Coherent neural oscillations inform early stroke motor recovery

Neural oscillations may contain important information pertaining to stroke rehabilitation. This study examined the predictive performance of electroencephalography‐derived neural oscillations following stroke using a data‐driven approach. Individuals with stroke admitted to an inpatient rehabilitation facility completed a resting‐state electroencephalography recording and structural neuroimaging around the time of admission and motor testing at admission and discharge. Using a lasso regression model with cross‐validation, we determined the extent of motor recovery (admission to discharge change in Functional Independence Measurement motor subscale score) prediction from electroencephalography, baseline motor status, and corticospinal tract injury. In 27 participants, coherence in a 1–30 Hz band between leads overlying ipsilesional primary motor cortex and 16 leads over bilateral hemispheres predicted 61.8% of the variance in motor recovery. High beta (20–30 Hz) and alpha (8–12 Hz) frequencies contributed most to the model demonstrating both positive and negative associations with motor recovery, including high beta leads in supplementary motor areas and ipsilesional ventral premotor and parietal regions and alpha leads overlying contralesional temporal–parietal and ipsilesional parietal regions. Electroencephalography power, baseline motor status, and corticospinal tract injury did not significantly predict motor recovery during hospitalization (R ² = 0–6.2%). Findings underscore the relevance of oscillatory synchronization in early stroke rehabilitation while highlighting contributions from beta and alpha frequency bands and frontal, parietal, and temporal–parietal regions overlooked by traditional hypothesis‐driven prediction models.     

Protein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation

Formation of NO by endothelial NOS (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation, and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and induce the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and G_q/G₁₁-mediated signaling, as well as by Ca²⁺ and phosphoinositide-dependent protein kinase 1 (PDK1), plays a pivotal role in this process. Active PKN2 promoted the phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved the phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation, whereas active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone, and blood pressure.     

The impact of humanoid robot presence in the paediatric emergency department waiting room: A prospective cohort study

BackgroundThe waiting room represents families’ first point of contact with the emergency department (ED). We wished to study if a humanoid robot technology presence in the waiting room would improve satisfaction and decrease anxiety for caregivers in the paediatric ED. MethodsThis observational cohort study was conducted from September to December 2018 at a Canadian paediatric ED. All caregivers and children >11 years in the ED waiting room were eligible. We compared a robotic intervention (RI) to standard of care (SOC) education in the waiting room. The RI was a 5-minute psychoeducational program describing the ED process and flow. Specific days were designated for RI or SOC. An anonymous survey was administered twice, at the same times, on both SOC and RI days. The primary outcomes were (a) caregiver satisfaction with waiting room experience using a 5-point Likert scale; and (b) caregiver-reported anxiety in the waiting room, as measured by the State Trait Anxiety Inventory – State Scale. ResultsSix hundred and thirty-three caregivers participated, with a median age of 37 years (IQR 32 to 42); 80 children participated, with a median age of 15 years (IQR 13 to 16). Caregivers reported greater overall satisfaction in the RI cohort (174/200, 87.0%) compared to the SOC cohort (144/229, 62.9%; P<0.0001). Caregivers also reported lower anxiety in the RI cohort (39.38±11.38) compared to the SOC cohort (42.04±11.99; P=0.009).ConclusionsA humanoid robot-based psycho educational intervention in the paediatric ED waiting room has a positive impact on caregiver satisfaction and anxiety.     

Study of Safety and Efficacy of Novel Sirolimus-Eluting Stent Incorporating Properties of Drug Coating Balloon Among Real World Patients Focusing Younger Population (<35 years)

ObjectiveAim of study was to evaluate safety and efficacy of abluminal Mitigator DES + Sirolimus Eluting Stent (Envision Scientific, Surat, India) incorporating novel technology of fusion coating of bioresorbable polymer on both abluminal surface of stent and exposed parts of balloon among real world patients specially focusing younger patients (<35 years).Method1293 patients received Mitigator DES + at LPS Institute of Cardiology, Kanpur, India. Primary outcome was target lesion failure (TLF)- composite of cardiovascular death, target vessel myocardial infarction (TVMI), and target lesion revascularization (TLR) and secondary end points including peri-procedural device failure (failure of stent delivery, change of stent, stent fracture), target vessel failure (TVF), and patient oriented composite end point (POCE)-composite of all deaths, MI, and revascularization and stent thrombosis (ST) at 1-year follow-up.ResultYounger population comprised of 374 (29%) patients. Various indications of interventions were STEMI (n = 614; 47.4%), NSTEMI (n = 416; 32.2%), UA (n = 161; 12.5%), and CCS (n = 102; 7.9%). TLF at 1 year in young and overall population were 3.4% and 3.5% respectively which was driven by TVMI and TLR in 1.3% and 1.1% patients respectively. POCE was observed in 9.5% in each group mainly contributed by any revascularization (3.9%). Device failure was significantly lower in young group than overall population (1.3% vs. 2.2%; p = 0.04) which was mainly driven by stent delivery (1.1%) and edge dissection (0.5%). Definite and probable ST was 1.3% and 1.7% respectively which was not significant. Young patients showed insignificantly lower TLF, TVF, ST and POCE and significantly lower device failure (1.3% vs. 2.6%; p = 0.04) when compared to patients >35 years. On multivariate regression analysis, complex lesion, in-stent restenosis, failure of stent delivery and edge dissection were independent predictors of events or device success rate.ConclusionMitigator DES+™ is safe among real world patients, including young population.     

Phase I study of weekly (day 1 and 8) docetaxel in combination with capecitabine in patients with advanced solid malignancies

Purpose Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in a number of tumor types, but at the expense of significant toxicity. To improve the therapeutic index, we evaluated a weekly regimen of docetaxel in combination with capecitabine, and determined the maximum tolerated dose, toxicities and pharmacokinetics of this combination.Patients and methods Patients with advanced solid malignancies were treated with docetaxel on days 1 and 8, and capecitabine, twice daily on days 1–14, of an every-21-day cycle. Pharmacokinetics of docetaxel were assessed on days 1 and 8 of the first cycle of chemotherapy.Results Enrolled in the study were 25 patients. The most frequent toxicities were asthenia, hand-foot syndrome and mucositis. Inability to deliver at least 75% of the planned doses of both drugs during the first two cycles of chemotherapy was noted at dose levels 2, 3 and 4. Dose level 1 (docetaxel 30 mg/m² and capecitabine 825 mg/m² twice daily) is the recommended dose for phase II studies. Five patients experienced a partial response, and eight patients had stabilization of disease. Coadministration of capecitabine did not alter the pharmacokinetics of docetaxel.Conclusion The regimen consisting of docetaxel 30 mg/m² (days 1, 8) and capecitabine 825 mg/m² twice daily (days 1–14) was well tolerated. Capecitabine did not alter pharmacokinetics of docetaxel. Further testing of this regimen in tumor-specific trials, especially gastric, lung and breast cancer, is warranted.Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, May 2003, Chicago, IL.     

Berry anthocyanidins synergistically suppress growth and invasive potential of human non-small-cell lung cancer cells

P-glycoprotein-mediated multidrug resistance (MDR) is a major limiting factor in the efficacy of most microtubule-targeting agents. Here, we investigated the novel, synthetic, and small-molecule microtubule-destabilizing agent, 2-(2-amino-5-(1-ethyl-1H-indol-5-yl) pyrimidin-4-yl) phenol (YHHU0895), for its anti-tumor activity and potential for overcoming P-glycoprotein-mediated MDR. YHHU0895 inhibited purified tubulin polymerization through binding to tubulin at the colchicine-binding site and significantly inhibited human tumor cell proliferation. Notably, P-glycoprotein-overexpressing KBV200 and K562/ADR cells, which are strongly resistant to colchicine, vinorelbine and paclitaxel, were sensitive to YHHU0895 both in vitro and in vivo. These findings indicate that YHHU0895 is a novel type of microtubule-destabilizing agent that has the potential for the treatment of patients with drug resistance mediated by P-glycoprotein.     

Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells

Cervical cancer is caused by human papilloma virus (HPV) expressing E6 and E7 oncoproteins, which are known to inactivate tumor suppressor proteins p53 and pRb, respectively. Repression of HPV oncoproteins would therefore result in reactivation of tumor suppressor pathways and cause apoptosis in cancer cells. Withaferin A (WA), the active component of the medicinal plant Withania Somnifera, has exhibited inhibitory effects against several different cancers. We examined the activity of WA on human cervical cancer cells in vitro and in vivo. WA potently inhibited proliferation of the cervical cancer cells, CaSki (IC(50) 0.45 ± 0.05 μM). Mechanistically, WA was found to (i) downregulate expression of HPV E6 and E7 oncoproteins, (ii) induce accumulation of p53, (iii) increase levels of p21(cip1/waf1) and its interaction with proliferating cell nuclear antigen (PCNA), (iv) cause G(2)/M cell cycle arrest, associated with modulation of cyclin B1, p34(cdc2) and PCNA levels, (v) decrease the levels of STAT3 and its phosphorylation at Tyr(705) and Ser(727) and (vi) alter expression levels of p53-mediated apoptotic markers-Bcl2, Bax, caspase-3 and cleaved PARP. In vivo, WA resulted in reduction of nearly 70% of the tumor volume in athymic nude mice with essentially similar trend in the modulation of molecular markers as in vitro. This is the first demonstration indicating that WA significantly downregulates expression of HPV E6/E7 oncogenes and restores the p53 pathway, resulting in apoptosis of cervical cancer cells. Together, our data suggest that WA can be exploited as a potent therapeutic agent for the treatment and prevention of cervical cancer without deleterious effects.     

Effect of exposure to fentanyl aerosol in mice on breathing pattern and respiratory variables

The breathing pattern of mice that were exposed to fentanyl aerosol was studied (2.7, 5.7, 6.0, 10.0, and 23.6 μg/m³; for 1 hour), using dimethyl sulfoxide as a vehicle. This study was conducted in a head-only exposure assembly. Body plethysmographs connected to a volumetric pressure transducer were used to capture the respiratory signals, and an on-line computer program capable of recognizing the changes in the breathing pattern was used for monitoring the respiratory pattern. The response of mice to fentanyl exposure was found to be concentration dependent. A lower concentration (2.7 μg/m³) showed fast recovery and no mortality, while 100% mortality was observed at a higher concentration (23.6 μg/m³). No sensory, pulmonary irritation, and airway limitation in mice was observed, and death occurred probably due to respiratory depression. The concentration that decreased 50% of the respiratory frequency (RD₅₀) was estimated to be 6.4 μg/m³. The extrapolated human threshold limit value, calculated from the RD₅₀ value, was found to be 0.192 μg/m³. The concentration that caused 50% mortality in exposed mice (LC₅₀) was estimated to be 8.8 μg/m³. This study shows that aerosolized fentanyl does not cause sensory and pulmonary irritation, and since the RD₅₀ and LC₅₀ are very close with a low safety margin, this type of sedative should not be used as an incapacitating agent.