ObjectiveDiabetic sensorimotor polyneuropathy (DSPN) affects approximately half of diabetic patients leading to significant morbidity. There is impaired neurotrophic growth factor signaling, AMP-activated protein kinase (AMPK) activity and mitochondrial function in dorsal root ganglia (DRG) of animal models of type 1 and type 2 diabetes. We hypothesized that sub-optimal insulin-like growth factor 1 (IGF-1) signaling in diabetes drives loss of AMPK activity and mitochondrial function, both contributing to development of DSPN.MethodsAge-matched control Sprague-Dawley rats and streptozotocin (STZ)-induced type 1 diabetic rats with/without IGF-1 therapy were used for in vivo studies. For in vitro studies, DRG neurons from control and STZ-diabetic rats were cultured and treated with/without IGF-1 in the presence or absence of inhibitors or siRNAs.ResultsDysregulation of mRNAs for IGF-1, AMPKα2, ATP5a1 (subunit of ATPase), and PGC-1β occurred in DRG of diabetic vs. control rats. IGF-1 up-regulated mRNA levels of these genes in cultured DRGs from control or diabetic rats. IGF-1 treatment of DRG cultures significantly (P < 0.05) increased phosphorylation of Akt, P70S6K, AMPK and acetyl-CoA carboxylase (ACC). Mitochondrial gene expression and oxygen consumption rate (spare respiratory capacity), ATP production, mtDNA/nDNA ratio and neurite outgrowth were augmented (P < 0.05). AMPK inhibitor, Compound C, or AMPKα1-specific siRNA suppressed IGF-1 elevation of mitochondrial function, mtDNA and neurite outgrowth. Diabetic rats treated with IGF-1 exhibited reversal of thermal hypoalgesia and, in a separate study, reversed the deficit in corneal nerve profiles. In diabetic rats, IGF-1 elevated the levels of AMPK and P70S6K phosphorylation, raised Complex IV-MTCO1 and Complex V-ATP5a protein expression, and restored the enzyme activities of Complex IV and I in the DRG. IGF-1 prevented TCA metabolite build-up in nerve.ConclusionsIn DRG neuron cultures IGF-1 signals via AMPK to elevate mitochondrial function and drive axonal outgrowth. We propose that this signaling axis mediates IGF-1-dependent protection from distal dying-back of fibers in diabetic neuropathy.
SummaryWe undertook the first clinical evaluation of a novel, non-invasive device for the continuous measurement of plasma haemoglobin concentration in 25 patients undergoing elective cardiac surgery. At four pre-determined intervals, samples of blood were taken for plasma haemoglobin estimation on a blood gas analyser and a laboratory device and were compared with the plasma haemoglobin estimation on the novel device using the Bland-Altman method. The 95% limits of agreement for estimation of plasma haemoglobin concentration for the device vs. laboratory, the device vs. the blood gas analyser and the blood gas analyser vs. the laboratory were 101.3 g.l
BackgroundThe avoidance of hypothermia is vital during prolonged and open surgery to improve patient outcomes. Hypothermia is particularly common during orthotopic liver transplantation (OLT) and associated with undesirable physiological effects that can adversely impact on perioperative morbidity. The KanMed WarmCloud (Bromma, Sweden) is a revolutionary, closed-loop, warm-air heating mattress developed to maintain normothermia and prevent pressure sores during major surgery. The clinical effectiveness of the WarmCloud device during OLT is unknown. Therefore, we conducted a randomized controlled trial to determine whether the WarmCloud device reduces hypothermia and prevents pressure injuries compared with the Bair Hugger underbody warming device.MethodsPatients were randomly allocated to receive either the WarmCloud or Bair Hugger warming device. Both groups also received other routine standardized multimodal thermoregulatory strategies. Temperatures were recorded by nasopharyngeal temperature probe at set time points during surgery. The primary endpoint was nasopharyngeal temperature recorded 5 minutes before reperfusion. Secondary endpoints included changes in temperature over the predefined intraoperative time points, number of patients whose nadir temperature was below 35.5°C and the development of pressure injuries during surgery.ResultsTwenty-six patients were recruited with 13 patients randomized to each group. One patient from the WarmCloud group was excluded because of a protocol violation. Baseline characteristics were similar. The mean (standard deviation) temperature before reperfusion was 36.0°C (0.7) in the WarmCloud group versus 36.3°C (0.6) in the Bairhugger group (P = 0.25). There were no statistical differences between the groups for any of the secondary endpoints.ConclusionsWhen combined with standardized multimodal thermoregulatory strategies, the WarmCloud device does not reduce hypothermia compared with the Bair Hugger device in patients undergoing OLT.
451 Background: TACE induces a peripheral anti-tumor immune response, which may be amplified by immune checkpoint inhibitors (ICI). Combining TACE with dual ICI therapy has been shown to be safe and feasible. Recent data has suggested that Day 1-only anti-CTLA4 dosing could potentially lead to a stronger immune response with a tolerable safety profile though this novel schedule has not previously been combined with TACE. Methods: Patients with HCC (Childs Pugh A/B7, Barcelona clinic liver cancer stage B/C; ECOG 0/1; sorafenib-naive or experienced) were enrolled in a pilot study of tremelimumab at 2 dose levels (DL1: 75mg IV q4-weekly x 4 and DL2: 300mg IV D1 only) in combination with durvalumab (1500mg IV q-28d) and TACE (D36 +/- 96 hours) until progression of disease (per irRECIST) or off-study criteria. Peripheral immune monitoring was performed and tumor biopsies were obtained at time of TACE. Results: 13 patients enrolled on study; N = 3 at DL1 and N = 10 at DL2. M:F 10:3. Median age 70 (65-74). BCLC B/C 4/9. Extrahepatic disease 6/7. Aetiology: NASH (N = 3), alcohol-related disease (N = 1), HCV (N = 2), hemochromatosis (N = 1), unknown (N = 6). 1 patient discontinued due to G3 colitis. All patients evaluable for response with 2/10 patients on DL2 experiencing PR (at 8 weeks) and overall 8/13 SD and 3/13 PD as best response. Updated PFS and OS data to be presented. Conclusions: Tremelimumab (Day 1 only) and Durvalumab in combination with TACE is safe and feasible in patients with HCC. Follow-up is ongoing and full safety and efficacy data will be presented. Clinical trial information: 2019-002767-98.
Background Tricuspid regurgitation (TR) and pulmonary hypertension (PHT) are highly dynamic cardiovascular lesions that may progress rapidly, particularly in the orthotopic liver transplantation (OLT) waitlist population. Severe TR and PHT are associated with poor outcomes in these patients, however it is rare for the two to be newly diagnosed intraoperatively at the time of OLT. Without preoperative information on pulmonary vascular and right heart function, the potential for reversibility of severe TR and PHT is unclear, making the decision to proceed to transplant fraught with difficulty. Case presentation We present a case of successful orthotopic liver transplantation (OLT) in a 48 year old female with severe (PHT) (mean pulmonary arterial pressure > 55 mmHg) and severe TR diagnosed post induction of anaesthesia. The degree of TR was associated with systemic venous pressures of > 100 mmHg resulting in massive haemorrhage during surgery and difficulty in distinguishing venous from arterial placement of vascular access devices. Intraoperative transoesophageal echocardiography (TOE) proved crucial in diagnosing functional TR due to tricuspid annular and right ventricular (RV) dilatation, and dynamically monitoring response to treatment. In response to positioning, judicious volatile anaesthesia administration, pulmonary vasodilator therapy and permissive hypovolemia during surgery we noted substantial improvement of the TR and pulmonary arterial pressures, confirming the reversibility of the TR and associated PHT. Conclusion TR and PHT are co-dependent, dynamic, load sensitive right heart conditions that are interdependent with chronic liver disease, and may progress rapidly in patients waitlisted for OLT. Use of intraoperative TOE and pulmonary artery catheterisation on the day of surgery will detect previously undiagnosed severe TR and PHT, enable rapid assessment of the cause and the potential for reversibility. These dynamic monitors permit real-time assessment of the response to interventions or events affecting right ventricular (RV) preload and afterload, providing critical information for prognosis and management. Furthermore, we suggest that TR and PHT should be specifically sought when waitlisted OLT patients present with hepatic decompensation. Electronic supplementary material The online version of this article (10.1186/s12871-019-0795-6) contains supplementary material, which is available to authorized users.
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