Coherent lidars based on intracavity heterodyning of echo signals

The development and technical realization of the method of laser sounding of the atmosphere based on the effects of mixing of reference and external fields of scattering inside a laser cavity are presented. An approximate theory of the method was developed on the basis of the investigations using the model of a three-mirror laser. The nonlinear effect of a wideband laser on frequency-dependent external influences of the atmosphere was investigated. The field measurements of gaseous composition of the atmosphere were performed on the basis of a given method of coherent reception using a tunable CO2 laser

Clinical pattern of tolvaptan-associated liver injury in trial participants with autosomal dominant polycystic kidney disease (ADPKD): An analysis of pivotal clinical trials

RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted. STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan. SETTING & PARTICIPANTS: Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure. INTERVENTION: Tolvaptan administered twice daily in split-dose regimens. OUTCOMES: Frequency of liver enzyme level increases detected by regular laboratory monitoring. RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to \u3e3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to \u3e3× ULN and total bilirubin increases to \u3e2× ULN ( Hy\u27s Law laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical adaptation after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan. LIMITATIONS: Retrospective analysis. CONCLUSIONS: The absence of Hy\u27s Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label. FUNDING: Otsuka Pharmaceutical Development & Commercialization, Inc. TRIAL REGISTRATION: Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension)

Candidate Risk Factors and Mechanisms for Tolvaptan-Induced Liver Injury Are Identified Using a Collaborative Cross Approach

Clinical trials of tolvaptan showed it to be a promising candidate for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) but also revealed potential for idiosyncratic drug-induced liver injury (DILI) in this patient population. To identify risk factors and mechanisms underlying tolvaptan DILI, 8 mice in each of 45 strains of the genetically diverse Collaborative Cross (CC) mouse population were treated with a single oral dose of either tolvaptan or vehicle. Significant elevations in plasma alanine aminotransferase (ALT) were observed in tolvaptan-treated animals in 3 of the 45 strains. Genetic mapping coupled with transcriptomic analysis in the liver was used to identify several candidate susceptibility genes including epoxide hydrolase 2, interferon regulatory factor 3, and mitochondrial fission factor. Gene pathway analysis revealed that oxidative stress and immune response pathways were activated in response to tolvaptan treatment across all strains, but genes involved in regulation of bile acid homeostasis were most associated with tolvaptan-induced elevations in ALT. Secretory leukocyte peptidase inhibitor (Slpi) mRNA was also induced in the susceptible strains and was associated with increased plasma levels of Slpi protein, suggesting a potential serum marker for DILI susceptibility. In summary, tolvaptan induced signs of oxidative stress, mitochondrial dysfunction, and innate immune response in all strains, but variation in bile acid homeostasis was most associated with susceptibility to the liver response. This CC study has indicated potential mechanisms underlying tolvaptan DILI and biomarkers of susceptibility that may be useful in managing the risk of DILI in ADPKD patients

Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors

Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based tolvaptan risk-mitigation strategies

REMAGNETIZATION PROCESSES IN SINTERED Sm-Co И Nd-Fe-B PERMANENT MAGNETS

The processes of remagnetization in permanent magnets of the Sm2Co17 and Nd2Fe14B systems were studied. The mechanism for the formation of coercivity is established via su-perposition coherent rotation or pinning in accordance of the Kondorski and Stoner-Wohlfarth models.Проект выполнен при финансовой поддержке Российского фонда фундаментальных исследований, грант № 20-32-90211\20

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

An investigation into the executive functioning of methadone-maintained patients

Recent studies of cognitive deficits associated with substance use have converged with extant neuroimaging literature upon the notion that chronic substance users exhibit impairments on executive-type tasks mediated by orbitofrontal and ventromedial prefrontal cortex. However, few studies have examined the executive functioning of patients on daily methadone-maintenance treatment. This thesis aimed to investigate the executive abilities of 16 methadone-maintained, chronic polydrug-using, patients compared with 14 non-drug using individuals. The groups did not differ significantly on premorbid IQ. current non-verbal reasoning, gender, ethnicity and employment status. Executive abilities related to response initiation and inhibition, responsivity to reward and rule attainment were explored because impairments on these tasks have been described as being of clinical significance. Executive skills related to planning and multi-tasking behaviour were also assessed on an "ecologically-valid" Hotel task, designed to mimic the skills involved in open-ended everyday activities faced in real- world settings. Self-ratings of executive problems on a dysexecutive questionnaire were explored in relation to independent ratings by patients' keyworkers and performance on executive tasks. Methadone-maintained users performed significantly more poorly on multitasking and appeared to use less efficient strategies compared with controls. These group differences were robust to covariance of depression, age and years of education. However, the same covariates influenced findings on tasks tapping response inhibition, reward responsivity and rule attainment. There was no evidence that substance users lacked insight into their executive difficulties, moreover keyworkers rated their patients' difficulties as less severe than patients' self-ratings. The results imply that methadone-maintained patients may have more difficulty than non-drug using individuals on activities that require intact planning and organisation skills, a finding which may have implications for their ability to engage in the tasks of therapy and rehabilitation. Similarly, the results suggest that cognitive deficits may underlie many of the difficulties faced by chronic substance users' in organising and maintaining their everyday lives. Techniques utilised in neurological rehabilitation research are discussed as potentially having a useful role in reducing the impact of executive deficits on substance-users' everyday lives