Immune Dysregulation in Autism Spectrum Disorder: What Do We Know about It?

Autism spectrum disorder (ASD) is a group of complex multifactorial neurodevelopmental disorders characterized by a wide and variable set of neuropsychiatric symptoms, including deficits in social communication, narrow and restricted interests, and repetitive behavior. The immune hypothesis is considered to be a major factor contributing to autism pathogenesis, as well as a way to explain the differences of the clinical phenotypes and comorbidities influencing disease course and severity. Evidence highlights a link between immune dysfunction and behavioral traits in autism from several types of evidence found in both cerebrospinal fluid and peripheral blood and their utility to identify autistic subgroups with specific immunophenotypes; underlying behavioral symptoms are also shown. This review summarizes current insights into immune dysfunction in ASD, with particular reference to the impact of immunological factors related to the maternal influence of autism development; comorbidities influencing autism disease course and severity; and others factors with particular relevance, including obesity. Finally, we described main elements of similarities between immunopathology overlapping neurodevelopmental and neurodegenerative disorders, taking as examples autism and Parkinson Disease, respectively.

Endocannabinoid System Dysregulation from Acetaminophen Use May Lead to Autism Spectrum Disorder: Could Cannabinoid Treatment Be Efficacious?

Persistent deficits in social communication and interaction, and restricted, repetitive patterns of behavior, interests or activities, are the core items characterizing autism spectrum disorder (ASD). Strong inflammation states have been reported to be associated with ASD. The endocannabinoid system (ECS) may be involved in ASD pathophysiology. This complex network of lipid signaling pathways comprises arachidonic acid and 2-arachidonoyl glycerol-derived compounds, their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. Alterations of the ECS have been reported in both the brain and the immune system of ASD subjects. ASD children show low EC tone as indicated by low blood levels of endocannabinoids. Acetaminophen use has been reported to be associated with an increased risk of ASD. This drug can act through the ECS to produce analgesia. It may be that acetaminophen use in children increases the risk for ASD by interfering with the ECS.This mini-review article summarizes the current knowledge on this topic.

Non-perturbing voltage measurement in a coaxial cable with slab-coupled optical sensors.

Voltage in a coaxial cable is measured by an electric-field optical fiber sensor exploiting the proportionality of voltage and electric field in a fixed structure. The sensor is inserted in a hole drilled through the dielectric of the RG-218 coaxial cable and sealed with epoxy to displace all air and prevent the adverse effects of charge buildup during high-voltage measurements. It is shown that the presence of the sensor in the coaxial cable does not significantly increase electrical reflections in the cable. A slab-coupled optical fiber sensor (SCOS) is used for its compact size and dielectric make. The dynamic range of 50 dB is shown experimentally with detection of signals as low as 1 V and up to 157 kV. A low corner of 0.3 Hz is demonstrated and the SCOS is shown to be able to measure 90 ns rise time.

Optical electric field sensor sensitivity direction rerouting and enhancement using a passive integrated dipole antenna.

This work introduces a passive dipole antenna integrated into the packaging of a slab-coupled optical sensor to enhance the directional sensitivity of electro-optic electric field measurements parallel to the fiber axis. Using the passive integrated dipole antenna described in this work, a sensor that can typically only sense fields transverse to the fiber direction is able to sense a 1.25 kV/m field along the fiber direction with a gain of 17.5. This is verified through simulation and experiment.

Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations.

Several studies highlight a key involvement of endocannabinoid (EC) system in autism pathophysiology. The EC system is a complex network of lipid signaling pathways comprised of arachidonic acid-derived compounds (anandamide, AEA) and 2-arachidonoyl glycerol (2-AG), their G-protein-coupled receptors (cannabinoid receptors CB1 and CB2) and the associated enzymes. In addition to autism, the EC system is also involved in several other psychiatric disorders (i.e., anxiety, major depression, bipolar disorder and schizophrenia). This system is a key regulator of metabolic and cellular pathways involved in autism, such as food intake, energy metabolism and immune system control. Early studies in autism animal models have demonstrated alterations in the brain's EC system. Autism is also characterized by immune system dysregulation. This alteration includes differential monocyte and macrophage responses, and abnormal cytokine and T cell levels. EC system dysfunction in a monocyte and macrophagic cellular model of autism has been demonstrated by showing that the mRNA and protein for CB2 receptor and EC enzymes were significantly dysregulated, further indicating the involvement of the EC system in autism-associated immunological disruptions. Taken together, these new findings offer a novel perspective in autism research and indicate that the EC system could represent a novel target option for autism pharmacotherapy.

High electric field measurement using slab-coupled optical sensors.

A fiber-optic electric field sensor was developed to measure electric field up to 18 MV/m. The sensor uses resonant coupling between an optical fiber and a nonlinear electro-optical crystal. The sensing system uses high dielectric strength materials to eliminate dielectric breakdown. A postprocessing nonlinear calibration method is developed that maps voltage change to wavelength shift and then converts the wavelength shift to electric field using the transmission spectrum. The nonlinear calibration method is compared against the linear method with electric field pulses having magnitudes from 1.5 to 18 MV/m.

Slab-coupled optical sensor fabrication using side-polished Panda fibers.

A new device structure used for slab-coupled optical sensor (SCOS) technology was developed to fabricate electric field sensors. This new device structure replaces the D-fiber used in traditional SCOS technology with a side-polished Panda fiber. Unlike the D-fiber SCOS, the Panda fiber SCOS is made from commercially available materials and is simpler to fabricate. The Panda SCOS interfaces easier with lab equipment and exhibits ∼3 dB less loss at link points than the D-fiber SCOS. The optical system for the D-fiber is bandwidth limited by a transimpedance amplifier (TIA) used to amplify to the electric signal. The Panda SCOS exhibits less loss than the D-fiber and, as a result, does not require as high a gain setting on the TIA, which results in an overall higher bandwidth range. Results show that the Panda sensor also achieves comparable sensitivity results to the D-fiber SCOS. Although the Panda SCOS is not as sensitive as other side-polished fiber electric field sensors, it can be fabricated much easier because the fabrication process does not require special alignment techniques, and it is made from commercially available materials.

Split Hopkinson bar measurement using high-speed full-spectrum fiber Bragg grating interrogation.

The development and validation of a high-speed, full-spectrum measurement technique is described for fiber Bragg grating (FBG) sensors. A FBG is surface-mounted to a split-Hopkinson tensile bar specimen to induce high strain rates. The high strain gradients and large strains that indicate material failure are analyzed under high strain rates up to 500 s-1. The FBG is interrogated using a high-speed full-spectrum solid-state interrogator with a repetition rate of 100 kHz. The captured deformed spectra are analyzed for strain gradients using a default interior point algorithm in combination with the modified transfer matrix approach. This paper shows that by using high-speed full-spectrum interrogation of an FBG and the modified transfer matrix method, highly localized strain gradients and discontinuities can be measured without a direct line of sight.

Push-pull slab coupled optical sensor for measuring electric fields in a vibrational environment.

Vibration-insensitive fiber optic electric field sensor is created by fabricating two sensing elements in close proximity onto the same optical fiber and subtracting the two signals. The device is used to measure an electric field of 10 kV/m, while the sensor is being bent and impacted.

Fabrication of high aspect ratio, non-line-of-sight vias in silicon carbide by a two-photon absorption method.

The future of Moore's Law for high-performance integrated circuits (ICs) is going to be driven more by advanced packaging and three-dimensional (3D) integration than by simply decreasing transistor size. 3D ICs offer low-power consumption, high-performance and a smaller footprint compared to conventional 2D ICs. The key enabling technology to 3D integration is the interposer that provides interconnects to route signals between the chiplets that comprise the IC. However, the fabrication of high-aspect ratio through wafer vias (TWVs), that provide electrical and mechanical connection between chiplets on the top and bottom of the interposer, is one of the important challenges that limit interposer performance. Current fabrication technologies are limited by tapering effects and the need for direct line of sight to the fabrication surface. These limit the possible aspect ratios of vias and require large, complicated surface traces to connect the vias to the chiplets. Here, we demonstrate the fabrication of high-aspect ratio, non-line-of-sight TWVs in silicon carbide (SiC). SiC provides better mechanical, chemical, and thermal performance than silicon (Si). The technique uses an electro-chemical etch process that utilizes two-photon absorption to create any arbitrary 3D structure in SiC allowing for direct, subsurface routing between chiplets.

Improvements in electric-field sensor sensitivity by exploiting a tangential field condition.

This paper presents improvements to slab-coupled optical fiber sensors for electric-field sensing. The sensors are comprised of a potassium titanyl phosphate (KTP) crystal mounted on a D-fiber. The improvements are based on changing the crystal orientation, which enhances sensitivity due to a combined increase in the effective electro-optic coefficient and electric-field penetration into the KTP crystal. The paper provides a detailed comparison of the improved sensor, which uses x-cut KTP to the previous sensor design using z-cut KTP. The measurements show an 8.6× improvement in the sensitivity.

Single tunable laser interrogation of slab-coupled optical sensors through resonance tuning.

This paper describes a method for tuning the resonant wavelengths of slab-coupled optical fiber sensors (SCOSs). This method allows multiple sensors to be interrogated simultaneously with a single tunable laser. The resonances are tuned by rotating a biaxial slab waveguide relative to an optical D-fiber. As the slab waveguide rotates, its effective index of refraction changes causing the coupling wavelengths of the slab waveguide and D-fiber to shift. A SCOS fabricated with potassium titanyl phosphate crystal as the slab waveguide is shown to have resonance tuning ranges of 6.67 and 22.24 nm, respectively, for TM and TE polarized modes.

Multiaxis electric field sensing using slab coupled optical sensors.

This paper provides the details of a multiaxis electric field sensor. The sensing element consists of three slab coupled optical-fiber sensors that are combined to allow directional electric field sensing. The packaged three-axis sensor has a small cross-sectional area of 0.5 cm×0.5 cm by using an x-cut crystal. A method is described that uses a sensitivity-matrix approach to map the measurements to field components. The calibration and testing are described, resulting in an average error of 1.5°.

Frequency dependence of slab coupled optical sensor sensitivity.

This paper presents the frequency-dependent sensitivity of slab-coupled optical fiber sensors (SCOSs). This dependence is caused by the frequency characteristics of the relative permittivity. We show experimentally the frequency dependence of SCOS sensitivity for frequencies in the range of 1 kHz to 1 MHz for SCOS fabricated with both potassium titanyl phosphate (KTP) and lithium niobate (LiNbO(3)). We conclude that x-cut KTP SCOSs are preferred for measuring fields above 300 kHz as they are 1.55× more sensitive than x-cut LiNbO(3) SCOSs to the higher frequency fields. However, since KTP SCOSs experience increasing permittivity for low frequencies, SCOSs made with LiNbO(3) may be used for low frequency sensing applications due to their flat sensitivity response. For a 10 kHz electric field, an x cut LiNbO(3) SCOS is approximately 3.43× more sensitive than an x-cut KTP SCOS.

Acute cannabidiol treatment enhances social interaction in adult male mice.

Cannabidiol (CBD) is a non-intoxicating phytochemical from Cannabis sativa that is increasingly used to manage pain. The potential for CBD to ameliorate dimensional behavior symptoms occurring in multiple psychiatric disorders was suggested, including social interaction impairments. To test this hypothesis, adult male BTBRT+Itpr3tf/J (BTBR) mice, a model of idiopathic autism exhibiting social preference deficits and restrictive repetitive behaviors, were acutely treated with vehicle or 0.1, 1, or 10 mg/kg CBD. Social interaction preference was assessed 50 min after treatment, followed by social novelty preference at 60 min, marble burying at 75 min and social dominance at 120 min. CBD (10 mg/kg) enhanced BTBR social interaction but not social novelty preference, marble burying or dominance, with serum levels = 29 ± 11 ng/mg at 3 h post-injection. Next, acute 10 mg/kg CBD was compared to vehicle treatment in male serotonin transporter (SERT) knock-out mice, since SERT deficiency is an autism risk factor, and in their wildtype background strain controls C57BL/6J mice. CBD treatment generally enhanced social interaction preference and attenuated social novelty preference, yet neither marble burying nor dominance was affected. These findings show acute treatment with as little as 10 mg/kg purified CBD can enhance social interaction preference in male mice that are otherwise socially deficient.

Effect of yoga in chronic obstructive pulmonary disease.

Yoga is adjunctively utilized outside the United States in the treatment of a variety of diseases, including chronic obstructive pulmonary disease (COPD), but there are no studies assessing its adjunctive efficacy in the United States. We prospectively evaluated the effects of yoga training on the quality of life (QOL) and the parameters of lung function in patients with COPD. Thirty-three patients with documented COPD, per Global Initiative for Obstructive Lung Disease criteria, were recruited. All patients received standard COPD care. The QOL was assessed by the St. George Respiratory questionnaire. Standard spirometry and maximum inspiratory (maximal inspiratory pressure) and expiratory pressure (maximal expiratory pressure) were measured. Patients were taught selected yoga exercises including breathing exercises, meditation, and yoga postures for 1 hour, thrice a week for 6 weeks by a certified yoga therapist. The quality of life and lung function were again assessed at the end of 6 weeks. Twenty-two patients completed the study. Differences in preyoga versus postyoga scores were evaluated using paired t-tests. Statistically significant improvements (P < 0.05) were observed for the St. George Respiratory questionnaire [95% confidence interval (CI) 43.13-58.47], vital capacity (95% CI 2.53-7.65), maximal inspiratory pressure (95% CI 6.62-23.64), and maximal expiratory pressure (95% CI 1.63-13.81). Yoga when practiced by patients with COPD results in improvement in the QOL and lung function on a short-term basis. Additional research is needed to confirm these findings in a randomized controlled trial and in the longer term.

Training Family Medicine Residents to Address the COVID-19 Pandemic: A National Survey of Program Directors.

BACKGROUND AND OBJECTIVES: Public health training became particularly important for family medicine (FM) residency training programs amid the COVID-19 pandemic; the Accreditation Council for Graduate Medical Education (ACGME IV.C.19) requires a structured curriculum in which residents address population health. Our primary goal was to understand if, and to what extent, public health interventions trainings were incorporated into FM residency training programs amid the COVID-19 pandemic. We hypothesized programs with more resources (eg, university affiliates) would be better able to incorporate the training compared to those without such resources (ie, nonuniversity affiliates). METHODS: In 2021, we incorporated items addressing COVID-19 public health training competencies into the 2021 Council of Academic Family Medicine Educational Research Alliance national survey of FM residency program directors. The items addressed the type of training provided, mode of delivery, barriers to providing training, perceived importance of training, and support in delivering training. RESULTS: The overall survey response rate was 46.4% (n=287/619). All programs offered at least some training to residents. There were no statistically significant differences in training intensity between university and nonuniversity affiliates. The length of time an FM residency director spent in their position was positively associated with training intensity (r=0.1430, P=.0252). The biggest barrier to providing the trainings was the need to devote time to other curriculum requirements. CONCLUSIONS: FM residency programs were able to provide some public health interventions training during the pandemic. With increased support and resources, FM resident training curricula may better prepare FM residents now in anticipation of a future pandemic.

Electric-field sensors utilizing coupling between a D-fiber and an electro-optic polymer slab.

This paper provides a detailed analysis of electric field sensing using a slab-coupled optical fiber sensor (SCOS). This analysis explains that the best material for the slab waveguide is an inorganic material because of the low RF permittivity combined with the high electro-optic coefficient. The paper also describes the fabrication and testing of a SCOS using an AJL chromophore in amorphous polycarbonate. The high uniform polymer slab waveguide is fabricated using a hot embossing process to create a slab with a thickness of 50 µm. The fabricated polymer SCOS was characterized to have a resonance slope of ΔP/Δλ=6.83E5 W/m and a resonance shift of Δλ/E=1.47E-16 m(2)/V.

The severity of oral/facial problems treated in Iraq March 2008 to February 2009.

BACKGROUND: The objective of this study was to describe the severity of oral/facial problems occurring in Navy and Marine Corps personnel deployed to Iraq. METHODS: Data documented by Navy Dental Officers deployed to Iraq were used to determine the number and type of oral/facial problems treated and to determine the percentages of severe, moderately severe, and pain/loss of function oral/facial problems treated in Iraq from March 2008 through February 2009. RESULTS: During the year of data collection, a total of 13,933 dental visits were documented for Navy and Marine Corps personnel. Of these, 1,641 were encounters to treat an oral/facial problem in Navy and Marine Corps personnel. In all, 37 (2.2%) of the 1,641 encounters for oral/facial problems were considered severe, 266 (16.2%) moderately severe, and 1,338 (81.5%) were for pain/loss of function. CONCLUSIONS: Although the majority of military personnel with oral/facial problems experience mild to moderate pain or loss of dental function, approximately 20% are of sufficient severity to cause the warfighter to experience a limitation of their operational capability.