Successful treatment of macrophage activation syndrome complicating adult Still disease with anakinra

A previously healthy 20‐year‐old man presented with adult Still disease (ASD). He developed life‐threatening macrophage activation syndrome (MAS), which was refractory to standard immunosuppression but responded dramatically to the IL‐1 receptor antagonist anakinra. Subsequent immunological investigations included assessment of the perforin expression of natural killer (NK) cells and CD8+ T cells, which confirmed MAS.     

Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease

BACKGROUND: Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly affect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. METHODS: Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being <70% of the predicted value in 18/36 (50%). Pulmonary hypertension was described in 7/37 (19%) patients and renal disease in 5/37 (14%). The Scl-70 antibody was positive in 18/32 (56%) and the anticentromere antibody in 10% of evaluable patients. Peripheral blood stem cell mobilisation was performed with cyclophosphamide or granulocyte colony stimulating factor, alone or in combination. Thirty eight patients had ex vivo CD34 stem cell selection, with additional T cell depletion in seven. Seven conditioning regimens were used, but six of these used haemoimmunoablative doses of cyclophosphamide +/- anti-thymocyte globulin +/- total body irradiation. The median duration of follow up was 12 months (3-55). RESULTS: An improvement in skin score of >25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. CONCLUSION: Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.     

Measurement of platelet loss in the blood compatibility assessment of biomaterials

In the assessment of the in vitro blood compatibility of biomaterials, platelet loss is often attributed solely to platelet adhesion and consideration is not given to platelets lost in platelet aggregate formation. In order to distinguish between those platelets lost to adhesion and those lost to aggregate formation, the Wu and Hoak method for the quantification of circulating platelet aggregates in patients has been modified to establish a new test procedure. This procedure, which measures both platelet adhesion (PA) in the absence of platelets lost to aggregate formation and also the tendency of a material to induce aggregate formation, has been used to evaluate the influence of a range of polyamides and a hydrogel. The evaluation demonstrated the ability of polymers to induce readily platelet aggregates during in vitro blood-material contact. The sensitivity of the aggregate measurement was exemplified by the polyamides, where PA was similar for materials of different porosity but platelet aggregate formation increased significantly with porosity. The importance of considering platelets lost to aggregate formation was emphasized with the hydrogel, where PA was low.     

Openness to experience predicts intrinsic value shifts after deliberating one’s own death

Individual differences that might moderate processes of value shifting during and after deliberating one’s own death remain largely unexplored. Two studies measured participants’ openness and relative intrinsic-to-extrinsic value orientation (RIEVO) before randomly assigning them to conditions in which they wrote about their own death or dental pain for 6 days, after which RIEVO was assessed again up to 12 days later. When participants confronted thoughts about their own death over a sustained period, high openness to experience helped them shift toward intrinsic values. Implications for understanding openness’ role in value reorientation from existential deliberation processes are discussed.     

Cell death by apoptosis in acute leukaemia

We have previously demonstrated that when freshly isolated childhood T-cell acute lymphoblastic leukaemia cells are incubated in growth medium after isolation from blood, chromatin is rapidly cleaved into nucleosomal sized fragments that are multiples of 200 bp. The fragmentation is similar to that observed in other types of cells undergoing apoptosis or programmed cell death. In this study we describe a more comprehensive approach to the study of DNA fragmentation in leukaemia. Fragmentation was observed in freshly isolated cells from patients with T-cell acute lymphoblastic leukaemia and in one with common acute lymphoblastic leukaemia. Frozen samples of T-cell acute lymphoblastic leukaemia, common acute lymphoblastic leukaemia, and acute myeloid leukaemia cells also showed fragmentation of DNA. However, no fragmentation was evident in normal leukocytes treated under the same conditions. Ultrastructural studies on the isolated leukaemia cells demonstrate that the chromatin cleavage observed biochemically is associated with morphological changes characteristic of apoptosis.     

Locomotor adaptations for changes in the slope of the walking surface

The goal of this study was to examine the transition of walking from a level surface onto different inclined surfaces. Kinematic data of limb and trunk segments were recorded from individuals as they approached and stepped onto four different ramped surfaces (slopes=3°, 6°, 9°, 12°). This transition introduced significant adaptations to the swing limb trajectory that were evident in even the lowest ramp condition and appear to be scaled to the ramp inclination although the nature of this scaling seemed to change between the 6° and 9° conditions. An increased forward pitch of the trunk orientation during all ramp conditions was initiated early on during the preceding stance phase on level ground. The swing limb modification essentially consisted of a two-stage response. The initial response of the limb trajectory changes was not specific to the degree of inclination but later changes were dependent on the ramp condition. The initial response is to ensure a safe toe clearance as the foot approaches the edge of the ramp and then later modifications provide the appropriate positioning of the limb to prepare for an elevated foot contact. Early changes were actively produced through an increased pull-off by the hip flexors and an elevation of the swing limb by the active muscle control of the stance limb. Ankle dorsiflexion also appears to have a supporting role increasing toe clearance. Absorption at the hip and knee during later swing contribute to control and position the limb in preparation for foot contact. These strategies were similar to those adopted for step changes in the level of the walking surface where there are similar demands of the quickly moving the limb forward and upward, however, the positioning of the limb for new angled landing surface requires further adaptations.