[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

Consensus on Recording Deep Endometriosis Surgery: the CORDES statement.

STUDY QUESTION: Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? SUMMARY ANSWER: A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. WHAT IS KNOWN ALREADY: Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. STUDY DESIGN, SIZE, DURATION: International expert consensus based on a systematic review of literature. PARTICIPANTS/MATERIALS, SETTING, METHODS: Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. MAIN RESULTS AND THE ROLE OF CHANCE: We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. LIMITATIONS, REASONS FOR CAUTION: The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. WIDER IMPLICATIONS OF THE FINDINGS: This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. STUDY FUNDING/COMPETING INTERESTS: None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. TRIAL REGISTRATION NUMBER: N/A.

Escape from extreme specialization: passionflowers, bats and the sword-billed hummingbird.

A striking example of plant/pollinator trait matching is found between Andean species of Passiflora with 6-14-cm-long nectar tubes and the sword-billed hummingbird, Ensifera ensifera, with up to 11-cm-long bills. Because of the position of their anthers and stigmas, and self-incompatibility, these passionflower species depend on E. ensifera for pollination. Field observations show that the bird and plant distribution match completely and that scarcity of Ensifera results in reduced passionflower seed set. We here use nuclear and plastid DNA sequences to investigate how often and when these mutualisms evolved and under which conditions, if ever, they were lost. The phylogeny includes 26 (70%) of the 37 extremely long-tubed species, 13 (68%) of the 19 species with tubes too short for Ensifera and four of the seven bat-pollinated species for a total of 43 (69%) of all species in Passiflora supersection Tacsonia (plus 11 outgroups). We time-calibrated the phylogeny to infer the speed of any pollinator switching. Results show that Tacsonia is monophyletic and that its stem group dates to 10.7 Ma, matching the divergence at 11.6 Ma of E. ensifera from its short-billed sister species. Whether pollination by short-billed hummingbirds or by Ensifera is the ancestral condition cannot be securely inferred, but extremely long-tubed flowers exclusively pollinated by Ensifera evolved early during the radiation of the Tacsonia clade. There is also evidence of several losses of Ensifera dependence, involving shifts to bat pollination and shorter billed birds. Besides being extremely asymmetric-a single bird species coevolving with a speciose plant clade-the Ensifera/Passiflora system is a prime example of a specialized pollinator not driving plant speciation, but instead being the precondition for the maintenance of isolated populations (through reliable seed set) that then underwent allopatric speciation.

Recommendations for the implementation and conduct of multidisciplinary team meetings for those providing endometriosis and adenomyosis care - a Delphi consensus of the European Endometriosis League (EEL).

Background: The treatment of endometriosis and adenomyosis requires a complex, multidisciplinary approach. Some centres have established multidisciplinary teams (MDT) and regular meetings. There are currently no international data or recommendations. Objectives: To examine existing MDT meetings and define consensus recommendations to support implementation and conduct. Materials and Methods: Online questionnaires were sent through the European Endometriosis League (EEL) based on a Delphi protocol. After a literature review and assessment of existing MDT meetings, essential aspects for consensus statements were identified. The consensus statements were evaluated using a 5-point Likert scale with the possibility to modify them. Results were analysed between rounds and reported to the respondents. Consensus, defined as ≥70% agreement, concluded the Delphi process when achieved in the majority of statements. Main outcome measures: Prevalence and type of existing MDT meetings and recommendations. Results: In round 1, 69 respondents participated, with 49.3% (34) having an MDT meeting at their institutions, of which 97% are multidisciplinary. 50 % meet once a month and 64.7% indicated that less than 25% of their patients are discussed. Throughout the three rounds, 47 respondents from 21 countries participated. During the process, 82 statements were defined, with an agreement of 92.7% on the statements. Conclusions: This study assessed existing MDT meetings for endometriosis and adenomyosis and developed recommendations for their implementation and conduct. The consensus group supports the strengths of MDT meetings, highlighting their role in offering guideline-based, multidisciplinary, and personalised care. What is new?: This study presents the first international data and recommendations on MDT meetings for endometriosis and adenomyosis.

Molecular cytogenetics (FISH, GISH) of Coccinia grandis : a ca. 3 myr-old species of cucurbitaceae with the largest Y/autosome divergence in flowering plants.

The independent evolution of heteromorphic sex chromosomes in 19 species from 4 families of flowering plants permits studying X/Y divergence after the initial recombination suppression. Here, we document autosome/Y divergence in the tropical Cucurbitaceae Coccinia grandis, which is ca. 3 myr old. Karyotyping and C-value measurements show that the C. grandis Y chromosome has twice the size of any of the other chromosomes, with a male/female C-value difference of 0.094 pg or 10% of the total genome. FISH staining revealed 5S and 45S rDNA sites on autosomes but not on the Y chromosome, making it unlikely that rDNA contributed to the elongation of the Y chromosome; recent end-to-end fusion also seems unlikely given the lack of interstitial telomeric signals. GISH with different concentrations of female blocking DNA detected a possible pseudo-autosomal region on the Y chromosome, and C-banding suggests that the entire Y chromosome in C. grandis is heterochromatic. During meiosis, there is an end-to-end connection between the X and the Y chromosome, but the X does not otherwise differ from the remaining chromosomes. These findings and a review of plants with heteromorphic sex chromosomes reveal no relationship between species age and degree of sex chromosome dimorphism. Its relatively small genome size (0.943 pg/2C in males), large Y chromosome, and phylogenetic proximity to the fully sequenced Cucumis sativus make C. grandis a promising model to study sex chromosome evolution.

Automatic texture-based analysis in ultrasound imaging of ovarian masses.

PURPOSE: To assess the diagnostic accuracy of a new automatic texture-based algorithm (ATBA) in ultrasound imaging of ovarian masses and to compare its performance to subjective assessment by examiners with different levels of ultrasound experience. MATERIALS AND METHODS: A total of 105 ultrasound images from three different groups of ovarian lesions (malignancies, functional cysts, and dermoid cysts) were evaluated using ATBA and by a total of 36 examiners with four different levels of experience (9 junior trainees, 8 senior trainees, 11 senior gynecologists, and 8 experts). Cohen's κ, Youden's indices, and the sensitivity and specificity of ATBA and of each observer were calculated for every subgroup of ovarian lesions. RESULTS: ATBA classified 78 of the 105 masses correctly (κ = 0.62) - results that were significantly better than those of the junior and senior trainees (p = 0.02 and p < 0.01), while differences from the group of level II examiners did not reach statistical significance (p = 0.27). The best diagnostic performance (κ = 0.70) was obtained by the group of expert level III ultrasonographers. The best classification rates overall, including both ATBA and subjective assessments, were achieved in the detection of functional cysts (Youden's indices from 0.73 to 0.85), while the poorest diagnostic performance was obtained for the classification of dermoid cysts (Youden's indices from 0.28 to 0.55). CONCLUSION: ATBA showed a significantly better diagnostic performance than observers with low or medium levels of experience, emphasizing its potential value for training purposes and in providing additional diagnostic assistance for inexperienced observers.

Charon's size and an upper limit on its atmosphere from a stellar occultation.

Pluto and its satellite, Charon (discovered in 1978; ref. 1), appear to form a double planet, rather than a hierarchical planet/satellite couple. Charon is about half Pluto's size and about one-eighth its mass. The precise radii of Pluto and Charon have remained uncertain, leading to large uncertainties on their densities. Although stellar occultations by Charon are in principle a powerful way of measuring its size, they are rare, as the satellite subtends less than 0.3 microradians (0.06 arcsec) on the sky. One occultation (in 1980) yielded a lower limit of 600 km for the satellite's radius, which was later refined to 601.5 km (ref. 4). Here we report observations from a multi-station stellar occultation by Charon, which we use to derive a radius, R(C) = 603.6 +/- 1.4 km (1sigma), and a density of rho = 1.71 +/- 0.08 g cm(-3). This occultation also provides upper limits of 110 and 15 (3sigma) nanobar for an atmosphere around Charon, assuming respectively a pure nitrogen or pure methane atmosphere.

Primary and coupled motions after cervical total disc replacement using a compressible six-degree-of-freedom prosthesis.

This study tested the hypotheses that (1) cervical total disc replacement with a compressible, six-degree-of-freedom prosthesis would allow restoration of physiologic range and quality of motion, and (2) the kinematic response would not be adversely affected by variability in prosthesis position in the sagittal plane. Twelve human cadaveric cervical spines were tested. Prostheses were implanted at C5-C6. Range of motion (ROM) was measured in flexion-extension, lateral bending, and axial rotation under ± 1.5 Nm moments. Motion coupling between axial rotation and lateral bending was calculated. Stiffness in the high flexibility zone was evaluated in all three testing modes, while the center of rotation (COR) was calculated using digital video fluoroscopic images in flexion-extension. Implantation in the middle position increased ROM in flexion-extension from 13.5 ± 2.3 to 15.7 ± 3.0° (p < 0.05), decreased axial rotation from 9.9 ± 1.7 to 8.3 ± 1.6° (p < 0.05), and decreased lateral bending from 8.0 ± 2.1 to 4.5 ± 1.1° (p < 0.05). Coupled lateral bending decreased from 0.62 ± 0.16 to 0.39 ± 0.15° for each degree of axial rotation (p < 0.05). Flexion-extension stiffness of the reconstructed segment with the prosthesis in the middle position did not deviate significantly from intact controls, whereas the lateral bending and axial rotation stiffness values were significantly larger than intact. Implanting the prosthesis in the posterior position as compared to the middle position did not significantly affect the ROM, motion coupling, or stiffness of the reconstructed segment; however, the COR location better approximated intact controls with the prosthesis midline located within ± 1 mm of the disc-space midline. Overall, the kinematic response after reconstruction with the compressible, six-degree-of-freedom prosthesis within ± 1 mm of the disc-space midline approximated the intact response in flexion-extension. Clinical studies are needed to understand and interpret the effects of limited restoration of lateral bending and axial rotation motions and motion coupling on clinical outcome.

Large changes in Pluto's atmosphere as revealed by recent stellar occultations.

Pluto's tenuous nitrogen atmosphere was first detected by the imprint left on the light curve of a star that was occulted by the planet in 1985 (ref. 1), and studied more extensively during a second occultation event in 1988 (refs 2-6). These events are, however, quite rare and Pluto's atmosphere remains poorly understood, as in particular the planet has not yet been visited by a spacecraft. Here we report data from the first occultations by Pluto since 1988. We find that, during the intervening 14 years, there seems to have been a doubling of the atmospheric pressure, a probable seasonal effect on Pluto.

A sex-linked SCAR marker in Bryonia dioica (Cucurbitaceae), a dioecious species with XY sex-determination and homomorphic sex chromosomes.

Genetic crosses between the dioecious Bryonia dioica (Cucurbitaceae) and the monoecious B. alba in 1903 provided the first clear evidence for Mendelian inheritance of dioecy and made B. dioica the first organism for which XY sex-determination was experimentally proven. Applying molecular tools to this system, we developed a sex-linked sequence-characterized amplified region (SCAR) marker for B. dioica and sequenced it for individuals representing the full geographic range of the species from Scotland to North Africa. For comparison, we also sequenced this marker for representatives of the dioecious B. cretica, B. multiflora and B. syriaca, and monoecious B. alba. In no case did any individual, male or female, yield more than two haplotypes. In northern Europe, we found strong linkage between our marker and sex, with all Y-sequences being identical to each other. In southern Europe, however, the linkage between our marker and sex was weak, with recombination detected within both the X- and the Y-homologues. Population genetic analyses suggest that the SCAR marker experienced different evolutionary pressures in northern and southern Europe. These findings fit with phylogenetic evidence that the XY system in Bryonia is labile and suggest that the genus may be a good system in which to study the early steps of sex chromosome evolution.

Assembly and melting of DNA nanotubes from single-sequence tiles.

DNA melting and renaturation studies are an extremely valuable tool to study the kinetics and thermodynamics of duplex dissociation and reassociation reactions. These are important not only in a biological or biotechnological context, but also for DNA nanotechnology which aims at the construction of molecular materials by DNA self-assembly. We here study experimentally the formation and melting of a DNA nanotube structure, which is composed of many copies of an oligonucleotide containing several palindromic sequences. This is done using temperature-controlled UV absorption measurements correlated with atomic force microscopy, fluorescence microscopy and transmission electron microscopy techniques. In the melting studies, important factors such as DNA strand concentration, hierarchy of assembly and annealing protocol are investigated. Assembly and melting of the nanotubes are shown to proceed via different pathways. Whereas assembly occurs in several hierarchical steps related to the formation of tiles, lattices and tubes, melting of DNA nanotubes appears to occur in a single step. This is proposed to relate to fundamental differences between closed, three-dimensional tube-like structures and open, two-dimensional lattices. DNA melting studies can lead to a better understanding of the many factors that affect the assembly process which will be essential for the assembly of increasingly complex DNA nanostructures.

Parasites in space and time: a case study of haemosporidian spatiotemporal prevalence in urban birds.

Prevalence responses to anthropic factors differ across hosts and parasite species. We here analyzed the spatiotemporal variation of avian haemosporidian prevalence in bird assemblages of the Mooswald forest (i.e., urban greenspace; Freiburg, Germany), in response to local environmental features (e.g., water sources, human presence (visited)/absence (unvisited)) and bird-level traits (e.g., body condition, age, sex) in 2 years. We used a nested PCR protocol (mitochondrial (mt)DNA cytochrome b (cyt b) gene) and microscopy to determine haemosporidian infections. Prevalence was analyzed using a general linear multi-model (glmulti) approach with Akaike information criterion corrected for small samples (AICc), with subsequent model inferences using a GLMM on the best selected model, considering bird species as a random factor. Analyses were conducted for the main understory bird species (Blackcap - Sylvia atricapilla, Chaffinch - Coereba flaveola, Great Tit - Parus major, Blue Tit - Cyanistes caeruleus, European Robin - Erithacus rubecula, Blackbird - Turdus merula, Song Thrush - Turdus philomelos). We further conducted spatial autocorrelation analyses for all haemosporidian infections, and classification and regression trees (CARTs) for focal species. We analyzed a total of 544 samples of seven bird species. In 2011 prevalence for Haemoproteus/Plasmodium was 25.8% and 11.7% for Leucocytozoon. In 2013 prevalence for Haemoproteus/Plasmodium was 26.5% and 35.5% for Leucocytozoon. Haemosporidian prevalence was significantly different between some focal species. There was a negative association between distance to the nearest water source and prevalence in the year 2011, and the opposite pattern for the year 2013. However, when analyzed for the six focal species separately, such a relationship could change from a negative to a positive one, or there could be no relationship at all. For Leucocytozoon there was higher prevalence in the section of the forest visited by humans. We did not find spatial autocorrelation for prevalence across the study site, but there were statistically significant local spatial clusters in the visited section. Although there were similar responses of prevalence to some factors, infection patterns were generally bird species-specific. Thus, prevalence is a labile epidemiological parameter, varying spatiotemporally in an idiosyncratic way.

Different nutrient intake and prevalence of gastrointestinal comorbidities in women with endometriosis.

Even though endometriosis presents one of the most common gynaecological diseases, the pathogenesis is insufficiently studied. Besides immunologic, inflammatory or oxidative processes, recent studies also suggest an influence of nutrition on disease onset and progression. Because data about the actual nutrient intake of endometriosis patients are scarce, we aimed to examine the actual nutrient intake and potential influencing factors in these women. A total of 156 women with endometriosis (EM) and 52 age-matched controls were included in this retrospective case-control study. All women filled in a validated food frequency questionnaire to acquire the nutrient intake of the past 12 months and a disease-related questionnaire for the determination of disease status, clinical symptoms and comorbidities. Patients with endometriosis suffered significantly more from diet-related comorbidities like food intolerances (25.6% versus 7.7%; P = 0.009) and allergies (57% versus 31%; P < 0.001) compared to controls. Also gastrointestinal symptoms, including constipation, flatulence, pyrosis, diarrhea or frequent defecation, were higher in the EM group (77% versus 29%; P < 0.001). The nutrient intake of patients with endometriosis differed significantly compared to controls with a significantly lower ingestion of organic acids (P = 0.006), maltose (P = 0.0.16), glycogen (P = 0.035), tetradecenoic acid (P = 0.041), methionine (P = 0.046), lysine (P = 0.048), threonine (P = 0.046) and histidine (P = 0.049). The total intake of animal proteins was significantly lower in the EM group compared to the controls (P = 0.047). EM patients showed a decreased intake of vitamin C (P = 0.031), vitamin B12 (P = 0.008) and magnesium (P = 0.043) compared to controls. This study confirms a high association of endometriosis and gastrointestinal disorders accompanied by an altered nutrient intake. A dietary intervention by a professional nutritionist may help to reduce disease burden in the affected women.

Higher incidence of linked malformations in siblings of Mayer-Rokitansky-Küster-Hauser-syndrome patients.

BACKGROUND: Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a malformation of the female genital tract (vaginal aplasia, rudimentary uterus, normal fallopian tubes and high ovaries). The incidence is one in 4000 female newborns. The aim of the present study was to record genital and associated malformations among siblings and relatives of MRKH patients in order to draw possible conclusions regarding the etiology of the syndrome: heredity (dominant versus recessive) or spontaneous malformation. METHODS: Using a standardized questionnaire, affected MRKH patients were asked about other cases of MRKH and/or associated malformations among siblings and relatives. RESULTS: No other cases of MRKH syndrome had occurred among the siblings or relatives of 73 MRKH patients; however, 13 associated malformations were recorded among a total of 103 siblings. Musculoskeletal malformations were markedly increased (3.27 times higher) in comparison with the prevalence of congenital malformations among newborns in the normal population. CONCLUSIONS: This study shows that dominant inheritance cannot play a role in the etiology of MRKH syndrome, as no further cases of MRKH syndrome occurred among any of the siblings. The study provides support for the view that the syndrome has a multifactorial pathogenesis. Siblings/relatives of MRKH patients should be examined for associated musculoskeletal/urogenital malformations.

The evolution of dioecy, heterodichogamy, and labile sex expression in Acer.

The northern hemisphere tree genus Acer comprises 124 species, most of them monoecious, but 13 dioecious. The monoecious species flower dichogamously, duodichogamously (male, female, male), or in some species heterodichogamously (two morphs that each produce male and female flowers but at reciprocal times). Dioecious species cannot engage in these temporal strategies. Using a phylogeny for 66 species and subspecies obtained from 6600 nucleotides of chloroplast introns, spacers, and a protein-coding gene, we address the hypothesis (Pannell and Verdú, Evolution 60: 660-673. 2006) that dioecy evolved from heterodichogamy. This hypothesis was based on phylogenetic analyses (Gleiser and Verdú, New Phytol. 165: 633-640. 2005) that included 29-39 species of Acer coded for five sexual strategies (duodichogamous monoecy, heterodichogamous androdioecy, heterodichogamous trioecy, dichogamous subdioecy, and dioecy) treated as ordered states or as a single continuous variable. When reviewing the basis for these scorings, we found errors that together with the small taxon sample, cast doubt on the earlier inferences. Based on published studies, we coded 56 species of Acer for four sexual strategies, dioecy, monoecy with dichogamous or duodichogamous flowering, monoecy with heterodichogamous flowering, or labile sex expression, in which individuals reverse their sex allocation depending on environment-phenotype interactions. Using Bayesian character mapping, we infer an average of 15 transformations, a third of them involving changes from monoecy-cum-duodichogamy to dioecy; less frequent were changes from this strategy to heterodichogamy; dioecy rarely reverts to other sexual systems. Contra the earlier inferences, we found no switches between heterodichogamy and dioecy. Unexpectedly, most of the species with labile sex expression are grouped together, suggesting that phenotypic plasticity in Acer may be a heritable sexual strategy. Because of the complex flowering phenologies, however, a concern remains that monoecy in Acer might not always be distinguishable from labile sex expression, which needs to be addressed by long-term monitoring of monoecious trees. The 13 dioecious species occur in phylogenetically disparate clades that date back to the Late Eocene and Oligocene, judging from a fossil-calibrated relaxed molecular clock.

Modulation of uterine contractility and peristalsis by oxytocin in estrogen-primed non-pregnant swine uteri.

Oxytocin is one of the most potent uterotonic agents and is known to fluctuate throughout the menstrual cycle, showing an increase during sexual stimulation and arousal, with a peak during orgasm in women. To date, limited data are available on the effects of oxytocin on the regulation of uterine contractility and transport mechanisms in human reproduction. The goal of this study was to evaluate the effects of oxytocin on uterine contractility and peristalsis in estrogen-primed non-pregnant uteri. In an extracorporeal perfusion model of the swine uterus the effect of dynamic changes in uterine contractility and peristalsis in response to oxytocin and estrogen administration was observed. Spontaneous uterine contractility and oxytocin-induced uterine contractility and peristalsis with and without estrogen perfusion were assessed using an intrauterine double-chip microcatheter. Spontaneous peristalsis and oxytocin induced contraction waves without estrogen perfusion resulted in a slightly higher intrauterine pressure in the isthmus uteri in comparison with the corpus uteri, while the peristaltic waves were seen to start mostly in the corpus uteri, moving in the direction of the cervix. While after estrogen perfusion oxytocin produced a significant increase in intrauterine pressure in the isthmus uteri compared to the corpus uteri, and 80% of the peristaltic waves started in the isthmus uteri, moving in the direction of the corpus uteri. This observation strengthens the view that oxytocin is able to support directed transport mechanism in the female genital tract only in the presence of estrogens. The biological role of oxytocin increase during sexual stimulation and arousal with a peak during orgasm for the mechanisms of reproduction may be to stimulate directed uterine transport mechanisms in the presence of estrogens.

BCL-X expression in multiple myeloma: possible indicator of chemoresistance.

Because murine myeloma plasma cells and normal human lymph node plasma cells express BCL-X, we evaluated BCL-X expression in malignant human plasma cells. BCL-X expression was detected in several human myeloma cell lines, as well as in CD38-sorted bone marrow cells obtained from some patients. Only the antiapoptotic long form of BCL-X (BCL-X-L), was detected. Because BCL-X-L expression can protect tumor cells from apoptotic death induced by chemotherapeutic agents, we tested the clinical relevance of expression in 55 archival bone marrow biopsies. The biopsies were stained by immunohistochemistry, and BCL-X expression was correlated with the subsequent response to treatment. BCL-X expression in malignant plasma cells strongly correlated with decreased response rates in patient groups treated with either melphalan and prednisone or vincristine, Adriamycin, and dexamethasone. Response rates were 83-87% in non-BCL-X-expressing cases and 20-31% in BCL-X-expressing cases. In addition, BCL-X expression was more frequent in specimens taken from patients at relapse (77%), when compared to those at initial diagnosis (29%). Further support for the association of drug resistance with BCL-X-L expression came from studies of the 8226 dox-40 cell line. This line, which expresses p-glycoprotein and serves as a model of multidrug resistance in multiple myeloma cells, demonstrated an up-regulated expression of BCL-X-L, which was relatively specific, in that BCL-2 or BAX expression was not altered. In addition, dox-40 cells demonstrated a generalized resistance to apoptosis that was induced by several different agents. These results indicate that malignant plasma cells can express BCL-X-L and that such expression may be a marker of chemoresistant disease.