Dissociated cerebellar contributions to feedforward gait adaptation.

The cerebellum is important for motor adaptation. Lesions to the vestibulo-cerebellum selectively cause gait ataxia. Here we investigate how such damage affects locomotor adaptation when performing the 'broken escalator' paradigm. Following an auditory cue, participants were required to step from the fixed surface onto a moving platform (akin to an airport travellator). The experiment included three conditions: 10 stationary (BEFORE), 15 moving (MOVING) and 10 stationary (AFTER) trials. We assessed both behavioural (gait approach velocity and trunk sway after stepping onto the moving platform) and neuromuscular outcomes (lower leg muscle activity, EMG). Unlike controls, cerebellar patients showed reduced after-effects (AFTER trials) with respect to gait approach velocity and leg EMG activity. However, patients with cerebellar damage maintain the ability to learn the trunk movement required to maximise stability after stepping onto the moving platform (i.e., reactive postural behaviours). Importantly, our findings reveal that these patients could even initiate these behaviours in a feedforward manner, leading to an after-effect. These findings reveal that the cerebellum is crucial for feedforward locomotor control, but that adaptive locomotor behaviours learned via feedback (i.e., reactive) mechanisms may be preserved following cerebellum damage.

The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling.

BACKGROUND: During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1/2 (ERK1/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored. METHODS: We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis-mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet-as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects. RESULTS: Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF-ß1, the major profibrotic cytokine, thereby suppressing downstream mTORC1 pathway activation. Additionally, trametinib reduced the expression of myofibroblast marker α-smooth muscle actin and the proliferation of renal fibroblasts, corroborating our in vivo data. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals subsequent to myofibroblast activation. CONCLUSIONS: Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.

Ischemic conditioning in solid organ transplantation: is it worth giving your right arm for?

PURPOSE OF REVIEW: Ischemia reperfusion injury (IRI) is an inevitable complication in solid organ transplantation. Limiting this injury can increase patient and graft survival and can decrease complications associated with transplantation. We provide an extensive literature review analyzing the available evidence for ischemic conditioning in solid organ transplantation, including kidney, liver, heart, and lung. RECENT FINDINGS: Ischemic conditioning strategies are a group of interventions, characterized by episodes of ischemia and reperfusion to an organ which confirm tissue protection. Arguably, transplantation is the ideal setting to use this novel strategy due to the predictable timing and duration of the ischemic insult. Liver transplantation has provided us with the most number of clinical trials, followed by kidney transplantation. Most of these trials have been negative but the methodology has been variable, making comparison difficult. SUMMARY: Despite the promising results seen in animal models, translating these results in clinical trials has proved to be difficult. The promising effects of ischemic conditioning are present in some trials with weaker positive signals existing in other trials. We believe that tailoring trials to allow better comparison will provide positive results in the future.

Major bleeding in hemodialysis patients using unfractionated or low molecular weight heparin: a single-center study.

BACKGROUND: Successful hemodialysis (HD) requires circuit anticoagulation, with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) - it is not clear if differences in risk or benefit between these agents exist. We report our experience of major bleeding in patients on hemodialysis receiving either LMWH or UFH for anticoagulation of the dialysis circuit. We also examined any effect of anti-platelet agents or oral anticoagulants on bleeding rates. METHODS: An observational, retrospective, single-center study. Bleeding episodes are described using the International Society of Thrombosis and Hemostasis (ISTH) definition of a major bleeding event, and by extending this group to include all bleeds that led to a hospital admission (clinically significant). Incident event rates are reported per 100 at risk patient years, and event-free survival calculated using multivariate analysis by Cox-proportional hazard ratio. RESULTS: We report on 522 patients (792 years of exposure) in the UFHHD cohort and 889 patients (1,200 years of exposure) in the LMWH-HD cohort. The incidence of a major bleed was 1.33%, and 1.92% bleeds respectively. The incidences of clinically significant bleeding rates were 3.33% and 3.96% respectively. There was no significant difference in bleed free survival between UFH compared to LMWH (OR 0.904, CI 0.557 – 1.468, p = 0.684). Warfarin or anti-platelet usage did not increase the risk of bleeding when comparing patients not on any anticoagulants. CONCLUSIONS: There is no difference in bleeding rates between hemodialysis patients treated with either UFH or LMWH for anticoagulation of the extracorporeal circuit. We believe that both heparins have similar safety profiles when used for extracorporeal anticoagulation and that bleeding risk should not determine the choice of anticoagulation.

Persistent colonization of exit site is associated with modality failure in peritoneal dialysis.

Exit-site infections (ESIs) increase the risk of developing peritoneal dialysis (PD) peritonitis and PD technique failure. There are no clear guidelines on how to monitor exit site (ES) after ESI with Staphylococcus aureus or Pseudomonas. We report on a 1-year observational study of 23 patients who developed an ESI with one of these serious pathogens. After completing initial antibiotic treatment, swabs were taken every month for 3 months. Primary treatment cure occurred in 19/23 (83%). Colonization of ES after primary cure occurred in 8/19 (42%) patients. In the eight colonized patients, five had subsequent PD technique failure due to infections. By contrast, during an average follow-up period of 7.2 months, none of the 11 patients who were proven noncolonized developed PD technique failure from infections; HR (colonized vs. noncolonized) = 10.89, 95% CI 2.6-45.43, p < 0.05. In conclusion, colonization significantly increased the risk of catheter loss. Increased surveillance and aggressive treatment may ameliorate this risk.