Immune responses in kidney preservation and reperfusion injury.

Organ preservation and reperfusion injury have significant detrimental effects on both short- and long-term organ function. Ischemia reperfusion injury (IRI) underlies organ transplant dysfunction, myocardial infarction, stroke, and shock. Multiple molecular pathways are engaged in reactive oxygen production, apoptosis, signaling, and tissue regeneration. There has been an increased understanding of the important role of immune and inflammatory pathways in IRI, both in humans and in experimental models. Both cellular and soluble components of the immune system are directly activated during IRI, and there is evidence that immune mediators directly contribute to organ dysfunction. Immune activation during IRI likely underlies the enhanced immunogenicity of ischemic organs, with resultant increased rejection and fibrosis. Novel human therapies targeting T and B cells for classic immune diseases can now be considered to prevent and treat IRI. Organ preservation injury and cold ischemia could well have distinct pathophysiology from warm IRI and represent an opportunity to develop improved preservation methods.     

Responses of calves to acute stress: individual consistency and relations between behavioral and physiological measures

The present study examined the consistency over time of individual differences in behavioral and physiological responsiveness of calves to intuitively alarming test situations as well as the relationships between behavioral and physiological measures. Twenty Holstein Friesian heifer calves were individually subjected to the same series of two behavioral and two hypothalamo-pituitary-adrenocortical (HPA) axis reactivity tests at 3, 13 and 26 weeks of age. Novel environment (open field, OF) and novel object (NO) tests involved measurement of behavioral, plasma cortisol and heart rate responses. Plasma ACTH and/or cortisol response profiles were determined after administration of exogenous CRH and ACTH, respectively, in the HPA axis reactivity tests. Principal component analysis (PCA) was used to condense correlated measures within ages into principal components reflecting independent dimensions underlying the calves' reactivity. Cortisol responses to the OF and NO tests were positively associated with the latency to contact and negatively related to the time spent in contact with the NO. Individual differences in scores of a principal component summarizing this pattern of inter-correlations, as well as differences in separate measures of adrenocortical and behavioral reactivity in the OF and NO tests proved highly consistent over time. The cardiac response to confinement in a start box prior to the OF test was positively associated with the cortisol responses to the OF and NO tests at 26 weeks of age. HPA axis reactivity to ACTH or CRH was unrelated to adrenocortical and behavioral responses to novelty. These findings strongly suggest that the responsiveness of calves was mediated by stable individual characteristics. Correlated adrenocortical and behavioral responses to novelty may reflect underlying fearfulness, defining the individual's susceptibility to the elicitation of fear. Other independent characteristics mediating reactivity may include activity or coping style (related to locomotion) and underlying sociality (associated with vocalization).     

Adaptation in human somatosensory cortex as a model of sensory memory construction: a study using high-density EEG

Adaptation in sensory cortices has been seen as a mechanism allowing the creation of transient memory representations. Here we tested the adapting properties of early responses in human somatosensory areas SI and SII by analysing somatosensory-evoked potentials over the very first repetitions of a stimulus. SI and SII generators were identified by well-defined scalp potentials and source localisation from high-density 128-channel EEG. Earliest responses (~20 ms) from area 3b in the depth of the post-central gyrus did not show significant adaptation to stimuli repeated at 300 ms intervals. In contrast, responses around 45 ms from the crown of the gyrus (areas 1 and 2) rapidly lessened to a plateau and abated at the 20th stimulation, and activities from SII in the parietal operculum at ~100 ms displayed strong adaptation with a steady amplitude decrease from the first repetition. Although responses in both SI (1–2) and SII areas showed adapting properties and hence sensory memory capacities, evidence of sensory mismatch detection has been demonstrated only for responses reflecting SII activation. This may index the passage from an early form of sensory storage in SI to more operational memory codes in SII, allowing the prediction of forthcoming input and the triggering of a specific signal when such input differs from the previous sequence. This is consistent with a model whereby the length of temporal receptive windows increases with progression in the cortical hierarchy, in parallel with the complexity and abstraction of neural representations.     

Predictors of return to desired activity 12 months following unicompartmental and total knee arthroplasty

Background and purpose — 1 in 5 patients are dissatisfied following unicompartmental or total knee arthroplasty (UKA or TKA). This may be partly explained by failing to return to desired activity post-arthroplasty. To facilitate return to desired activity, a greater understanding of predictors of return to desired activity in UKA and TKA patients is needed. We compared rates of return to desired activity 12 months following UKA vs. TKA, and identified and compared predictors of return to desired activity 12 months following UKA vs. TKA.

Patients and methods — Patients were prospectively recruited from 2 hospitals prior to undergoing UKA or primary TKA. Patients reported preoperatively the activity/activities that were limited due to their knee that they wished to return to after arthroplasty. At 12-months postoperatively, patients reported whether they had returned to these activities (‘return to desired activity’). Preoperative predictors evaluated were age, sex, BMI, education, comorbidities, pain expectations, Oxford Knee Score (OKS), UCLA Activity Score, and EQ-5D. Generalized linear models assessed the relationship between potential predictors and return-to-desired-activity.

Results — The response rate of all patients eligible for 12-month follow-up was 74%. TKA patients (n = 575) were older (mean (SD) 70 (9) vs. 67 (10)) with a greater BMI (31 (6) vs. 30 (5)) than patients undergoing UKA (n = 420). 75% of UKA and 59% of TKA patients returned to desired activity. TKA patients had a greater risk of non-return to desired activity than patients undergoing UKA (risk ratio (95% CI) 1.5 (1.2–1.8)). Predictors of non-return to desired activity following UKA were worse OKS (0.96 (0.93–0.99)), higher BMI (1.04 (1.01–1.08)), and worse expectations (1.9 (1.2–2.8)). Predictors of non-return to desired activity following TKA were worse EQ-5D (0.53 (0.33–0.85)) and worse OKS (0.98 (0.96–1.0)).

Interpretation — UKA patients were more likely to return to desired activity than TKA patients. Predictors of return to desired activity differed following UKA and TKA. Optimizing selection of arthroplasty procedure based on patient characteristics and targeting predictors of poor outcome may facilitate return to desired activity with potential to enhance postoperative satisfaction.     

Calreticulin-independent regulation of the platelet integrin alphaIIbbeta3 by the KVGFFKR alphaIIb-cytoplasmic motif

The platelet integrin alphaIIbbeta3 alters conformation in response to platelet activation and ligand binding, although the molecular mechanisms involved are not known. We previously showed that a lipid modified peptide, corresponding to the membrane proximal 989KVGFFKR995 portion of the alphaIIb cytoplasmic tail, independently activates platelet alphaIIbbeta3. Calreticulin (CRT) is a potential integrin regulatory protein based on its interaction with the highly conserved alpha-integrin sequence KxGFFKR. We therefore examined the possible interaction of calreticulin and alphaIIbbeta3 in human platelets. We demonstrate that calreticulin in platelets is localised to the granulomere. In contrast, the known integrin-binding protein talin accumulates at the periphery of spreading platelets and colocalises with alphaIIbbeta3 during the process of adhesion. An interaction between calreticulin and alphaIIbbeta3 could not be demonstrated using co-immunoprecipitation techniques under various platelet activation states, even in the presence of covalent chemical crosslinkers. Thus, calreticulin does not functionally interact with the major integrin in human platelets. In order to identify proteins that interact with the integrin KVGFFKR motif we then used a peptide 'pull-down' assay from platelet lysates with biotinylated peptides and demonstrate that only the alphaIIb and beta3 subunits selectively and individually interact with this sequence. This interaction is divalent cation-dependent, has high-affinity, and occurs both with purified alphaIIbbeta3 complex and with electroeluted alpha and beta subunits. Thus, our data show that the conserved integrin KVGFFKR domain interacts primarily with the alpha and beta cytoplasmic tails and not with CRT in human platelets.     

Adding Pertuzumab to Trastuzumab and Taxanes in HER2 positive breast cancer

Introduction: The monoclonal antibody trastuzumab has improved the median disease free and overall survival of patients with early stage breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). Despite this advance, some patients experience cancer relapse and novel approaches are always needed. One such advance is the monoclonal antibody pertuzumab, which prevents dimerisation between members of the HER family of transmembrane glycoprotein receptors.

Areas covered: In this review, the authors analyse recent research which has focused on the development of new HER2 targeting agents for HER2-positive breast cancer, particularly pertuzumab, and its addition to trastuzumab and taxanes.

Expert opinion: Pertuzumab has significantly improved disease control in patients with advanced HER2 positive breast cancer when added to chemotherapy and trastuzumab. Although pertuzumab has also increased response rates in the preoperative setting, this has not yet translated into increased overall survival. The authors believe that future research should focus on improvements in novel biomarkers to select patients for new treatments.