INAUGURAL ARTICLE by a Recently Elected Academy Member:B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression

Human tumors contain populations of both cancerous and host immune cells whose malignant signaling interactions may define each patient''s disease trajectory. We used multiplexed phospho-flow cytometry to profile single cells within human follicular lymphoma tumors and discovered a subpopulation of lymphoma cells with impaired B cell antigen receptor (BCR) signaling. The abundance of BCR-insensitive cells in each tumor negatively correlated with overall patient survival. These lymphoma negative prognostic (LNP) cells increased as tumors relapsed following chemotherapy. Loss of antigen receptor expression did not explain the absence of BCR signaling in LNP tumor cells, and other signaling responses were intact in these cells. Furthermore, BCR signaling responses could be reactivated in LNP cells, indicating that BCR signaling is not missing but rather specifically suppressed. LNP cells were also associated with changes to signaling interactions in the tumor microenvironment. Lower IL-7 signaling in tumor infiltrating T cells was observed in tumors with high LNP cell counts. The strength of signaling through T cell mediator of B cell function CD40 also stratified patient survival, particularly for those whose tumors contained few LNP cells. Thus, analysis of cell–cell interactions in heterogeneous primary tumors using signaling network profiles can identify and mechanistically define new populations of rare and clinically significant cells. Both the existence of these LNP cells and their aberrant signaling profiles provide targets for new therapies for follicular lymphoma.     

Occupational therapists' perception of their practice: A phenomenological study

Background:  International literature seems consistent in reporting that occupational therapists value their methods. However, little empirical evidence has been generated supporting the basic system of belief for occupational therapy. Few studies have explored the nature of the occupational therapists' experiences and thoughts about their use of occupation as means and ends, and which strategies they use to implement their tools in their current practice. Accordingly, the aim of this study was to explore how occupational therapists understood and presented their practice and interventions.
Methods:  A sample of six occupational therapists graduated in different decades, from diverse client populations and health-care settings was selected to participate in a semistructured interview.
Results:  Three main themes were developed: 'To make the client's potentials visible', 'reaching a position one values' and 'looking with other eyes'. Whatever their specialities, the participants were unanimous in the way they described their role. Their common focus was 'activities of daily living'. However, they had problems describing their therapeutic tools, and were not able to clearly articulate the 'common sense aspects' of their own methods. The participants were engaged in constructing their professional identities, and stressed the need to construct professional boundaries relevant to their particular work.
Conclusion:  The occupational therapists perceived their practice and interventions as distinctly different from other team members, thus, they provided a 'counterpoint'. The participants used various ways of marketing their perspectives. While the novices tended to go along with the team, the experienced therapists tended to assert their own special contribution.     

Clinical assessment techniques for detecting ligament and membrane injuries in the upper cervical spine region--a comparison with MRI results

In this study we examined whether results from a clinical test of passive mobility of soft tissue structures in the upper cervical spine, corresponded with signs of physical injuries, as judged by magnetic resonance imaging (MRI). Results were based on examinations of 122 study participants, 92 with and 30 without a diagnosis of whiplash-associated disorder, type 2. The structures considered were the alar and the transverse ligaments, and the tectorial and the posterior atlanto-occipital membranes. Ordinary and weighted kappa coefficients were used as a measure of agreement, whereas McNemar's test was used for evaluating differences in rating. The clinical classification and the MRI examination both comprised four response categories (grades 0-3), with 0 representing a normal structure, and 3 indicating a structure with pronounced abnormality. In our sample, an abnormal clinical test reflected a hyper- rather than hypo-mobility. Considering all four-response categories, the kappa coefficient indicated moderate agreement (range 0.45-0.60) between the clinical and the MRI classification. The results for the membranes appeared somewhat better than for the ligaments. When there was disagreement, the classifications obtained by the clinical test were significantly lower than the MRI grading, but mainly within one grade difference. When combining grade 0-1 (normal) and 2-3 (abnormal), the agreement improved considerably (range 0.70-0.90). Although results from the clinical test seem to be slightly more conservative than the MRI assessment, we believe that a clinical test can serve as valuable clinical tool in the assessment of WAD patients. However, further validity- and reliability studies are needed.     

Massive fetomaternal hemorrhage: clearance of fetal red blood cells after intravenous anti-D prophylaxis monitored by flow cytometry

BACKGROUND: The clearance of D+ red blood cells (RBCs) from the circulation in D- individuals mediated by passively administered anti-D occurs by opsonization with the antibody and subsequent removal in the spleen. Few data exist on the kinetics of clearance of large volumes of D+ RBCs from the maternal circulation by anti-D in clinical cases of massive fetomaternal hemorrhage (FMH). CASE REPORT: A 33-year-old D- woman delivered a D+ female infant by emergency cesarean section for suspected fetal anemia. A massive FMH, initially estimated to be approximately 142 mL of RBCs, was found. In addition to the standard dose of intramuscular (IM) anti-D (300 microg) given immediately after delivery, 2700 microg of anti-D was administered intravenously (IV). The clearance of D+ fetal cells from the maternal circulation was monitored by flow cytometry in samples obtained on a daily basis using anti-D. The mother had no detectable anti-D 6 months after delivery. RESULTS: No clearance of fetal cells was apparent after the insufficient dose of IM anti-D. The IV administration of anti-D caused accelerated clearance of D+ fetal RBCs with a t1/2 of 24.5 hours. D+ reticulocytes comprised 4.2 percent of all D+ cells in the maternal circulation at delivery suggesting acute fetal blood loss. CONCLUSIONS: The approach used in this report allowed a detailed analysis of the kinetics related to the clearance of fetal D+ RBCs. Simultaneous measurements of fetal reticulocytes and fetal RBCs in maternal blood may establish the timing of an FMH.     

CPR quality improvement during in-hospital cardiac arrest using a real-time audiovisual feedback system

BACKGROUND: Cardiopulmonary resuscitation (CPR) quality during actual cardiac arrest has been found to be deficient in several recent investigations. We hypothesized that real-time feedback during CPR would improve the performance of chest compressions and ventilations during in-hospital cardiac arrest. METHODS: An investigational monitor/defibrillator with CPR-sensing and feedback capabilities was used during in-hospital cardiac arrests from December 2004 to December 2005. Chest compression and ventilation characteristics were recorded and quantified for the first 5 min of resuscitation and compared to a baseline cohort of arrest episodes without feedback, from December 2002 to April 2004. RESULTS: Data from 55 resuscitation episodes in the baseline pre-intervention group were compared to 101 resuscitations in the feedback intervention group. There was a trend toward improvement in the mean values of CPR variables in the feedback group with a statistically significant narrowing of CPR variable distributions including chest compression rate (104+/-18 to 100+/-13 min(-1); test of means, p=0.16; test of variance, p=0.003) and ventilation rate (20+/-10 to 18+/-8 min(-1); test of means, p=0.12; test of variance, p=0.04). There were no statistically significant differences between the groups in either return of spontaneous circulation or survival to hospital discharge. CONCLUSIONS: Real-time CPR-sensing and feedback technology modestly improved the quality of CPR during in-hospital cardiac arrest, and may serve as a useful adjunct for rescuers during resuscitation efforts. However, feedback specifics should be optimized for maximal benefit and additional studies will be required to assess whether gains in CPR quality translate to improvements in survival.     

Progressively increasing fracture risk with advancing age after initial incident fragility fracture: The Tromsø Study

The risk of subsequent fracture is increased after initial fractures; however, proper understanding of its magnitude is lacking. This population‐based study examines the subsequent fracture risk in women and men by age and type of initial incident fracture. All incident nonvertebral fractures between 1994 and 2009 were registered in 27,158 participants in the Tromsø Study, Norway. The analysis included 3108 subjects with an initial incident fracture after the age of 49 years. Subsequent fracture (n = 664) risk was expressed as rate ratios (RR) and absolute proportions irrespective of death. The rates of both initial and subsequent fractures increased with age, the latter with the steepest curve. Compared with initial incident fracture rate of 30.8 per 1000 in women and 12.9 per 1000 in men, the overall age‐adjusted RR of subsequent fracture was 1.3 (95% CI, 1.2–1.5) in women, and 2.0 (95% CI, 1.6–2.4) in men. Although the RRs decreased with age, the absolute proportions of those with initial fracture who suffered a subsequent fracture increased with age; from 9% to 30% in women and from 10% to 26% in men, between the age groups 50–59 to 80+ years. The type of subsequent fracture varied by age from mostly minor fractures in the youngest to hip or other major fractures in the oldest age groups, irrespective of type and severity of initial fracture. In women and men, 45% and 38% of the subsequent hip or other major fractures, respectively, were preceded by initial minor fractures. The risk of subsequent fracture is high in all age groups. At older age, severe subsequent fracture types follow both clinically severe and minor initial incident fractures. Any fragility fracture in the elderly reflects the need for specific osteoporosis management to reduce further fracture risk. © 2013 American Society for Bone and Mineral Research.     

Prednisolone maintenance dose in relation to starting dose in the treatment of polymyalgia rheumatica and temporal arteritis. A prospective two-year study in 273 patients.

OBJECTIVE: To describe the maintenance dose and annual cessation rate of oral corticosteroids in relation to the starting dose in patients with polymyalgia rheumatica (PMR) and temporal arteritis (TA). METHODS: A prospective two-years observational study of 273 patients with PMR and TA followed by rheumatologists. RESULTS: Mean daily maintenance dose of prednisolone during the first and second year was 5.7 mg and 4.3 mg for PMR, 6.6 mg and 4.1 mg for TA, and 8.3 mg and 4.7 mg for PMR with TA. There was a strong association between the initial dose and maintenance dose. The rate of steroid cessation after two years in PMR was 24%, in TA 16%, and in PMR with TA 5%. CONCLUSION: Low initial dose of prednisolone is associated with low maintenance dose. This is important as the majority of patients with PMR and TA will be treated for more than two years.     

Feasibility of shock advice analysis during CPR through removal of CPR artefacts from the human ECG

Mechanical activity from chest compressions and ventilations during cardiopulmonary resuscitation (CPR) introduces artefact components into the electrocardiogram (ECG). CPR must therefore be discontinued for reliable shock advice analysis in automated external defibrillators. Reducing or eliminating this detrimental "hands-off" time by removing the CPR artefacts, should significantly improve the defibrillation success rate. The feasibility of this was tested by removing the CPR artefacts using a multichannel adaptive filter, the multichannel recursive adaptive matching pursuit (MC-RAMP) algorithm. Human ECG and reference channel data from episodes with both shockable and non-shockable underlying heart rhythms were recorded from 105 patients with out-of-hospital cardiac arrest. The performance of a shock advice algorithm was evaluated before and after artefact removal using the MC-RAMP algorithm. From a test set consisting of 92 shockable and 174 non-shockable episodes a sensitivity of 96.7% and specificity of 79.9% was achieved, an increase of approximately 15 and 13%, respectively, compared to no filtering. Good sensitivity was achieved, enabling ECG analysis during CPR that would reduce the hands-off time on patients with shockable rhythms. However, CPR artefact removal on non-shockable rhythms proved a more difficult problem. We need a better understanding of the physiological mixing of artefacts and the underlying heart rhythm and suggest clinical trials to investigate the nature of CPR artefacts further.     

Diurnal secretion of ghrelin, growth hormone, insulin binding proteins, and prolactin in normal weight and overweight subjects with and without the night eating syndrome

The regulatory peptide ghrelin has been proposed to help mediate both hunger and sleep. The neuroendocrine circadian patterns in the night eating syndrome (NES) have been distinguished by an attenuated nocturnal rise in the plasma concentrations of melatonin and leptin and a greater increase in the concentrations of cortisol. In this study we wanted to test the hypothesis that night eaters have disturbances in the circadian levels of ghrelin, growth hormone (GH) and associated regulatory peptides. In 12 female night eaters (6 normal weight and 6 overweight), and 25 healthy controls (12 normal weight and 13 overweight), blood was sampled over a 24-hour period. Four meals were served from 8 AM to 8 PM, and blood samples were drawn every second hour for determination of plasma ghrelin concentrations and GH by radioimmunoassay (RIA). Analysis of serum GH, IGF-1, IGFBP-3 and prolactin were performed by ELISA. In healthy normal weight subjects there was a slight but non significant nocturnal increase of ghrelin, whereas a more or less flat curve was observed for healthy overweight, NES normal weight and NES overweight patients. The RMANOVA analysis showed a significant independent lowering effect of overweight on the grand mean of ghrelin. No direct effects on NES normal weight and overweight subjects were found, but a near-significant interaction was found between healthy overweight and overweight NES subjects. There were independent significant lowering effects of overweight and NES on the serum GH levels. During the time course no changes in the serum levels of IGF-1 or IGFB-3 were observed. Independent significant lowering effects of overweight and NES on the levels of IGF-1 were detected, whereas a near significant reduction in the global levels of IGFBP-3 was observed in both NES groups. Finally, significant nocturnal changes were observed for serum levels of prolactin in all four subgroups. Grand mean levels tended to be higher in NES subjects whereas the opposite was observed in healthy overweight (ns). We conclude that in both NES groups and in healthy overweight subjects more or less attenuated ghrelin and GH secretions were observed, whereas divergent secretions were observed for prolactin.