A protocol for the management of hyponatremia peri-liver transplant reduces post-transplant neurological complications.

Rapid changes in serum sodium (ΔSNa) peri-liver transplant (LT) predispose to post-LT neurological complications (NC). We aimed to assess whether implementation of a protocol directed at limiting peri-LT ΔSNa reduced post-LT NC. A retrospective single-center review of adult LT recipients from 1/2016 to 10/2017 was performed. Patients with hyponatremia (SNa < 135 mEq/L) within 7 days of LT were analyzed in two eras: pre-protocol (1/2016-9/2016) and post-protocol (10/2016-10/2017). The primary outcome was the development of NC within 1 month of LT. Perioperative ΔSNa (ΔSNaPost-LT) was assessed as a secondary outcome. Among 85 and 107 patients who underwent LT pre- and post-protocol, 39 (46%) and 42 (39%) were hyponatremic within 7 days of LT, respectively. Significantly fewer patients in the post-protocol era developed NC vs. pre-protocol (7.1% vs. 25.6%, p = .02). Additionally, fewer LT recipients in the post-protocol era developed ΔSNaPost-LT ≥ 10 mEq/L (9.5% vs. 30.7%, p = .02). Intraoperatively, more patients post-protocol received hypotonic saline (33.3% vs. 2.6%, p < .01). Multivariable logistic regression revealed that transplantation in the post-protocol era was associated with significantly reduced odds (odds ratio 0.11, 95% confidence interval 0.01-0.50) of developing NC. In conclusion, the implementation of a multidisciplinary protocol aimed at reducing ΔSNa peri-LT was independently associated with a reduction in post-LT NC.

Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET.

Direct visualization and light control of several cellular processes is a challenge, owing to the spectral overlap of available genetically encoded probes. Here we report the most red-shifted monomeric near-infrared (NIR) fluorescent protein, miRFP720, and the fully NIR Förster resonance energy transfer (FRET) pair miRFP670-miRFP720, which together enabled design of biosensors compatible with CFP-YFP imaging and blue-green optogenetic tools. We developed a NIR biosensor for Rac1 GTPase and demonstrated its use in multiplexed imaging and light control of Rho GTPase signaling pathways. Specifically, we combined the Rac1 biosensor with CFP-YFP FRET biosensors for RhoA and for Rac1-GDI binding, and concurrently used the LOV-TRAP tool for upstream Rac1 activation. We directly observed and quantified antagonism between RhoA and Rac1 dependent on the RhoA-downstream effector ROCK; showed that Rac1 activity and GDI binding closely depend on the spatiotemporal coordination between these two molecules; and simultaneously observed Rac1 activity during optogenetic manipulation of Rac1.

Publisher Correction: Direct multiplex imaging and optogenetics of Rho GTPases enabled by near-infrared FRET.

In the version of this article originally published, the values for time shown on the x axis of Figure 5c were incorrect. The error has been corrected in all versions of the paper.

Experimental and Investigational Targeted Therapies for the Management of Fibrosis in NASH: An Update.

There have been major advances in the treatment of HBV and HCV with anti-viral treatments, which is reducing the prevalence of fibrosis due to these viruses and obviating the need for anti-fibrotic therapies in these diseases. At the same time, however, the prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing, of which a substantial fraction of patients have non-alcoholic steatohepatitis (NASH), which may progress to cirrhosis. Accordingly, NASH is emerging as the leading indication for liver transplantation in North America and Europe. Progress in uncovering pathogenic determinants of fibrosis in NASH include metabolic dysregulation in hepatocytes that induce inflammation and cytokine secretion leading to cell injury and apoptosis, among others. These pathogenic events converge upon hepatic stellate cells, which are the primary fibrogenic cell in liver, and represent a target of new therapeutic candidates that are currently being evaluated in animal models and clinical trials. This review highlights key experimental and investigational therapies for NASH fibrosis, whose evaluation will be accelerated as new non-invasive markers of fibrosis are established. While no drugs are approved yet for NASH fibrosis, there is growing optimism that new pharmacotherapies are likely to emerge within the next 3 years that will favorably alter the natural history of disease.

Older patients are significantly more likely to have colon ischaemia-associated conditions that are chronic and complex.

BACKGROUND: Colon ischaemia is a common disease which has been associated with various medications and comorbidities. AIM: To test the hypothesis that there are differences in the frequencies of these associations in older compared with younger patients. METHODS: A retrospective cohort study was performed of patients hospitalized with colon ischaemia at two major medical centres from 2005-2017. Clinical, colonoscopic and pathologic criteria were used to identify patients admitted with colon ischaemia; patients with other types of colitis were excluded. Demographic and medical data were extracted. Two cohorts were created: patients aged 18-64 years and patients > 65 years. These were compared using SAS 14.3. RESULTS: A total of 788 patients were included, of which 271 (34.4%) were of ages 18-64 years, and 517 (66.6%) were 65 years old or older. In the older cohort, constipation-inducing medications (83.8% vs 64.1%; P = <0.0001), diuretics (38.1% vs 25.1%; P = <0.001) and nonsteroidal anti-inflammatory drugs (58% vs 41.5%; P = <0.0001) were more common than in the younger cohort. Antipsychotic medication use was more common in the younger cohort (10.4% vs 5.4%; P = 0.01). There was a higher percentage of younger patients with a history of hypercoaguable state (1.9% vs 0.2%; P = 0.03) and dialysis dependence (22.9% vs 8.7%; P = <0.01), while a higher percentage of patients in the older cohort had a history of chronic obstructive pulmonary disease (12% vs 6.3%; P = 0.01) or atrial fibrillation (18.9% vs 10.3%; P = <0.01). CONCLUSIONS: Our study shows that older patients are more likely to have colon ischaemia-associated conditions that are chronic and complex, while younger patients are more likely to have acute colon ischaemia-associated conditions.