The Use of Heart Rate Responses Extracted From Functional Near-Infrared Spectroscopy Data as a Measure of Speech Discrimination Ability in Sleeping Infants.

OBJECTIVES: Cardiac responses (e.g., heart rate changes) due to an autonomous response to sensory stimuli have been reported in several studies. This study investigated whether heart rate information extracted from functional near-infrared spectroscopy (fNIRS) data can be used to assess the discrimination of speech sounds in sleeping infants. This study also investigated the adaptation of the heart rate response over multiple, sequential stimulus presentations. DESIGN: fNIRS data were recorded from 23 infants with no known hearing loss, aged 2 to 10 months. Speech syllables were presented using a habituation/dishabituation test paradigm: the infant's heart rate response was first habituated by repeating blocks of one speech sound; then, the heart rate response was dishabituated with the contrasting (novel) speech sound. This stimulus presentation sequence was repeated for as long as the infants were asleep. RESULTS: The group-level average heart rate response to the novel stimulus was greater than that to the habituated first sound, indicating that sleeping infants were able to discriminate the speech sound contrast. A significant adaptation of the heart rate responses was seen over the session duration. CONCLUSION: The dishabituation response could be a valuable marker for speech discrimination, especially when used in conjunction with the fNIRS hemodynamic response.

Analysis and dissociation of anti-HIV effects of shRNA to CCR5 and the fusion inhibitor C46.

BACKGROUND: The gene therapeutic Cal-1 comprises the anti-HIV agents: (i) sh5, a short hairpin RNA to CCR5 that down-regulates CCR5 expression and (ii) maC46 (C46), a peptide that inhibits viral fusion with the cell membrane. These constructs were assessed for inhibition of viral replication and selective cell expansion in a number of settings. METHODS: HIV replication, selective outgrowth and cell surface viral binding were analysed with a single cycle infection assay of six pseudotyped HIV strains and a static and longitudinal passaging of MOLT4/CCR5 cells with HIV. Pronase digestion of surface virus and fluorescence microscopy assessed interactions between HIV virions and transduced cells. RESULTS: Cal-1 reduced CCR5 expression in peripheral blood mononuclear cells to CCR5Δ32 heterozygote levels. Even low level transduction resulted in significant preferential expansion in MOLT4/CCR5 gene-containing cells over a 3-week HIV challenge regardless of viral suppression [12.5% to 47.0% (C46), 46.7% (sh5), 62.2% (Dual), respectively]. The sh5 and Dual constructs at > 95% transduction also significantly suppressed virus to day 12 in the passage assay and all constructs, at varying percentage transduction inhibited virus in static culture. No escape mutations were present through 9 weeks of challenge. The Dual construct significantly suppressed infection by a panel of CCR5-using viruses, with its efficacy being independently determined from the single constructs. Dual and sh5 inhibited virion internalisation, as determined via pronase digestion of surface bound virus, by 70% compared to 13% for C46. CONCLUSIONS: The use of two anti-HIV genes allows optimal preferential survival and inhibition of HIV replication, with the impact on viral load being dependent on the percentage of gene marked cells.

A quantitative comparison of anti-HIV gene therapy delivered to hematopoietic stem cells versus CD4+ T cells.

Gene therapy represents an alternative and promising anti-HIV modality to highly active antiretroviral therapy. It involves the introduction of a protective gene into a cell, thereby conferring protection against HIV. While clinical trials to date have delivered gene therapy to CD4+T cells or to CD34+ hematopoietic stem cells (HSC), the relative benefits of each of these two cellular targets have not been conclusively determined. In the present analysis, we investigated the relative merits of delivering a dual construct (CCR5 entry inhibitor + C46 fusion inhibitor) to either CD4+T cells or to CD34+ HSC. Using mathematical modelling, we determined the impact of each scenario in terms of total CD4+T cell counts over a 10 year period, and also in terms of inhibition of CCR5 and CXCR4 tropic virus. Our modelling determined that therapy delivery to CD34+ HSC generally resulted in better outcomes than delivery to CD4+T cells. An early one-off therapy delivery to CD34+ HSC, assuming that 20% of CD34+ HSC in the bone marrow were gene-modified (G+), resulted in total CD4+T cell counts ≥ 180 cells/ µL in peripheral blood after 10 years. If the uninfected G+ CD4+T cells (in addition to exhibiting lower likelihood of becoming productively infected) also exhibited reduced levels of bystander apoptosis (92.5% reduction) over non gene-modified (G-) CD4+T cells, then total CD4+T cell counts of ≥ 350 cells/ µL were observed after 10 years, even if initially only 10% of CD34+ HSC in the bone marrow received the protective gene. Taken together our results indicate that: 1.) therapy delivery to CD34+ HSC will result in better outcomes than delivery to CD4+T cells, and 2.) a greater impact of gene therapy will be observed if G+ CD4+T cells exhibit reduced levels of bystander apoptosis over G- CD4+T cells.

Research on the Effect of Load and Rotation Speed on Resistance to Combined Wear of Stainless Steels Using ANOVA Analysis.

This research was carried out with the aim of obtaining appropriate principles for describing the influence of working parameters and the aggressive action of an acidic medium on the wear and corrosion resistance of martensitic stainless steels. Tribological tests were performed on induction-hardened surfaces of stainless steels X20Cr13 and X17CrNi16-2 under combined wear conditions at a load of 100 to 300 N and a rotation speed of 382 to 754 min-1. The wear test was carried out on a tribometer with the use of an aggressive medium in the chamber. After each wear cycle on the tribometer, the samples were exposed to corrosion action in a corrosion test bath. Analysis of variance revealed a significant influence of rotation speed and load due to wear on the tribometer. Testing the difference in the mass loss values of the samples due to corrosion using the Mann-Whitney U test did not show a significant effect of corrosion. Steel X20Cr13 showed greater resistance to combined wear, which had a 27% lower wear intensity compared to steel X17CrNi16-2. The increase in wear resistance of X20Cr13 steel can be attributed to the higher surface hardness achieved and the effective depth of hardening. The mentioned resistance is the result of the creation of a martensitic surface layer with dispersed carbides, which increases the resistance to abrasion, dynamic durability, and fatigue of the surface of the protective layer.

T-lymphocyte perturbation following large-scale apheresis and hematopoietic stem cell transplantation in HIV-infected individuals.

Analysis and mathematical modeling of T-lymphocyte perturbation following administration of granulocyte colony stimulating factor (G-CSF) and two large-scale aphereses are reported. 74 HIV-1 positive antiretroviral-treated individuals were infused with gene- or sham-transduced CD34+ hematopoietic stem cells (HSC) in a Phase II clinical trial. T cell numbers were examined in four phases: 1) during steady state; 2) increases in peripheral blood (PB) following G-CSF administration; 3) depletion post-aphereses and 4) reconstitution post HSC infusion. The present analysis provides the first direct estimate of CD4+ T cell distribution and trafficking in HIV-infected individuals on stable HAART, indicating that CD4+ T lymphocytes in PB represent 5.5% of the pool of CD4+ T lymphocytes that traffic to PB.

Speech token detection and discrimination in individual infants using functional near-infrared spectroscopy.

Speech detection and discrimination ability are important measures of hearing ability that may inform crucial audiological intervention decisions for individuals with a hearing impairment. However, behavioral assessment of speech discrimination can be difficult and inaccurate in infants, prompting the need for an objective measure of speech detection and discrimination ability. In this study, the authors used functional near-infrared spectroscopy (fNIRS) as the objective measure. Twenty-three infants, 2 to 10 months of age participated, all of whom had passed newborn hearing screening or diagnostic audiology testing. They were presented with speech tokens at a comfortable listening level in a natural sleep state using a habituation/dishabituation paradigm. The authors hypothesized that fNIRS responses to speech token detection as well as speech token contrast discrimination could be measured in individual infants. The authors found significant fNIRS responses to speech detection in 87% of tested infants (false positive rate 0%), as well as to speech discrimination in 35% of tested infants (false positive rate 9%). The results show initial promise for the use of fNIRS as an objective clinical tool for measuring infant speech detection and discrimination ability; the authors highlight the further optimizations of test procedures and analysis techniques that would be required to improve accuracy and reliability to levels needed for clinical decision-making.

Comparative Characteristics of Ductile Iron and Austempered Ductile Iron Modeled by Neural Network.

Experimental research of cutting force components during dry face milling operations are presented in the paper. The study was provided when milling of ductile cast iron alloyed with copper and its austempered ductile iron after the proper austempering process. In the study, virtual instrumentation designed for cutting forces components monitoring was used. During the research, orthogonal cutting forces components versus time were monitored and relationship of cutting forces components versus speed, feed and depth of cut were determined by artificial neural network and response surface methodology. An analysis was made regarding the consistency of the measured cutting forces and the values obtained from the model supported by an artificial neural network for the investigated interval of the cutting regime. Based on the results, an analysis of the feasibility of the application of austempered ductile iron in the industrial sector with the aspect of machinability as well as the application of the models based on artificial intelligence, was given. At the end of the presentation, the influence of the aforementioned cutting regimes on cutting force components is presented as well.

Stochastic model of in-vivo X4 emergence during HIV infection: implications for the CCR5 inhibitor maraviroc.

The emergence of X4 tropic viral strains throughout the course of HIV infection is associated with poorer prognostic outcomes and faster progressions to AIDS than for patients in whom R5 viral strains predominate. Here we investigate a stochastic model to account for the emergence of X4 virus via mutational intermediates of lower fitness that exhibit dual/mixed (D/M) tropism, and employ the model to investigate whether the administration of CCR5 blockers in-vivo is likely to promote a shift towards X4 tropism. We show that the proposed stochastic model can account for X4 emergence with a median time of approximately 4 years post-infection as a result of: 1.) random stochastic mutations in the V3 region of env during the reverse transcription step of infection; 2.) increasing numbers of CXCR4-expressing activated naive CD4+ T cells with declining total CD4+ T cell counts, thereby providing increased numbers of activated target cells for productive infection by X4 virus. Our model indicates that administration of the CCR5 blocker maraviroc does not promote a shift towards X4 tropism, assuming sufficient efficacy of background therapy (BT). However our modelling also indicates that administration of maraviroc as a monotherapy or with BT of suboptimal efficacy can promote emergence of X4 tropic virus, resulting in accelerated progression to AIDS. Taken together, our results demonstrate that maraviroc is safe and effective if co-administered with sufficiently potent BT, but that suboptimal BT may promote X4 emergence and accelerated progression to AIDS. These results underscore the clinical importance for careful selection of BT when CCR5 blockers are administered in-vivo.