The corticofugal oscillatory modulation of the cochlear receptor during auditory and visual attention is preserved in tinnitus.

Introduction: The mechanisms underlying tinnitus perception are still under research. One of the proposed hypotheses involves an alteration in top-down processing of auditory activity. Low-frequency oscillations in the delta and theta bands have been recently described in brain and cochlear infrasonic signals during selective attention paradigms in normal hearing controls. Here, we propose that the top-down oscillatory activity observed in brain and cochlear signals during auditory and visual selective attention in normal subjects, is altered in tinnitus patients, reflecting an abnormal functioning of the corticofugal pathways that connect brain circuits with the cochlear receptor. Methods: To test this hypothesis, we used a behavioral task that alternates between auditory and visual top-down attention while we simultaneously measured electroencephalogram (EEG) and distortion-product otoacoustic emissions (DPOAE) signals in 14 tinnitus and 14 control subjects. Results: We found oscillatory activity in the delta and theta bands in cortical and cochlear channels in control and tinnitus patients. There were significant decreases in the DPOAE oscillatory amplitude during the visual attention period as compared to the auditory attention period in tinnitus and control groups. We did not find significant differences when using a between-subjects statistical approach comparing tinnitus and control groups. On the other hand, we found a significant cluster in the delta band in tinnitus when using within-group statistics to compare the difference between auditory and visual DPOAE oscillatory power. Conclusion: These results confirm the presence of top-down infrasonic low-frequency cochlear oscillatory activity in the delta and theta bands in tinnitus patients, showing that the corticofugal suppression of cochlear oscillations during visual and auditory attention in tinnitus patients is preserved.

Study protocol and rationale of the "Cogni-action project" a cross-sectional and randomized controlled trial about physical activity, brain health, cognition, and educational achievement in schoolchildren.

BACKGROUND: Education and health are crucial topics for public policies as both largely determine the future wellbeing of the society. Currently, several studies recognize that physical activity (PA) benefits brain health in children. However, most of these studies have not been carried out in developing countries or lack the transference into the education field. The Cogni-Action Project is divided into two stages, a cross-sectional study and a crossover-randomized trial. The aim of the first part is to establish the associations of PA, sedentarism, and physical fitness with brain structure and function, cognitive performance and academic achievement in Chilean schoolchildren (10-13 years-old). The aim of the second part is to determinate the acute effects of three PA protocols on neuroelectric indices during a working memory and a reading task. METHODS: PA and sedentarism will be self-reported and objectively-assessed with accelerometers in a representative subsample, whilst physical fitness will be evaluated through the ALPHA fitness test battery. Brain structure and function will be assessed by magnetic resonance imaging (MRI) in a randomized subsample. Cognitive performance will be assessed through the NeuroCognitive Performance Test, and academic achievement by school grades. In the second part 32 adolescents (12-13 year-old) will be cross-over randomized to these condition (i) "Moderate-Intensity Continuous Training" (MICT), (ii) "Cooperative High-Intensity Interval Training" (C-HIIT), and (iii) Sedentary condition. Neuroelectric indices will be measures by electroencephalogram (EEG) and eye-tracking, working memory by n-back task and reading comprehension by a reading task. DISCUSSION: The main strength of this project is that, to our knowledge, this is the first study analysing the potential association of PA, sedentarism, and physical fitness on brain structure and function, cognitive performance, and academic achievement in a developing country, which presents an important sociocultural gap. For this purpose, this project will use advanced technologies in neuroimaging (MRI), electrophysiology (EEG), and eye-tracking, as well as objective and quality measurements of several physical and cognitive health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03894241 Date of register: March 28, 2019. Retrospectively Registered.

Oscillatory infrasonic modulation of the cochlear amplifier by selective attention.

Evidence shows that selective attention to visual stimuli modulates the gain of cochlear responses, probably through auditory-cortex descending pathways. At the cerebral cortex level, amplitude and phase changes of neural oscillations have been proposed as a correlate of selective attention. However, whether sensory receptors are also influenced by the oscillatory network during attention tasks remains unknown. Here, we searched for oscillatory attention-related activity at the cochlear receptor level in humans. We used an alternating visual/auditory selective attention task and measured electroencephalographic activity simultaneously to distortion product otoacoustic emissions (a measure of cochlear receptor-cell activity). In order to search for cochlear oscillatory activity, the otoacoustic emission signal, was included as an additional channel in the electroencephalogram analyses. This method allowed us to evaluate dynamic changes in cochlear oscillations within the same range of frequencies (1-35 Hz) in which cognitive effects are commonly observed in electroencephalogram works. We found the presence of low frequency (<10 Hz) brain and cochlear amplifier oscillations during selective attention to visual and auditory stimuli. Notably, switching between auditory and visual attention modulates the amplitude and the temporal order of brain and inner ear oscillations. These results extend the role of the oscillatory activity network during cognition in neural systems to the receptor level.

On the Origin of the 1,000 Hz Peak in the Spectrum of the Human Tympanic Electrical Noise.

The spectral analysis of the spontaneous activity recorded with an electrode positioned near the round window of the guinea pig cochlea shows a broad energy peak between 800 and 1,000 Hz. This spontaneous electric activity is called round window noise or ensemble background activity. In guinea pigs, the proposed origin of this peak is the random sum of the extracellular field potentials generated by action potentials of auditory nerve neurons. In this study, we used a non-invasive method to record the tympanic electric noise (TEN) in humans by means of a tympanic wick electrode. We recorded a total of 24 volunteers, under silent conditions or in response to stimuli of different modalities, including auditory, vestibular, and motor activity. Our results show a reliable peak of spontaneous activity at ~1,000 Hz in all studied subjects. In addition, we found stimulus-driven responses with broad-band noise that in most subjects produced an increase in the magnitude of the energy band around 1,000 Hz (between 650 and 1,200 Hz). Our results with the vestibular stimulation were not conclusive, as we found responses with all caloric stimuli, including 37°C. No responses were observed with motor tasks, like eye movements or blinking. We demonstrate the feasibility of recording neural activity from the electric noise of the tympanic membrane with a non-invasive method. From our results, we suggest that the 1,000 Hz component of the TEN has a mixed origin including peripheral and central auditory pathways. This research opens up the possibility of future clinical non-invasive techniques for the functional study of auditory and vestibular nerves in humans.

Anti-vimentin Antibodies Present at the Time of Transplantation May Predict Early Development of Interstitial Fibrosis/Tubular Atrophy.

BACKGROUND: Anti-vimentin (a cytoskeletal protein) autoantibodies in renal transplant recipients have been correlated with interstitial fibrosis/tubular atrophy (IFTA). In this study, we examine the association between pretransplantation anti-vimentin antibodies and the subsequent development of IFTA. METHODS: Sera obtained before renal transplantation from 97 transplant recipients were analyzed for the presence of anti-vimentin antibodies via Luminex assays to determine the concentration of anti-vimentin antibodies. Results were correlated with findings of IFTA on biopsy as well as graft function and patient and graft survival. RESULTS: In our patient population, 56 of 97 patients were diagnosed by biopsy with IFTA 2.9 (±2.1) years after renal transplantation. Patients with IFTA on biopsy had higher mean concentration of anti-vimentin antibodies when compared to patients without IFTA (32.2 µg/mL [3.97-269.12 µg/mL] vs 14.57 µg/mL [4.71-87.81 µg/mL]). The risk of developing IFTA with a concentration of anti-vimentin antibody >15 µg/mL before transplantation was 1.96 (95% CI = 1.38-2.79, P = .011). Patients with elevated anti-vimentin antibody concentrations (>15 µg/mL) at the time of transplantation also had a higher risk of developing IFTA (81.4% vs 41.2%; P < .05). In addition, graft function was worse at 1, 3, and 5 years posttransplantation in patients with elevated concentrations of pretransplantation anti-vimentin antibody. Although there were more graft losses in the IFTA groups (49.12% vs 25.64%, P = .021) and the IFTA patients loss their grafts earlier (4.3 years vs 3.6 years), there was no statistical difference in graft loss rates. CONCLUSIONS: Pretransplantation anti-vimentin antibody concentrations >15 µg/mL may be a risk factor for IFTA.

Verticillin A Inhibits Leiomyosarcoma and Malignant Peripheral Nerve Sheath Tumor Growth via Induction of Apoptosis.

OBJECTIVE: The heterogeneity of soft tissue sarcoma (STS) represents a major challenge for the development of effective therapeutics. Comprised of over 50 different histology subtypes of various etiologies, STS subsets are further characterized as either karyotypically simple or complex. Due to the number of genetic anomalies associated with genetically complex STS, development of therapies demonstrating potency against this STS cluster is especially challenging and yet greatly needed. Verticillin A is a small molecule natural product with demonstrated anticancer activity; however, the efficacy of this agent has never been evaluated in STS. Therefore, the goal of this study was to explore verticillin A as a potential STS therapeutic. METHODS: We performed survival (MTS) and clonogenic analyses to measure the impact of this agent on the viability and colony formation capability of karyotypically complex STS cell lines: malignant peripheral nerve sheath tumor (MPNST) and leiomyosarcoma (LMS). The in vitro effects of verticillin A on apoptosis were investigated through annexin V/PI flow cytometry analysis and by measuring fluorescently-labeled cleaved caspase 3/7 activity. The impact on cell cycle progression was assessed via cytometric measurement of propidium iodide intercalation. In vivo studies were performed using MPNST xenograft models. Tumors were processed and analyzed using immunohistochemistry (IHC) for verticillin A effects on growth (Ki67) and apoptosis (cleaved caspase 3). RESULTS: Treatment with verticillin A resulted in decreased STS growth and an increase in apoptotic levels after 24 h. 100 nM verticillin A induced significant cellular growth abrogation after 24 h (96.7, 88.7, 72.7, 57, and 39.7% reduction in LMS1, S462, ST88, SKLMS1, and MPNST724, respectively). We observed no arrest in cell cycle, elevated annexin, and a nearly two-fold increase in cleaved caspase 3/7 activity in all MPNST and LMS cell lines. Control normal human Schwann (HSC) and aortic smooth muscle (HASMC) cells displayed higher tolerance to verticillin A treatment compared to sarcoma cell lines, although toxicity was seen in HSC at the highest treatment dose. In vivo studies mirrored the in vitro results: by day 11, tumor size was significantly reduced in MPNST724 xenograft models with treatment of 0.25 and 0.5 mg/kg verticillin A. Additionally, IHC assessment of tumors demonstrated increased cleaved caspase 3 and decreased proliferation (Ki67) following treatment with verticillin A. CONCLUSION: Advancement in the treatment of karyotypically complex STS is confounded by the high level of genetic abnormalities found in these diseases. Consequently, the identification and investigation of novel therapies is greatly needed. Our data suggest that verticillin A selectively inhibits MPNST and LMS growth via induction of apoptosis while exhibiting minimal to moderate effects on normal cells, pointing to verticillin A as a potential treatment for MPNST and LMS, after additional preclinical validation.

The olivocochlear reflex strength and cochlear sensitivity are independently modulated by auditory cortex microstimulation.

In mammals, efferent projections to the cochlear receptor are constituted by olivocochlear (OC) fibers that originate in the superior olivary complex. Medial and lateral OC neurons make synapses with outer hair cells and with auditory nerve fibers, respectively. In addition to the OC system, there are also descending projections from the auditory cortex that are directed towards the thalamus, inferior colliculus, cochlear nucleus, and superior olivary complex. Olivocochlear function can be assessed by measuring a brainstem reflex mediated by auditory nerve fibers, cochlear nucleus neurons, and OC fibers. Although it is known that the OC reflex is activated by contralateral acoustic stimulation and produces a suppression of cochlear responses, the influence of cortical descending pathways in the OC reflex is largely unknown. Here, we used auditory cortex electrical microstimulation in chinchillas to study a possible cortical modulation of cochlear and auditory nerve responses to tones in the absence and presence of contralateral noise. We found that cortical microstimulation produces two different peripheral modulations: (i) changes in cochlear sensitivity evidenced by amplitude modulation of cochlear microphonics and auditory nerve compound action potentials and (ii) enhancement or suppression of the OC reflex strength as measured by auditory nerve responses, which depended on the intersubject variability of the OC reflex. Moreover, both corticofugal effects were not correlated, suggesting the presence of two functionally different efferent pathways. These results demonstrate that auditory cortex electrical microstimulation independently modulates the OC reflex strength and cochlear sensitivity.

Scale-up of a programme for malaria vector control using long-lasting insecticide-treated nets: lessons from South Sudan.

PROBLEM: Long-lasting insecticidal nets (LLINs) are important tools in malaria control. South Sudan, like many other endemic countries, has struggled to improve LLIN coverage and utilization. APPROACH: In 2006, Southern Sudan - known as South Sudan after independence in 2011 - initiated a strategic plan to increase LLIN coverage so that at least 60% of households had at least one LLIN each. By 2008, the target coverage was 80% of households and the Global Fund had financed a phased scale-up of LLIN distribution in the region. LOCAL SETTING: South Sudan's entire population is considered to be at risk of malaria. Poor control of the vectors and the large-scale movements of returnees, internally displaced people and refugees have exacerbated the problem. RELEVANT CHANGES: By 2012, approximately 8.0 million LLINs had been distributed in South Sudan. Between 2006 and 2009, the percentage of households possessing at least one LLIN increased from about 12% to 53% and LLIN utilization rates increased from 5 to 25% among children younger than 5 years and from 5 to 36% among pregnant women. The number of recorded malaria cases increased from 71 948 in 2008 to 1 198 357 in 2012. LESSONS LEARNT: In post-conflict settings, a phased programme for the national scale-up of LLIN coverage may not have a substantial impact. A nationwide campaign that is centrally coordinated and based on sound guidelines may offer greater benefits. A strong partnership base and effective channels for the timely and supplementary deployment of LLINs may be essential for universal coverage.

Malaria indicator survey 2009, South Sudan: baseline results at household level.

BACKGROUND: South Sudan has borne the brunt of years of chronic warfare and probably has the highest malaria burden in sub-Saharan Africa. Malaria is the leading cause of morbidity and mortality in the country. This nationally representative survey aimed to provide data on malaria indicators at household level across the country. METHODS: In 2009, data were collected using a two-stage random cluster sample of 2,797 households in 150 census enumeration areas during a Malaria Indicator Survey (MIS) in South Sudan. The survey determined parasite and anaemia prevalence in vulnerable population groups and evaluated coverage, use and access to malaria control services. Standardized Roll Back Malaria Monitoring and Evaluation Reference Group (RBM-MERG) MIS household and women's questionnaires were adapted to the local situation and used for collection of data that were analysed and summarized using descriptive statistics. RESULTS: The results of this survey showed that 59.3% (95% CI: 57.5-61.1) of households owned at least one mosquito net. The proportion of the population with access to an ITN in their household was 49.7% (95% CI: 48.2-51.2). The utilization of insecticide-treated nets was low; 25.3% (95% CI: 23.9-26.7) for children under five (U5) and 35.9% (95% CI: 31.9-40.2) of pregnant women (OR: 1.66 (1.36-2.01); P =0.175). Prevalence of infection was 24.5% (95% CI: 23.0-26.1) in children U5 and 9.9% (95% CI: 7.4-13.1) in pregnant women. About two thirds (64%) of children U5 and 46% of pregnant women were anaemic. Only 2% of households were covered by indoor residual spraying (IRS) the previous year. Data shows that 58% reported that malaria is transmitted by mosquitoes, 34% mentioned that the use of mosquito nets could prevent malaria, 41% knew the correct treatment for malaria, and 52% of the children received treatment at a health facility. CONCLUSION: The observed high malaria prevalence could be due to low levels of coverage and utilization of interventions coupled with low knowledge levels. Therefore, access and utilization of malaria control tools should be increased through scaling up coverage and improving behaviour change communication.

TNF-alpha, IL-6, IFN-gamma, and IL-10 gene expression polymorphisms and the IL-4 receptor alpha-chain variant Q576R: effects on renal allograft outcome.

BACKGROUND: There has been much interest recently in the effects of various cytokine gene expression polymorphisms on graft outcome. However, the results of these investigations reveal the outcomes to be organ-specific and center-specific. We sought to confirm and add to some of the earlier findings by studying the impact of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6) polymorphisms and the interleukin-4 (IL-4) receptor alpha-chain variant on posttransplant renal allograft outcome. METHOD: TNF-alpha, IL-6, IFN-gamma, and IL-10 gene promoter region polymorphisms were assayed genotypically by PCR-SSP on 120 patients transplanted at the Albany Medical Center. These patients were also typed for the IL-4 receptor alpha-chain variant Q576R. RESULTS: Producers of high levels of the proinflammatory cytokine TNF-alpha were found to be at increased risk for acute rejection episodes if the allograft was mismatched for the molecular products of the class II region of the human major histocompatibility complex (HLA-DR). Expression level polymorphisms of the IL-6, IFN-gamma, and IL-10 genes were not associated with acute rejection episodes, nor was the IL-4 receptor alpha-chain variant Q576R. CONCLUSIONS: These data would suggest that the production of high levels of the cytokine TNF-alpha is especially detrimental to graft survival when the recipient's T-helper lymphocytes are being activated by mismatched donor HLA-class II antigens. Typing all potential kidney recipients for TNF-alpha, and providing well-matched organs for high producers of this cytokines, may be expected to increase rejection-free graft survival in these patients.

Promoter-region alleles of the TNF-alpha and IL-10 genes have no effect on pretransplant alloantibody production.

BACKGROUND: The presence of high levels of alloantibodies are known to be a risk factor in renal graft outcome. Expression level polymorphisms in cytokine genes are also thought to have an effect on allograft outcome, but the studies examining this have been inconsistent. This may be due to center-specific differences in immunosuppressive protocols. Therefore, we studied the effects of these polymorphisms on pretransplant class I alloantibody production in nonexogenously immunosuppressed candidates. METHODS: Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) gene polymorphisms were assayed genotypically by PCR-SSP on 177 renal transplant candidates. Candidates with a peak goat antihuman immunoglobulin-enhanced T-cell panel reactive antibody (PRA) of >or=10% were considered to be positive for alloantibody (32% of 177 total). RESULTS: Previous transplants, transfusions, or pregnancies were all associated with alloantibody production, but TNF-alpha and IL-10 phenotypes were not. High levels of alloantibody production (peak PRA >50%) were also not effected by cytokine phenotype. CONCLUSIONS: These data suggest that differences in TNF-alpha and IL-10 phenotype do not effect a patient's likelihood of becoming sensitized by transfusions, pregnancies, and prior transplants.

Prevalence of donor-specific anti-HLA antibodies during episodes of renal allograft rejection.

BACKGROUND: Recent studies suggest that the appearance of anti-HLA antibodies in the early posttransplant period is associated with an increased incidence of acute and chronic rejection months later. However, very little is known about the prevalence of anti-HLA antibodies at the time that the rejection episodes are diagnosed. The purpose of this study was to analyze retrospectively 420 sera from 263 renal allograft recipients who were readmitted to the hospital for any reason between 1989 and 1998 in order to determine if a correlation existed between the presence of donor-specific anti-HLA antibodies and graft rejection. METHODS: Sera were assayed for IgG HLA class I and II antibodies by ELISA. The ELISA results were analyzed using contingency tables with Fisher's exact test and compared with mismatched antigens in the donor. RESULTS: Antibodies to donor HLA class I molecules in the posttransplant sera were extremely rare, occurring in only 6 of the 420 sera (1.4%) analyzed. Antibodies to donor class II antigens were slightly more common, occurring in 25 of the 420 sera (6%). In 21 of these 25 cases (84%), the presence of donor-specific HLA class II antibodies was associated with episodes of either acute (n=14) or chronic rejection (n=7). Five patients had antibodies to both class I and class II donor antigens, and all five of them lost their grafts to rejection. CONCLUSION: Although the presence of donor-specific HLA antibodies presented a significant risk for acute or chronic rejection, 77% of all acute and chronic rejections occurred in patients without detectable HLA antibodies.