Determinants of lenalidomide response with or without erythropoiesis-stimulating agents in myelodysplastic syndromes: the HOVON89 trial.

A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

New Bounds from Positronium Decays on Massless Mirror Dark Photons.

We present the results of a search for a hidden mirror sector in positronium decays with a sensitivity comparable with the bounds set by the prediction of the primordial He^{4} abundance from big bang nucleosynthesis. No excess of events compatible with decays into the dark sector is observed, resulting in an upper limit for the branching ratio of this process of 3.0×10^{-5} (90% C.L.). This is an order of magnitude more stringent than the current existing laboratory bounds and it constrains the mixing strength of ordinary photons to dark mirror photons at a level of ϵ<5.0×10^{-8}.

Comparison of performance, health and welfare aspects between commercially housed hatchery-hatched and on-farm hatched broiler flocks.

On-farm hatching systems for broiler chicks are increasingly used in practice. We studied whether or not performance, health and welfare aspects differed between commercial flocks hatched on-farm or in a hatchery (control). In two successive production cycles on seven farms, a total of 16 on-farm hatched flocks were paired to 16 control flocks, housed at the same farm. Paired flocks originated from the same batch of eggs and were subjected to similar on-farm management. On-farm hatched and control flocks only differed with respect to hatching conditions, with on-farm hatched flocks not being exposed to, for example, chick handling, post-hatch feed and water deprivation and transport, in contrast to control flocks that were subjected to standard hatchery procedures, subsequently transported and placed in the poultry house. Day-old chick quality (navel and hock scores), 1st week mortality, total mortality, BW at day (d) 0, d7 and at depopulation, and (total) feed conversion ratio were determined. Prevalence of footpad dermatitis, hock burn, breast discoloration/blisters and cleanliness, litter quality and gait score were determined at d21 of age and around depopulation (d39 on average). Gross pathology and gut morphology were examined at depopulation age in a sample of birds of five flocks per treatment. On-farm hatching resulted in a higher BW at d0 (Δ=5.4 g) and d7 (Δ=11.5 g) (P<0.001), but day-old chick quality as measured by navel (P=0.003) and hock (P=0.01) quality was worse for on-farm hatched compared to control birds. Body weight, 1st week and total mortality, and feed conversion ratio at slaughter age were similar for both on-farm hatched and control flocks. On-farm hatched flocks had less footpad dermatitis (P=0.05), which indicated a better welfare. This was likely related to a tendency for better litter quality in on-farm hatched flocks at 21 days of age in comparison to control flocks (P=0.08). No major differences in gross pathology or in intestinal morphology at depopulation age were found between treatments. In conclusion, on-farm hatching resulted in better 1st week broiler performance and better welfare compared to conventional hatching in a hatchery.

Impact of anthracycline dose on quality of life and rehabilitation in breast cancer treatment.

BACKGROUND: In 2005 the Dutch national guidelines for treatment of breast cancer were updated. From then onwards, patients with operable breast cancer, who formerly received four cycles of adjuvant chemotherapy with doxorubicin/cyclophosphamide (AC), were treated with five cycles of 5-fluorouracil/epirubicin/cyclophosphamide (FEC), based on data suggesting survival benefit. PRIMARY OBJECTIVE: evaluation of the effect on quality-of-life and trainability after four AC versus five FEC cycles of polychemotherapy. SECONDARY OBJECTIVE: evaluation of the effectiveness of an 18-week training programme for breast cancer survivors. METHODS: A prospective cohort study design was used, comparing two chemotherapy regimens historically. The first cohort (group 1) received 4AC (A 60 mg/m2, C 600 mg/m2) (n=25) and the second cohort (group 2) received 5FE C (F 500 mg/m2, E 90 mg/m2, C 500 mg/m2) (n=50) adjuvant polychemotherapy. Both groups completed an 18-week high-intensity strength-training programme. Outcome measures were changes in quality-of-life (EORTC-QLQ-C30, MFI -20), muscular strength (one-repetition maximum; leg press) and cardiopulmonary function (VO2max) between baseline and follow-up. RESULTS: Between March 2002 and February 2006, 75 female subjects with breast cancer participated in this study. Baseline characteristics were similar in both groups. After completing the training programme, both groups showed a significant improvement in all outcome measures. No significant differences in changes of the EORTC-QLQ-C30 and MFI-20, one repetition maximum of the leg press and the VO2max between the two groups were demonstrated. CONCLUSION: After adaptation of the Dutch national breast cancer treatment guidelines, patients received prolonged and increased doses of anthracyclines. This, however, did not result in a difference in the baseline situation before rehabilitation and in training response, nor in quality of life between the two groups.

Heart rate and skin conductance in four-year-old children with aggressive behavior.

Autonomic underarousal, indicated by low heart rate (HR) and skin conductance level (SCL), is related to childhood aggression. However, results are inconsistent in preschoolers. We assessed HR, SCL, heart rate reactivity and skin conductance reactivity in four-year-old children. Comparisons were made between children with a high level and with a low level of aggressive behavior according to the Child Behavior Checklist 1 1/2-5 as well as between children who were diagnosed with Oppositional Defiant Disorder or Conduct Disorder (ODD/CD) and children with a low level of aggression. Preschool children with a high level of aggressive behavior showed lower SCL and SCR and children with ODD/CD showed lower SCL. In contrast, we did not find lower HR and HRR in preschool children with a high level of aggressive behavior or ODD/CD. Thus, results suggest that decreased SCL, but not HR, is a characteristic of preschool children with aggressive behavior or ODD/CD.

ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia.

ATP-binding-cassette (ABC) transporters are evolutionary extremely well-conserved transmembrane proteins that are highly expressed in hematopoietic stem cells (HSCs). The physiological function in human stem cells is believed to be protection against genetic damage caused by both environmental and naturally occurring xenobiotics. Additionally, ABC transporters have been implicated in the maintenance of quiescence and cell fate decisions of stem cells. These physiological roles suggest a potential role in the pathogenesis and biology of stem cell-derived hematological malignancies such as acute and chronic myeloid leukemia. This paper reviews the (patho)physiological role of ABC transporters in human normal and malignant HSCs and discusses its implications for their utility as therapeutical targets to eradicate leukemic stem cells in these diseases.

The number of therapeutic sessions in logopedic care: a description and analysis.

The aim of this study was (i) to describe the number of therapeutic sessions in logopedic care in the Netherlands and (ii) to analyse which factors determine the number of sessions. An analysis was performed on a data set of 517 patients who received logopedic treatment. Data concerning patient characteristics, medical diagnosis, logopedic diagnosis (in terms of impairments, disabilities and handicaps) and the number of sessions were available. The mean number of sessions was 17.2 (SD 10.7). In a multivariate analysis 19.4% of the total amount of variance in the number of sessions was explained; impairments were the only significant determinant. Language development impairments, aural impairments and impairments of auditory functions were associated with a relatively large number of sessions; impairments in reading and writing were associated with relatively few sessions. Recommendations for the design of future studies on the optimal number of sessions are derived from these findings.

Diagnostic assessment and treatment goals in logopedics: impairments, disabilities and handicaps.

This study was aimed to investigate to what extent impairments, disabilities and handicaps are used as diagnostic assessments and treatment goals in logopedics. Traditionally, logopedists are mainly concerned with impairments. These days, increasing attention is demanded for disabilities and handicaps as well. A survey study was carried out on 1,567 patients in logopedic practices in the Netherlands to provide an empirical quantitative description of diagnostic assessments and treatment goals, formulated in terms of impairments, disabilities and handicaps. Results show that logopedists indeed often indicate impairments as diagnostic assessments and as treatment goals, particularly language development impairments and phonetic/phonological articulation impairments. Interestingly, also large numbers of diagnostic assessments and treatment goals were indicated at the level of disabilities and handicaps; the most important being disability in expressing communication and occupational handicap. These results demonstrate that disabilities and handicaps may serve an important function in logopedics, in that they may guide assessment as well as therapy. It is concluded that disabilities and handicaps should be considered in the future development of the profession of logopedics.

Medical and educational fields in logopedics in The Netherlands: a comparison in historical and European perspective.

This study describes differences between medical and educational fields in logopedics practice in The Netherlands. This dichotomy of fields is also found in other Western European countries and may result from the historical development of the profession. The four settings where logopedists work the most (institutional care, private practice, community care and special schools) were studied. One hundred and seventy-two logopedists in 103 practices or departments collected data on 1,761 patients. For each patient a standard registration form was filled in, containing information on (i) patient characteristics, (ii) logopedic diagnostic assessment, and (iii) aspects of treatment. The historical dichotomy into medical and educational fields is still demonstrable in present-day logopedics in The Netherlands. However, the settings within each field also show some differences. Private practice shows a mixture of medical and educational characteristics.

Reliability of the assessment of impairments, disabilities and handicaps in survey research on speech therapy.

An important aspect to the practice of speech therapy is the diagnostic assessment. This assessment is complementary to the medical diagnosis. The International Classification of Impairments, Disabilities and Handicaps (ICIDH) is regarded as a good starting point for the classification of speech therapy assessments. Based on the ICIDH, a form was developed for the registration of impairments, disabilities and handicaps in survey research on speech therapy. The aim of this study was to evaluate the reliability of the assessment of impairments, disabilities and handicaps based on clinical observations and examinations by speech therapists. On the basis of the percentage of agreement and kappa values it is concluded that the reliability of the assessment of the impairments, disabilities and handicaps was satisfactory to excellent for most of the categories.

The phonological representation of [voice] in speech perception.

This paper examines to what extent phonological representations affect word identification. The contrast under investigation involves the interaction between voicing and vowel length in Dutch. Dutch has underlying contrasts both in obstruent voicing and in vowel length. The voicing contrast is neutralized on the surface in syllable-final position. Also, both long and short vowels are lengthened by some 25 msec when followed by medial voiced obstruents. The present study investigated whether this vowel length cue influenced listeners when hearing stimuli with ambiguous vowel duration in an identical, neutralized consonantal context in which the underlying representation of the obstruent following the vowel differed in voicing. A vowel length continuum ([at] to [a:t]) was created and appended to initial consonants to make two pairs of real words. Each pair differed in vowel length with opposite underlying final consonant representations: /zat/-/za:d/, and /stad/-/sta:t/. Our question was whether the vowel category boundaries would be different in pairs like /zat/-/za:d/ as compared to /stad/-/sta:t/. Although the underlying consonant is either voiced or voiceless, the surface word-final consonant for both pairs of stimuli is always voiceless ([t]). If the listener uses a surface representation with a voiceless consonant to recognize the words, there should be no difference in categorization of the vowel-length continua. The results of a vowel categorization task, however, showed a significant difference in the location of the phoneme boundaries between the two continua, suggesting that listeners' perception seems to be guided by the underlying phonological representation of words.

Thionine-Feulgen-Congo red staining of cervical smears for the BioPEPR image-analysis system.

A staining method developed for use with BioPEPR (Biological Precision Encoding and Pattern Recognition), an automated image-analysis system for cervical smears, is described. The stain is a combination of the Feulgen procedure, with thionine-SO2 as the Schiff reagent, and Congo red, which is used as a counterstain. The stain resulted in smears suitable both for microscopic diagnosis and for BioPEPR measurements made on photonegatives at a single wavelength 545 nm. A high level of reproducibility and accuracy of nuclear and cytoplasmic area measurements was obtained. Nuclear integrated optical density could be well measured and was shown to be useful in discriminating between normal and abnormal cells. Using a combination of morphologic features, a high level of cell classification accuracy was reached. The possibility of using the stain for more detailed studies is discussed.

The development of a cervical smear preparation procedure from the BioPEPR image analysis system.

The preparation procedure for the BioPEPR automated image analysis system is described. Cervical cells are collected in a preservative solution and disaggregated by an automated syringing apparatus, giving about 50% single cells. After centrifugation, the preservative solution is discarded, 2% polyethyleneglycol in 50% ethanol (carbowax) is added, and the cell solution is automatically spread onto a glass slide, resulting in a cell density of about 50 cells/sq mm in the central area of the smear. Increasing cell density is shown to lead to a gradual linear decrease in single cells. All preparation steps have been critically evaluated, and the possibility of implementing this preparation procedure in a fully automated system is discussed.

Field test results using the BioPEPR cervical smear prescreening system.

BioPEPR is a cathode ray tube scanning device that has been developed for the prescreening of cervical smears. Cervical samples are collected in suspension, syringed, counted and spread across a microscope slide. Feulgen-Thionine with Congo Red is used as the staining procedure. Fields of 6 X 8 mm are scanned at 1 mu resolution, using an intermediate photographic step. Morphologic parameters of the cells are measured, as called for by a hierarchical decision strategy. Analysis speed is currently about 4 min per smear; improvements of at least a factor of four are expected. A field test of BioPEPR is being undertaken in cooperation with a local population screening program. In the study two smears are made from each woman; the first is prepared according to the Papanicolaou technique while the second is prepared and stained according to the BioPEPR methods. In addition to smears from the population screening program a number of possibly abnormal smears are obtained from several gynecological clinics. To date approximately 3500 "second" smears have been analyzed by the BioPEPR system. The results show a missed positive rate on the order of a few percent (no missed positives were more severe than a slight dysplasia), and a false alarm rate of about 24%. A further analysis of the age distribution of the false alarm rate shows that a large proportion came from women above the age of 50; the false alarm rate is about 20% for women under the age of 50.

BioPEPR: a system for the automatic prescreening of cervical smears.

A feasibility study has indicated that a Prescion Encoding and Pattern Recognition (PEPR) cathode ray tube prescreening system for cervical smears can be both accurate and fast. Smears are prepared using a syringing technique and are stained with a Feulgen-type nuclear stain and a protein counter-stain. The use of film as an intermediate step between the cells and Bio PEPR allows the scanning of fields as large as 8 x 8 mm. The morphological features of the cells are measured as directed by a hierarchical decision strategy. Additional programs detect artifacts, overlaps, and leukocytes. For clean samples, false positive and false negative rates on the cell level have been obtained that will allow acceptable smear level rates (10% false positive, 1% false negative). These rates have been reached without compromising the required speed goals of 120 to 180 smears per hr. The efficiency of the system is dependent on the quality of the smears. Measurements on a set of 192 routinely prepared smears indicate acceptable false negative rates and a false positive rate of about 18%. A reduction of this rate is expected with small improvements in cell preparation and measuring software, leading to the overall system efficiency required for commercial feasibility.