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Rob AB Oostendorp,1– 4 JW Hans Elvers,5,6 Emiel van Trijffel,7,8 Geert M Rutten,9,10 Gwendolyne GM Scholten-Peeters,11 Marcel Heijmans,4 Erik Hendriks,12,13 Emilia Mikolajewska,14,15 Margot De Kooning,3,16 Marjan Laekeman,17,18 Jo Nijs,3,16,19 Nathalie Roussel,20 Han Samwel21 1Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 2Department of Manual Therapy, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium; 3Pain in Motion International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; 4Practice Physiotherapy and Manual Therapy, Heeswijk-Dinther, the Netherlands; 5Department of Public Health and Research, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 6Department of Allied Health Care, Methodological Health-Skilled Institute, Beuningen, the Netherlands; 7Department of Master Education, SOMT University of Physiotherapy, Amersfoort, the Netherlands; 8Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; 9Institute of Health Studies, Faculty of Health and Social Studies, HAN University of Applied Science, Nijmegen, the Netherlands; 10Campus Venlo, Faculty of Science and Engineering, Maastricht University, Maastricht, the Netherlands; 11Department of Human Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands; 12Department of Epidemiology, Center of Evidence Based Physiotherapy, Maastricht University, Maastricht, the Netherlands; 13Practice Physiotherapy ‘Maasstaete, Druten, the Netherlands; 14Department of Physiotherapy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland; 15Neurocognitive Laboratory, Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń, Poland; 16Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium; 17Department of Nursing Sciences, Ph.D.-Kolleg, Faculty of Health, University Witten/Herdecke, Witten, Germany; 18Department of Physiological Psychology, University of Bamberg, Bamberg, Germany; 19Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden; 20Department of Physiotherapy and Rehabilitation Sciences (MOVANT), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; 21Revalis Pain Rehabilitation Centre, S Hertogenbosch, the NetherlandsCorrespondence: Rob AB OostendorpScientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Centre, p/a Oude Kleefsebaan 325, AT Berg En Dal 6572, Nijmegen, the NetherlandsTel +31 246423419Email oostendorp.rob@gmail.comBackground: Whiplash-associated disorders (WADs) constitute a state of health characterized by a wide diversity of symptoms as a result of impairments of functions, activity limitations, and participation restrictions. Patient-reported outcome measurements (PROMs) and patient-reported outcomes (PROs) seem appropriate when describing and evaluating the health status of patients with WAD.Aim: To measure the use of PROMs and PROs as quality indicators in clinical reasoning, and to analyze and evaluate pre- and post-treatment ‘pain intensity’ and ‘functioning’, and for ‘perceived improvement’ in patients with WAD in primary care physiotherapy practice by year of referral, with the phase after accident and prognostic health profile embedded in the clinical reasoning process.Materials and Methods: Data were collected over a period of 10 years. Pain intensity, functioning, and perceived improvement were measured using the Visual Analogue Scale for Pain (VAS-P), the Neck Disability Index (NDI) and the Global Perceived Effect scale (GPE). Pre- and post-treatment mean differences were tested for statistical significance and compared to minimal clinically important differences (MCID). Effect sizes were expressed as Cohen’s d. Multivariable regression analysis was performed to explore independent associations of year of referral, phase after the accident, and the patient’s prognostic health profile with post-treatment pain intensity and functioning.Results: A consecutive sample of 523 patients was included. Pre- and post-treatment mean differences on VAS-P and NDI were statistically significant (P< 0.000) and clinically relevant, with ‘large’ effect sizes for pain intensity and functioning. MCIDs were achieved by 80% for VAS-P and for 60% for NDI. Year of referral and phase after the accident were independently associated with worse post-treatment functioning. About half of the patients (n=241 [46.1%]) perceived themselves as improved.Conclusion: The PROMs and PROs pain intensity, functioning and perceived improvement were integrated as quality indicators in the physiotherapy clinical reasoning process for patients with WAD. Significant differences in pain intensity and functioning were found but were unrelated to year of referral, phase after whiplash-related injury or prognostic health profile. The MCID VAS-P scores did not differ depending on experienced pain.Keywords: whiplash-Associated Disorders, neck pain, physiotherapy, patient-reported outcomes measures, routinely collected data

Rob AB Oostendorp, 1–4 JW Hans Elvers, 5, 6 Emiel van Trijffel, 7, 8 Geert M Rutten, 9, 10 Gwendolyne GM Scholten–Peeters, 11 Marcel Heijmans, 4 Erik Hendriks, 12, 13 Emilia Mikolajewska, 14, 15 Margot De Kooning, 3, 16 Marjan Laekeman, 17 Jo Nijs, 3, 16 Nathalie Roussel, 18 Han Samwel 19 1Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 2Department of Manual Therapy, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium; 3Pain in Motion International Research Group, Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; 4Practice Physiotherapy and Manual Therapy, Heeswijk-Dinther, the Netherlands; 5Department of Public Health and Research, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 6Methodological Health-Skilled Institute, Beuningen, the Netherlands; 7SOMT University of Physiotherapy, Amersfoort, the Netherlands; 8Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; 9Institute of Health Studies, Faculty of Health and Social Studies, HAN University of Applied Science, Nijmegen, the Netherlands; 10Faculty of Science and Engineering, Maastricht University, Maastricht, the Netherlands; 11Department of Human Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Free University Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands; 12Department of Epidemiology, Center of Evidence Based Physiotherapy, Maastricht University, Maastricht, the Netherlands; 13Practice Physiotherapy ‘Klepperheide’, Druten, the Netherlands; 14Department of Physiotherapy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus Univerisity, Toruń, Poland; 15Neurocognitive Laboratory, Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń, Poland; 16Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium; 17Department of Nursing Sciences, Ph.D.-Kolleg, Faculty of Health, University Witten/Herdecke, Witten, Germany; 18Department of Physiotherapy and Rehabilitation Sciences (MOVANT), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; 19Revalis Pain Rehabilitation Centre, ‘s Hertogenbosch, the NetherlandsCorrespondence: Rob AB OostendorpScientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Centre, p/a Oude Kleefsebaan 325, Berg en Dal 6572 AT, the NetherlandsTel +31 2464234219Email oostendorp.rob@gmail.comBackground: Quality indicators (QIs) are measurable elements of practice performance and may relate to context, process, outcome and structure. A valid set of QIs have been developed, reflecting the clinical reasoning used in primary care physiotherapy for patients with whiplash-associated disorders (WAD). Donabedian’s model postulates relationships between the constructs of quality of care, acting in a virtuous circle.Aim: To explore the relative strengths of the relationships between context, process, and outcome indicators in the assessment of primary care physiotherapy in patients with WAD.Materials and Methods: Data on WAD patients (N=810) were collected over a period of 16 years in primary care physiotherapy practices by means of patients records. This routinely collected dataset (RCD-WAD) was classified in context, process, and outcome variables and analyzed retrospectively. Clinically relevant variables were selected based on expert consensus. Associations were expressed, using zero-order, as Spearman rank correlation coefficients (criterion: rs > 0.25 [minimum: fair]; α-value = 0.05).Results: In round 1, 62 of 85 (72.9%) variables were selected by an expert panel as relevant for clinical reasoning; in round 2, 34 of 62 (54.8%) (context variables 9 of 18 [50.0%]; process variables 18 of 34 [52.9]; outcome variables 8 of 10 [90.0%]) as highly relevant. Associations between the selected context and process variables ranged from 0.27 to 0.53 (p≤ 0.00), between selected context and outcome variables from 0.26 to 0.55 (p≤ 0.00), and between selected process and outcome variables from 0.29 to 0.59 (p≤ 0.00). Moderate associations (rs > 0.50; p≤ 0.00) were found between “pain coping” and “fear avoidance” as process variables, and “pain intensity” and “functioning” as outcome variables.Conclusion: The identified associations between selected context, process, and outcome variables were fair to moderate. Ongoing work may clarify some of these associations and provide guidance to physiotherapists on how best to improve the quality of clinical reasoning in terms of relationships between context, process, and outcome in the management of patients with WAD.Keywords: physiotherapy, whiplash injuries, outcome and process assessment, healthcare quality indicators, collected data

Rob AB Oostendorp,1–4 Hans Elvers,5,6 Emiel van Trijffel,7,8 Geert M Rutten,9,10 Gwendolyne GM Scholten–Peeters,11 Marcel Heijmans,4 Erik Hendriks,12,13 Emilia Mikolajewska,14,15 Margot De Kooning,3,8,16 Marjan Laekeman,17 Jo Nijs,3,8,16 Nathalie Roussel,18 Han Samwel191Scientific Institute for Quality of Healthcare, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 2Department of Manual Therapy, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium; 3Pain in Motion International Research Group, Free University Brussels, Brussels, Belgium; 4Practice Physiotherapy and Manual Therapy, Heeswijk-Dinther, the Netherlands; 5Department of Public Health and Research, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; 6Methodological Health-Skilled Institute, Beuningen, the Netherlands; 7SOMT University of Physiotherapy, Amersfoort, the Netherlands; 8Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Free University Brussels, Brussels, Belgium; 9Institute of Health Studies, Faculty of Health and Social Studies, HAN University of Applied Science, Nijmegen, the Netherlands; 10Faculty of Science and Engineering, University College Venlo, Maastricht University, Maastricht, the Netherlands; 11Department of Human Movement Sciences, Faculty of Behavioral and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; 12Department of Epidemiology, Center of Evidence-Based Physiotherapy, Maastricht University, Maastricht, the Netherlands; 13Practice Physiotherapy ‘Klepperheide’, Druten, the Netherlands; 14Department of Physiotherapy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Torun, Poland; 15Neurocognitive Laboratory, Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Torun, Poland; 16Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium; 17Department of Nursing Sciences, Faculty of Health, University Witten/Herdecke, Witten, Germany; 18Department of Rehabilitation Sciences and Physiotherapy (MOVANT), Faculty of Medicine and Health Sciences, University of Antwerp, Belgium; 19Department of Medical Psychology, Canisius Wilhelmina Hospital, Nijmegen, the NetherlandsPurpose: To develop valid quality indicators (QIs) for physiotherapy care based on best available evidence, and to use these QIs to explore trends in the quality of physiotherapy care of patients with Whiplash-associated disorders (WAD) using guideline-based routinely collected data (RCD) gathered between 1996 and 2011.Materials and methods: The study consisted of two phases: 1) development of QIs and 2) analysis of patient records. A set of QIs was developed based on recommendations in the scientific literature and the Dutch Clinical Practice Guideline (CPG) “Physiotherapy Management and WAD”. QIs were expressed as percentages, allowing target performance levels to be defined (≥80% or ≤30% depending on whether desired performance required a high or low score on a QI). We then analyzed WAD patient data (N = 810) collected over a period of 16 years in two physiotherapy practices, separating patients into two groups defined as before (Group A 1996–2002; n = 353) and after (Group B 2003–2011; n = 457) implementation and transition to the Dutch CPG “Physiotherapy Management and WAD”.Results: Using an iterative process and input from both experts and users, 28 QIs were developed and subsequently classified per step of the clinical reasoning process for physiotherapy care. Based on 16 years of RCD, we found that the clinical reasoning process differed significantly (P ≤ 0.05) between the groups, in favor of Group B. Twelve of the 25 indicators (48.0%) in Group A and 19 of 26 indicators (73.1%) in Group B met predetermined performance targets. The number of target indicators also differed significantly between groups, favoring Group B (P ≤ 0.05).Conclusion: A preliminary set of novel QIs was developed. Using RCD and these QIs, we conclude that physiotherapy care in our study setting improved over the period 1996–2011. Furthermore, the QIs met the performance targets set for the clinical reasoning process after the transition to the Dutch CPG “Physiotherapy Management and WAD”. Keywords: quality of physiotherapy care, Whiplash-associated disorders, clinical guidelines, quality indicators, clinical reasoning process, routinely collected data

Objective: To assess migration of CD34(+) human stem cells to the bone marrow of athymic mice by using magnetic resonance (MR) imaging and Resovist, a contrast agent containing superparamagnetic iron oxide (SPIO) particles.Methods: All animal and human procedures were approved by our institution's ethics committee, and women had given consent to donate umbilical cord blood (UCB). Balb/c-AnN Foxn1(nu)/Crl mice received intravenous injection of 1 x 10(6) (n=3), 5 x 10(6) (n=3) or 1 x 10(7) (n=3) human Resovist-labelled CD34(+) cells; control mice received Resovist (n=3). MR imaging was performed before, 2 and 24 h after transplantation. Signal intensities of liver, muscle and bone marrow were measured and analysed by ANOVA and post hoc Student's t tests. MR imaging data were verified by histological and immunological detection of both human cell surface markers and carboxydextrancoating of the contrast agent.Results: CD34(+) cells were efficiently labelled by Resovist without impairment of functionality. Twenty-four hours after administration of labelled cells, MR imaging revealed a significant signal decline in the bone marrow, and histological and immunological analyses confirmed the presence of transplanted human CD34(+) cells.Conclusion: Intravenously administered Resovist-labelled CD34(+) cells home to bone marrow of mice. Homing can be tracked in vivo by using clinical 1.5-T MR imaging technology. [ABSTRACT FROM AUTHOR]

Our objective was to investigate whether behavioral graded activity (BGA) has particular benefit in specific subgroups of osteoarthritis (OA) patients. Two hundred participants with OA of hip or knee, or both (clinical American College of Rheumatology, ACR, criteria) participated in a randomized clinical trial on the efficacy of BGA compared to treatment according to the Dutch physiotherapy guideline (usual care; UC). Changes in pain (Visual Analog Scale, VAS), physical functioning (Western Ontario and McMaster Universities Osteoarthritis Index, WOMAC, and McMaster Toronto Arthritis Questionnaire, MACTAR), and patient global assessment were compared for specific subgroups. Subgroups were assigned by the median split method and were analyzed using analysis of covariance. Beneficial effects of BGA were found for patients with a relatively low level of physical functioning (p?0.03). Furthermore, beneficial effects of BGA in patients with a low level of internal locus of control were marginally significant (p = .05). Patients with a relatively low level of physical functioning benefit more from BGA compared to UC. Compared to UC, BGA is the preferred treatment option in patients with a low level of physical functioning. [ABSTRACT FROM AUTHOR]

This study examined the test-retest reliability, inter-rater reliability, convergent validity and discriminant validity of the Fine Motor Scale of the Peabody Developmental Motor Scales-second edition (PDMS-FM-2). Participants included two groups of 18 children between the ages of 4 and 5 years with and without mild fine motor problems. The PDMS-FM-2 was administered twice to 12 children and rated by two occupational therapists. The PDMS-FM-2 results were compared with scores on the Movement Assessment Battery for Children (M-ABC). In addition, the scores of the children with and without fine motor problems were compared. For the test-retest reliability and the inter-rater reliability, correlation coefficients varied from r = 0. 84 to r = 0. 99. These results suggest that PDMS-FM-2 has excellent test¢retest and inter-rater reliability. Convergent validity with the fine motor section of the M-ABC and discriminant validity have been confirmed. Only 39% of the children in the group with problems in fine motor activities had fine motor problems according to the PDMS-FM-2. This finding seems to indicate that the PDMS-FM-2 may not be sensitive enough for this population. [ABSTRACT FROM AUTHOR]

Background : Clinical Practice Guidelines for low back pain emphasize implementing assessment and addressing of psychosocial context. It is unknown to what extent manual physiotherapists incorporate psychological factors in their diagnostic management of patients with nonspecific low back pain. Methods : An online survey among Dutch manual physiotherapists was conducted exploring the use of 10 psychological constructs. Frequencies of attention to psychological factors during history-taking and use of questionnaires were calculated. Associations between therapists characteristics and use of psychological questionnaires were analyzed using Spearmans rank correlation coefficient (r s) and logistic regression. In addition, a retrospective patient record review was conducted. Results : One hundred and twelve manual physiotherapists returned completed surveys. Although respondents indicated psychological factors were assessed, they rarely used psychological questionnaires. Significant but negligible associations were found for age and working hours and the use of specific questionnaires. From 95 patient records reviewed, seven were identified that mentioned one psychological factor each during history taking. Conclusions : Dutch MPTs, regardless of their age and work characteristics, rarely use psychological questionnaires in patients with LBP, although they report addressing these constructs implicitly during history taking. Educational and implementation strategies are needed to warrant the use of psychological constructs and validated psychological questionnaires at all phases of the clinical reasoning process.

Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of disorders characterized by defective hematopoiesis, impaired stem cell function, and cancer susceptibility. Diagnosis of IBMFS presents a major challenge due to the large variety of associated phenotypes, and novel, clinically relevant biomarkers are urgently needed. Our study identified nuclear interaction partner of ALK (NIPA) as an IBMFS gene, as it is significantly downregulated in a distinct subset of myelodysplastic syndrome-type (MDS-type) refractory cytopenia in children. Mechanistically, we showed that NIPA is major player in the Fanconi anemia (FA) pathway, which binds FANCD2 and regulates its nuclear abundance, making it essential for a functional DNA repair/FA/BRCA pathway. In a knockout mouse model, Nipa deficiency led to major cell-intrinsic defects, including a premature aging phenotype, with accumulation of DNA damage in hematopoietic stem cells (HSCs). Induction of replication stress triggered a reduction in and functional decline of murine HSCs, resulting in complete bone marrow failure and death of the knockout mice with 100% penetrance. Taken together, the results of our study add NIPA to the short list of FA-associated proteins, thereby highlighting its potential as a diagnostic marker and/or possible target in diseases characterized by hematopoietic failure.

Schistosomiasis is a nontransplacental helminth infection. Chronic infection during pregnancy suppresses allergic airway responses in offspring. We addressed the question whether in utero exposure to chronic schistosome infection (Reg phase) in mice affects B-cell and T-cell development. Therefore, we focused our analyses on T-cell differentiation capacity induced by epigenetic changes in promoter regions of signature cytokines in offspring. Here, we show that naïve T cells from offspring of schistosome infected female mice had a strong capacity to differentiate into T H 1 cells, whereas T H 2 differentiation was impaired. In accordance, reduced levels of histone acetylation of the IL-4 promoter regions were observed in naïve T cells. To conclude, our mouse model revealed distinct epigenetic changes within the naïve T-cell compartment affecting T H 2 and T H 1 cell differentiation in offspring of mothers with chronic helminth infection. These findings could eventually help understand how helminths alter T-cell driven immune responses induced by allergens, bacterial or viral infections, as well as vaccines., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Here, we show that the Wnt5a-haploinsufficient niche regenerates dysfunctional HSCs, which do not successfully engraft in secondary recipients. RNA sequencing of the regenerated donor Lin - SCA-1 + KIT + (LSK) cells shows dysregulated expression of ZEB1-associated genes involved in the small GTPase-dependent actin polymerization pathway. Misexpression of DOCK2, WAVE2, and activation of CDC42 results in apolar F-actin localization, leading to defects in adhesion, migration and homing of HSCs regenerated in a Wnt5a-haploinsufficient microenvironment. Moreover, these cells show increased differentiation in vitro, with rapid loss of HSC-enriched LSK cells. Our study further shows that the Wnt5a-haploinsufficient environment similarly affects BCR-ABL p185 leukemia-initiating cells, which fail to generate leukemia in 42% of the studied recipients, or to transfer leukemia to secondary hosts. Thus, we show that WNT5A in the bone marrow niche is required to regenerate HSCs and leukemic cells with functional ability to rearrange the actin cytoskeleton and engraft successfully., (© 2017 Schreck et al.)

Sfrp2 is overexpressed in stromal cells which maintain hematopoietic stem cells (HSCs) during in vitro culture. We here showed, that coculture of hematopoetic cells with stromal cells with reduced expression of Sfrp2 increases the number lineage-negative Kit(+) Sca-1(+) (LSK) and progenitor cells in vitro. The LSK cells from these cocultures showed activation of canonical Wnt signaling, higher levels of Ki-67, BrdU incorporation, and the number of γH2A.X positive foci. Total repopulating activity of these cultures was, however, diminished, indicating loss of HSC. To extend these in vitro data, we modelled stress in vivo, i.e., by aging, or 5-FU treatment in Sfrp2(-) (/) (-) mice, or replicative stress in regeneration of HSCs in Sfrp2(-) (/) (-) recipients. In all three in vivo stress situations, we noted an increase of LSK cells, characterized by increased levels of β-catenin and cyclin D1. In the transplantation experiments, the increase in LSK cells in primary recipients was subsequently associated with a progressive loss of HSCs in serial transplantations. Similar to the in vitro coculture stress, in vivo genotoxic stress in 5-FU-treated Sfrp2(-) (/) (-) mice increased cell cycle activity of LSK cells with higher levels of BrdU incorporation, increased expression of Ki-67, and canonical Wnt signaling. Importantly, as noted in vitro, increased cycling of LSKs in vivo was accompanied by a defective γH2A.X-dependent DNA damage response and depolarized localization of acetylated H4K16. Our experiments support the view that Sfrp2 expression in the niche is required to maintain the HSC pool by limiting stress-induced DNA damage and attenuating canonical Wnt-mediated HSC activation. Stem Cells 2016;34:2381-2392., (© 2016 AlphaMed Press.)

Objectives: The term 'cephalalgiaphobia' was introduced in the mid-1980s and defined as fear of migraine (attacks). We hypothesized that a specific subtype of cephalalgiaphobia affects patients with cervicogenic headache (CEH). This study aimed to: (1) define the term 'cervico-cephalalgiaphobia'; (2) develop a set of indicators for phobia relevant to patients with CEH; and (3) apply this set to a practice test in order to estimate the frequency of cervico-cephalalgiaphobia in the Dutch primary care practice of manual physical therapy., Methods: A systematic approach was used to develop a definition and potential indicators for cervico-cephalalgiaphobia. An expert group appraised the definition and the set of indicators (score per indicator: never; sometimes; often/always). An invitation to participate in the practice test was sent to Dutch manual physical therapy practices (n = 56) representing 134 manual physical therapists (MPTs). The cut-off point for percentages of scores for coverage of the indicators was set at ≥ 60%., Results: The expert group agreed with the proposed definition of cervico-cephalalgiaphobia. A set of eight indicators for cervico-cephalalgiaphobia was selected from 10 initial indicators. Thirty-six MPTs provided data from 46 patients diagnosed with CEH. The coverage of 'often/always' was substantial for the indicators, 'Short-term positive results in previous manual physical therapeutic treatment', 'Shorter interval between treatment sessions', 'Fear of "locked facet joints" of the neck', 'More frequent manipulation', and 'Fear of increase in headaches'. Coverage was also substantial for 'never' regarding 'Long-term positive results in previous manual physical therapeutic treatment'. 'Confirmation of "locked facet joints" of the cervical spine by MPT as a cause for increase of CEH' scored 'often/always' in all patients. Coverage for 'Increased use of medication with insufficient effect' was substantial, scoring as 'sometimes' in 39 (84.8%) patients., Discussion: Cervico-cephalalgiaphobia was defined and a set of eight indicators formulated based on the literature and clinical expertise. The practice test provides valuable information on the frequency of indicators for cervico-cephalalgiaphobia in the Dutch manual physical therapy practice, suggesting that cervico-cephalalgiaphobia is common in patients with CEH.

Purpose: To evaluate the cost-effectiveness of manual therapy according to the Utrecht School (MTU) in comparison with physiotherapy (PT) in sub-acute and chronic non-specific neck pain patients from a societal perspective., Methods: An economic evaluation was conducted alongside a 52-week randomized controlled trial, in which 90 patients were randomized to the MTU group and 91 to the PT group. Clinical outcomes included perceived recovery (yes/no), functional status (continuous and yes/no), and quality-adjusted life-years (QALYs). Costs were measured from a societal perspective using self-reported questionnaires. Missing data were imputed using multiple imputation. To estimate statistical uncertainty, bootstrapping techniques were used., Results: After 52 weeks, there were no significant between-group differences in clinical outcomes. During follow-up, intervention costs (β:€-32; 95 %CI: -54 to -10) and healthcare costs (β:€-126; 95 %CI: -235 to -32) were significantly lower in the MTU group than in the PT group, whereas unpaid productivity costs were significantly higher (β:€186; 95 %CI:19-557). Societal costs did not significantly differ between groups (β:€-96; 95 %CI:-1975-2022). For QALYs and functional status (yes/no), the maximum probability of MTU being cost-effective in comparison with PT was low (≤0.54). For perceived recovery (yes/no) and functional status (continuous), a large amount of money must be paid per additional unit of effect to reach a reasonable probability of cost-effectiveness., Conclusions: From a societal perspective, MTU was not cost-effective in comparison with PT in patients with sub-acute and chronic non-specific neck pain for perceived recovery, functional status, and QALYs. As no clear total societal cost and effect differences were found between MTU and PT, the decision about what intervention to administer, reimburse, and/or implement can be based on the preferences of the patient and the decision-maker at hand., Trial Registration: ClinicalTrials.gov Identifier: NCT00713843.

Objectives: The aim of this study was to evaluate the efficacy of Manual Therapy Utrecht (MTU) plus education in patients with cervicogenic somatosensory tinnitus (CeT)., Study Design: Pretest-posttest design., Method: Five hundred and six patients were referred or referred themselves. A subgroup of patients was identified with CeT, and within this a subgroup with tinnitus sensitization (TS). Two CeT groups were created based on the presence or absence of TS. Both groups underwent manual therapy combined with tinnitus education. Tinnitus intensity (VAS-tin 0-100 mm) was the primary outcome measure. Number of treatments and adverse effects were the secondary outcome measures., Results: A total of 122 patients with CeT (24.1%) were included (average age 53.3 years [±9.8], female 38.5% and duration of tinnitus 7.3 years [±8.9]). Patients were divided into two groups: 55 patients (45.1%) with TS (CeT + TS group) and 67 patients (54.9%) without TS (CeT - TS group). Pretest to posttest differences on the VAS-tin were statistically significant within both groups (CeT - TS group: difference VAS-tin 5.9 [p = 0.01]; CeT + TS group: difference VAS-tin 18.2 [p = 0.00]), and between the groups in favor of the CeT + TS group (difference VAS-tin 12.3 [p = 0.01]). Pretest to posttest differences were clinically significant for the CeT + TS group (difference VAS-tin 18.2 [MCIC = ≥10 mm VAS-tin]) and between the groups (difference VAS-tin 12.3 in favor of the CeT + TS group). The average number of treatment sessions was 9.6 (±2.6) for the CeT - TS group and 10.3 (±2.5) for the CeT + TS group, a non-significant difference. There were no adverse effects in either group., Conclusions: Despite its limitations, this study provides valuable information on both the characteristics of patients with CeT and TS in a Dutch primary care manual therapy practice and on the potential effectiveness of MTU combined with tinnitus education for the subgroup of CeT + TS patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Tinnitus can be evoked or modulated by input from the somatosensory and somatomotor systems. This means that the loudness or intensity of tinnitus can be changed by sensory or motor stimuli such as muscle contractions, mechanical pressure on myofascial trigger points, transcutaneous electrical stimulation or joint movements. The neural connections and integration of the auditory and somatosensory systems of the upper cervical region and head have been confirmed by many studies. These connections can give rise to a form of tinnitus known as somatosensory tinnitus. To date only a handful of publications have focussed on (cervicogenic) somatosensory tinnitus and manual therapy. Broadening the current understanding of somatosensory tinnitus would represent a first step towards providing therapeutic approaches relevant to manual therapists. Treatment modalities involving the somatosensory systems, and particularly manual therapy, should now be re-assessed in the subgroup of patients with cervicogenic somatosensory tinnitus. The conceptual phase of this study aims to uncover underlying mechanisms linking the auditory and somatosensory systems in relation to subjective tinnitus through (i) review of the literature (part 1) and (ii) through design of a pilot study that will explore characteristics of the study population and identify relevant components and outcomes of manual therapy in patients with cervicogenic somatosensory tinnitus (part 2). This manuscript focusses the theoretical concept of (cervicogenic) somatosensory tinnitus, either with or without secondary central tinnitus or tinnitus sensitization., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

JAK2V617F(+) myeloproliferative neoplasms (MPNs) frequently progress into leukemias, but the factors driving this process are not understood. Here, we find excess Hedgehog (HH) ligand secretion and loss of PTCH2 in myeloproliferative disease, which drives canonical and noncanonical HH-signaling. Interestingly, Ptch2(-/-) mice mimic dual pathway activation and develop a MPN-phenotype with leukocytosis (neutrophils and monocytes), strong progenitor and LKS mobilization, splenomegaly, anemia, and loss of lymphoid lineages. HSCs exhibit increased cell cycling with improved stress hematopoiesis after 5-FU treatment, and this results in HSC exhaustion over time. Cytopenias, LKS loss, and mobilization are all caused by loss of Ptch2 in the niche, whereas hematopoietic loss of Ptch2 drives leukocytosis and promotes LKS maintenance and replating capacity in vitro. Ptch2(-/-) niche cells show hyperactive noncanonical HH signaling, resulting in reduced production of essential HSC regulators (Scf, Cxcl12, and Jag1) and depletion of osteoblasts. Interestingly, Ptch2 loss in either the niche or in hematopoietic cells dramatically accelerated human JAK2V617F-driven pathogenesis, causing transformation of nonlethal chronic MPNs into aggressive lethal leukemias with >30% blasts in the peripheral blood. Our findings suggest HH ligand inhibitors as possible drug candidates that act on hematopoiesis and the niche to prevent transformation of MPNs into leukemias., (© 2016 Klein et al.)

Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

Cancer pathogenesis involves tumor-intrinsic genomic aberrations and tumor-cell extrinsic mechanisms such as failure of immunosurveillance and structural and functional changes in the microenvironment. Using Myc as a model oncogene we established a conditional mouse bone marrow transduction/transplantation model where the conditional activation of the oncoprotein Myc expressed in the hematopoietic system could be assessed for influencing the host microenvironment. Constitutive ectopic expression of Myc resulted in rapid onset of a lethal myeloproliferative disorder with a median survival of 21 days. In contrast, brief 4-day Myc activation by means of the estrogen receptor (ER) agonist tamoxifen did not result in gross changes in the percentage/frequency of hematopoietic lineages or hematopoietic stem/ progenitor cell (HSPC) subsets, nor did Myc activation significantly change the composition of the non-hematopoietic microenvironment defined by phenotyping for CD31, ALCAM, and Sca-1 expression. Transcriptome analysis of endothelial CD45- Ter119- cells from tamoxifen-treated MycER bone marrow graft recipients revealed a gene expression signature characterized by specific changes in the Rho subfamily pathway members, in the transcription-translation-machinery and in angiogenesis. In conclusion, intra-hematopoietic Myc activation results in significant transcriptome alterations that can be attributed to oncogene-induced signals from hematopoietic cells towards the microenvironment, e. g. endothelial cells, supporting the idea that even pre-leukemic HSPC highjack components of the niche which then could protect and support the cancer-initiating population.

In this issue of Blood, Kabiri and coworkers report the hematopoietic deletion of the endoplasmic reticulum–localized O-acyltransferase porcupine (PORCN), which is necessary for acylation of Wnts in the endoplasmic reticulum, enabling their secretion and binding to the frizzled receptors. Unexpectedly, the absence of secreted Wnt factors does not have major effects on steady-state in vivo hematopoiesis or on long-term repopulating activity of Wnt-deficient hematopoietic stem cells.

Hematopoietic stem cells (HSCs) generate highly dividing hematopoietic progenitor cells (HPCs), which produce all blood cell lineages. HSCs are usually quiescent, retained by integrins in specific niches, and become activated when the pools of HPCs decrease. We report that Kindlin-3-mediated integrin activation controls homing of HSCs to the bone marrow (BM) and the retention of activated HSCs and HPCs but not of quiescent HSCs in their BM niches. Consequently, Kindlin-3-deficient HSCs enter quiescence and remain in the BM when cotransplanted with wild-type hematopoietic stem and progenitor cells (HSPCs), whereas they are hyperactivated and lost in the circulation when wild-type HSPCs are absent, leading to their exhaustion and reduced survival of recipients. The accumulation of HSPCs in the circulation of leukocyte adhesion deficiency type III patients, who lack Kindlin-3, underlines the conserved functions of Kindlin-3 in man and the importance of our findings for human disease., (© 2015 Ruppert et al.)

Cyclin-dependent kinase subunit 1 (Cks1) is a critical rate-limiting component of the Skp1-Cullin1-Skp2 (SCF(Skp2)) ubiquitin ligase that controls cell cycle inhibitor abundance. Cyclin-dependent kinase (Cdk) inhibitors (CKIs) regulate hematopoietic stem cell (HSC) self-renewal, regeneration after cytotoxic stress and tumor cell proliferation. We thus studied the role of Cks1 in HSC and in a prototypic stem cell disorder, chronic myeloid leukemia (CML). Cks1 transcript was highly expressed in Lin-Sca-1+Kit+ (LSK) HSC, and the loss resulted in accumulation of the SCF(Skp2)/Cks1 substrates p21, p27, p57 and p130 particularly in CD150+ LSK cells. This accumulation correlated with decreased proliferation and accumulation of Cks1(-/-) HSC, slower regeneration after stress and prolonged HSC quiescence. At the hematopoietic progenitor (HPC) level, loss of Cks1 sensitized towards apoptosis. In CML, Cks1 expression was increased, and treatment with the Abl kinase inhibitor, imatinib, reduced Cks1 expression. Also, we found that Cks1 is critical for Bcr-Abl-induced cytokine-independent clonogenic activity. In conclusion, our study presents a novel function of Cks1 in maintaining HSC/HPC homeostasis and shows that Cks1 is a possible target in therapies aimed at the SCF(Skp2)/Cks1 complex that controls CKI abundance and cancer cell proliferation.

Objective: To develop and evaluate process indicators relevant to biopsychosocial history taking in patients with chronic back and neck pain., Methods: The SCEBS method, covering the Somatic, Psychological (Cognition, Emotion, and Behavior), and Social dimensions of chronic pain, was used to evaluate biopsychosocial history taking by manual physical therapists (MPTs). In Phase I, process indicators were developed while in Phase II indicators were tested in practice., Results: Literature-based recommendations were transformed into 51 process indicators. Twenty MTPs contributed 108 patient audio recordings. History taking was excellent (98.3%) for the Somatic dimension, very inadequate for Cognition (43.1%) and Behavior (38.3%), weak (27.8%) for Emotion, and low (18.2%) for the Social dimension. MTPs estimated their coverage of the Somatic dimension as excellent (100%), as adequate for Cognition, Emotion, and Behavior (60.1%), and as very inadequate for the Social dimension (39.8%)., Conclusion: MTPs perform screening for musculoskeletal pain mainly through the use of somatic dimension of (chronic) pain. Psychological and social dimensions of chronic pain were inadequately covered by MPTs. Furthermore, a substantial discrepancy between actual and self-estimated use of biopsychosocial history taking was noted. We strongly recommend full implementation of the SCEBS method in educational programs in manual physical therapy.

Thymocyte selection-associated high mobility group box protein family member 2 (TOX2) is a transcription factor belonging to the TOX family that shares a highly conserved high mobility group DNA-binding domain with the other TOX members. Although TOX1 has been shown to be an essential regulator of T-cell and natural killer (NK) cell differentiation in mice, little is known about the roles of the other TOX family members in lymphocyte development, particularly in humans. In this study, we found that TOX2 was preferentially expressed in mature human NK cells (mNK) and was upregulated during in vitro differentiation of NK cells from human umbilical cord blood (UCB)-derived CD34(+) cells. Gene silencing of TOX2 intrinsically hindered the transition between early developmental stages of NK cells, whereas overexpression of TOX2 enhanced the development of mNK cells from UCB CD34(+) cells. We subsequently found that TOX2 was independent of ETS-1 but could directly upregulate the transcription of TBX21 (encoding T-BET). Overexpression of T-BET rescued the TOX2 knockdown phenotypes. Given the essential function of T-BET in NK cell differentiation, TOX2 therefore plays a crucial role in controlling normal NK cell development by acting upstream of TBX21 transcriptional regulation., (© 2014 by The American Society of Hematology.)

T cells have been proven to be therapeutically effective in patients with relapsed leukemias, although target antigens on leukemic cells as well as T-cell receptors (TCRs), potentially recognizing those antigens, are mostly unknown. We have applied an immunopeptidomic approach and isolated human leukocyte antigen (HLA) ligands from primary leukemia cells. We identified a number of ligands derived from different genes that are restrictedly expressed in the hematopoietic system. We exemplarily selected myeloperoxidase (MPO) as a potential target and isolated a high-avidity TCR with specificity for a HLA-B*07:02-(HLA-B7)-restricted epitope of MPO in the single HLA-mismatched setting. T cells transgenic for this TCR demonstrated high peptide and antigen specificity as well as leukemia reactivity in vitro and in vivo. In contrast, no significant on- and off-target toxicity could be observed. In conclusion, we here demonstrate, exemplarily for MPO, that leukemia-derived HLA ligands can be selected for specific effector tool development to redirect T cells to be used for graft manipulation or adoptive T-cell therapies in diverse transplant settings. This approach can be extended to other HLA ligands and HLA molecules in order to provide better treatment options for this life-threatening disease.

Hematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Manual spinal joint mobilisations and manipulations are widely used treatments in patients with neck and low-back pain. Inter-examiner reliability of passive intervertebral motion assessment of the cervical and lumbar spine, perceived as important for indicating these interventions, is poor within a univariable approach. The diagnostic process as a whole in daily practice in manual therapy has a multivariable character, however, in which the use and interpretation of passive intervertebral motion assessment depend on earlier results from the diagnostic process. To date, the inter-examiner reliability among manual therapists of a multivariable diagnostic decision-making process in patients with neck or low-back pain is unknown., Methods: This study will be conducted as a repeated-measures design in which 14 pairs of manual therapists independently examine a consecutive series of a planned total of 165 patients with neck or low-back pain presenting in primary care physiotherapy. Primary outcome measure is therapists' decision about whether or not manual spinal joint mobilisations or manipulations, or both, are indicated in each patient, alone or as part of a multimodal treatment. Therapists will largely be free to conduct the full diagnostic process based on their formulated examination objectives. For each pair of therapists, 2×2 tables will be constructed and reliability for the dichotomous decision will be expressed using Cohen's kappa. In addition, observed agreement, prevalence of positive decisions, prevalence index, bias index, and specific agreement in positive and negative decisions will be calculated. Univariable logistic regression analysis of concordant decisions will be performed to explore which demographic, professional, or clinical factors contributed to reliability., Discussion: This study will provide an estimate of the inter-examiner reliability among manual therapists of indicating spinal joint mobilisations or manipulations in patients with neck or low-back pain based on a multivariable diagnostic reasoning and decision-making process, as opposed to reliability of individual tests. As such, it is proposed as an initial step toward the development of an alternative approach to current classification systems and prediction rules for identifying those patients with spinal disorders that may show a better response to manual therapy which can be incorporated in randomised clinical trials. Potential methodological limitations of this study are discussed.

Hematopoietic stem cells (HSCs) are a rare population of somatic stem cells that have the ability to regenerate the entire mature blood system in a hierarchical way for the duration of an adult life. Adult HSCs reside in the bone marrow niche. Different niche cell types and molecules regulate the balance of HSC dormancy and activation as well as HSC behavior in both normal and malignant hematopoiesis. Here, we describe the interplay of HSCs and their niche, in particular the involvement of the Wnt signaling pathway. Although the prevailing notion has been that malignant transformation of HSCs is the main cause of leukemia, evidence is mounting that disruption of niche regulation by transformed hematopoietic cells, which may overexpress Wnt signaling or intrinsic stromal defects in gene expression, is at least a collaborative factor in leukemogenesis. Thus, insights into the normal and altered functions of niche components will help to obtain a better understanding of normal and malignant hematopoiesis and how environmental factors affect these processes., (© 2014 New York Academy of Sciences.)

Background: Systematic planning could improve the generally moderate effectiveness of interventions to enhance adherence to clinical practice guidelines. The aim of our study was to demonstrate how the process of Intervention Mapping was used to develop an intervention to address the lack of adherence to the national CPG for low back pain by Dutch physical therapists., Methods: We systematically developed a program to improve adherence to the Dutch physical therapy guidelines for low back pain. Based on multi-method formative research, we formulated program and change objectives. Selected theory-based methods of change and practical applications were combined into an intervention program. Implementation and evaluation plans were developed., Results: Formative research revealed influential determinants for physical therapists and practice quality managers. Self-regulation was appropriate because both the physical therapists and the practice managers needed to monitor current practice and make and implement plans for change. The program stimulated interaction between practice levels by emphasizing collective goal setting. It combined practical applications, such as knowledge transfer and discussion-and-feedback, based on theory-based methods, such as consciousness raising and active learning. The implementation plan incorporated the wider environment. The evaluation plan included an effect and process evaluation., Conclusions: Intervention Mapping is a useful framework for formative data in program planning in the field of clinical guideline implementation. However, a decision aid to select determinants of guideline adherence identified in the formative research to analyse the problem may increase the efficiency of the application of the Intervention Mapping process.

Rationale, Aims and Objectives: Little is currently known about the quality of physiotherapy care for patients with musculoskeletal pain. Neck pain was used as an example. The aim is to develop a set of quality indicators, including a practice test., Methods: A systematic method is used to develop potential process and outcome indicators. An expert and user panel is used to appraise the potential quality indicators regarding clarity, relevancy, feasibility, acceptability and improvement potential. An invitation to participate in the practice test was sent to physiotherapy practices. The resulting algorithm is used to calculate the degree to which physiotherapists met these indicators (0-100%). Differences in valid outcomes are tested for significance (Student's t-test; α = 0.05) and compared with established values for clinical relevance [minimal clinically important change (MCIC)]., Results: A representative set of 40 quality indicators (28 process indicators and 12 outcome indicators) is selected from 44 initial guidelines and literature-based recommendations. The process indicators (n = 28) are classified per step of the clinical reasoning process of physiotherapy care. Of the 106 potential participants from 27 practices, 38 physiotherapists (35.8%) submitted data on 96 patients with non-specific neck pain. On average, the participating physiotherapists showed a 55.6% adherence to process indicators with a great variation in scores per step of the clinical reasoning process. The outcomes for 'pain', 'headache' and 'daily functioning' were significantly better compared with baseline, and the mean differences exceeded established values for MCICs., Conclusion: Guardedly, we can conclude that a systematic approach is a valuable means to develop a preliminary set of process and outcome indicators for physiotherapy care for patients with non-specific neck pain, and a practice test should be an intrinsic part of such a systematic approach as it provides valuable information on the key attributes of the set indicators., (© 2013 John Wiley & Sons Ltd.)

Many organs with a high cell turnover (for example, skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Ageing results in the inability of these tissues to maintain homeostasis and it is believed that somatic stem-cell ageing is one underlying cause of tissue attrition with age or age-related diseases. Ageing of haematopoietic stem cells (HSCs) is associated with impaired haematopoiesis in the elderly. Despite a large amount of data describing the decline of HSC function on ageing, the molecular mechanisms of this process remain largely unknown, which precludes rational approaches to attenuate stem-cell ageing. Here we report an unexpected shift from canonical to non-canonical Wnt signalling in mice due to elevated expression of Wnt5a in aged HSCs, which causes stem-cell ageing. Wnt5a treatment of young HSCs induces ageing-associated stem-cell apolarity, reduction of regenerative capacity and an ageing-like myeloid-lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. Conversely, Wnt5a haploinsufficiency attenuates HSC ageing, whereas stem-cell-intrinsic reduction of Wnt5a expression results in functionally rejuvenated aged HSCs. Our data demonstrate a critical role for stem-cell-intrinsic non-canonical Wnt5a signalling in HSC ageing.

Purpose: To examine a process for evaluating physiotherapy (PT) students' knowledge of and adherence to the Ambassador Low Back Pain (LBP) guideline using vignettes., Methods: The study used a cross-sectional survey design. Participants were PT students who had received information related to the guideline as part of their curriculum. Primary measures were responses to questions about the management of four clinical vignettes. Adherence to guideline recommendations was measured by comparing participant scores to a "guideline-based" set of responses from a physiotherapist involved in developing the Ambassador guideline, which was considered a criterion standard., Results: A total of 74 respondents provided complete data, for a response rate of 89%; 65 (88%) reported no knowledge of the guideline. Overall consistency with the criterion standard was high (>70%). Respondents demonstrated high adherence when identifying red flags and deciding whether to refer to another provider., Conclusion: Despite known exposure, knowledge of the guideline was low in this sample of Canadian PT students. Nevertheless, in several key areas, unconscious adherence was high relative to the guideline-based criterion standard. With minor modifications, the vignettes are suitable for evaluating the Ambassador LBP guidelines in a larger study.

Background: Guideline adherence in physical therapy is far from optimal, which has consequences for the effectiveness and efficiency of physical therapy care. Programmes to enhance guideline adherence have, so far, been relatively ineffective. We systematically developed a theory-based Quality Improvement in Physical Therapy (QUIP) programme aimed at the individual performance level (practicing physiotherapists; PTs) and the practice organization level (practice quality manager; PQM). The aim of the study was to pilot test the multilevel QUIP programme's effectiveness and the fidelity, acceptability and feasibility of its implementation., Methods: A one-group, pre-test, post-test pilot study (N = 8 practices; N = 32 PTs, 8 of whom were also PQMs) done between September and December 2009. Guideline adherence was measured using clinical vignettes that addressed 12 quality indicators reflecting the guidelines' main recommendations. Determinants of adherence were measured using quantitative methods (questionnaires). Delivery of the programme and management changes were assessed using qualitative methods (observations, group interviews, and document analyses). Changes in adherence and determinants were tested in the paired samples T-tests and expressed in effect sizes (Cohen's d)., Results: Overall adherence did not change (3.1%; p = .138). Adherence to three quality indicators improved (8%, 24%, 43%; .000 ≤ p ≤ .023). Adherence to one quality indicator decreased (-15.7%; p = .004). Scores on various determinants of individual performance improved and favourable changes at practice organizational level were observed. Improvements were associated with the programme's multilevel approach, collective goal setting, and the application of self-regulation; unfavourable findings with programme deficits. The one-group pre-test post-test design limits the internal validity of the study, the self-selected sample its external validity., Conclusions: The QUIP programme has the potential to change physical therapy practice but needs considerable revision to induce the ongoing quality improvement process that is required to optimize overall guideline adherence. To assess its value, the programme needs to be tested in a randomized controlled trial.

We describe a method to derive cell lines and clones from cells of the murine midgestation aorta-gonads-mesonephros (AGM) microenvironment. We start from subdissected AGM regions in "explant" or "single cell suspension" type cultures from embryos transgenic for tsA58, a temperature-sensitive mutant of the SV40 T antigen gene. The number of cells in such cultures initially expand, but in most cases, this expansion phase is followed by a stable or even decline in cell number. After this so-called crisis phase, cell proliferation is noticeable in more than 90% of the cultures. Stromal cell clones can be isolated from these cultures, some of which have been cultured for more than 50 population doublings, and functionally characterized using various methods These stromal cell clones are valuable tools for the study of the regulation of hematopoietic stem and progenitor cells in the midgestation mouse embryo.

Objectives: To explore consultation reports for patient and employment characteristics and recommendations on employment regarding patients with neuromuscular diseases (NMDs)., Design: Retrospective study of multidisciplinary reports., Setting: An outpatient neuromuscular clinic at a university hospital., Participants: Reports (N=102) of patients with NMDs., Interventions: Based on one-off consultations by occupational therapists, physical therapists, and speech therapists and a multidisciplinary meeting, recommendations were developed regarding therapy content and volume in primary care or rehabilitation settings., Main Outcome Measures: A checklist has been developed to examine employment characteristics. A general questionnaire has been used including demographic variables and data on employment., Results: Of the 102 reports available, 86 were included for analysis. Sixty-nine reports contained information on employment. Thirty-seven patients (43%) with NMD were employed, most in white-collar or moderately strenuous jobs. Of the 37 employed patients, 28 (76%) worked using adaptations. Thirty-two (87%) had employment problems; of these, 15 (40%) needed improvement in 1 or more environmental factors. Twenty patients (54%) needed advice regarding participation in employment, of whom 19 were referred to primary care or rehabilitation settings for treatment to enhance employment participation., Conclusions: Eighty percent of the included consultation reports contained information on employment. Less than half the patients with NMD were employed, most in office-related jobs, using some kind of adaptations. Nineteen of 20 patients who agreed to recommendations regarding therapy were adequately referred by occupational therapists and physical therapists for treatment of employment problems., (Copyright © 2012 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Transcutaneous electrical nerve stimulation (TENS) is an easy to use analgesic intervention. However, long-term randomized placebo-controlled studies with treatment periods of more than 3 months have not been executed to date. The aim of our study is to explore the long-term (1 year) time course of the treatment effects of TENS compared to placebo (sham TENS)., Method: We performed a randomized placebo-controlled trial in patients with chronic pain (165), referred to a multidisciplinary pain center of a university hospital. Main outcome measures are the proportion of patients satisfied with treatment result and willing to continue treatment, pain intensity, pain disability, and perceived health status., Results: Survival analysis of time courses of proportions of satisfied patients revealed no significant differences (P = 0.79; log-rank test) for TENS treatment compared to sham TENS. After 1 year, 30% (24/81) of the patients of the TENS group and 23% (19/82) of the sham TENS group were satisfied with treatment result. These patients experienced a mean overall improvement of 62.7% (n = 43). This effect was not significantly different between both groups. For satisfied patients, there were no differences in pain intensity or disability and perceived health status between the TENS and sham TENS group., Conclusions: Transcutaneous electrical nerve stimulation and sham TENS show similar effects in patients with chronic pain over a period of 1 year. We found support for a long sustained placebo effect., (© 2012 The Authors. Pain Practice © 2012 World Institute of Pain.)

Background: Pain Exposure Physical Therapy is a new treatment option for patients with Complex Regional Pain Syndrome type 1. It has been evaluated in retrospective as well as in prospective studies and proven to be safe and possibly effective. This indicates that Pain Exposure Physical Therapy is now ready for clinical evaluation. The results of an earlier performed pilot study with an n = 1 design, in which 20 patients with Complex Regional Pain Syndrome type 1 were treated with Pain Exposure Physical Therapy, were used for the design and power calculation of the present study.After completion and evaluation of this phase III study, a multi-centre implementation study will be conducted.The aim of this study is to determine whether Pain Exposure Physical Therapy can improve functional outcomes in patients with Complex Regional Pain Syndrome type 1., Methods/design: This study is designed as a single-blinded, randomized clinical trial. 62 patients will be randomized with a follow-up of 9 months to demonstrate the expected treatment effect. Complex Regional Pain Syndrome type 1 is diagnosed in accordance with the Bruehl/International Association for the Study of Pain criteria. Conventional therapy in accordance with the Dutch guideline will be compared with Pain Exposure Physical Therapy. Primary outcome measure is the Impairment level SumScore, restricted version., Discussion: This is the first randomized controlled study with single blinding that has ever been planned in patients with Complex Regional Pain Syndrome type 1 and does not focus on a single aspect of the pain syndrome but compares treatment strategies based on completely different pathophysiological and cognitive theories.

Background: Pediatric physical therapists assess the quantity and quality of children's motor skills. Several quantitative motor tests are currently available, but a concise measurement tool of observable movement quality (OMQ) is lacking., Objective: The purpose of this study was to develop an OMQ measurement tool for children from the perspective of pediatric physical therapists., Design: A qualitative, 3-phase study involving pediatric physical therapists was conducted., Methods: The first phase consisted of 7 semistructured interviews. The second phase comprised a structured meeting using a nominal group technique, with the interviewees required to identify the most relevant OMQ aspects. The third phase comprised a Delphi technique involving 61 pediatric physical therapy experts with the aim of achieving at least 80% agreement on relevance, terminology, and definitions of OMQ aspects., Results: Across all 3 phases, 32 aspects based on different theoretical constructs were considered. Fifteen aspects were included in the measurement. The pediatric physical therapy experts achieved at least 80% agreement on the definitions of 14 OMQ aspects: automated movements, asymmetry in movements, variation in movements, appropriate gross motor movements, fluency of movements, reduced muscle tone, increased muscle tone, involuntary movements, accuracy, slow/delayed movements, accelerated/abrupt movements, tremors, strength regulation, and stereotyped movements. The definition of appropriate fine motor movements achieved 75% agreement. This aspect was included because gross and fine motor movements are complementary. The aspects were scored using a 5-point Likert scale, with a total score ranging from 15 to 75 and with a higher score indicating a better OMQ., Conclusion: The OMQ scale, a concise measurement tool with 15 defined aspects, was developed. Content validity was obtained, but before the OMQ scale can be used in clinical practice, studies on reliability, construct validity, and responsiveness are needed.

Transcutaneous electrical nerve stimulation (TENS) has existed since the early 1970s. However, randomized placebo controlled studies show inconclusive results in the treatment of chronic pain. These results could be explained by assuming that TENS elicits a placebo response. However, in animal research TENS has been found to decrease hyperalgesia, which contradicts this assumption. The aim of this study is to use quantitative sensory testing to explore changes in pain processing during sham versus real TENS in patients with chronic pain. Patients with chronic pain (N = 20) were randomly allocated to real TENS or sham TENS application. Electrical pain thresholds (EPTs) were determined inside and outside the segment stimulated, before and after the first 20 minutes of the intervention, and after a period of 10 days of daily real/sham TENS application. Pain relief did not differ significantly for real versus sham TENS. However, by comparing time courses of EPTs, it was found that EPT values outside the segment of stimulation increased for sham TENS, whereas for real TENS these values decreased. There were, however, no differences for EPT measurements inside the segment stimulated. These results illustrate the importance of including mechanism-reflecting parameters in addition to symptoms when conducting pain research.

The stem cell microenvironment (in vivo known as niche) is a specific space in the bone marrow (BM), which nurses hematopoietic stem cells and regulates their self-renewal and differentiation using extrinsic cues, such as secreted factors. The niche plays a major role in regulating the number of blood cells and also protects stem cells against excessive proliferation. Till date, several possible secreted regulators of HSC function have been reported. Many of these were originally isolated from stromal cells and the cell lines isolated from hematopoietic tissues. These secreted factors act in concert and not only regulate HSC, but also the niche cells. It has also become clear that deregulation of the niche function is a potential cooperating factor during the development of hematological malignancies. An understanding of how the niche participates in HSC maintenance and repair through soluble factors can offer new opportunities for the development of novel therapeutic tools against hematological malignancies.

Pleiotrophin (Ptn) is strongly expressed by stromal cells which maintain HSCs. However, in vivo, Ptn deficiency does not alter steady-state hematopoiesis. However, knockdown of Ptn (Ptn(KD)) in stromal cells increases production of hematopoietic progenitors as well as HSC activity in cocultures, suggesting that Ptn may have a role in HSC activation. Indeed, transplantations of wild-type (Ptn(+/+)) HSCs into Ptn(-/-) mice show increased donor cell production in serial transplantations and dominant myeloid regeneration caused by Ptn-dependent regulation of HSC repopulation behavior. This regulation of Lin(-)Kit(+)Sca1(+) function is associated with increased proliferation and, on a molecular level, with up-regulated expression of cyclin D1 (Ccnd1) and C/EBPα (Cepba), but reduced of PPARγ. The known HSC regulator β-catenin is, however, not altered in the absence of Ptn. In conclusion, our results point to different Ptn-mediated regulatory mechanisms in normal hemostasis and in hematopoietic regeneration and in maintaining the balance of myeloid and lymphoid regeneration. Moreover, our results support the idea that microenvironmental Ptn regulates hematopoietic regeneration through β-catenin-independent regulation of Ccnd1 and Cebpa.

Background: Myotonic dystrophy type 1 (MD1) is one of the most prevalent neuromuscular diseases, yet very little is known about how MD1 affects the lives of couples and how they themselves manage individually and together. To better match health care to their problems, concerns and needs, it is important to understand their perspective of living with this hereditary, systemic disease., Methods: A qualitative study was carried out with a purposive sample of five middle-aged couples, including three men and two women with MD1 and their partners. Fifteen in-depth interviews with persons with MD1, with their partners and with both of them as a couple took place in the homes of the couples in two cities and three villages in the Netherlands in 2009., Results: People with MD1 associate this progressive, neuromuscular condition with decreasing abilities, describing physical, cognitive and psychosocial barriers to everyday activities and social participation. Partners highlighted the increasing care giving burden, giving directions and using reminders to compensate for the lack of initiative and avoidant behaviour due to MD1. Couples portrayed the dilemmas and frustrations of renegotiating roles and responsibilities; stressing the importance of achieving a balance between individual and shared activities. All participants experienced a lack of understanding from relatives, friends, and society, including health care, leading to withdrawal and isolation. Health care was perceived as fragmentary, with specialists focusing on specific aspects of the disease rather than seeking to understand the implications of the systemic disorder on daily life., Conclusions: Learning from these couples has resulted in recommendations that challenge the tendency to treat MD1 as a condition with primarily physical impairments. It is vital to listen to couples, to elicit the impact of MD1, as a multisystem disorder that influences every aspect of their life together. Couple management, supporting the self-management skills of both partners is proposed as a way of reducing the mismatch between health services and health needs.