Oral dydrogesterone versus micronized vaginal progesterone for luteal phase support: a double-blind crossover study investigating pharmacokinetics and impact on the endometrium.

STUDY QUESTION: How do plasma progesterone (P) and dydrogesterone (D) concentrations together with endometrial histology, transcriptomic signatures, and immune cell composition differ when oral dydrogesterone (O-DYD) or micronized vaginal progesterone (MVP) is used for luteal phase support (LPS)? SUMMARY ANSWER: Although after O-DYD intake, even at steady-state, plasma D and 20αdihydrodydrogesterone (DHD) concentrations spiked in comparison to P concentrations, a similar endometrial signature was observed by histological and transcriptomic analysis of the endometrium. WHAT IS KNOWN ALREADY: O-DYD for LPS has been proven to be noninferior compared to MVP in two phase III randomized controlled trials. Additionally, a combined individual participant data and aggregate data meta-analysis indicated that a higher pregnancy rate and live birth rate may be obtained in women receiving O-DYD versus MVP for LPS in fresh IVF/ICSI cycles. Little data are available on the pharmacokinetic (PK) profiles of O-DYD versus MVP and their potential molecular differences at the level of the reproductive organs, particularly at the endometrial level. STUDY DESIGN, SIZE, DURATION: Thirty oocyte donors were planned to undergo two ovarian stimulation (OS) cycles with dual triggering (1.000 IU hCG + 0.2 mg triptorelin), each followed by 1 week of LPS: O-DYD or MVP, in a randomized, cross-over, double-blind, double-dummy fashion. On both the first and eighth days of LPS, serial blood samples upon first dosing were harvested for plasma D, DHD, and P concentration analyses. On Day 8 of LPS, an endometrial biopsy was collected for histologic examination, transcriptomics, and immune cell analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: All oocyte donors were <35 years old, had regular menstrual cycles, no intrauterine contraceptive device, anti-Müllerian hormone within normal range and a BMI ≤29 kg/m2. OS was performed on a GnRH antagonist protocol followed by dual triggering (1.000 IU hCG + 0.2 mg triptorelin) as soon as ≥3 follicles of 20 mm were present. Following oocyte retrieval, subjects initiated LPS consisting of MVP 200 mg or O-DYD 10 mg, both three times daily. D, DHD, and P plasma levels were measured using liquid chromatography-tandem mass spectrometry. Histological assessment was carried out using the Noyes criteria. Endometrial RNA-sequencing was performed for individual biopsies and differential gene expression was analyzed. Endometrial single-cell suspensions were created followed by flow cytometry for immune cell typing. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 women completed the entire study protocol. Subjects and stimulation characteristics were found to be similar between groups. Following the first dose of O-DYD, the average observed maximal plasma concentrations (Cmax) for D and DHD were 2.9 and 77 ng/ml, respectively. The Cmax for D and DHD was reached after 1.5 and 1.6 h (=Tmax), respectively. On the eighth day of LPS, the first administration of that day gave rise to a Cmax of 3.6 and 88 ng/ml for D and DHD, respectively. For both, the observed Tmax was 1.5 h. Following the first dose of MVP, the Cmax for P was 16 ng/ml with a Tmax of 4.2 h. On the eighth day of LPS, the first administration of that day showed a Cmax for P of 21 ng/ml with a Tmax of 7.3 h. All 42 biopsies showed endometrium in the secretory phase. The mean cycle day was 23.9 (±1.2) in the O-DYD group versus 24.0 (±1.3) in the MVP group. RNA-sequencing did not reveal significantly differentially expressed genes between samples of both study groups. The average Euclidean distance between samples following O-DYD was significantly lower than following MVP (respectively 12.1 versus 18.8, Mann-Whitney P = 6.98e-14). Immune cell profiling showed a decrease of CD3 T-cell, γδ T-cell, and B-cell frequencies after MVP treatment compared to O-DYD, while the frequency of natural killer (NK) cells was significantly increased. LIMITATIONS, REASONS FOR CAUTION: The main reason for caution is the small sample size, given the basic research nature of the project. The plasma concentrations are best estimates as this was not a formal PK study. Whole tissue bulk RNA-sequencing has been performed not correcting for bias caused by different tissue compositions across biopsies. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study comparing O-DYD/MVP, head-to-head, in a randomized design on a molecular level in IVF/ICSI. Plasma serum concentrations suggest that administration frequency is important, in addition to dose, specifically for O-DYD showing a rapid clearance. The molecular endometrial data are overall comparable and thus support the previously reported noninferior reproductive outcomes for O-DYD as compared to MVP. Further research is needed to explore the smaller intersample distance following O-DYD and the subtle changes detected in endometrial immune cells. STUDY FUNDING/COMPETING INTEREST(S): Not related to this work, C.Bl. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Organon, Cooper Surgical, Gedeon-Richter, IBSA, and Merck. H.T. has received honoraria for lectures, presentations, manuscript writing, educational events, or scientific advice from Abbott, Ferring, Cooper Surgical, Gedeon-Richter, Cook, and Goodlife. S.M. has received honoraria for lectures, presentations, educational events, or scientific advice from Abbott, Cooper Surgical, Gedeon-Richter, IBSA, and Merck and Oxolife. G.G. has received honoraria for lectures, presentations, educational events, or scientific advice from Merck, MSD, Organon, Ferring, Theramex, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, Guerbet, Cooper, Igyxos, and OxoLife. S.V.-S. is listed as inventor on two patents (WO2019115755A1 and WO2022073973A1), which are not related to this work. TRIAL REGISTRATION NUMBER: EUDRACT 2018-000105-23.

[Rupture of the pectoralis major tendon and other extra-articular tendons of the shoulder : Recognition and treatment]. / Ruptur der Pectoralis-major-Sehne und anderer extraartikulärer Sehnen an der Schulter : Wie erkennen und behandeln?

Ruptures of the pectoralis major (PM) tendon are rare but have increased in recent years, especially during fitness exercising, such as bench pressing. The pathomechanism is an eccentric load under pretension of the PM (falling onto the outstretched arm, injuries during ground combat, boxing and during downward movement when bench pressing). The rupture sequence starts from superior to inferior at the insertion site with initial rupture of the most inferior muscle parts, followed by the sternal part and the clavicular part. Most classifications are based on rupture location, extent and time of injury. In addition to clinical presentation and sonography, magnetic resonance imaging is now established as the gold standard in diagnosing PM pathologies. Surgical management is indicated for all lateral PM ruptures with relevant strength deficits. Treatment in the acute interval (<3 weeks) is the primary goal; however, even in chronic cases or after failed conservative management a secondary operative approach enables notable clinical improvement. Conservative therapy mostly affects patients who have muscular injuries close to the anatomic origin and smaller partial tears. Surgical management aims for anatomic reconstruction of the PM unit with restoration of the original tension to enable optimal strength transmission. Surgical refixation or reconstruction (with autograft/allograft) of acute and chronic PM ruptures shows excellent clinical results with high patient satisfaction. Latissimus dorsi (LD) and teres major (TM) tendon ruptures are rare injuries but can lead to significant impairments in high-performance athletes. In contrast to PM ruptures, LD and TM injuries are primarily treated conservatively with very satisfactory results.

[Which patients with rheumatoid arthritis do not receive DMARD treatment? Analysis of data from the German Collaborative Arthritis Centers]. / Welche Patienten mit rheumatoider Arthritis erhalten keine DMARD-Therapie? Eine Analyse von Daten der Kerndokumentation.

BACKGROUND: The vast majority of patients with rheumatoid arthritis (RA) included in the national database of the German Collaborative Arthritis Centers are treated with disease-modifying antirheumatic drugs (DMARD). The clinical and patient-related characteristics of patients who did not have DMARD treatment in the longer term were investigated. METHODOLOGY: Between 2012 and 2016 a total of 10,289 patients with RA were documented. Patient characteristics, disease activity and severity, comorbidities and concomitant treatment were descriptively evaluated. Patients who were without DMARDs for more than 1 year and not in remission (disease activity score 28, simple disease activity index or Boolean remission) were analyzed separately. Logistic regression was used to investigate which variables were associated with DMARD treatment. RESULTS: A total of 426 patients were ≤1 year without DMARDs, 1090 > 1 year without DMARDs and 8773 (85%) currently had DMARD treatment. Of the patients who were without DMARDs for more than 1 year, 51% were in remission. Even if no remission criteria were met, the rheumatologists nevertheless found the strived for RA situation in the majority of patients. Of the patients who were without DMARDs for more than 1 year, 13% received glucocorticoid treatment >5 mg/day. In patients with a high degree of severity (odds ratio, OR severe vs. asymptomatic/mild 2.33, 95% confidence interval, CI 1.80;3.02) or positive rheumatoid factor (OR 2.24, CI 1.96;2.56) the chance of receiving DMARD treatment was twice as high. Existing comorbidities did not reduce the chance of receiving DMARD treatment. CONCLUSION: The RA patients in the national database who had no DMARDs for more than 1 year were mostly in remission or with low disease activity. Signs of inadequate disease control were found in only 11% of all patients without DMARD treatment.

[How frequent are poor prognostic markers in rheumatoid arthritis? : An estimate based on three epidemiologic cohorts]. / Wie häufig sind prognostisch ungünstige Faktoren bei Patienten mit rheumatoider Arthritis? : Eine Abschätzung anhand von 3 epidemiologischen Kohorten.

BACKGROUND: Unfavorable prognostic factors-high disease activity, early erosions, and autoantibodies-should be considered when making treatment decisions in rheumatoid arthritis (RA). There are little data on the frequency of individual poor prognostic factors among RA patients in daily care. METHODS: Disease activity (Disease Activity Score, DAS28), erosions, antibodies against citrullinated peptides or rheumatoid factor (ACPA/RF+), previous treatment failure, inflammation markers, and functional disability (FFbH < 70) were defined as prognostic factors. Different treatment decision making situations were evaluated in disease-modifying antirheumatic drug (DMARD)-naïve patients from the early RA CAPEA cohort (n = 1059), and in patients from the biologics register RABBIT after failure of one (n = 2217) or more (n = 3280) conventional synthetic (cs)DMARDs or one (n = 1134) or more (n = 795) biologic (b)DMARDs. With the national database of German arthritis centers (NDB), the frequency of these factors was analyzed according to treatment strata (no/1st/2nd/3rd DMARD; n = 5707). RESULTS: In DMARD-naïve patients (CAPEA), 50% presented with DAS28 > 5.1, 64% were ACPA/RF+, 13% had erosions, and 37% functional disability (FFbH < 70). In RABBIT, 63 (1st csDMARD failure) to 81% (≥2 bDMARD failures) were ACPA/RF+, 29 to 70% had erosions, 33 to 52% DAS28 > 5.1, and 41 to 66% had FFbH < 70, respectively. In the NDB, between 47 (DMARD-naïve) and 82% (≥2 previous DMARDs) were ACPA/RF+, 5 to 11%, had high disease activity under treatment (DAS28 > 5.1), and 26 to 50% had functional disability (FFbH < 70), respectively. CONCLUSION: With growing numbers of previous DMARD therapies, increasing proportions of patients have poor prognostic factors. This underlines the importance of these factors for a difficult-to-treat disease course.

[Distal biceps tendon rupture : Overview and own procedure]. / Distale Bizepssehnenruptur : Überblick und eigenes Vorgehen.

Mainly males in their 40s and 50s suffer from distal biceps tendon rupture. The diagnosis is made by clinical evaluation and is usually confirmed by magnetic resonance imaging. Different approaches and reconstruction techniques have been described in the past, and the clinical results are mostly good and excellent. Thereby the decision regarding which technique to use lies with the surgeon. However, specific complications have been described and should be considered.

[The Berlin diagnostic algorithm for painful knee TKA]. / Berliner diagnostischer Algorithmus der schmerzhaften Knie-TEP.

BACKGROUND: Approximately 20% of patients are unsatisfied with their postoperative results after total knee arthroplasty (TKA). Main causes for revision surgery are periprosthetic infection, aseptic loosing, instability and malalignment. In rare cases secondary progression of osteoarthritis of the patella, periprosthetic fractures, extensor mechanism insufficiency, polyethylene wear and arthrofibrosis can cause the necessity for a reintervention. Identifying the reason for a painful knee arthroplasty can be very difficult, but is a prerequisite for a successful therapy. AIM: The aim of this article is to provide an efficient analysis of the painful TKA by using a reproducible algorithm. DISCUSSION: Basic building blocks are the medical history with the core issues of pain character and the time curve of pain concerning surgery. This is followed by the basic diagnostics, including clinical, radiological, and infectiological investigations. Unique failures like periprosthetic infection or aseptic loosening can thereby be diagnosed in the majority of cases. If the cause of pain is not clearly attributable using the basic diagnostics tool, further infectiological investigation or diagnostic imaging are necessary. If the findings are inconsistent, uncommon causes of symptoms, such as extra-articular pathologies, causalgia or arthrofibrosis, have to be considered. In cases of ongoing unexplained pain, a revision is not indicated. These patients should be re-evaluated after a period of time.

[Quadriceps tendon insufficiency and rupture : Treatment options in total knee arthroplasty]. / Quadrizepssehneninsuffizienzen und -rupturen : Verfahren zur Behandlung in der Knieendoprothetik.

Quadriceps tendon injuries and insufficiencies in total knee arthroplasty are rare, but are followed by a devastating complication that left untreated leads to a complete loss of function of the knee. This review article summarizes the functional anatomy, risk factors, and the prevalence and diagnosis of quadriceps tendon injuries, in addition to the possible management options for partial and complete ruptures. The treatment options are adapted according to the extent of the loss of function (partial, complete) and the duration of the injury (acute vs chronic). Furthermore, the choice of treatment should take into account the quality and availability of primary tissue, the patient's general health, along with their likely functional requirements. Conservative treatment is often justified in partial ruptures with good results. Complete ruptures require surgical intervention and multiple operative techniques are described. Treatment options for acute ruptures include direct primary repair with autogenous or synthetic tissue augmentation. In the case of chronic insufficiency and a lack of soft-tissue surroundings, reconstruction with the aid of a muscle flap or allograft tissue can be considered. All surgical intervention techniques used so far have been fraught with complications and rarely lead to satisfactory results. A new surgical approach to the reconstruction and augmentation of the extensor mechanism consists of the use of a synthetic mesh. The technique is described here in detail.

[Trends of work force participation of patients with rheumatic diseases : results from German social insurance data and the national database of the German collaborative arthritis centers]. / Trends der Erwerbstätigkeit von Rheumakranken : Ergebnisse aus Sozialversicherungsdaten und Kerndokumentation der Rheumazentren in Deutschland.

Positive therapeutic effects on the work force participation derived from international clinical trials may not be directly transferable to the community based care in Germany. Therefore recent changes of data regarding sick leave (SL), work disability pension (WDP) and employment from the social insurance and from the national database of the German collaborative arthritis centers were analyzed covering a time period of at least 10 years. Health insurance data showed a steeper decline in the average duration of SL caused by rheumatoid arthritis (RA), ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) compared with all other diseases. In RA patients from the collaborative arthritis centers the mean duration of SL was much more reduced than the average duration of SL for members of the compulsory health insurance. The proportion of gainfully employed RA patients in collaborative arthritis centers has particularly increased in women. According to data from the pension insurance fund less incident cases of WDP due to RA, AS, and SLE have been observed than WDP caused by all other diseases. Thus different nationwide data show positive changes of the work force participation of individuals suffering from inflammatory rheumatic diseases in Germany.

[Trends in rehabilitation of patients with rheumatic diseases in Germany]. / Leistungstrends der rehabilitativen rheumatologischen Versorgung in Deutschland.

Recent Deutsche Gesellschaft für Rheumatologie (DGRh, German Society of Rheumatology) guidelines emphasized the significance of coordinated multidisciplinary care and rehabilitation of patients with inflammatory rheumatic diseases. Nationwide data from the German pension insurance funds showed that inpatient rehabilitation due to rheumatoid arthritis (RA) varied by a factor of 2.6 between the different German states. From 2000 to 2012 rehabilitation measures were reduced by one third, most significantly in men with ankylosing spondylitis (AS). Rehabilitation measures because of RA or AS were provided up to 14 times more frequently by the German statutory pension insurance scheme compared with a large compulsory health insurance which is responsible for rehabilitation measures after retirement. In rehabilitation centers with high numbers of patients with inflammatory rheumatic diseases, higher structural and process quality were demonstrated. In 2011 a total of 40 % of RA patients in the national database of the collaborative arthritis centers showed medium or severe functional limitations. Among these disabled RA patients inpatient rehabilitation was reduced by about 50 % between 1995 and 2011. Out of all RA patients from outpatient rheumatology care with severe functional limitations 38 % had no functional restoration therapy within the previous 12 months with a high variation between rheumatologists. Experiences from other European countries may inspire German rheumatologists and other involved health professionals to initiate a wider range of rehabilitative interventions in the future.

Detection of Acidovorax valerianellae, the causing agent of bacterial leaf spots in corn salad [Valerianella locusta (L.) Laterr.], in corn salad seeds.

AIM: The black leaf spot disease on corn salad caused by the bacterium Acidovorax valerianellae has been observed in Europe for several years and causes economic losses in corn salad cropping. Contaminated seeds or infested soil are considered as the major infection sources. The use of healthy seed material is the only way to prevent disease outbreaks. Therefore, a sensitive diagnostic method for seed testing should be developed. METHODS AND RESULTS: Using a triple antibody sandwich ELISA with a high-specific monoclonal antibody, a quick and reliable detection method for contamination of seed lots with the pathogen was developed. This method allowed to detect contaminated seed lots as well as contamination with A. valerianellae in single seeds. Furthermore, the occurrence and distribution of the pathogen could be shown in symptomatic corn salad leaves and in naturally infested seeds by transmission electron microscopy and immunogold labelling for the first time. CONCLUSION: Our results confirm the seed transmission of this corn salad disease. Pathogen load and distribution vary between positively tested seed lots. SIGNIFICANCE AND IMPACT OF THE STUDY: With this method, not only routine testing of seed material to eliminate contaminated seed lots from production is possible but also the control of sanitation procedures to reduce contamination.

HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus.

OBJECTIVES: Monitoring of peripheral B-cell subsets in patients with systemic lupus erythematosus (SLE) revealed an activity-related expansion of CD27(++)CD20(-)CD19(dim) Ig-secreting cells. A similar subset has also been identified 6-8 days after tetanus/diphtheria vaccination in normal individuals and in patients with infectious disease. METHODS: This subset was analysed further focussing on the HLA-DR surface expression in a cohort of 25 patients with SLE. RESULTS: This study revealed that 86% (range 59-97%) of CD27(++)CD20(-)CD19(dim) cells express high levels of HLA-DR, are also expanded in the bone marrow, and represent plasmablasts enriched with anti-dsDNA secreting cells. The remaining CD27(++)CD20(-)CD19(dim) cells were HLA-DR(low) and represent mature plasma cells. Importantly, HLA-DR(high) plasmablasts showed a closer correlation with lupus activity and anti-dsDNA levels than the previously identified CD27(++)CD20(-)CD19(dim) cells. CONCLUSION: HLA-DR(high)CD27(++)CD20(-)CD19(dim) plasmablasts represent a more precise indicator of lupus activity and suggest that there is an overproduction or lack of negative selection of these cells in SLE.

[Lack of new trainees in trauma surgery and orthopedics. An approach to a solution]. / Nachwuchsmangel in der unfallchirurgie und orthopädie. Ein lösungsansatz.

The reasons for a shortage of young people in trauma surgery and orthopedics have often been discussed. Atypical progression of medical operating levels, antisocial working hours and an inadequate financial compensation for on-call duties have been given as the reasons for a lack of interest in the discipline. Additionally a progressive feminization of the medical profession and rejection of surgical disciplines because of a mismatch with family interests and the demands of advanced surgical training have also been named. Surveys on the choice of medical specialization reveal that experiences during the course of studying have a great influence on future prospects and are immensely important for the further focusing on the future as a medical doctor. In order to increase the attractiveness of the specialization, programs for students were initiated by the heads of the Conventions of Higher Education Lecturers for Orthopedics and Trauma Surgery and the management of the German Society for Orthopedics and Trauma Surgery. Due to the enormous popularity auxiliary projects were demanded. Consequently a "Trauma Surgery and Orthopedic Day for Students" was organized on 16th February 2010 in the Musculoskeletal Centre of the Charité in Berlin. The aim was to convey practical skills and to inspire the choice of this specialization in the future.

Dose-related patterns of glucocorticoid-induced side effects.

OBJECTIVE: To identify patterns of self-reported health problems relating to dose and duration of glucocorticoid intake in unselected patients with rheumatoid arthritis from routine practice. METHODS: Data from 1066 patients were analysed. The clinical status and drug treatment were reported by the physician, health problems during the past 6 months by the patient using a comprehensive list of symptoms. Patients with ongoing glucocorticoid treatment for more than 6 months and current doses of less than 5, 5-7.5 and over 7.5 mg/day prednisone equivalent were compared with a group without any glucocorticoid treatment for at least 12 months. RESULTS: The frequency of self-reported health problems was lowest in the group without glucocorticoid exposition and increased with dosage. Two distinct dose-related patterns of adverse events were observed. A "linear" rising with increasing dose was found for cushingoid phenotype, ecchymosis, leg oedema, mycosis, parchment-like skin, shortness of breath and sleep disturbance. A "threshold pattern" describing an elevated frequency of events beyond a certain threshold value was observed at dosages of over 7.5 mg/day for glaucoma, depression/listlessness and increase in blood pressure. Dosages of 5 mg/day or more were associated with epistaxis and weight gain. A very low threshold was seen for eye cataract (<5 mg/day). CONCLUSION: The associations found are in agreement with biological mechanisms and clinical observations. As there is a paucity of real-life data on adverse effects of glucocorticoids prescribed to unselected groups of patients, these data may help the clinician to adapt therapy with glucocorticoids accordingly and improve the benefit-risk ratio.

[Risk of Hip Dislocation - which Patients Need Special Treatment?]. / Risiko Hüftluxation - welche Patienten brauchen besondere Maßnahmen?

INTRODUCTION: Dislocation of a hip arthroplasty is one of the main complications after primary or revision surgery. Definition of specific risk factors concerning patient, indication and surgery makes it possible to determine risk patients for dislocation. AIM: The aim of this study is to identify patient-specific risk factors, such as body mass index (BMI), age and gender, in order to evaluate primary dislocation and to correlate with secondary dislocation. It is investigated whether high BMI, advanced age or female gender are able to promote secondary dislocation. METHOD: In order to identify risk factors for dislocation after primary and revision hip arthroplasty, a retrospective analysis for dislocation was performed of all hip arthroplasties treated in our hospital between 2007 and 2011. 106 patients without an indication for surgical revision were included and treated conservatively. The patient cohort was divided into two groups, depending on the success of the therapy and were analysed for BMI, age and gender. Group I (n = 32) included patients without a re-dislocation event, in contrast to group II (n = 74), which included patients with re-dislocation of the hip arthroplasty. RESULTS: The mean age at the time of primary dislocation was 68 ± 14 years (32 % male and 68 % female). Re-dislocation was presented in 74 cases (70 %). Group II showed a significantly higher BMI (27.11 ± 6.24 kg/m(2)) than group I (24.49 ± 4.86 kg/m(2); p = 0.02). There was no significant effect of age (p = 0.70). The mean age in group I was 71 ± 16 years and in group II of 70 ± 13 years. The incidence of hip dislocation was 2.33-fold higher in women than in men. There was no significant difference between the genders with respect to the risk of re-dislocation. SUMMARY: A higher BMI correlates significantly with a greater risk of re-dislocation of a hip arthroplasty. On the other hand, age and gender do not influence the risk. However, the dislocation of a hip arthroplasty is a multifactorial event, which can be influenced by patient-specific factors as well as specific factors for indication and operation technique.

The promoter of the H1zero histone gene contains a DNA element bound by retinoic acid receptors.

Retinoic-acid mediated differentiation of F9 cells is accompanied by an increased transcription of the histone H1zero gene. This increase is an early response after addition of retinoic acid, suggesting a direct effect of the hormone on transcription of the gene. We show now that the promoter of histone H1zero contains a DNA element, localized 531 base-pairs upstream of the cap site, that is composed of a direct repeat of the sequence PuGGTCA separated by eight base-pairs. This element confers retinoic acid responsiveness to a heterologous thymidine kinase promoter in F9 and HeLa cells. Furthermore, the element forms retarded complexes not only with bacterially expressed retinoic acid receptors (RARs) and retinoid X receptors (RXRs), but also with endogenous F9 receptors. Our results suggest therefore that retinoic acid receptors can control the expression of a chromatin structural gene the expression of which is associated with a differentiated phenotype.

Idarubicin, melphalan and cyclophosphamide: an intensified high-dose regimen for the treatment of myeloma patients.

Following conventional chemotherapy, eight myeloma patients presenting with advanced tumor stages were treated with an intensified high-dose regimen and autologous peripheral blood stem cell transplantation. High-dose chemotherapy consisted of idarubicin 20 mg/m2 on days -13, -12 and -11, melphalan 100 mg/m2 on days -5 and -4 and cyclophosphamide 60 mg/kg (plus mesna 60 mg/kg) on days -3 and -2 (IMC). Seven patients achieved a complete remission or a very good partial remission (reduction of M-component > or =90%). There were no toxic deaths. Severe mucositis and fever of unknown origin were seen in all patients. Reversible supraventricular tachycardias without clinical signs of cardiac failure occurred in five patients. One patient developed a persistent deterioration of cardiac function. We surmise that high-dose chemotherapy with IMC is very effective and well tolerated in myeloma patients.

Interleukin-17 stimulates the expression of IkappaB alpha mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines.

Interleukin-17 (IL-17) has been characterized as a proinflammatory cytokine produced by CD4+ activated memory T cells. In an effort to elucidate the biological effects of IL-17 in glial cells, we investigated the ability of this cytokine in order to activate nuclear factor (NF)-kappaB, which is being discussed as one of the most important transcription factors in the regulation of neuronal and glial cell function. Activation of NF-kappaB involves the degradation of its cytoplasmatic inhibitor IkappaB-alpha, which allows the nuclear translocation of NF-kappaB, and ensures transcriptional activation of genes including IkappaB-alpha itself. Using a competitive RT-PCR, we examined the IL-17-induced IkappaB-alpha mRNA expression in glioblastoma cells, and we examined IL-17 up-regulated IkappaB-alpha mRNA expression in a dose- and time-dependent fashion with a maximum time between 1 and 3 h. This induction could be inhibited by Calphostin C (protein kinase C inhibitor) and genistein (tyrosine kinase inhibitor). After 60 min of IL-17 stimulation, a degradation of the IkappaB-alpha protein was detectable. Furthermore, IL-17 stimulated the secretion of IL-6 and IL-8 in glial cells, and IL-17 and IL-1beta in combination showed a superadditive effect. We suggest IL-17 to play a role as an immune factor, possibly involved in complex pathophysiological interactions of neurodegenerative diseases.

Constitutive expression of HLA class II mRNA in synovial fibroblast-like cells from patients with rheumatoid arthritis .

We describe the quantification of the absolute amounts of HLA class II mRNA and class II transactivator (CIITA) mRNA by competitive reverse transcription polymerase chain reaction in cultured synovial fibroblast-like cells (SFC) of patients with rheumatoid arthritis. High basal levels of transcription of class II mRNA (10(7)-10(9) molecules/microgram total RNA) and CIITA mRNA were detected in cultured SFC, with DPB < DRB = DQB, although SFC only express small amounts of MHC class II proteins. In contrast to SFC, we did not detect class II mRNA nor CIITA mRNA in skin fibroblasts. After treatment with IFN-gamma, we observed a 3- to 28-fold increase in class II mRNA in SFC and an increase of DRB and DPB in skin fibroblasts from undetectable levels to 10(8)-10(9) molecules/microgram total RNA.

Temporary remission of an alveolar rhabdomyosarcoma diagnosed and treated as acute leukemia.

A 29-year-old man with alveolar rhabdomyosarcoma was considered to be suffering from acute leukemia. A bone marrow aspirate had revealed extensive infiltration by atypical blast-like cells which were interpreted as acute lymphoblastic leukemia. Although there was no confirmation of this diagnosis by immunophenotyping chemotherapy with a protocol suited for the treatment of acute lymphoblastic leukemia was started prior to histological analysis and resulted in a complete temporary remission after the first cycle. Histological analysis of a bone marrow biopsy revealed an alveolar rhabdomyosarcoma, as further confirmed by molecular genetic analysis. Two months after the end of chemotherapy, there was an extensive recurrence and the patient died one year after initial diagnosis with chemotherapy refractory disease. In conclusion, rhabdomyosarcoma should always be included in the differential diagnosis of systemic diseases with extensive bone marrow infiltration by tumor cells which could otherwise be misinterpreted as a haematological malignancy.

Cell-cell contact of human T cells with fibroblasts changes lymphocytic mRNA expression: increased mRNA expression of interleukin-17 and interleukin-17 receptor.

Using random arbitrarily primed-reverse transcribed-PCR and sequence analysis, we investigated changes in lymphocytic molecules after cell-cell contact with fibroblasts. An mRNA species which was upregulated in Jurkat T cells by cell-cell contact with MRHF cells (a human foreskin fibroblast line) was identified as coding for the human interleukin-17 receptor. This finding was confirmed by quantitative RT-PCR for the HUT78 and Jurkat T cell lines, for peripheral blood lymphocytes, and for tonsillar T cells. Furthermore, the interleukin-17 mRNA, coding for a proinflammatory cytokine, was also upregulated in peripheral blood lymphocytes and tonsillar T cells after cell-cell contact with fibroblasts. Supernatants obtained from cell-cell contact-stimulated peripheral blood lymphocytes enhance the production of interleukin-6 and interleukin-8 by fibroblast-like synoviocytes and this effect could be blocked by interleukin-17 antibodies. Changes in the mRNA levels of Jurkat T cells induced by cell-cell contact with adherent cells were also found for M-type pyruvate kinase, for tropomyosin TM30 and for the p54nrb gene product.