation to its potential to activate DNA-PK, which has been considered to act as an upstream activator of p53.

cDNA cloning, recombinant expression and characterization of polypetides with exceptional DNA affinity.

Polypeptides remaining tightly associated with isolated genomic DNA are of interest with respect to their potential involvement in the topological organization and/or function of genomic DNA. Such residual DNA-polypeptide complexes were used for raising monoclonal antibodies by in vitro immunization. Screening of a murine lambdagt11 cDNA library with these antibodies released a positive cDNA (MC1D) encoding a 16 kDa polypeptide. The cloned homologous human cDNA (HC1D) was identified in the dbest data base by partial sequence comparison, and it was sequenced full length. The cDNA-derived amino acid sequences comprise nuclear location signals but none of the known DNA-binding motifs. However, the recombinantly expressed proteins show in vitro DNA binding affinities. A polyclonal antiserum to the recombinant MC1D protein immunostains sub-nuclear structures, and it detects a residual 16 kDa polypeptide on western blots of DNA digests. These results support the conclusion that the cloned cDNAs reflect mRNAs encoding one of the chemically-resistant polypeptides which can be detected in isolated genomic DNA by sensitive techniques, e.g. by125Iodine labeling and SDS-PAGE.

A multifunctional protein: involvement of the alpha-1 serum protease inhibitor in SDS and high salt-stable DNA-protein complexes.

Occasionally new and intriguing roles arise for proteins with well established functions. The alpha-1 serum protease inhibitor (alpha-1 PI) represents another example. Sequence identities exist in the alpha-1 PI and in a nuclear 52-kDa glycoprotein which is involved in resistant DNA-polypeptide complexes. The results of Western blots support the identity of the two proteins and immunocytochemical studies indicate the nuclear location of the alpha-1 PI. Consistently, e.g. Ehrlich ascites tumor cells express the alpha-1 PI, and the fusion protein between the alpha-1 PI and the green fluorescent protein from Aequorea victoria shows intracellular accumulation and partly nuclear location.

Evaluation of the noninvasive estimates of cardiac output by Doppler aortoechography according to test-theoretical principles.

The usability of noninvasive methods can be quantified by a formal assessment of empirical quality criteria based on test-theoretical principles. The ACVF Doppler aortoechography is a pulsed dual-beam ultrasound technique with online estimates of cardiac output (CO) based upon the measurement of the mean Doppler shift frequency across the ascending aorta, its estimated cross-sectional area and the cycle's heart rate. The method has a relatively high reliability, sensitivity, and pharmacosensitivity (for inodilatory changes in particular), but tends to underestimate cardiac output. Furthermore, the method lacks objectivity because it is highly observer-dependent. Precise method description and stringent standardization thus are required. Because of the method specificity of its estimates, data should not be combined with those of other methods. The inherently poor validity of its CO estimates, using this method, call for caution in the mechanistic interpretation of its observations.

The centrosomal protein centrosomin A and the nuclear protein centrosomin B derive from one gene by post-transcriptional processes involving RNA editing.

The identification of a gene encoding concomitantly a nuclear protein and an intrinsic centrosomal protein further emphasizes the close and presumably developmental relationship between the cell nucleus and the centrosome. Screening of a murine RNA-based cDNA library with an antiserum to a centrosomal protein and rescreening with the insert of an initial clone released two complete cDNAs (1.2 kbp and 2.2 kpb) coding for proteins with notable characteristics. The amino-terminal sections of centrosomin A (276 amino acid residues, molecular mass 34.5 kDa) and of centrosomin B (447 amino acid residues, molecular mass 54.8 kDa) are identical over 272 amino acid residues. The carboxy-terminal section of the larger protein comprises additional 175 amino acid residues including nuclear location signals. The mRNAs encoding centrosomin A and B derive from a single gene. Chromogenomic DNA as template and primer pairs complementary to the sequence which is identical in centrosomin A and B cDNAs results in amplification of only one DNA fragment. Moreover, one exon of the genomic sequence and the centrosomin B-encoding cDNA sequence include a G which is deleted in the centrosomin A-encoding cDNA. Accordingly, the two mRNAs are the products of either alternative splicing or alternative polyadenylation in combination with RNA editing. The recombinantly expressed chimeric protein consisting of centrosomin A and the green fluorescent protein from Aequorea victoria accumulates in centrosomes while the corresponding fusion protein with the centrosomin B sequence is transported into nuclei.

Activation and enzyme characteristics of a DNA-restrained phosphatase in chromatin-associated complexes.

DNA-bound polypeptide complexes composed of several non-histone polypeptides that resisted harsh DNA deproteinization procedures were characterized. The three major polypeptides of these complexes have molecular masses of 62, 52, and 40 kDa. They constitute supramolecular structures that reside on isolated DNA in dense clusters. The supramolecular complexes were released from DNA as globular 12.8 +/- 0.8-nm particles; these particles were gradually disassembled to form smaller supramolecular structures. The DNA-bound complexes comprise of an encrypted adenosinetriphosphatase/phosphatase activity, which is a minor but intrinsic component of the complexes. The enzyme remained inactive as long as the complexes were bound to DNA. However, the enzyme was activated concomitantly with the progression of DNA digestion, which indicated that DNA was involved in the downregulation of the enzyme. The inactive DNA-restrained complex could not be restored in vitro, which indicated its non-trivial nature. Once released from DNA, the enzyme was inactivated over a period of several hours. However, in the DNA-associated complexes its potential to become activated during DNA digestion was conserved for several months. In the activated state, the enzyme showed an optimum activity at pH 9.5, was stimulated by Mg2+, inhibited by vanadate and EDTA, but was not significantly inhibited by okadaic acid. The active enzyme, which consists of two subunits of 56 kDa and 59 kDa, can be released from the supramolecular structures by agarose gel electrophoresis. A regulatory mechanism therefore exists for the downregulation of this phosphatase by DNA.

Prognostic factors in outpatient psychotherapy of bulimia.

Little is known about prognostic factors in the treatment of bulimic patients. In the context of an ongoing study we looked at 1-year symptomatic outcome of 37 outpatients fulfilling DSM-III-R criteria for bulimia nervosa in relation to a variety of measures at first assessment. These included multiple measures of depression, measures of borderline personality disorder, a personality inventory, a symptom checklist and information about the history and the severity of the illness. Results add evidence to the importance of personality variables in predicting outcome: patients with high scores on the Borderline Syndrome Index indicating a severe disturbance tend to have poorer symptomatic outcome, especially when they also experience themselves as dominant (Giessen-Test). Other factors, including abuse of alcohol and history of anorexia did not allow prediction of outcome.

[Late results following endoprosthetic lunate bone replacement]. / Spätergebnisse nach endoprothetischen Lunatumersatz.

Long-term results of silastic lunate spacer implantation are reported especially concerning late complications in the form of reactive synovitis and intraosseous cysts. As result one case of silicon cyst and no silicon synovitis was found.