Single Session Intermittent Heat Exposure With More Frequent and Shorter Cooling Breaks Facilitates Greater Training Intensity and Elicits Physiological Responses Comparable to Continuous Heat Exposure.

PURPOSE: To investigate the influence of shorter, more frequent rest breaks with per-cooling as an alternative heat-acclimation session on physiological, perceptual, and self-paced maximal cycling performance, compared with continuous heat exposure. METHODS: Thirteen participants completed 1 continuous and 3 intermittent-heat-exposure (IHE) maximal self-paced cycling protocols in a random order in heat (36 °C, 80% relative humidity): 1 × 60-minute exercise (CON), 3 × 20-minute exercise with 7.5-minute rest between sets (IHE-20), 4 × 15-minute exercise with 5-minute rest between sets (IHE-15), and 6 × 10-minute exercise with 3-minute rest between sets (IHE-10). Mixed-method per-cooling (crushed-ice ingestion and cooling vest) was applied during rest periods of all IHE protocols. RESULTS: Total distance completed was greater in IHE-10, IHE-15, and IHE-20 than in CON (+11%, +9%, and +8%, respectively), with no difference observed between IHE protocols. Total time spent above 38.5 °C core temperature was longer in CON compared with IHE-15 and IHE-20 (+62% and +78%, respectively) but similar to IHE-10 (+5%). Furthermore, a longer time above 38.5 °C core temperature occurred in IHE-10 versus IHE-15 and IHE-20 (+54% and +69%, respectively). Sweat loss did not differ between conditions. CONCLUSION: IHE with per-cooling may be a viable alternative heat-acclimation protocol in situations where training quality takes precedence over thermal stimulus or when both factors hold equal priority.

Mixed-Method Precooling Enhances Self-Paced 20-km Cycling Time-Trial Performance When Apparent Temperature Is >46 °C but May Not Be a Priority in <46 °C.

PURPOSE: Precooling (PreC) may only benefit performance when thermal strain experienced by an individual is sufficiently high. We explored the effect of mixed-method PreC on 20-km cycling time-trial (CTT) performance under 3 different apparent temperatures (AT). METHODS: On separate days, 12 trained or highly trained male cyclists/triathletes completed six 20-km CTTs in 3 different ATs: hot-dry (35 °C AT), moderately hot-humid (40 °C AT), and hot-humid (46 °C AT). All trials were preceded by 30 minutes of mixed-method PreC or no PreC (control [CON]). RESULTS: Faster 2.5-km-split completion times occurred in PreC compared with CON in 46 °C AT (P = .02), but not in 40 °C AT (P = .62) or 35 °C AT (P = .57). PreC did not affect rectal and body temperature during the 20-km CTT. Skin temperature was lower throughout the CTT in PreC compared with CON in 46 °C AT (P = .01), but not in 40 °C AT (P = 1.00) and 35 °C AT (P = 1.00). Heart rate had a greater rate of increase during the CTT for PreC compared with CON in 46 °C AT (P = .01), but not in 40 °C AT (P = .57) and 35 °C AT (P = 1.00). Ratings of perceived exertion (P < .001) and thermal comfort (P = .04) were lower for PreC compared with CON in 46 °C AT only, while thermal sensation was not different between PreC and CON. CONCLUSION: Mixed-method PreC should be applied prior to 20-km CTTs conducted in hot-humid conditions (≥46 °C AT). Alternatively, mixed-method PreC may be a priority in moderately hot-humid (∼40 °C AT) conditions but should not be in hot-dry (∼35 °C AT) conditions for 20-km CTT.

West Nile virus emergence in humans in Extremadura, Spain 2020.

In Spain, the largest human West Nile virus (WNV) outbreak among humans was reported in 2020, constituting the second most important outbreak in Europe that season. Extremadura (southwestern Spain) was one of the affected areas, reporting six human cases. The first autochthonous human case in Spain was reported in Extremadura in 2004, and no other human cases were reported until 2020. In this work, we describe the first WNV human outbreak registered in Extremadura, focusing on the most important clinical aspects, diagnostic results, and control actions which followed. In 2020, from September to October, human WNV infections were diagnosed using a combination of molecular and serological methods (an in-house specific qRT-PCR and a commercial ELISA for anti-WNV IgM and IgG antibodies) and by analysing serum, urine, and/or cerebrospinal fluid samples. Serological positive serum samples were further tested using commercial kits against related flaviviruses Usutu and Tick-borne encephalitis in order to analyse serological reactivity and to confirm the results by neutralisation assays. In total, six cases of WNV infection (five with neuroinvasive disease and one with fever) were identified. Clinical presentation and laboratory findings are described. No viral RNA was detected in any of the analysed samples, but serological cross-reactivity was detected against the other tested flaviviruses. Molecular and serological methods for WNV detection in various samples as well as differential diagnosis are recommended. The largest number of human cases of WNV infection ever registered in Extremadura, Spain, occurred in 2020 in areas where circulation of WNV and other flaviviruses has been previously reported in humans and animals. Therefore, it is necessary to enhance surveillance not only for the early detection and implementation of response measures for WNV but also for other emerging flaviviruses that could be endemic in this area.

Two-Capacitor Direct Interface Circuit for Resistive Sensor Measurements.

Direct interface circuits (DICs) avoid the need for signal conditioning circuits and analog-to-digital converters (ADCs) to obtain digital measurements of resistive sensors using only a few passive elements. However, such simple hardware can lead to quantization errors when measuring small resistance values as well as high measurement times and uncertainties for high resistances. Different solutions to some of these problems have been presented in the literature over recent years, although the increased uncertainty in measurements at higher resistance values is a problem that has remained unaddressed. This article presents an economical hardware solution that only requires an extra capacitor to reduce this problem. The circuit is implemented with a field-programmable gate array (FPGA) as a programmable digital device. The new proposal significantly reduces the uncertainty in the time measurements. As a result, the high resistance errors decreased by up to 90%. The circuit requires three capacitor discharge cycles, as is needed in a classic DIC. Therefore, the time to estimate resistance increases slightly, between 2.7% and 4.6%.

Micro-dystrophin Gene Therapy Partially Enhances Exercise Capacity in Older Adult mdx Mice.

Micro-dystrophin (µDys) gene therapeutics can improve striated muscle structure and function in different animal models of Duchenne muscular dystrophy. Most studies, however, used young mdx mice that lack a pronounced dystrophic phenotype, short treatment periods, and limited muscle function tests. We, therefore, determined the relative efficacy of two previously described µDys gene therapeutics (rAAV6:µDysH3 and rAAV6:µDys5) in 6-month-old mdx mice using a 6-month treatment regimen and forced exercise. Forelimb and hindlimb grip strength, metabolic rate (VO2 max), running efficiency (energy expenditure), and serum creatine kinase levels similarly improved in mdx mice treated with either vector. Both vectors produced nearly identical dose-responses in all assays. They also partially prevented the degenerative effects of repeated high-intensity exercise on muscle histology, although none of the metrics examined was restored to normal wild-type levels. Moreover, neither vector had any consistent effect on respiration while exercising. These data together suggest that, although µDys gene therapy can improve isolated and systemic muscle function, it may be only partially effective when dystrophinopathies are advanced or when muscle structure is significantly challenged, as with high-intensity exercise. This further suggests that restoring muscle function to near-normal levels will likely require ancillary or combinatorial treatments capable of enhancing muscle strength.

Aplicación ecográfica con cuantificación de la estructura acústica (ASQ) en las enfermedades pulmonares intersticiales / Ultrasound Application with Acoustic Structure Quantification (ASQ) in Interstitial Lung Diseases

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Targeting a therapeutic LIF transgene to muscle via the immune system ameliorates muscular dystrophy.

Many potentially therapeutic molecules have been identified for treating Duchenne muscular dystrophy. However, targeting those molecules only to sites of active pathology is an obstacle to their clinical use. Because dystrophic muscles become extensively inflamed, we tested whether expressing a therapeutic transgene in leukocyte progenitors that invade muscle would provide selective, timely delivery to diseased muscle. We designed a transgene in which leukemia inhibitory factor (LIF) is under control of a leukocyte-specific promoter and transplanted transgenic cells into dystrophic mice. Transplantation diminishes pathology, reduces Th2 cytokines in muscle and biases macrophages away from a CD163+/CD206+ phenotype that promotes fibrosis. Transgenic cells also abrogate TGFß signaling, reduce fibro/adipogenic progenitor cells and reduce fibrogenesis of muscle cells. These findings indicate that leukocytes expressing a LIF transgene reduce fibrosis by suppressing type 2 immunity and highlight a novel application by which immune cells can be genetically modified as potential therapeutics to treat muscle disease.

Development of Novel Micro-dystrophins with Enhanced Functionality.

Gene therapies using adeno-associated viral (AAV) vectors have advanced into clinical trials for several diseases, including Duchenne muscular dystrophy (DMD). A limitation of AAV is the carrying capacity (∼5 kb) available for genes and regulatory cassettes (RCs). These size constraints are problematic for the 2.2-Mb dystrophin gene. We previously designed a variety of miniaturized micro-dystrophins (µDys) that displayed significant, albeit incomplete, function in striated muscles. To develop µDys proteins with improved performance, we explored structural modifications of the dystrophin central rod domain. Eight µDys variants were studied that carried unique combinations of between four and six of the 24 spectrin-like repeats present in the full-length protein, as well as various hinge domains. Expression of µDys was regulated by a strong but compact muscle-restricted RC (CK8e) or by the ubiquitously active cytomegalovirus (CMV) RC. Vectors were evaluated by intramuscular injection and systemic delivery to dystrophic mdx4cv mice, followed by analysis of skeletal muscle pathophysiology. Two µDys designs were identified that led to increased force generation compared with previous µDys while also localizing neuronal nitric oxide synthase to the sarcolemma. An AAV vector expressing the smaller of these (µDys5) from the CK8e RC is currently being evaluated in a DMD clinical trial.

Assistive Handlebar Based on Tactile Sensors: Control Inputs and Human Factors.

Tactile sensors can be used to build human-machine interfaces, for instance in isometric joysticks or handlebars. When used as input sensor device for control, questions arise related to the contact with the human, which involve ergonomic aspects. This paper focuses on the example application of driving a powered wheelchair as attendant. Since other proposals use force and torque sensors as control input variables, this paper explores the relationship between these variables and others obtained from the tactile sensor. For this purpose, a handlebar is instrumented with tactile sensors and a 6-axis force torque sensor. Several experiments are carried out with this handlebar mounted on a wheelchair and also fixed to a table. It is seen that it is possible to obtain variables well correlated with those provided by force and torque sensors. However, it is necessary to contemplate the influence of issues such as the gripping force of the human hand on the sensor or the different kinds of grasps due to different physical constitutions of humans and to the inherent random nature of the grasp. Moreover, it is seen that a first step is necessary where the contact with the hands has to stabilize, and its characteristics and settle time are obtained.

High-Accuracy Readout Electronics for Piezoresistive Tactile Sensors.

The typical layout in a piezoresistive tactile sensor arranges individual sensors to form an array with M rows and N columns. While this layout reduces the wiring involved, it does not allow the values of the sensor resistors to be measured individually due to the appearance of crosstalk caused by the nonidealities of the array reading circuits. In this paper, two reading methods that minimize errors resulting from this phenomenon are assessed by designing an electronic system for array reading, and the results are compared to those obtained using the traditional method, obviating the nonidealities of the reading circuit. The different models were compared by testing the system with an array of discrete resistors. The system was later connected to a tactile sensor with 8 × 7 taxels.

A Five-Repeat Micro-Dystrophin Gene Ameliorated Dystrophic Phenotype in the Severe DBA/2J-mdx Model of Duchenne Muscular Dystrophy.

Micro-dystrophins are highly promising candidates for treating Duchenne muscular dystrophy, a lethal muscle disease caused by dystrophin deficiency. Here, we report robust disease rescue in the severe DBA/2J-mdx model with a neuronal nitric oxide synthase (nNOS)-binding micro-dystrophin vector. 2 × 1013 vector genome particles/mouse of the vector were delivered intravenously to 10-week-old mice and were evaluated at 6 months of age. Saturated micro-dystrophin expression was detected in all skeletal muscles and the heart and restored the dystrophin-associated glycoprotein complex and nNOS. In skeletal muscle, therapy substantially reduced fibrosis and calcification and significantly attenuated inflammation. Centronucleation was significantly decreased in the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles but not in the quadriceps. Muscle function was normalized in the TA and significantly improved in the EDL muscle. Heart histology and function were also evaluated. Consistent with the literature, DBA/2J-mdx mice showed myocardial calcification and fibrosis and cardiac hemodynamics was compromised. Surprisingly, similar myocardial pathology and hemodynamic defects were detected in control DBA/2J mice. As a result, interpretation of the cardiac data proved difficult due to the confounding phenotype in control DBA/2J mice. Our results support further development of this microgene vector for clinical translation. Further, DBA/2J-mdx mice are not good models for Duchenne cardiomyopathy.

Vigilancia en salud pública: una necesidad inaplazable / Public health surveillance: a pressing need

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Klotho gene silencing promotes pathology in the mdx mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal muscle disease involving progressive loss of muscle regenerative capacity and increased fibrosis. We tested whether epigenetic silencing of the klotho gene occurs in the mdx mouse model of DMD and whether klotho silencing is an important feature of the disease. Our findings show that klotho undergoes muscle-specific silencing at the acute onset of mdx pathology. Klotho experiences increased methylation of CpG sites in its promoter region, which is associated with gene silencing, and increases in a repressive histone mark, H3K9me2. Expression of a klotho transgene in mdx mice restored their longevity, reduced muscle wasting, improved function and greatly increased the pool of muscle-resident stem cells required for regeneration. Reductions of fibrosis in late, progressive stages of the mdx pathology achieved by transgene expression were paralleled by reduced expression of Wnt target genes (axin-2), transforming growth factor-beta (TGF-ß1) and collagens types 1 and 3, indicating that Klotho inhibition of the profibrotic Wnt/TGFß axis underlies its anti-fibrotic effect in aging, dystrophic muscle. Thus, epigenetic silencing of klotho during muscular dystrophy contributes substantially to lost regenerative capacity and increased fibrosis of dystrophic muscle during late progressive stages of the disease.

Accuracy and Resolution Analysis of a Direct Resistive Sensor Array to FPGA Interface.

Resistive sensor arrays are formed by a large number of individual sensors which are distributed in different ways. This paper proposes a direct connection between an FPGA and a resistive array distributed in M rows and N columns, without the need of analog-to-digital converters to obtain resistance values in the sensor and where the conditioning circuit is reduced to the use of a capacitor in each of the columns of the matrix. The circuit allows parallel measurements of the N resistors which form each of the rows of the array, eliminating the resistive crosstalk which is typical of these circuits. This is achieved by an addressing technique which does not require external elements to the FPGA. Although the typical resistive crosstalk between resistors which are measured simultaneously is eliminated, other elements that have an impact on the measurement of discharge times appear in the proposed architecture and, therefore, affect the uncertainty in resistance value measurements; these elements need to be studied. Finally, the performance of different calibration techniques is assessed experimentally on a discrete resistor array, obtaining for a new model of calibration, a maximum relative error of 0.066% in a range of resistor values which correspond to a tactile sensor.

Improved Circuits with Capacitive Feedback for Readout Resistive Sensor Arrays.

One of the most suitable ways of distributing a resistive sensor array for reading is an array with M rows and N columns. This allows reduced wiring and a certain degree of parallelism in the implementation, although it also introduces crosstalk effects. Several types of circuits can carry out the analogue-digital conversion of this type of sensors. This article focuses on the use of operational amplifiers with capacitive feedback and FPGAs for this task. Specifically, modifications of a previously reported circuit are proposed to reduce the errors due to the non-idealities of the amplifiers and the I/O drivers of the FPGA. Moreover, calibration algorithms are derived from the analysis of the proposed circuitry to reduce the crosstalk error and improve the accuracy. Finally, the performances of the proposals is evaluated experimentally on an array of resistors and for different ranges.