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Background: Deployment-related neurotoxicant exposures are implicated in the etiology of Gulf War illness (GWI), the multisymptom condition associated with military service in the 1990–1991 Gulf War (GW). A Q/R polymorphism at position 192 of the paraoxonase (PON)-1 enzyme produce PON1192 variants with different capacities for neutralizing specific chemicals, including certain acetylcholinesterase inhibitors. Methods: We evaluated PON1192 status and GW exposures in 295 GWI cases and 103 GW veteran controls. Multivariable logistic regression determined independent associations of GWI with GW exposures overall and in PON1192 subgroups. Exact logistic regression explored effects of exposure combinations in PON1192 subgroups. Results: Hearing chemical alarms (proxy for possible nerve agent exposure) was associated with GWI only among RR status veterans (OR = 8.60, p = 0.014). Deployment-related skin pesticide use was associated with GWI only among QQ (OR = 3.30, p = 0.010) and QR (OR = 4.22, p < 0.001) status veterans. Exploratory assessments indicated that chemical alarms were associated with GWI in the subgroup of RR status veterans who took pyridostigmine bromide (PB) (exact OR = 19.02, p = 0.009) but not RR veterans who did not take PB (exact OR = 0.97, p = 1.00). Similarly, skin pesticide use was associated with GWI among QQ status veterans who took PB (exact OR = 6.34, p = 0.001) but not QQ veterans who did not take PB (exact OR = 0.59, p = 0.782). Conclusion: Study results suggest a complex pattern of PON1192 exposures and exposure–exposure interactions in the development of GWI.

Unraveling the multisymptomatic Gulf War Illness (GWI) pathology and finding an effective cure have eluded researchers for decades. The chronic symptom persistence and limitations for studying the etiologies in mouse models that differ significantly from those in humans pose challenges for drug discovery and finding effective therapeutic regimens. The GWI exposome differs significantly in the study cohorts, and the above makes it difficult to recreate a model closely resembling the GWI symptom pathology. We have used a double engraftment strategy for reconstituting a human immune system coupled with human microbiome transfer to create a humanized-mouse model for GWI. Using whole-genome shotgun sequencing and blood immune cytokine enzyme linked immunosorbent assay (ELISA), we show that our double humanized mice treated with Gulf War (GW) chemicals show significantly altered gut microbiomes, similar to those reported in a Veteran cohort of GWI. The results also showed similar cytokine profiles, such as increased levels of IL-1β, IL-6, and TNF R-1, in the double humanized model, as found previously in a human cohort. Further, a novel GWI Veteran fecal microbiota transfer was used to create a second alternative model that closely resembled the microbiome and immune-system-associated pathology of a GWI Veteran. A GWI Veteran microbiota transplant in humanized mice showed a human microbiome reconstitution and a systemic inflammatory pathology, as reflected by increases in interleukins 1β, 6, 8 (IL-1β, IL-6, IL-8), tumor necrosis factor receptor 1 (TNF R-1), and endotoxemia. In conclusion, though preliminary, we report a novel in vivo model with a human microbiome reconstitution and an engrafted human immune phenotype that may help to better understand gut-immune interactions in GWI.

Abstract The role that cities play in enhancing biodiversity conservation is increasingly recognized. However, since locations for conservation within metropolitan areas are often spatially restricted, and management for biodiversity may conflict with interventions on behalf of other desirable objectives, it is important that the outcomes of urban conservation projects are carefully monitored. Such monitoring is relatively rare. In this study we explored the value of employing soundscape analysis to provide a holistic evaluation of biotic communities at urban sites undergoing different forms of vegetation management. Using readily affordable audio recorders, we evaluated soundscapes in replicated areas within a 481-hectare urban park in Chicago, Illinois. Areas within the park are managed to achieve multiple objectives including both recreational use and nature conservation. We found that relatively small areas within the park that had been subjected primarily to restorative vegetation management supported different acoustic environments with higher avian activity and more prevalent biophonic sound than was the case in managed lawn spaces. The use of a variety of acoustic indices supplemented the analysis of these soundscapes, and whereas all indices affirmed seasonal differences, the Acoustic Complexity Index (ACI) was more helpful than the other indices we employed in discriminating between management practices. We conclude that vegetation management employed even at a small spatial scale in an urban environment can enhance faunal diversity, and that these results can be evaluated using inexpensive sound monitoring equipment.

Abstract Oxidative stress and apoptosis are highly engaged in development of diabetic nephropathy (DN). In monotherapy, dapagliflozin and pioglitazone positively modulate target organ damage even independently of their hypoglycaemic effect. This study evaluated whether a simultaneous PPARγ activation and SGLT cotransporter inhibition offer superior protection against DN-related oxidative and apoptotic processes in a T1DM rat model. Diabetes was induced in Wistar rats using streptozotocin (55 mg/kg, i.p.). The rats received daily chow containing dapagliflozin (10 mg/kg), pioglitazone (12 mg/kg) or their combination. Six weeks after STZ administration, histological and molecular analyses were performed in excised kidneys. STZ-induced DN was demonstrated by the propagation of apoptotic (Bax, p53, Casp3) and oxidative reactions (Gp91phox, MnSOD) and disrupted nitric oxide signalling (eNOS, Hsp90, Cav1). Kidney damage molecule expression (Kim1, Nphs1) revealed a deceleration of kidney damage by pioglitazone and dapagliflozine monotherapies. The monotherapy also reduced apoptosis, oxidative stress, and partially restored NO signalling. The combined therapy ameliorated glomerulosclerosis but in other measured parameters, it reached the effect of the monotherapies except for Hsp90 expression modulation. Both dapagliflozin and pioglitazone exert protective character in kidneys when used in monotherapy. The combined therapy does not exhibit an expected additive effect within modulating oxidative stress, NO signalling or apoptosis.

Introduction: Gulf War Illness (GWI), also called Chronic Multisymptom Illness (CMI), is a multi-faceted condition that plagues an estimated 250,000 Gulf War (GW) veterans. Symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. We previously reported that 12% of a convenience sample of middle aged (median age 52 years) GW veterans met criteria for mild cognitive impairment (MCI), a clinical syndrome most prevalent in older adults (e.g., ≥70 years). The current study sought to replicate and extend this finding. Methods: We used the actuarial neuropsychological criteria and the Montreal Cognitive Assessment (MoCA) to assess the cognitive status of 952 GW veterans. We also examined regional brain volumes in a subset of GW veterans (n = 368) who had three Tesla magnetic resonance images (MRIs). Results: We replicated our previous finding of a greater than 10% rate of MCI in four additional cohorts of GW veterans. In the combined sample of 952 GW veterans (median age 51 years at time of cognitive testing), 17% met criteria for MCI. Veterans classified as MCI were more likely to have CMI, history of depression, and prolonged (≥31 days) deployment-related exposures to smoke from oil well fires and chemical nerve agents compared to veterans with unimpaired and intermediate cognitive status. We also replicated our previous finding of hippocampal atrophy in veterans with MCI, and found significant group differences in lateral ventricle volumes. Discussion: Because MCI increases the risk for late-life dementia and impacts quality of life, it may be prudent to counsel GW veterans with cognitive dysfunction, CMI, history of depression, and high levels of exposures to deployment-related toxicants to adopt lifestyle habits that have been associated with lowering dementia risk. With the Food and Drug Administration’s recent approval of and the VA’s decision to cover the cost for anti-amyloid β (Aβ) therapies, a logical next step for this research is to determine if GW veterans with MCI have elevated Aβ in their brains.

Abstract Background Chronic overlapping pain conditions (COPCs), pain-related conditions that frequently occur together, may occur in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and could impact illness severity. This study aimed to identify comorbid COPCs in patients with ME/CFS and evaluate their impact on illness severity. Methods We used data from 923 participants in the Multi-Site Clinical Assessment of ME/CFS study, conducted in seven U.S. specialty clinics between 2012 and 2020, who completed the baseline assessment (595 ME/CFS and 328 healthy controls (HC)). COPCs included chronic low back pain (cLBP), chronic migraine/headache (cMHA), fibromyalgia (FM), interstitial cystitis/irritable bladder (IC/IB), irritable bowel syndrome (IBS), temporomandibular disorder (TMD). Illness severity was assessed through questionnaires measuring symptoms and functioning. Multivariate analysis of variance and analysis of covariance models were used for analyses. Log-binomial regression analyses were used to compute prevalence of COPCs and prevalence ratios (PR) between groups with 95% confidence intervals. Both unadjusted and adjusted results with age and sex are presented. Results 76% of participants with ME/CFS had at least one COPCs compared to 17.4% of HC. Among ME/CFS participants, cMHA was most prevalent (48.1%), followed by FM (45.0%), cLBP (33.1%), and IBS (31.6%). All individual COPCs, except TMD, were significantly more frequent in females than males. The unadjusted PR (ME/CFS compared to HC) was highest for FM [147.74 (95% confidence interval (CI) = 20.83-1047.75], followed by cLBP [39.45 (12.73-122.27)], and IC/IB [13.78 (1.88-101.24)]. The significance and order did not change after age and sex adjustment. The COPC comorbidities of cLBP and FM each had a significant impact on most health measures, particularly in pain attributes (Cohen’s d effect size 0.8 or larger). While the impact of COPC comorbidities on non-pain attributes and quality of life measures was less pronounced than that on pain, statistically significant differences between ME/CFS participants with and without COPCs were still evident. Conclusions More than 75% of ME/CFS participants had one or more COPCs. Multiple COPCs further exacerbated illness severity, especially among females with ME/CFS. Assessment and management of COPCs may help improve the health and quality of life for patients with ME/CFS.

Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.

Bone cancers in children are uncommon, making up approximately 5,5 % of all pediatric cancers. Childhood cancers are characterized by rapid development, and any delay in diagnosis can lead to serious consequences and even be life-threatening. The most common malignant tumors in key practice are: osteosarcoma (OS) and Ewing sarcoma (EWS). OS and EWS in children and adolescents require integrated diagnostics and age-appropriate therapy to ensure the best possible treatment outcomes. In recent years, the survival rates of pediatric cancer patients have improved and, consequently, it is necessary to reduce the long-term, late effects of treatment in order to promote the reduction of the deterioration in quality of life caused by treatment and to ensure the best possible return to everyday life.

With today's technological advances, people spend more and more time using various devices that emit non-ionizing radiation (NIR), such as mobile phones, laptops or WiFi networks. Nowadays, the role of these devices in the human lifestyle seems to make exposure to NIR unavoidable. This exposure, especially when prolonged, has been reported as one of the possible lifestyle factors contributing to reduced fertility, especially in men. The aim of the study was to analyse the current state of knowledge on the impact of NIR emitted by modern devices on the functioning of the male reproductive system and to identify possible mechanisms behind it. The research method used was a literature review on the PubMed platform. A total number of 35 articles from years 2007-2024 were analysed. According to the scientific literature, exposure to NIR may affect spermatozoa through thermal and non-thermal mechanisms, the most important of which appears to be increased production of reactive oxygen species (ROS), which leads to oxidative stress and cellular damage in the reproductive system. NIR exposure can adversely affect semen parameters such as sperm motility, viability and concentration, alter hormonal mechanisms regulating reproduction and induce morphological changes in reproductive tissues. However, studies conducted in this context often provide inconsistent results, hence the exact effect of NIR on the male reproductive system remains unknown. Therefore, further research is needed to accurately determine the effects of NIR on male fertility and to provide appropriate health recommendations.

Currently, antimicrobial-resistant bacteria and the global repercussions of this resistance are emerging as one of the most significant threats to public health. The global scope of the problem is discussed, with recent data showing that antimicrobial resistance (AMR) causes over a million fatalities annually, and projections suggest that this number will rise sharply by 2050. This review aims to provide a comprehensive analysis of this issue, focusing on the mechanisms of antibiotic resistance, its impact on public health and the economy, proposed strategies for addressing the problem, and potential alternative therapeutic approaches. This review is based on a thorough examination of current publications from the World Health Organization (WHO), European Centre for Disease Prevention and Control (ECDC), and relevant scientific literature obtained from databases such as PubMed. The primary objective of this publication is to highlight the escalating nature of this problem and to promote education and awareness in this critical area of healthcare.

Low back pain (LBP) is a common condition affecting many individuals worldwide. Furthermore, it represents a significant economic challenge for healthcare systems due to its substantial associated costs. The etiology of LBP is complex but, in most cases, is not caused by serious underlying diseases. Physical examination remains the cornerstone of diagnosis, while additional tests, including imaging, are determined based on the clinical context. Treatment involves a combination of non-pharmacological, pharmacological, and invasive interventions. Despite numerous attempts to prevent LBP, only a few methods have been scientifically proven to be effective. The aim of this review was to provide a comprehensive summary of evidence-based information and approaches regarding the pathogenesis, treatment, and prevention of LBP. The literature reviewed was sourced from PubMed and Google Scholar Rusing the key words "low back pain" combined with terms such as "pathogenesis," "diagnostics," "imaging diagnostics," "treatment," and "prevention."

Fungal infections are a serious public health threat, affecting a wide variety of populations worldwide. This review presents the current state of knowledge on fungal infections, focusing on epidemiology, etiology, clinical manifestations, and emerging trends. Findings are based on 35 peer-reviewed studies and focus on both well-known and emerging fungal pathogens, diagnostic advances, and therapeutic challenges. In addition, this review emphasizes the role of environmental and social factors in shaping the dynamics of fungal disease and highlights the importance of a global, multidisciplinary effort to combat the rise in fungal disease. The literature for this review was collected from PubMed and Google Scholar using the key words “fungal infections” combined with “epidemiology”, “etiology”, “risk factors”, “symptoms”, “complications”, “treatment”, and “trends”.

Vitamin D is a fat-soluble vitamin that plays a huge role in the metabolism of bones and teeth, which is especially important among pediatric patients. Its deficiency in the developmental period is associated with a decrease in bone mass, bone mineralization disorders, as well as the development of rickets. In addition, vitamin D has an immunomodulatory effect, and its reduced level correlates with a higher incidence of certain autoimmune diseases and cancer. However, it is worth noting that nowadays, in the era of high availability of over-the-counter (OTC) drugs and dietary supplements, not only hypovitaminosis D can be dangerous and pose a significant clinical problem. More and more parents decide to administer exogenous vitamin D preparations, often without prior consultation with a doctor to determine the optimal dose or duration of supplementation. Unfortunately, it happens that over-the-counter supplements contain a higher dose of vitamin D than the manufacturer suggests. This is very often due to inadequate control of supplement production. Restrictions similar to those in the case of drug production should be sought. It should be remembered that the human body, thanks to exposure to sunlight, under the influence of UV radiation, is able to synthesize endogenous vitamin D on its own. Another source of vitamin D is many foods such as fatty fish, eggs, mushrooms or dairy products, which should be in the diet of every person, especially a child. Therefore, it becomes necessary to define uniform recommendations for doctors and parents regarding vitamin D supplementation in children, as well as to educate the public about possible toxic effects resulting from excessive supply.

On a daily basis, everyone is exposed to many chemical compounds that have been classified as endocrine disrupting chemicals (EDCs). These are natural and artificially produced substances that are widely available in the environment today. The aim of the study is to determine the effect of endocrine disrupting chemicals on hormonal processes occurring in the human body and to determine their mechanisms of action. The research method used was a literature review on the Pubmed platform. Studies show that EDCs affect prenatal growth, thyroid function, glucose metabolism, obesity development, and puberty and fertility processes by mimicking hormones naturally occurring in the human body, which very often leads to disorders in the hormonal axis at various levels. Recent research reports say that EDCs interact through epigenetic mechanisms. These substances are considered safe individually, but the subject of research remains the "cocktail effect", which consists in exposing several EDCs to the body at the same time. The key here is to limit human contact with these substances as much as possible. Studies have so far proven the negativin effects of many of them on our body, but many of the long-term effects have yet to be studied. Fortunately, more and more countries are introducing restrictions on the use of these substances and are looking for methods to replace them with less harmful substitutes. Further research is needed to understand the effects of these substances on humans, which will further enable the development of appropriate regulation of EDCs.

Long COVID is a major health concern because many patients develop chronic neuropsychiatric symptoms, but the precise pathogenesis is unknown. Matrix metalloproteinase-9 (MMP-9) can disrupt neuronal connectivity and be elevated in patients with long COVID.

A workshop titled Beyond the Symptom: The Biology of Fatigue was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

IntroductionPatients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience cognitive problems with attention, information processing speed, working memory, learning efficiency, and executive function. Commonly, patients report worsening of cognitive symptoms over time after physical and/or cognitive challenges. To determine, monitor, and manage longitudinal decrements in cognitive function after such exposures, it is important to be able to screen for cognitive dysfunction and changes over time in clinic and also remotely at home. The primary objectives of this paper were: (1) to determine whether a brief computerized cognitive screening battery will detect differences in cognitive function between ME/CFS and Healthy Controls (HC), (2) to monitor the impact of a full-day study visit on cognitive function over time, and (3) to evaluate the impact of exercise testing on cognitive dysfunction.MethodsThis cognitive sub-study was conducted between 2013 and 2019 across seven U.S. ME/CFS clinics as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study. The analysis included 426 participants (261 ME/CFS and 165 HC), who completed cognitive assessments including a computerized CogState Brief Screening Battery (CBSB) administered across five timepoints (T0-T4) at the start of and following a full day in-clinic visit that included exercise testing for a subset of participants (182 ME/CFS and 160 HC). Exercise testing consisted of ramped cycle ergometry to volitional exhaustion. The primary outcomes are performance accuracy and latency (performance speed) on the computerized CBSB administered online in clinic (T0 and T1) and at home (T2-T4).ResultsNo difference was found in performance accuracy between ME/CFS and HCs whereas information processing speed was significantly slower for ME/CFS at most timepoints with Cohen’s d effect sizes ranging from 0.3–0.5 (p < 0.01). The cognitive decline over time on all CBSB tasks was similar for patients with ME/CFS independent of whether exercise testing was included in the clinic visit.ConclusionThe challenges of a clinic visit (including cognitive testing) can lead to further cognitive deficits. A single short session of intense exercise does not further reduce speed of performance on any CBSB tasks.

Neurovascular unit (NVU) inflammation via activation of glial cells and neuronal damage plays a critical role in neurodegenerative diseases. Though the exact mechanism of disease pathogenesis is not understood, certain biomarkers provide valuable insight into the disease pathogenesis, severity, progression and therapeutic efficacy. These markers can be used to assess pathophysiological status of brain cells including neurons, astrocytes, microglia, oligodendrocytes, specialized microvascular endothelial cells, pericytes, NVU, and blood-brain barrier (BBB) disruption. Damage or derangements in tight junction (TJ), adherens junction (AdJ), and gap junction (GJ) components of the BBB lead to increased permeability and neuroinflammation in various brain disorders including neurodegenerative disorders. Thus, neuroinflammatory markers can be evaluated in blood, cerebrospinal fluid (CSF), or brain tissues to determine neurological disease severity, progression, and therapeutic responsiveness. Chronic inflammation is common in age-related neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia. Neurotrauma/traumatic brain injury (TBI) also leads to acute and chronic neuroinflammatory responses. The expression of some markers may also be altered many years or even decades before the onset of neurodegenerative disorders. In this review, we discuss markers of neuroinflammation, and neurodegeneration associated with acute and chronic brain disorders, especially those associated with neurovascular pathologies. These biomarkers can be evaluated in CSF, or brain tissues. Neurofilament light (NfL), ubiquitin C-terminal hydrolase-L1 (UCHL1), glial fibrillary acidic protein (GFAP), Ionized calcium-binding adaptor molecule 1 (Iba-1), transmembrane protein 119 (TMEM119), aquaporin, endothelin-1, and platelet-derived growth factor receptor beta (PDGFRβ) are some important neuroinflammatory markers. Recent BBB-on-a-chip modeling offers promising potential for providing an in-depth understanding of brain disorders and neurotherapeutics. Integration of these markers in clinical practice could potentially enhance early diagnosis, monitor disease progression, and improve therapeutic outcomes.

Background: Negative body image in female adolescents is a sign of the times, but it is also a current global issue due to its implications for the onset of health-compromising behaviours and the increasing power of appearance-based social media. The aim of this study is to investigate the protective role of a life-skills based intervention during PE classes in adolescent girls against increasing body dissatisfaction resulting from body composition changes and to assess the impact of intervention on the skill of setting goals.