Preconditioning-specific reduction of c-fos expression in hippocampal granule and pyramidal but not other forebrain neurons of ischemic brain: a quantitative immunohistochemical study

To specify targets for an ischemic preconditioning paradigm (ischemic tolerance), c-fos expressions in ischemic (induced by 10 min bilateral carotid-occlusions subsequent to coagulation of vertebral arteries) and preconditioned rats (treated for 4 min carotid-occlusions 72 h before ischemia) were compared in 12 forebrain areas/nuclei. Fos immunostaining was applied to serial sections of the forebrain and the density (cell number/area measured) of Fos-immunopositive (Fos+) neurons, as well as their percentile changes were determined in five hippocampal and seven extrahippocampal areas/nuclei of ischemic and preconditioned rats. The ratio of counts found in ischemic over control animals showed several fold increase of Fos+ cells in the three layers (granule cell, molecular and polymorphic) of the dentate gyrus, CA3 and CA1 pyramidal neurons, as well as in thalamic and hypothalamic nuclei and limbic cortical areas. In contrast, preconditioning did not alter c-fos expressions significantly in the extrahippocampal brain areas investigated. These results strengthen the hypothesis that the hippocampal and dentate neurons are more susceptible to ischemic tolerance than cells in other brain regions. In fact stress-response and induction of ischemic tolerance in different forebrain areas can be distinguished.     

A Web-Based Interactive Patient-Provider Software Platform Does Not Increase Patient Satisfaction or Decrease Hospital Resource Utilization in Total Knee and Hip Arthroplasty Patients in a Single Large Hospital System

BackgroundWeb-based platforms used to enhance patient-provider communication are being explored to improve patient satisfaction and care delivery, and decrease cost. This study tested a web-based interactive patient-provider software platform (IPSP), JointCOACH, which enabled patient communication with their care team and preparatory/recovery guidance. The aims of this study are to compare (1) patient satisfaction and (2) healthcare resource utilization by patients who underwent total knee and hip replacements and added IPSP to standard of care (SOC).MethodsThis study is a prospective, randomized clinical trial at a single large academic healthcare system. Between May 2018 and March 2020, 399 patients undergoing elective total hip or knee arthroplasty were randomized to SOC arm (n = 204) or SOC + IPSP arm (n = 195). Patient demographics, surgical details, and comorbidities were collected. Patient satisfaction was assessed using Visual Analog Scale and the Picker Patient Experience-15. Healthcare utilization was measured using length of stay, emergency department and office visits, office calls, readmissions, and reoperations at 30 and 90 days after surgery.ResultsNo difference was found in length of stay between SOC and SOC + IPSP. No differences were found in 30-day or 90-day satisfaction or in healthcare resource utilization (P > .05) including number of office and emergency department visits, phone calls, and readmissions.ConclusionStatistical differences were not found in satisfaction and healthcare utilization with the addition of IPSP to SOC. IPSP can be used to reinforce patient education and communication between the patient and provider, and should be evaluated as an element of virtual care rather than supplementing traditional in-office follow-up.Clinicaltrials.govMore information on this study can be found at clinicaltrials.gov NCT03499028.     

Treatment feasibility of a digital tool for brief self-help behavioural therapy for insomnia (FastAsleep)

Cognitive behavioural therapy for insomnia is efficacious and recommended for insomnia, but availability is scarce. Cognitive behavioural therapy for insomnia self-help interventions could increase availability, especially if unguided. Optimizing cognitive behavioural therapy for insomnia methods and system user-friendliness, we developed a short, digital, self-help programme—FastAsleep—based on the behavioural components of sleep restriction and stimulus control. This study investigated its feasibility and preliminary effects. Thirty media-recruited participants with moderate to severe insomnia were assessed via telephone before using FastAsleep for 4 weeks, and were interviewed afterwards. Self-ratings with web questionnaires were conducted at screening, pre-, mid- and post-treatment, and at 3-month follow-up. Primary outcomes were feasibility (credibility, adherence, system user-friendliness and adverse effects), and secondary outcomes were changes in symptom severity (insomnia, depression and anxiety). Adherence was generally high, participants' feasibility ratings were favourable, and adverse effects matched previously reported levels for cognitive behavioural therapy for insomnia. Symptoms of insomnia decreased after the treatment period (Hedge's g = 1.79, 95% confidence interval = 1.20–2.39), as did symptoms of depression and anxiety. FastAsleep can be considered feasible and promising for alleviating insomnia symptoms among patients fit for self-care. Future controlled trials are needed to establish the efficacy of FastAsleep and its suitability in a stepped care model.     

Intraoperative retinal light damage reflected in electrophysiologic data

In a series of 30 unilaterally pseudophakic patients, electroretinograms and electrooculograms were recorded 6 months postoperatively. The unoperated on fellow eyes served as controls High intraoperative retinal light exposure (3.4–7.3 mW/cm², Zeiss OPMI 6 operating microscope) caused a substantial reduction of electrophysiologic potentials. Light protection prevented deterioration of electroretinogram and electro-oculogram potentials; reducing the bulb voltage, tilting the axis of illumination, filtering short wavelengths and the use of light shields resulted in 4-log-unit lower intensities (0.8–3.7 W/cm²).Abbreviations ACL anterior chamber lens - ECCE extracapsular cataract extraction - ICCE intracapsular cataract extraction - PCL posterior chamber lens     

Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients.

CCI-779 is an ester of rapamycin and inhibitor of mammalian target of rapamycin (mTOR) currently in Phase II clinical development for the treatment of patients with cancer. CCI-779 interacts with mTOR and inhibits its kinase activity, resulting in inhibition of the mTOR-regulated translational controllers p70(s6) kinase and 4E-BP1. Ultimately, CCI-779 decreases the translation of mRNAs involved in the control of the cell cycle, resulting in cell cycle arrest. The objective of this study was to develop a method to determine the pharmacodynamic effects of CCI-779 suitable for use in clinical trials. Exposure of Raji lymphoblastoid cells to increasing concentrations of rapamycin resulted in a linear concentration-dependent inhibition of p70(s6) kinase activity, suggesting that p70(s6) kinase activity could be an appropriate marker for mTOR-interacting agents. In subsequent experiments, treatment of nude mice bearing the CCI-779 susceptible breast cancer cell line MDA-468 with a single dose of 10 mg/kg CCI-779 resulted in a >80% inhibition of p70(s6) kinase activity in peripheral blood mononuclear cells (PBMCs) 72 h after treatment. Importantly, the degree of p70(s6) kinase inhibition was identical in PBMCs and simultaneously collected tumor tissue, suggesting that the PBMCs are an adequate surrogate tissue for p70(s6) kinase activity in vivo. The intrasubject coefficient of variation of p70(s6) kinase activity measured in PBMCs collected from five healthy volunteers on days 1, 4, and 8 was 14%, indicating that p70(s6) kinase activity in PBMCs remains relatively stable over time. Finally, p70(s6) kinase activity was measured in PBMCs from nine patients with renal cell cancer treated with a single dose of 25, 75, or 250 mg of CCI-779 i.v. (three patients each). PBMCs were collected on days 2, 4, and 8 after CCI-779 treatment. In this small data set, eight of the nine patients had evidence of p70(s6) kinase activity inhibition after treatment that was independent of the administered dose. There was a significant linear association between time to disease progression and inhibition of p70(s6) kinase activity 24 h after treatment. In conclusion, these results indicate that the pharmacodynamic effects of CCI-779 can be determined using a p70(s6) kinase assay in PBMCs. This assay is currently being incorporated in Phase I and II studies with CCI-779 to determine its relationship with dose and plasma concentration of the agent and its value as a predictor of treatment efficacy.     

Evolutionary Classification of Homeodomains

Purpose and Methods: We performed multiple comparisons between available amino acid (aa) sequences of homeodomain(HOM)-containing proteins from a wide spectrum of animals to create an evolutionary classification of the proteins. Results: Based on results of statistical and special computational analyses of over 500 homeodomain aa sequences (HOMs) a novel system of concepts describing complex structural correlations between homologous proteins is proposed. This system includes such notions as differentiated isofunctionality of aa, chemotype, stereotype, local functional motifs, gradual conservativeness of aa positions, and group-specific domain patterns, as well as major categories of the evolutionary classification of HOMs (Division, Type, Branch, Class, Family, Series, Variety, Sort). Using this approach, a complete structural systematics of HOMs belonging to proteomes of eukaryotic animals is proposed. Conclusions: The proposed structural classification of HOMs is in full agreement with the bulk of experimental data revealing complex functional similarities and differences among HOMs in terms of their expression patterns in developing embryos. It turn, this classification can provide answers regarding homology among homeodomains when experimental data are conflicting.     

TNF-α gene polymorphisms: association with age-related macular degeneration in Russian population

AIM: To study polymorphisms in promotor regions of tumor necrosis factor (TNF)-α TNF-863A/C (rs1800630), TNF-308A/G (rs1800629), and TNF-238A/G (rs361525) in patients with age-related macular degeneration (AMD) and associations of complex TNF-α genotypes with AMD. METHODS: One hundred and two patients (82 women, 20 men; mean age 64.2±1.2y) with AMD and 100 healthy age- and sex-matched controls (82 women, 18 men; 60±1.4y) were included in the study. All subjects were Caucasian, all subjects and their parents were inhabitants of Russia. Genomic DNA was obtained from EDTA-preserved blood using the standard phenol-chloroform method. Polymorphisms were detected by polymerase chain reaction followed by the restriction fragment length polymorphism method. The following TNF-α genotypes were studied: TNF-α-238 AA, GA, GG, TNF-α-308 AA, GA, GG, TNF-α-863 AA, CA, CC. RESULTS: Differences in TNF-α-863 and TNF-α-238 genotypes frequencies in patients with AMD and healthy controls were not found. The distribution of TNF-α-308 AA and TNF-α-308 GA genotypes was significantly different between the studied group and the controls [odds ratios (OR) =0.22, P=0.0287 and OR=2.91, P=0.0063, respectively]. TNF-863CC/TNF-308GA and TNF-308GA/TNF-238GG genotypes were associated with the increased risk of AMD (OR=2.48, P=0.0332 and OR=2.51, P=0.0187, respectively). Five genotypes combinations appeared to be protective. CONCLUSION: In the present study, single nucleotide polymorphisms and complex polymorphisms of one of the key inflammatory cytokines TNF-α, and a number of significant associations of these polymorphisms with AMD in Russian population have been shown. Complex analysis of genotypes could be important in AMD risk factors detection and studying pathogenesis.