A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion.

The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes.

Restoring the Multiple Sclerosis Associated Imbalance of Gut Indole Metabolites Promotes Remyelination and Suppresses Neuroinflammation.

In multiple sclerosis (MS) the circulating metabolome is dysregulated, with indole lactate (ILA) being one of the most significantly reduced metabolites. We demonstrate that oral supplementation of ILA impacts key MS disease processes in two preclinical models. ILA reduces neuroinflammation by dampening immune cell activation as well as infiltration; and promotes remyelination and oligodendrocyte differentiation through the aryl hydrocarbon receptor (AhR).

Rehabilitation therapy versus drug-only therapy in patients with multiple sclerosis.

Background/aim: The treatment for multiple sclerosis (MS) does not cure the disease, but it is intended to reduce the intensity, duration, and frequency of symptoms. Rehabilitation therapy (RT), including an individualized physical therapy program (PTP) and adapted occupational therapy (OT), has benefits in terms of aerobic capacity, muscle strength, coordination, and ability to perform activities of daily living (ADL). The primary objective of this study was to examine the efficacy of RT comprising PTP, OT, and drug treatment (DT) versus DT alone in patients with MS.

A randomized feasibility trial of the modified Atkins diet in older adults with mild cognitive impairment due to Alzheimer's disease.

Background: Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in persons with mild cognitive impairment due to early AD and explores potential mechanisms of action.

Methods: We conducted a 12-week, parallel-group, controlled feasibility trial of a ketogenic diet, the modified Atkins diet (MAD), compared to a control diet in patients with cognitive impairments attributed to AD.

Subcutaneous lysophosphatidylcholine administration promotes a febrile and immune response in Holstein heifer calves.

Lysophosphatidylcholine (LPC) is immunomodulatory in nonruminants; however, the actions of LPC on immunity in cattle are undefined. Our objective was to study the effects of LPC administration on measures of immunity, liver health, and growth in calves. Healthy Holstein heifer calves (n = 46; age 7 ± 3 d) were randomly assigned to 1 of 4 treatments (n = 10 to 11 calves/treatment): a milk replacer diet unsupplemented with lecithin in the absence (CON) or presence of subcutaneously (s.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model.

Background: Cognitive decline in Alzheimer's disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity.

Key regulator PNPLA8 drives phospholipid reprogramming induced proliferation and migration in triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and leads to the poorest patient outcomes despite surgery and chemotherapy treatment. Exploring new molecular mechanisms of TNBC that could lead to the development of novel molecular targets are critically important for improving therapeutic options for treating TNBC.

Methods: We sought to identify novel therapeutic targets in TNBC by combining genomic and functional studies with lipidomic analysis, which included mechanistic studies to elucidate the pathways that tie lipid profile to critical cancer cell properties.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer's disease.

Background: Cognitive decline in Alzheimer's disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EV). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity.

Inhibition of neutral sphingomyelinase 2 impairs HIV-1 envelope formation and substantially delays or eliminates viral rebound.

Although HIV-1 Gag is known to drive viral assembly and budding, the precise mechanisms by which the lipid composition of the plasma membrane is remodeled during assembly are incompletely understood. Here, we provide evidence that the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) interacts with HIV-1 Gag and through the hydrolysis of sphingomyelin creates ceramide that is necessary for proper formation of the viral envelope and viral maturation. Inhibition or depletion of nSMase2 resulted in the production of noninfectious HIV-1 virions with incomplete Gag lattices lacking condensed conical cores.

Neuronal deletion of nSMase2 reduces the production of Aβ and directly protects neurons.

Extracellular vesicles (EVs) have been proposed to regulate the deposition of Aβ. Multiple publications have shown that APP, amyloid processing enzymes and Aβ peptides are associated with EVs. However, very little Aβ is associated with EVs compared with the total amount Aβ present in human plasma, CSF, or supernatants from cultured neurons.

Oxysterol misbalance critically contributes to Wilson disease pathogenesis.

Wilson disease (WD) is a metabolic disorder caused by inactivation of the copper-transporting ATPase 2 (ATP7B) and copper (Cu) overload in tissues. Excess Cu causes oxidative stress and pathologic changes with poorly understood mechanistic connections. In mice with established liver disease, Cu overload activates the stress-sensitive transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2).

Association of Plasma Eicosanoid Levels With Immune, Viral, and Cognitive Outcomes in People With HIV.

Background And Objectives: To determine whether plasma eicosanoid levels are associated with immune, viral, and cognitive outcomes in people with HIV (PWH).

Methods: We measured 42 eicosanoids in a longitudinal study of 95 PWH and 25 demographically comparable uninfected participants. Routine clinical chemistry, virologic, immune markers, and a neuropsychological test battery assessing 7 cognitive domains were administered to all participants at 2 study visits over an average of 6.

Wilson's disease: neuropsychiatric presentation and delayed diagnosis.

A woman in her 30s with unclear history of cirrhosis presented to the emergency department with 8 months of worsening bilateral hand tremors, falls, depressed mood, altered mental status, difficulty swallowing and faecal/urinary incontinence. The patient was diagnosed with liver cirrhosis 6 years prior based on outside hospital ultrasound and liver biopsy. The hospital inpatient neurology team was promptly consulted for evaluation of worsening mental status.

Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy.

Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH).

Methods: Serum obtained from HIV-infected ( = 278) and geographically matched HIV seronegative control subjects ( = 300) from Rakai Uganda were used in this study.

Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice.

Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences.

High-Fat Diet and Short-Term Unpredictable Stress Increase Long-Chain Ceramides Without Enhancing Behavioral Despair.

Clinical and preclinical studies suggest that increases in long-chain ceramides in blood may contribute to the development of depressive-like behavior. However, which factors contribute to these increases and whether the increases are sufficient to induce depressive-like behaviors is unclear. To begin to address this issue, we examined the effects of high fat diet (HFD) and short-term unpredictable (STU) stress on long-chain ceramides in the serum of male and female rats.

Trends in Racial and Ethnic Representation Among Neurosurgery Applicants and Residents: A Comparative Analysis of Procedural Specialties.

Background: Diversity, equity, and inclusion within the healthcare workforce are conducive to providing culturally competent care. However, few existing studies have assessed the level of racial and ethnic diversity among resident physicians and residency applicants. Our objective was to provide a comparative analysis of the trends in racial and ethnic representation within different subspecialties in medicine.

Political Campaign Contributions of Surgeons in the United States Throughout the 2020 Election Cycle.

Importance: Political engagement by the physician workforce is necessary to ensure continued representation of their interests in health care legislation. Limited data are available pertaining to the political involvement of US surgeons.

Objective: To analyze the magnitude and distribution of political donations made by all US surgeons throughout the 2020 election cycle.

Psoas Muscle Index as a Predictor of Perioperative Outcomes in Geriatric Patients Undergoing Spine Surgery.

Study Design: Single-center retrospective study.

Objective: The objective of this study was to evaluate the association of psoas muscle mass defined sarcopenia with perioperative outcomes in geriatric patients undergoing elective spine surgery.

Methods: We included geriatric patients undergoing thoracolumbar spinal surgery.

Decisional Regret Among Older Adults Undergoing Corrective Surgery for Adult Spinal Deformity: A Single Institutional Study.

Study Design: Retrospective.

Objective: To investigate the prevalence of decisional regret among older adults undergoing surgery for adult spinal deformity (ASD).

Summary Of Background Data: Among older adults (≥65 years old), ASD is a leading cause of disability, with a population prevalence of 60% to 70%.

Patient and Spine Surgeon Perceptions on Shared Decision-Making in the Treatment of Older Adults Undergoing Corrective Surgery for Adult Spinal Deformity.

Study Design: Retrospective.

Objective: To understand patients' and spine surgeons' perspectives about decision-making around surgery for adult spinal deformity.

Summary Of Background Data: Surgery for correction of adult spinal deformity is often beneficial; however, in over 20% of older adults (≥ 65 yrs of age), outcomes from surgery are less desirable.

Intestinal and Hepatic Uptake of Dietary Peroxidized Lipids and Their Decomposition Products, and Their Subsequent Effects on Apolipoprotein A1 and Paraoxonase1.

Both pro- and antiatherosclerotic effects have been ascribed to dietary peroxidized lipids. Confusion on the role of peroxidized lipids in atherosclerotic cardiovascular disease is punctuated by a lack of understanding regarding the metabolic fate and potential physiological effects of dietary peroxidized lipids and their decomposition products. This study sought to determine the metabolic fate and physiological ramifications of 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 13-HODE (13-hydroxyoctadecadienoic acid) supplementation in intestinal and hepatic cell lines, as well as any effects resulting from 13-HPODE or 13-HODE degradation products.