A receptor tyrosine kinase ROR1 inhibitor (KAN0439834) induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib.

There is a great unmet medical need in pancreatic carcinoma (PC) for novel drugs with other mechanisms of action than existing. PC cells express the onco-fetal RTK ROR1, absent on most normal post-partem cells. ROR1 is involved in proliferation, survival, EMT and metastasis of tumor cells in various malignancies. A small molecule inhibitor (KAN0439834) (530 Da) targeting the TK domain of ROR1 was developed and the activity in ROR1 expressing human PC cell lines (n = 8) evaluated. The effects were compared to a murine mAb against the external part of ROR1, gemcitabine, erlotinib and ibrutinib. KAN0439834 induced significant apoptosis of the tumor cells. EC50 values for KAN0439834 varied between 250-650 nM depending on the cell line. The corresponding values for erlotinib and ibrutinib were 10-40 folds higher. KAN0439834 was much more effective in inducing tumor cell death than the ROR1 mAb although both inhibited ROR1 phosphorylation and downstream non-canonical Wnt pathway molecules. Combination of KAN0439834 with erlotinib or ibrutinib had significant additive effects on tumor cell death. A first-in-class small molecule ROR1 inhibitor (KAN0439834) showed promising in vitro activity against a number of human PC cell lines. Interesting is the additive effects of erlotinib and ibrutinib which warrants further studies as both these agents are in clinical trials for pancreatic carcinoma.

Physical activity level in people with age related white matter changes correlates to better motor performance, lower comorbidity and higher cognitive level.

BACKGROUND: Physical activity plays a pivotal role in the development of disability and may modify the negative effect of vascular risk factors on progression of both cardio and cerebrovascular disorders. The aim of this study was to evaluate the activity level in people with age-related white matter changes as identified on magnetic resonance imaging (MRI) in relation to motor performance, cognition and perceived health. METHODS: Data came from the first year follow up of one participating centers of the LADIS study. Fifty one subjects were first enrolled in the study. Complete first year follow up data was available for 41 subjects. Information on comorbidity, physical activity level, physical function, cognition, level of white matter changes and perceived health was collected. Physical activity level was classified with a yes or no question and with the Frenchay Activities Index (FAI). RESULTS: Only 36% of the subjects in this study were physically active according to the yes/no question. 27.5% of the subjects were active according to the FAI score which evaluates the everyday activities. Being active discriminated subjects with better physical function. Subjects active according to the FAI score had a higher cognitive level (p ≤ 0.01), lower comorbidity (p = 0.02) and performed better on all motor function tasks as assessed by walking speed (p ≤ 0.01) and the Short Physical Performance battery (SPPB) (p ≤ 0.01). CONCLUSIONS: Being physically active seems to be a long term protective factor. In our study, the majority of subjects with Age Related White Mattter Changes (ARWMC) with no or mild Instrumental Activity of Daily Living (IADL) disability did not attain recommended level of activity at first year follow up. Whether or not increasing physical activity may slow down cognitive decline and lessen development of disability in physically inactive subjects with manifest ARWC remains to be studied. TRIAL REGISTRATION: not applicable.

Long-term effects of new progressive group balance training for elderly people with increased risk of falling - a randomized controlled trial.

OBJECTIVE: To evaluate the long-term effects of a progressive and specific balance group-based program in healthy elderly individuals with increased risk of falling. DESIGN: Follow-up of a randomized controlled trial at nine and 15 months on a population that has previously been described at three months. SETTING: The study was conducted in Stockholm, Sweden. SUBJECTS: 59 community-dwelling elderly (age 67-93 years), recruited by advertisement, were randomly allocated to training or to serve as controls. INTERVENTION: Group balance training three times per week during 12 weeks with a 15 month follow-up time. MAIN MEASURES: Participants were assessed at baseline, three, nine, and 15 months thereafter for gait function (preferred and fast walking), rapid step execution (single and dual task), fear of falling, and likelihood of depression. RESULTS: Fast gait speed (p = 0.004), dual task step execution (p = 0.006) and fear of falling (p = 0.001) were still improved in the training group at nine months follow-up. Only self-perceived fear of falling remained significantly improved (p = 0.012) at 15 months follow-up. Although fast gait speed had decreased to baseline level in the training group (1.49 m/s) it remained significantly higher than in the control group (1.37 m/s) at the end of the study, a difference between the groups that was not seen at baseline. CONCLUSION: This training program provided important positive short and long-term benefits to gait, balance function, and fear of falling.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) in consumer products in Norway - a pilot study.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are used in numerous industrial and consumer products because of their special chemical properties, for instance the ability to repel both water and oil. A broad variety of PFAS have been introduced into the Norwegian market through industrial use (e.g. via fire fighting foams and paints) as well as in treated customer products such as textiles and coated paper. Our present knowledge of the exact chemical PFAS compositions in preparations using perfluorinated compounds is limited. This lack of knowledge means that it is difficult to provide an accurate assessment of human exposure to these compounds or to the amount of waste that may contain treated products. It is a growing concern that these potentially harmful compounds can now be found throughout the global environment. Samples of consumer products and preparations were collected in Norway, with supplemental samples from Sweden. In 27 of the 30 analyzed consumer products and preparations a number of polyfluorinated substances that were analyzed were detected but this does not exclude the occurrence of unknown PFAS. Notable was that perfluorooctanesulphonate (PFOS), which has been strictly regulated in Norway since 2007, was found in amounts close to or exceeding the EU regulatory level in 4 of the 30 analyzed products, all within the leather or carpet product groups. High amounts of fluorotelomer alcohols (FTOHs) were found in waterproofing agents, carpets and textiles, consistent with earlier findings by Fiedler et al. (2010). The presence of PFAS in a broad range of consumer products can give rise to a constant diffuse human exposure that might eventually result in harm to humans.

Relative and absolute reliability of the new "Step-Ex" step-execution test in elderly people with and without balance problems.

PURPOSE: To evaluate the relative and absolute test-re-test reliability of a new step-execution test, "Step-Ex", for clinical use in elderly with and without balance problems. METHOD: Test-re-test design to assess intrarater reliability. Thirty-four healthy community-dwelling elderly (65-87 years), 16 with balance problems, were tested twice two weeks apart. Step-Ex consists of two portable force platforms that register vertical ground reaction forces connected to a computer for easy detection of temporal events and phases (reaction-, preparation-, stepping- and step execution phase). Standing with one foot on each platform, the subjects were given a tactile stimulus on the heel to initiate rapid steps forward. RESULTS: Test-re-test agreement was good to very good: ICC(2)(.6) 0.83-0.87 (without balance problems) and 0.71-0.83 (with balance problems) with no apparent systematic differences between the tests. The SEM, i.e. the smallest detectable change that may indicate a real clinical improvement for a group of individuals was small, 4.6-8.6%. The smallest real difference, representing the smallest change that reveals clinical improvement for a single individual, was 13-24%. CONCLUSION: Step-Ex is a highly reliable instrument and can be recommended as an outcome measure evaluating the effects of balance training in elderly people with and without balance deficits. IMPLICATIONS FOR REHABILITATION: • Balance deficits are common in the elderly population. • To evaluate the effects of treatment or changes over time it is of great importance to have reliable instruments. • Step-Ex is a highly reliable instrument and can be recommended as an outcome measure evaluating the effects of treatment or changes over time in elderly people with and without balance deficits.

Balance in relation to walking deterioration in adults with spastic bilateral cerebral palsy.

BACKGROUND: Balance function is central in walking, and impaired balance function may be related to walking deterioration in adults with spastic bilateral cerebral palsy (CP). OBJECTIVES: The purposes of this study were: (1) to compare balance confidence, fear of falling, and balance ability in adults with spastic bilateral CP, with and without self-reported walking deterioration; (2) to characterize balance confidence, fear of falling, and balance ability across all participants; and (3) to examine the relationship between balance confidence and balance ability across all participants. DESIGN: A case-control design was used. METHODS: Sixteen adults from a 7-year follow-up study who had spastic bilateral CP and were under 40 years of age in the 2006 survey participated. Eight participants reported walking deterioration (cases), and 8 participants did not report walking deterioration (controls). Outcome variables were: the Activities-specific Balance Confidence (ABC) Scale, the Falls Efficacy Scale-International (FES-I), and the Balance Evaluation Systems Test (BESTest). RESULTS: No differences in any of the outcome variables were found between the cases and the controls. Across all participants, the ABC Scale and FES-I scores were 62% and 24 points, respectively. Reduced ABC Scale scores and increased FES-I scores were found when using escalators, walking in crowds, and walking on slippery surfaces. The BESTest subscale scores were 60% to 79% of the maximum score, but only 31% and 42% of the maximum score in postural responses and anticipatory adjustments, respectively. Balance confidence correlated positively with postural responses, sensory orientation, stability in gait, and BESTest total score. LIMITATIONS: The lack of reliability and validity tests for the outcome variables in this study population and the small number of participants were limitations of the study. CONCLUSIONS: Self-reported walking deterioration in this group could not be explained by differences in balance confidence, fear of falling, or balance ability. Across all participants, most balance problems seemed related to reduced postural responses and anticipatory adjustments.

Effects of new, individually adjusted, progressive balance group training for elderly people with fear of falling and tend to fall: a randomized controlled trial.

OBJECTIVE: To evaluate the effects of a new, individually adjusted, progressive and specific balance group training programme on fear of falling, step execution, and gait in healthy elderly people with fear of falling and tend to fall. DESIGN: Randomized controlled trial. SETTING: The study was conducted in Stockholm County, Sweden. SUBJECTS: Fifty-nine community dwelling elderly people were recruited by advertisement, and allocated at random to an intervention group (n = 38) or a control group (n = 21). INTERVENTION: Individually adjusted, progressive and specific balance group training was given three times a week for three months. The training incorporated elements included in, and required for, independent activities of daily living, and for reactions to loss of balance during dual or multiple tasks. MAIN MEASURES: Fear of falling was assessed with Falls Efficacy Scale International (FES-I). The reaction time of step execution was measured with the step-execution test, and gait was measured with GAITRite®. RESULTS: After three months the intervention group showed significant positive changes in the FES-I (P = 0.008), in the step-execution phase of dual-task performance (P = 0.012), and in gait at preferred speed during single-task performance; in cadence (P = 0.030) and, at fast speed, in velocity (P = 0.004) and cadence (P = 0.001). Significant decreases were also found for the likelihood of depression after participating in the training programme. CONCLUSION: This new balance training programme is feasible and leads to decreased fear of falling, decreased time for step execution during dual-task performance and increased velocity during fast walking.

Physical and mental components of health-related quality of life and musculoskeletal pain sites over seven years in adults with spastic cerebral palsy.

OBJECTIVE: To analyse the number of musculoskeletal pain sites in adults with spastic cerebral palsy, to correlate these with physical and mental components of health-related quality of life, and to describe changes in pain site prevalence over 7 years and the factors improving or worsening the pain. DESIGN: Seven-year follow-up of a national survey of adults with spastic cerebral palsy (CP). SUBJECTS/PATIENTS: A total of 149 persons: 46% spastic bilateral CP, 54% unilateral CP, 51% females, mean age 40 years. METHODS: Pain sites were recorded and physical and mental component summaries computed using Short Form 36. RESULTS: The median number of pain sites was 3. The mental components showed little, if any correlation (r= -0.08), but the physical components correlated negatively with the number of pain sites (r= -0.36). Back, neck and foot/ankle pain were most common, with an increased prevalence of neck pain. A higher prevalence of hip and foot/ankle pain was found in spastic bilateral CP, and for all pain sites in females. Exertion and physiotherapy were the most important factors for increased and reduced pain, respectively. CONCLUSION: In contrast to the general population, there was hardly any correlation between the number of pain sites and psychological health. Improved pain management, evidence-based physiotherapy and rehabilitation programmes with a life-span perspective are recommended.

Walking function, pain, and fatigue in adults with cerebral palsy: a 7-year follow-up study.

AIM: To compare walking function, pain, and fatigue in adults with cerebral palsy (CP) 7 years after an initial survey. METHOD: A multidimensional questionnaire was mailed to 226 people with unilateral (hemiplegic) or bilateral (diplegic) spastic CP who had participated in a 1999 survey. People with additional diagnoses were excluded. Special emphasis was placed on participants with deterioration in walking. The questionnaire was the same as in 1999. RESULTS: One hundred and forty-nine participants (76 males, 73 females; mean age 40y 5mo, SD 10y 7mo, range 24-76y) with a diagnosis of unilateral (n=81) or bilateral (n=68) spastic CP responded. Fifty-two per cent of all participants reported deterioration in walking function since debut of walking, compared with 39% 7 years previously. In participants with bilateral CP, 71% reported deteriorated walking, compared with 37% of participants with unilateral CP. Participants with deteriorated walking function had greater pain frequency, pain intensity, impact of pain on daily activities, and physical fatigue and reduced balance. The number of people reporting overall mobility problems was almost double compared with 7 years previously. INTERPRETATION: The main finding was an increased prevalence of deteriorated walking, significantly associated with bilateral spastic CP, pain, fatigue, and reduced balance. Rehabilitation programmes addressing these areas are needed.

Intramuscular and periosteal acupuncture in patients suffering from chronic musculoskeletal pain - a controlled trial.

BACKGROUND: Periosteal acupuncture has shown promising results in clinical practice. The aim was to compare three patient groups: one with intramuscular acupuncture, one with periosteal acupuncture, and a third information control group, with respect to clinically relevant pain relief, physical functioning and intake of analgesics in patients with chronic musculoskeletal pain in the neck or low back or both. We reported the psychological changes in these patients in a previous issue of this journal. METHODS: 144 consecutive patients with nociceptive pain for >3 months, aged 18-70 years were alternately allocated to: intramuscular acupuncture (n=59); periosteal acupuncture (n=55); or control group with information only (n=30). All patients were encouraged to stay active. Acupuncture was administered with eight treatments during five weeks, and two optional additional treatments after one month. Pain was estimated with a daily VAS in a pain diary and with an average weekly pain score. Clinically relevant pain relief was defined as at least a 30% decrease from the initial value. Physical functioning was evaluated with Disability Rating Index. All estimations were performed prior to treatment, one week after, and one, three and six months after treatment. RESULTS: There were no differences between the effects of the two acupuncture methods. There were differences between each of the two acupuncture groups compared with the control group on all test occasions up to one month after treatment with respect to the pain diary and one week after treatment with respect to pain last week (P<0.05). Pain relief as measured by a pain diary was obtained in 29 patients in the intramuscular acupuncture group, 25 in the periosteal acupuncture group, and 5 patients in the control group. Six months after treatment, 46% of the intramuscular acupuncture patients and 45% of the periosteal acupuncture patients had obtained pain relief in terms of the pain diary. The corresponding figure for pain last week was 29% in each group. CONCLUSIONS: Periosteal pecking was no more effective than standard intramuscular acupuncture, but both were more effective than information only.

Intramuscular and periosteal acupuncture for anxiety and sleep quality in patients with chronic musculoskeletal pain--an evaluator blind, controlled study.

OBJECTIVES: Periosteal acupuncture seems clinically to have a stronger effect on pain than standard intramuscular acupuncture. The aim of the present study was to compare their relative effectiveness on promoting psychological functioning and quality of sleep. METHODS: Consecutive patients (n=144) referred to a physiotherapist for treatment of chronic nociceptive pain in the neck or low back for more than three months, aged 18-70, were alternately allocated to an intramuscular acupuncture group (n=59), to a periosteal acupuncture group (n=55), and, for the latter part of the study, to an information control group (n=30). Eight treatments were administered during a five week period with two optional treatments after one month. All patients were encouraged to stay active. Psychological functioning was estimated with the Hospital Anxiety and Depression Scale (HAD) and quality of sleep with a visual analogue scale. All estimations were performed prior to treatment, one week after the end of treatment, and one, three and six months after end of treatment. Non-parametric statistics were used. RESULTS: There were no significant differences between the acupuncture groups, nor between the acupuncture and control groups during the treatment period. One month after treatment, the level of anxiety was lower in both acupuncture groups compared with the control group. The proportions of non-cases (HAD score 0-7) increased in the intramuscular acupuncture group from 39 to 47 (not significant), in the periosteal acupuncture group from 37 to 49 (P<0.001), and in the control group from 15 to 16. CONCLUSION: No differences between periosteal and intramuscular acupuncture were found. One month after treatment both acupuncture interventions reduced anxiety in patients suffering from chronic nociceptive musculoskeletal pain in the neck or low back when compared with a control intervention.

Tests of walking ability at different speeds in patients with knee osteoarthritis.

BACKGROUND AND PURPOSE: Measurements of walking speeds are commonly used as an objective measure of functional performance in patients with knee osteoarthritis (OA) and are easily performed in a clinical setting. However, the choice in which the walking speed evaluation should be performed is controversial. The aim of this study was to identify the most discriminating walking speed after surgical interventions in patients with knee osteoarthritis, and to compare the responsiveness of the different gait speeds. METHOD: A prospective clinical one-year follow-up study involving 54 patients with knee osteoarthritis (63 (+/-5) years of age) who were operated with either a unicompartmental knee arthroplasty or a high tibial osteotomy was undertaken. Thirty-nine patients had unilateral knee OA and 15 patients had bilateral knee OA or other symptoms from the lower extremities that could influence walking. The patients were examined at a gait laboratory before surgery, and one year after surgery. The patients were instructed to walk at slow, normal and fast walking speed. RESULTS: All patients (n=54) walked.faster one year after the surgical intervention compared to before surgery (p = 0.001) at slow (+15%), normal (+8%) and fast (+7%) walking speed. This increase was similar for the three walking speeds (p = 0.171). Patients with unilateral knee OA (n=39) reached an average change of +0.12 m/s, which was considered clinically important, while patients with bilateral knee OA (n=15) did not increase their walking speed > 0.12 m/s. Effect size was moderate for slow walking speed and small for normal and fast walking speeds, respectively. CONCLUSIONS: The different walking speeds were equally good in detecting changes one year after surgical interventions. In this study, responsiveness favoured slow walking speed, however, the advantages of normal walking speed are discussed.

Effect of divided attention on gait in subjects with and without cognitive impairment.

The aim of this study was to investigate the influence of cognition on motor function using 2 simple everyday tasks, talking and walking, in younger subjects with Alzheimer's disease and mild cognitive impairment. A second aim was to evaluate reliability for the dual-task test Talking While Walking. Walking speed during single and dual task and time change between single and dual task were compared between groups. The test procedure was repeated after 1 week. Subjects with AD had lower walking speed and greater time change between single and dual task compared with healthy controls. Reliability for Talking While Walking was very good. The results show that motor function in combination with a cognitive task, as well as motor function alone, influences subjects with Alzheimer's disease in a negative way and that decreased walking speed during single- and dual-task performance may be an early symptom in Alzheimer's disease.

Functional ability in female leg ulcer patients--a challenge for physiotherapy.

BACKGROUND AND PURPOSE: Venous leg ulceration represents a global health problem affecting predominantly elderly women. Traditionally, functional problems in this group of patients have attracted modest attention from wound care providers and physiotherapists. The aim of the present study was to describe and quantify disease consequences in female leg ulcer patients as a background for future physiotherapy interventions, using the nomenclature of the WHO International Classification of Functioning, Disability and Health (ICF). METHOD: A prospective study was conducted in 34 women aged 60-85 years with current or previous venous leg ulcer as compared to 27 age-matched non-ulcer subjects. The outcome variables were pain, ankle range of motion, walking speed, walking endurance, self-perceived exertion, mobility, activities of daily living (ADL), physical activity, general health, life satisfaction and use of walking aids and community services. Established instruments were utilized and categorized within ICF domains to provide a conceptual framework and basis for physiotherapeutic research. RESULTS: Leg ulcer patients showed significantly reduced values of ankle range of motion, walking speed and endurance, self-perceived exertion, mobility, ADL and physical activity level as compared to control subjects. Patients suffering from active ulceration were more negatively affected, and more of them had pain than post-ulcer fellows. By contrast, general health and life satisfaction were similarly rated by the two study groups. CONCLUSIONS: Elderly females in our study with chronic leg ulcer of venous aetiology had significant mobility impairments, but the reasons and consequences of these impairments remain to be elucidated. The potential of preventive measures and physical rehabilitation to aid functioning and prospects of leg ulcer repair need to be investigated in future studies.