Related Pathologies Research Articles

All roads lead to IgA: Mapping the many pathways of IgA induction in the gut.

The increasing prevalence of food allergy and related pathologies in recent years has underscored the need to understand the factors affecting adverse reactions to food. Food allergy is caused when food-specific IgE triggers the release of histamine from mast cells. However, other food-specific antibody isotypes exist as well, including IgG and IgA. IgA is the main antibody isotype in the gut and mediates noninflammatory reactions to toxins, commensal bacteria, and food antigens. It has also been thought to induce tolerance to food, thus antagonizing the role of food-specific IgE. However, this has remained unclear as food-specific IgA generation is poorly understood. Particularly, the location of IgA induction, the role of T cell help, and the fates of food-specific B cells remain elusive. In this review, we outline what is known about food-specific IgA induction and highlight areas requiring further study. We also explore how knowledge of food-specific IgA induction can be informed by and subsequently contribute to our overall knowledge of gut immunity.

Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer’s Disease: The A4 Study

BackgroundStronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer’s disease related pathology and neurodegeneration in smaller cohort studies.ObjectivesWe investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aβ).DesignLongitudinal mixed.SettingThe Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study.ParticipantsA sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aβ positive).MeasurementsGlobal cognitive performance (Preclinical Alzheimer’s Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aβ and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version.ResultsMixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aβ on cognitive change (p =.025) such that stronger connectivity was associated with reduced Aβ-related cognitive decline.ConclusionsOur results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aβ-related cognitive decline.

Microfluidics as a Powerful Tool to Investigate Microvascular Dysfunction in Trauma Conditions: A Review of the State-of-the-Art.

Skeletal muscle trauma such as fracture or crush injury can result in a life-threatening condition called acute compartment syndrome (ACS), which involves elevated compartmental pressure within a closed osteo-fascial compartment, leading to collapse of the microvasculature and resulting in necrosis of the tissue due to ischemia. Diagnosis of ACS is complex and controversial due to the lack of standardized objective methods, which results in high rates of misdiagnosis/late diagnosis, leading to permanent neuro-muscular damage. ACS pathophysiology is poorly understood at a cellular level due to the lack of physiologically relevant models. In this context, microfluidics organ-on-chip systems (OOCs) provide an exciting opportunity to investigate the cellular mechanisms of microvascular dysfunction that leads to ACS. In this article, the state-of-the-art OOCs designs and strategies used to investigate microvasculature dysfunction mechanisms is reviewed. The differential effects of hemodynamic shear stress on endothelial cell characteristics such as morphology, permeability, and inflammation, all of which are altered during microvascular dysfunction is highlighted. The article then critically reviews the importance of microfluidics to investigate closely related microvascular pathologies that cause ACS. The article concludes by discussing potential biomarkers of ACS with a special emphasis on glycocalyx and providing a future perspective.

Long-Term Dietary Consumption of Grapes Affects Kidney Health in C57BL/6J Mice.

Starting at 4 weeks of age, male and female C57BL/6J mice were provided with a semi-synthetic diet for a period of one year and then continued on the semi-synthetic diet with or without grape supplementation for the duration of their lives. During the course of the study, no variation of body weights was noted between the groups. At 2.5 years of age, the body-weight-to-tissue-weight ratios did not vary for the liver, colon, muscle, prostate, or ovary. However, relative to the standard diet, the body/kidney weight ratio was significantly lower in the male and female groups with grape-supplemented diets. With the mice provided with the standard diet, the BUN/creatinine ratios were 125 and 152 for males and females, respectively, and reduced to 63.7 and 40.4, respectively, when provided with the grape diet. A histological evaluation suggested that this may be due to enhanced/improved perfusion in the kidney as a preventive/protective effect. In response to the dietary grapes, an RNA seq analysis revealed up-regulation of 21 and 109 genes with male and female mice, respectively, with a corresponding down-regulation of 108 and 65 genes. The downward movement of the FPKM values in the males (alox5, btk, fga, fpr1, hmox1, lox, ltf, lyve1, marco, mmp8, prg4, s100a8/9, serpina3n, and vsig4) and upward movement of the FPKM values in the females (camp, cd300lf, cd72, fcgr4, fgr, fpr2, htra4, il10, lilrb4b, lipg, pilra, and tlr8) suggest beneficial kidney effects. The expression of some genes related to the immunological activity was also modulated by the grape diet, mainly downward in the males and upward in the females. The reactome pathway analysis, KEGG analysis, and GSEA normalized enrichment scores illustrate that several pathways related to immune function, collagenase degradation, extracellular matrix regulation, metabolism of vitamins and cofactors, pancreatic secretion, aging, and mitochondrial function were enriched in both the males and females provided with the grape diet. Overall, these results indicate that the long-term dietary consumption of grapes contributes to renal health and resilience against fibrosis and related pathologies.

Beyond Hypertension: Examining Variable Blood Pressure's Role in Cognition and Brain Structure.

Hypertension or high blood pressure (BP) is one of the 12 modifiable risk factors that contribute to 40% of dementia cases that could be delayed or prevented. Although hypertension is associated with cognitive decline and structural brain changes, less is known about the long-term association between variable BP and cognitive/brain changes. This study examined the relationship between variable BP and longitudinal cognitive, white matter hyperintensity (WMH), gray matter (GM), and white matter (WM) volume change over time and postmortem neuropathology. A total of 4,606 participants (32,776 follow-ups) from RADC Research Resource Sharing Hub (RUSH) and 2,114 participants (9,827 follow-ups) fromtheAlzheimer's Disease Neuroimaging Initiative (ADNI) were included. Participants were divided into 1 of 3 groups: normal, high, or variable BP. Linear-mixed models investigated the relationship between BP and cognition, brain structure, and neuropathology. Older adults with variable BP exhibited the highest rate of cognitive decline followed by high and then normal BP. Increased GM volume loss and WMH burden were also observed in variable compared to high and normal BP. In postmortem neuropathology, both variable and high BP had increased rates compared to normal BP. Results were consistent across the RUSH and ADNI participants, supporting the generalizability of the findings. Damages potentially associated with variable BP may reduce resilience to future dementia-related pathology and increased the risk of dementia more than that caused by high BP. Improved treatment and management of variable BP may help reduce cognitive decline in the older adult population.

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [11C]MPC-6827 PET imaging in rodent models of Alzheimer's-related pathology.

Microtubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation is critical for connecting amyloid beta (Aβ) and tau-based degenerative events and early changes in presymptomatic Alzheimer's disease (AD). Herein we present positron emission tomography (PET) imaging properties of our MT-PET radiotracer, [11C]MPC-6827, in multiple established AD mouse models. Longitudinal PET, biodistribution, autoradiography, immunohistochemistry, and behavioral studies were conducted at multiple time points in APPswe/PSEN1dE9 (APP/PS1), P301S-PS19 (P301S), 5xFAD, and age-matched control mice. Longitudinal [11C]MPC-6827 brain imaging showed significant increases in APP/PS1, P301S, and 5xFAD mice compared to controls. Longitudinal MT-PET correlated positively with biodistribution, autoradiography, and immunohistochemistry results and negatively with behavior data. Our study demonstrated significant longitudinal [11C]MPC-6827 PET increases in multiple AD mouse models for the first time. Strong correlations between PET and biomarker data underscored the interplay of MT destabilization, amyloid, and tau pathology in AD. These results suggest [11C]MPC-6827 PET as a promising tool for monitoring MT dysregulation early in AD progression. Longitudinal positron emission tomography (PET) imaging studies using [11C]MPC-6827 in multiple established Alzheimer's disease (AD) mouse models revealed an early onset of microtubule dysregulation, with significant changes in brain radiotracer uptake evident from 2 to 4 months of age. Intra-group analysis showed a progressive increase in microtubule dysregulation with increasing AD burden, supported by significant correlations between PET imaging data and biodistribution, autoradiography, and molecular pathological markers. [11C]MPC-6827 PET imaging demonstrated its efficacy in detecting early microtubule alterations preceding observable behavioral changes in AD mouse models, suggesting its potential for early AD imaging. The inclusion of the 5xFAD mouse model further elucidated the impact of amyloid beta (Aβ) toxicity on inducing tau hyperphosphorylation-mediated microtubule dysregulation, highlighting the versatility of [11C]MPC-6827 in delineating various aspects of AD pathology. Our study provides immediate clarity on high uptake of the microtubule-based radiotracer in AD brains in a longitudinal setting, which directly informs clinical utility in Aβ/tau-based studies.

Are the complications after laparo-assisted endo-rectal pull-through for Hirschsprung disease related to the change of the anal tone?

The main advantage of the laparo-assisted transanal endorectal pull-through technique (LA - TERPT) for Hirschsprung Disease (HD) is the respect to the rectal-anal anatomy. Postoperative complications have been observed recently. The present study aims to determine how often these postoperative complications occur in these patients. From January 2009 to December 2018, a retrospective analysis was conducted on 36 children (25 males) with HD who underwent LA-TERPT. Data were collected on the age of diagnosis and surgery, sex, the presence of other pathologies, and cases of enterocolitis. In all cases, anorectal manometry (ARM) was performed to evaluate the anal tone. The median age at diagnosis was 2 months and the mean age at surgery was 5 months. Nine related pathologies were identified: five cases of Down syndrome, one case of hypertrophic stenosis of the pylorus, atresia of the esophagus, polydactyly, and anorectal malformation. A patient with total colonic aganglionosis was identified through laparoscopic serummuscular biopsies. Enterocolitis was diagnosed in 7 cases before and 6 after surgery. At follow-up, the complications recorded were: 5 cases of constipation (treated with fecal softeners), one case of anal stenosis (patient with anorectal malformation), 16 cases of soiling (treated with enemas) and 1 child with fecal incontinence (treated with a transanal irrigation system). The ARM was performed in all 36 cases and showed normal anal tone, except for one case with anal hypotonia. LA-TERPT is an important surgical technique for HD. According to the literature, soiling is the most main complication after HD surgery, probably due to "pseudo-incontinence" with normal anal sphincter tone.

O-071 Stringent statistical analysis of 108,684 oocyte donation cycles identifies 2.6% of donors with specific oocyte/embryo developmental arrest phenotypes for genome association studies

Abstract Study question Can statistical modelling accurately identify an outlier group of presumed fertile donors with specific reduced embryological outcomes suggestive of an underlying infertility-related genomic condition? Summary answer Statistical modelling identified a highly specific group of donors as embryologically under-performing outliers across multiple treatment cycles for the optimisation of downstream genomic association studies. What is known already Female infertility has a wide range of clinical presentations. While some causes of infertility are well defined, the aetiology of most infertility remains unexplained. Since IVF allows for in vitro monitoring of oocyte and embryo, it is now possible to identify subtle infertility endophenotypes, characterized by specific developmental failure that would otherwise go undetected in natural conception. Currently, the lack of large and well-categorized datasets of infertility endophenotypes has limited research in the area. Therefore, a clear and methodological definition of infertility endophenotypes in IVF is the first crucial step towards a better understanding of their mechanism and biological/genetic aetiology. Study design, size, duration A retrospective analysis was performed on clinical and embryological data from 40497 egg donors, undergoing 108.684 stimulations, with 4.235.036 oocytes retrieved. The data also included information on the 85482 recipients and their 190996 oocyte reception cycles, spanning from 1999 to 2023. Infertility endophenotypes were able to be well categorized as oocyte donors are presumed fertile based on their young age and on normal ranges displayed for the parameters assessed during typical oocyte donation work-up. Participants/materials, setting, methods Donor performance was calculated according to: (I) oocyte maturation rate (MR); (ii) survival rate of cryopreserved oocytes (SR); (iii) oocyte fertilization rate (FR;2PN/Injected MII); and (iii) blastulation rate (BR;blastocyst/2PN). Donors with significantly impaired rates, considering ≥2 stimulations and/or recipients, were identified as outliers using probabilistic modelling (Binomial test, Bonferroni corrected P < 0.05). Outliers were computed for each rate on data subsets after applying this stringent filtering criteria and excluding inconsistent or missing data. Main results and the role of chance 2.6% of donors were identified as underperforming outliers when summing the rate observed for each embryological outcome using the stringent statistical modelling. The average MR was 79.8% (95%CI: 79.6-80). Taking into account the correlation of follicle size during ultrasound tracking and the number of mature oocytes collected, a total of 168/29768 (0.56%) donors with statistically lower MR (mean MR = 43% 95%CI:40.1-45.7) across ≥2 egg collection cycles were identified as outliers. The average SR was 88% (95%CI:87.9-88.2). A total of 176/18544 (0.95%) donors with ≥2 stimulations and ≥2 recipient cycles were deemed outliers, showing a statistically reduced SR (mean SR = 51% 95%CI:48.9-53.1). The average FR was 74% (95%CI: 73.8-74.2). 164/31657 (0.52%) donors were found to have statistically low FR (mean FR = 37% 95%CI:34.6-38.7) and deemed outliers when assessed over ≥2 stimulation cycles with ≥2 recipient cycles. The average BR was 53.4% (95%CI: 53.1-53.7). After considering only donors with ≥2 recipients and ≥2 stimulations, a total of 142/24716 (0.57%) donors with statistically low BR (mean BR = 14% 95%CI:12.4-15.3) were considered outliers. Limitations, reasons for caution The stringent criteria applied to our statistical modelling has likely resulted in underestimating the true level of outlier donors. This is also likely compounded by the selection bias associated with donor recruitment and the retention policies after the first stimulation cycle preventing the evaluation of recurrent patterns in some cases. Wider implications of the findings The analytical tools developed on this unprecedentedly large dataset are fundamental to define a methodological workflow for accurately identifying unexpectedly infertile individuals. This is crucial for investigating the genetic and biological mechanisms underlying infertility endophenotypes, leading to improvements in treatment and developing screening tool to predict infertility and related pathologies. Trial registration number not applicable

Poster 131: Loop 'N' Tack Tenodesis: A Multi-Center Retrospective Case Series of Clinical and Patient Reported Outcomes of a Novel Suture Technique for Proximal Biceps Tenodesis

Objectives: Tenodesis and tenotomy of the long head of the biceps are treatment options for a wide range of pathologies without clear superior technique or site of fixation. Tenotomy may result in a cosmetic “Popeye” deformity and fatigue pain. The Loop ‘N’ Tack technique is a quick, simple, and knotless technique for tenodesis of the long head of the biceps that can be completed entirely arthroscopically. The tensionless repair allows the biceps to scar within the biceps groove, thereby reducing subsidence and formation of a “Popeye" deformity and fatigue pain in the biceps seen with tenotomy alone while eliminating the ability to overtension. The primary objective will be to retrospectively report the clinical outcomes and associated complications of patients undergoing biceps tenodesis utilizing the Loop ‘N’ Tack technique at multiple institutions from 1/1/2015 – 7/25/2021. Methods: CPT procedure codes (29827,29823, 29826) were used to identify participants in the EHR (i.e., Epic) who underwent the Loop ‘N’ Tack biceps tenodesis technique by each author at 9 separate institutions. Patient reported outcomes (PRO) including Visual Analog Scale (VAS), American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), Single Assessment Numeric Evaluation (SANE), UCLA Shoulder Rating Scale (UCLA), and Simple Shoulder Test (SST) were recorded at multiple time points throughout the patient’s preoperative and postoperative course. Scores were compared to the established minimal clinically important difference (MCID) for each PRO to assess the viability of this tenodesis technique. Additional metrics including bicipital groove pain, Popeye deformity, and need for revision surgery were also recorded. Results: 1,473 patients were initially screened who underwent the Loop ‘N’ Tack biceps tenodesis technique. 82 patients were excluded secondary to limited follow up or lack of PRO data within the EHR. The average patient age was 64.7 years old with average follow up of 8.11 months. Mean preoperative PRO scores were 5.64 (2.13), 43.31 (20.38), 15.14 (3.52), 5.81 (1.92), and 49.24 (15.06) for the VAS, SANE, UCLA, SST, and ASES scores, respectively. Postoperative PRO scores at most recent follow up respectively measured 1.05 (1.66), 89.56 (17.06), 31.50 (4.01), 10.69 (1.92), and 89.48 (13.81). MCID was reached for each PRO at the 1-2 month mark postoperatively. 36 patients (2.6%) underwent revision surgery for biceps related pathology, while 40 patients (2.9%) required revision shoulder surgery for a separate pathology. Postoperative Popeye deformity was noted in 15 patients (1.08%). Conclusions: The Loop ‘N’ Tack technique results in high rates of patient satisfaction with improvement in shoulder related patient reported outcomes, low incidence of postoperative pain, and low rates of Popeye deformity. This case series establishes the Loop ‘N’ Tack technique as a viable tenodesis approach during shoulder arthroscopy for biceps related pathology.

The Relevance of Implanted Percutaneous Electrical Nerve Stimulation in Orthopedics Surgery: A Systematic Review.

Background: Percutaneous peripheral nerve stimulation (PNS) is a form of neuromodulation that involves the transmission of electrical energy via metal contacts known as leads or electrodes. PNS has gained popularity in orthopedic surgery as several studies have supported its use as a pain control device for patients suffering from pain due to orthopedic pathologies involving the knee, shoulder, and foot. The purpose of this systematic review is to summarize the literature involving peripheral nerve stimulation in orthopedic surgery. The existing body of literature provides support for further research regarding the use of PNS in the management of knee pain, hip pain, shoulder pain, foot pain, and orthopedic trauma. Notably, the evidence for its efficacy in addressing knee and shoulder pain is present. Methods: This study was conducted following PRISMA guidelines. Seven hundred and forty-five unique entries were identified. Two blinded reviewers assessed each article by title and abstract to determine its relevance and categorized them as "include", "exclude", and "maybe". After a preliminary review was completed, reviewers were unblinded and a third reviewer retrieved articles labeled as "maybe" and those with conflicting labels to determine their relevance. Twenty-eight articles were included, and seven hundred and seventeen articles were excluded. Articles discussing the use of PNS in the field of orthopedic surgery in patients > 18 years of age after 2010 were included. Exclusion criteria included neuropathic pain, phantom limb pain, amputation, non-musculoskeletal related pathology, non-orthopedic surgery related pathology, spinal cord stimulator, no reported outcomes, review articles, abstracts only, non-human subjects. Results: A total of 16 studies analyzing 69 patients were included. All studies were either case series or case reports. Most articles involved the application of PNS in the knee (8) and shoulder (6) joint. Few articles discussed its application in the foot and orthopedic trauma. All studies demonstrated that PNS was effective in reducing pain. Discussion: Peripheral nerve stimulation can be effective in managing postoperative or chronic pain in patients suffering from orthopedic pathology. This systematic review is limited by the scarcity of robust studies with substantial sample sizes and extended follow up periods in the existing literature.

Nicotinamide N-Methyltransferase (NNMT): A New Hope for Treating Aging and Age-Related Conditions.

The complex process of aging leads to a gradual deterioration in the function of cells, tissues, and the entire organism, thereby increasing the risk of disease and death. Nicotinamide N-methyltransferase (NNMT) has attracted attention as a potential target for combating aging and its related pathologies. Studies have shown that NNMT activity increases over time, which is closely associated with the onset and progression of age-related diseases. NNMT uses S-adenosylmethionine (SAM) as a methyl donor to facilitate the methylation of nicotinamide (NAM), converting NAM into S-adenosyl-L-homocysteine (SAH) and methylnicotinamide (MNA). This enzymatic action depletes NAM, a precursor of nicotinamide adenine dinucleotide (NAD+), and generates SAH, a precursor of homocysteine (Hcy). The reduction in the NAD+ levels and the increase in the Hcy levels are considered important factors in the aging process and age-related diseases. The efficacy of RNA interference (RNAi) therapies and small-molecule inhibitors targeting NNMT demonstrates the potential of NNMT as a therapeutic target. Despite these advances, the exact mechanisms by which NNMT influences aging and age-related diseases remain unclear, and there is a lack of clinical trials involving NNMT inhibitors and RNAi drugs. Therefore, more in-depth research is needed to elucidate the precise functions of NNMT in aging and promote the development of targeted pharmaceutical interventions. This paper aims to explore the specific role of NNMT in aging, and to evaluate its potential as a therapeutic target.

Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer’s disease fold

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer’s disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36–63 years of age by spectral confocal imaging with conformation-specific dyes and cryo–electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II–like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

Time-dependent effects of high-fat diet on cognition and cerebral insulin signaling: Window for recovery and potential therapeutic target

While high-fat diet (HFD)-induced obesity is a major threat to global public health, the effect of HFD on cognition and insulin signaling during ageing remains controversial. The aim of this study was to characterize the dynamic alterations in cognition and cerebral insulin signaling during 6-month HFD consumption, and to investigate the potential therapeutic target and optimal timing to rescue obesity-related cognitive deficits. In the present study, impaired memory retention induced by 2-month HFD was recovered after 4 months on HFD. Prolonged (6-month) HFD did not further enhance tau hyperphosphorylation and β-amyloid deposition, which was consistent with the alleviation of memory retention. In brain insulin signaling, 2-month HFD increased IRS-1 and p-IRS-1(Ser307)/IRS-1, while decreasing pAKT(Ser473)/AKT, PI3K and mTOR; 4-month HFD decreased IRS-1 and pAKT(Ser473)/AKT, while increasing AKT; 6-month HFD increased IRS-1, pAKT(Ser473)/AKT, and mTOR, while decreasing p-IRS-1(Ser307)/IRS-1, PI3K and AKT. Notably, bioinformatic analysis revealed a rhythmic process presented only in 4-month HFD group, with Srebf1 emerging as a link between circadian rhythms and insulin signaling pathway. These results suggest that prolonged HFD prevents further cognitive decline and the progression of Alzheimer’s disease (AD)-related pathologies during ageing. Moreover, there may be a window for recovery, in which Srebf1 acts as a self-recovery switch to address obesity-related cognitive disorders in elders.

Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer’s disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer’s disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aβ42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer’s disease who do not have HIV infection.

Gossypetin targets the liver-brain axis to alleviate pre-existing liver fibrosis and hippocampal neuroinflammation in mice.

Liver fibrosis occurs in response to chronic damage and inflammation to the liver. Leaving untreated, it can lead to decreased liver function and can eventually progress to cirrhosis, a more advanced and irreversible state of liver damage. Clinical investigations showed that chronic liver disease associated with neurological symptoms including anxiety, depression, and cognitive decline. However, few therapeutic options are available for treating liver and related brain pathologies simultaneously. In this study, we aim to find therapeutic candidates that target the liver-brain axis. Gossypetin, a flavonoid from sedum, shows promising capability in treating liver and brain pathologies in CCl4-induced mouse model. Short term of gossypetin administration is sufficient to ameliorate impaired liver function and pre-existing liver fibrosis, suppress MKK3/6-p38 MAPK and p53 activation, and abolish the activation of hepatic stellate cells and Kupffer cells. Although we observe no neuronal loss in the brain of mice with liver fibrosis, we do observe astrogliosis and microglial activation in certain brain regions, especially the hippocampus. Brief gossypetin administration also shows potential in alleviating neuroinflammation in these regions. These results suggest that gossypetin can target the liver-brain axis and be a promising candidate for treating chronic liver fibrosis patients with neurological symptoms.

Effects of voluntary and forced physical exercise on the retinal health of aging Wistar rats

Aging is accompanied by an increased prevalence of degenerative conditions, including those affecting ocular health, which significantly impact quality of life and increase the burden on healthcare systems. Among these, retinal aging is of particular concern due to its direct link to vision impairment, a leading cause of disability in the elderly. Vision loss in the aging population is associated with heightened risks of cognitive decline, social isolation, and morbidity. This study addresses the critical gap in our understanding of modifiable lifestyle factors, such as physical exercise, that may mitigate retinal aging and its related pathologies. We investigated the effects of different exercise regimens—voluntary (recreational-type) and forced (high-intensity)—on the retinal health of aging Wistar rats (18-month-old), serving as a model for studying the translational potential of exercise interventions in humans. Male Wistar rats were divided into four groups: a young control (3-month-old) for baseline comparison, an aged sedentary control, an aged group engaging in voluntary exercise via a running wheel in their cage, and an aged group subjected to forced exercise on a treadmill for six sessions of 20 min each per week. After a 6-month experimental period, we assessed retinal function via electroretinography (ERG), measured retinal thickness histologically, and analyzed protein expression changes relevant to oxidative stress, inflammation, and anti-aging mechanisms. Our findings reveal that voluntary exercise positively impacts retinal function and morphology, reducing oxidative stress and inflammation markers while enhancing anti-aging protein expression. In contrast, forced exercise showed diminished benefits. These insights underscore the importance of exercise intensity and preference in preserving retinal health during aging. The study highlights the potential of recreational physical activity as a non-invasive strategy to counteract retinal aging, advocating for further research into exercise regimens as preventative therapies for age-related ocular degenerations.

Cholesteatoma in the pediatric aerodigestive population

ObjectivesTo report the prevalence of cholesteatoma and related comorbidities in pediatric aerodigestive patients requiring tracheostomy or airway reconstruction procedures. To use study findings to inform clinical management of these complex patients. MethodsA repository of clinical data drawn from our institution's electronic medical records was queried to identify airway reconstruction (airway) and complex hospital control (control) patient cohorts. Retrospective chart review was then performed to investigate the occurrence of cholesteatoma and related pathologies in these patients, as well as clinical management. ResultsThe prevalence of cholesteatoma in airway and control patients was 6/374 (1.60 %) and 35/30,565 (0.11 %), respectively. The relative risk of cholesteatoma diagnosis in airway patients was 14.01 (95 % CI 6.06–32.14). Airway patients were more likely than control patients to have pressure equalization tube history (relative risk 3.25, 95 % CI 2.73–3.82). Age at cholesteatoma diagnosis and first surgical intervention was younger in airway compared to control patients (5.43 vs. 8.33, p = 0.0182, and 6.07 vs. 8.82, p = 0.0236). However, time from diagnosis to intervention and extent of surgery were similar between the groups. ConclusionThis is the first study to investigate the prevalence of cholesteatoma in the pediatric aerodigestive population. The relative risk of cholesteatoma diagnosis was found to be 14 times higher in patients with tracheostomy or airway reconstruction history. Underlying eustachian tube and palatal dysfunction are likely contributing factors to the elevated risk. Additionally, cholesteatoma in this population was diagnosed and required surgical intervention at a younger age, which may suggest a more aggressive disease course. Providers should maintain a high degree of suspicion for cholesteatoma in this complex population.

Novel coumarins from green sweet bell pepper seeds: Their isolation, characterization, oxidative stress-mitigating, anticancer, anti-inflammatory, and antidiabetic properties

In an attempt to develop a potent, eco-friendly, and selective technique for isolating natural coumarins, this study introduced a novel extraction technique called kinetic thermomagnetic. It involved the application of four different variables: temperature, time interval, magnetic, and rotation speed. Phytochemical analysis was performed on the eighty one crude chloroform extracts of green sweet bell pepper seeds collected, identifying the presence of many botanical categories. Nine extracts were found to have the same two extraction variables—a 90-minute extraction period and a 55 °C extraction temperature—and to have the coumarin chemical class. Two of these extracts with coumarin were selected so that their coumarin contents could be chemically isolated and chromatographically purified. The molecular frameworks of four novel phytocoumarins have been discovered and differentiated by the analysis of their mass, 1H NMR, 13C NMR, and FTIR spectra. These phytocoumarins were found to have anticancer properties against eight malignant populations by MTT probing and to mitigate oxidative stress in human SH-SY5Y populations. Likewise, three and two related enzymes were used to specify the anti-inflammatory and antidiabetic capabilities, respectively. Comparing the isolated phytocoumarins to a positive control, the results showed that they had outstanding oxidative stress-mitigating properties, ranging from 71.51 to 81.48 %. Additionally, they demonstrated excellent cytotoxicity (IC50 values of 46.76–81.45 μg/ml) against the test malignant populations. The isolates also demonstrated an intriguing selective anti-inflammatory action, making them worthy of consideration as dual COX-2/5-LOX antagonists. Ultimately, when they submitted to the test against two blood-controlling enzymes, they showed a moderate antidiabetic effect. The authors concluded that by adjusting its factors, the approach used is effective and adaptable for extraction. Furthermore, natural-B4 in particular and other isolated phytocoumarins in general offer naturally derived remedies for alleviating oxidative stress and its related pathologies.

How calcineurin inhibitors affect cognition.

With a focus on the discrepancy between preclinical and clinical findings, this review will gather comprehensive information about the effects of calcineurin inhibitors (CNI) on cognitive function and related brain pathology from in vitro, in vivo, and clinical studies. We also summarize the potential mechanisms that underlie the pathways related to CNI-induced cognitive impairment. We systematically searched articles in PubMed using keywords 'calcineurin inhibitor*' and 'cognition' to identify related articles, which the final list pertaining to underlying mechanisms of CNI on cognition. Several studies have reported an association between calcineurin and the neuropathology of Alzheimer's disease (AD). AD is the most common neurocognitive disorder associated with amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive impairment. CNI, including tacrolimus and cyclosporin A, are commonly prescribed for patients with transplantation of solid organs such as kidney, liver, or heart, those drugs are currently being used as long-term immunosuppressive therapy. Although preclinical models emphasize the favorable effects of CNI on the restoration of brain pathology due to the impacts of calcineurin on the alleviation of amyloid-beta deposition and tau hyperphosphorylation, or rescuing synaptic and mitochondrial functions, treatment-related neurotoxicity, resulting in cognitive dysfunctions has been observed in clinical settings of patients who received CNI. Inconsistent results of CNI on cognition from clinical studies have been observed due to impairment of the blood-brain barrier, neuroinflammation mediated by reactive oxygen species, and alteration in mitochondrial fission, and extended research is required to confirm its promising use in cognitive impairment.

Modulation of Serotonin-Related Genes by Extracellular Vesicles of the Probiotic Escherichia coli Nissle 1917 in the Interleukin-1β-Induced Inflammation Model of Intestinal Epithelial Cells.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition involving dysregulated immune responses and imbalances in the gut microbiota in genetically susceptible individuals. Current therapies for IBD often have significant side-effects and limited success, prompting the search for novel therapeutic strategies. Microbiome-based approaches aim to restore the gut microbiota balance towards anti-inflammatory and mucosa-healing profiles. Extracellular vesicles (EVs) from beneficial gut microbes are emerging as potential postbiotics. Serotonin plays a crucial role in intestinal homeostasis, and its dysregulation is associated with IBD severity. Our study investigated the impact of EVs from the probiotic Nissle 1917 (EcN) and commensal E. coli on intestinal serotonin metabolism under inflammatory conditions using an IL-1β-induced inflammation model in Caco-2 cells. We found strain-specific effects. Specifically, EcN EVs reduced free serotonin levels by upregulating SERT expression through the downregulation of miR-24, miR-200a, TLR4, and NOD1. Additionally, EcN EVs mitigated IL-1β-induced changes in tight junction proteins and oxidative stress markers. These findings underscore the potential of postbiotic interventions as a therapeutic approach for IBD and related pathologies, with EcN EVs exhibiting promise in modulating serotonin metabolism and preserving intestinal barrier integrity. This study is the first to demonstrate the regulation of miR-24 and miR-200a by probiotic-derived EVs.