Regional neuroinflammation induced by peripheral infection contributes to fatigue-like symptoms: a [18F]DPA-714 positron emission tomography study in rats.

Introduction: A series of symptoms, including fever, widespread pain, fatigue, and even ageusia, have frequently been reported in the context of various infections, such as COVID-19. Although the pathogenic mechanisms underlying an infection causing fever and pain have been well established, the mechanisms of fatigue induced by infection in specific brain regions remain unclear. Methods: To elucidate whether and how the peripheral infection cause fatigue via regional neuroinflammation, we performed a brain-wide investigation of neuroinflammation in a peripheral pseudoinfection rat model using [18F]DPA-714 positron emission tomography (PET) imaging analysis, in which the polyriboinosinic: polyribocytidylic acid (poly I:C) was intraperitoneally injected. Results: Transient fever lasting for several hours and subsequent suppression of spontaneous activity lasting a few days were induced by poly I:C treatment. Significant increase in plasma interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α were observed at 2 and 4 h following poly I:C treatment. PET imaging analysis revealed that the brain uptake of [18F]DPA-714 was significantly increased in several brain regions one day after poly I:C treatment, such as the dorsal raphe (DR), parvicellular part of red nucleus (RPC), A5 and A7 noradrenergic nucleus, compared with the control group. The accumulation of [18F]DPA-714 in the DR, RPC and A5 was positively correlated with subsequent fatigue-like behavior, and that in the A7 tended to positively correlate with fever. Discussion: These findings suggest that peripheral infection may trigger regional neuroinflammation, which may cause specific symptoms such as fatigue. A similar mechanism might be involved in COVID-19.

Electrolyzed Hydrogen Water Alleviates Abdominal Pain through Suppression of Colonic Tissue Inflammation in a Rat Model of Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive tract and is typically accompanied by characteristic symptoms, such as abdominal pain, diarrhea, and bloody stool, severely deteriorating the quality of the patient's life. Electrolyzed hydrogen water (EHW) has been shown to alleviate inflammation in several diseases, such as renal disease and polymyositis/dermatomyositis. To investigate whether and how daily EHW consumption alleviates abdominal pain, the most common symptom of IBD, we examined the antioxidative and anti-inflammatory effects of EHW in an IBD rat model, wherein colonic inflammation was induced by colorectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). We found that EHW significantly alleviated TNBS-induced abdominal pain and tissue inflammation. Moreover, the production of proinflammatory cytokines in inflamed colon tissue was also decreased significantly. Meanwhile, the overproduction of reactive oxygen species (ROS), which is intricately involved in intestinal inflammation, was significantly suppressed by EHW. Additionally, expression of S100A9, an inflammatory biomarker of IBD, was significantly suppressed by EHW. These results suggest that the EHW prevented the overproduction of ROS due to its powerful free-radical scavenging ability and blocked the crosstalk between oxidative stress and inflammation, thereby suppressing colonic inflammation and alleviating abdominal pain.

Alleviation of the chronic stress response attributed to the antioxidant and anti-inflammatory effects of electrolyzed hydrogen water.

Reactive oxygen species (ROS) are highly reactive and directly attack surrounding biomolecules to deteriorate cellular and tissue functions. Meanwhile, ROS also serve as signaling mediators to upregulate pro-inflammatory cytokine expression via activation of the nuclear factor kappa B signaling pathway, and the increased pro-inflammatory cytokines trigger respiratory burst of inflammatory cells that further accelerates ROS production in the inflamed tissue. Such crosstalk between ROS and inflammatory responses leads to a chain reaction of negativity, and cause progression of several chronic pathologies. Since molecular hydrogen is known to preferentially remove cytotoxic hydroxyl radicals and peroxynitrites, and to prevent cell and tissue damage, we here examined whether electrolyzed hydrogen water (EHW) enriched with molecular hydrogen and reactive hydrogen storing platinum nanoparticles dissolved from an electrode could alleviate oxidative stress and inflammation induced by continuous stress challenges. Five-day continuous stress loading to rats elevated reactive oxygen metabolites-derived compounds (d-ROMs), interleukin (IL)-1ß, and adrenocorticotropic hormone (ACTH) levels and decreased the biological antioxidant potential (BAP) level. Drinking EHW during 5-day continuous stress loading significantly alleviated all of these changes. The results suggest that EHW could suppress stress-response-associated oxidative stress and IL-1ß level elevation in vivo, and that drinking of EHW is effective for controlling stress responses via its antioxidant potential.

Homeostatic disturbance of thermoregulatory functions in rats with chronic fatigue.

Chronic fatigue syndrome (CFS) is characterized by long-lasting fatigue, and a range of symptoms, and is involved in homeostasis disruption. CFS patients frequently complain of low grade fever or chill even under normal body temperature indicating that thermosensory or thermoregulatory functions might be disturbed in CFS. However, little is known about the detailed mechanisms. To elucidate whether and how thermoregulatory function was altered during the development of chronic fatigue, we investigated temporal changes in body temperature with advance of fatigue accumulation in a chronic fatigue rat model using a wireless transponder. Our findings demonstrated that the body temperature was adaptively increased in response to fatigue loading in the early phase, but unable to retain in the late phase. The tail heat dissipation was often observed and the frequency of tail heat dissipation gradually increased initially, then decreased. In the late phase of fatigue loading, the body temperature for the tail heat dissipation phase decreased to a value lower than that for the non-dissipation phase. These results suggest that adaptive changes in thermoregulatory function occurred with fatigue progression, but this system might be disrupted by long-lasting fatigue, which may underlie the mechanism of fatigue chronification.

Positron emission tomography with additional γ-ray detectors for multiple-tracer imaging.

PURPOSE: Positron emission tomography (PET) is a useful imaging modality that quantifies the physiological distributions of radiolabeled tracers in vivo in humans and animals. However, this technique is unsuitable for multiple-tracer imaging because the annihilation photons used for PET imaging have a fixed energy regardless of the selection of the radionuclide tracer. This study developed a multi-isotope PET (MI-PET) system and evaluated its imaging performance. METHODS: Our MI-PET system is composed of a PET system and additional γ-ray detectors. The PET system consists of pixelized gadolinium orthosilicate (GSO) scintillation detectors and has a ring geometry that is 95 mm in diameter with an axial field of view of 37.5 mm. The additional detectors are eight bismuth germanium oxide (BGO) scintillation detectors, each of which is 50 × 50 × 30 mm3 , arranged into two rings mounted on each side of the PET ring with a 92-mm-inner diameter. This system can distinguish between different tracers using the additional γ-ray detectors to observe prompt γ-rays, which are emitted after positron emission and have an energy intrinsic to each radionuclide. Our system can simultaneously acquire double- (two annihilation photons) and triple- (two annihilation photons and a prompt γ-ray) coincidence events. The system's efficiency for detecting prompt de-excitation γ-rays was measured using a positron-γ emitter, 22 Na. Dual-radionuclide (18 F and 22 Na) imaging of a rod phantom and a mouse was performed to demonstrate the performance of the developed system. Our system's basic performance was evaluated by reconstructing two images, one containing both tracers and the other containing just the second tracer, from list-mode data sets that were categorized by the presence or absence of the prompt γ-ray. RESULTS: The maximum detection efficiency for 1275 keV γ-rays emitted from 22 Na was approximately 7% at the scanner's center, and the minimum detection efficiency was 5.1% at the edge of the field of view. Dual-radionuclide imaging of the point sources and rod phantom revealed that our system maintained PET's intrinsic spatial resolution and quantitative nature for the second tracer. We also successfully acquired simultaneous double- and triple-coincidence events from a mouse containing 18 F-fluoro-deoxyglucose and 22 Na dissolved in water. The dual-tracer distributions in the mouse obtained by our MI-PET were reasonable from the viewpoints of physiology and pharmacokinetics. CONCLUSIONS: This study demonstrates the feasibility of multiple-tracer imaging using PET with additional γ-ray detectors. This method holds promise for enabling the reconstruction of quantitative multiple-tracer images and could be very useful for analyzing multiple-molecular dynamics.

Two Japanese cases of dermatitis herpetiformis associated each with lung cancer and autoimmune pancreatitis but showing no intestinal symptom or circulating immunoglobulin A antibodies to any known antigens.

Dermatitis herpetiformis (DH) is common in some Caucasian populations but extremely rare in Japanese, probably because of different immunogenetic backgrounds. We report two Japanese DH cases with typical clinical, histological and direct immunofluorescence features. However, no symptom of gluten-sensitive enteropathy was shown. The diagnosis was confirmed by eliminating other autoimmune blistering diseases by indirect immunofluorescence, enzyme-linked immunosorbent assays and immunoblotting. However, circulating immunoglobulin (Ig)A anti-endomysium, reticulin and gliadin antibodies were not detected. IgA antibodies to tissue and epidermal transglutaminases were also negative. One case was associated with lung cancer and the other one with autoimmune pancreatitis. On review of 17 cases of DH reported in Japan over the previous 10 years, including our cases, one case was associated with gluten-sensitive enteropathy, four with malignant neoplasms, two with autoimmune systemic disorders and one with psoriasis. Although our cases were typical of DH in clinical, histopathological and IgA deposit features, they showed different human leukocyte antigen haplotypes, no gluten-sensitive enteropathy and no DH-specific IgA antibodies, including those to epidermal and tissue transglutaminases. These results suggest that studies of unique characteristics in Japanese DH patients should facilitate further understanding of pathogenesis in DH.