Neuro-ophthalmic challenges and multi-morbidity in vasculitis among the older adults.

INTRODUCTION: Vasculitides are a heterogeneous group of disorders producing inflammation of blood vessels (e.g. arteries or veins). All major vasculitides potentially have ophthalmological symptoms and signs including visual loss. Co-morbidity, multimorbidity, polypharmacy, and geriatric syndromes all play important roles in patient outcomes for these rheumatic conditions in the elderly. This monograph reviews the NCBI PubMed database (Feb 2023) literature on the neuro-ophthalmic and geriatric considerations in vasculitis. AREAS COVERED: Cogan Syndrome, Granulomatosis with Polyangiitis, Giant Cell Arteritis, Polyarteritis Nodosa, Takayasu Arteritis, Vasculitis epidemiology, and neuro-ophthalmological symptoms. EXPERT OPINION: Geriatric patient care for vasculitis with neuro-ophthalmological manifestations can be complicated by the interplay of multiple co-morbidities, polypharmacy, and specific geriatric syndromes. The valuation and treatment of vasculitis and the complications associated with the disease can negatively impact patient care. Advances in noninvasive imaging and updates in diagnostic criteria have enabled increased identification of patients at earlier stages with less severe disease burden. Novel therapeutic agents can be glucocorticoid sparing and might reduce the adverse effects of chronic steroid use. Holistic care models like the 5 M geriatric care model (mind, mobility, medications, multicomplexity, and matters most) allow patients' needs to be in the forefront with biopsychosocial aspects of a patient being addressed.

Alzheimer's disease and its related dementias in US Native Americans: A major public health concern.

Alzheimer's disease (AD) and Alzheimer's related dementias (ADRD) are growing public health concerns in aged populations of all ethnic and racial groups. AD and ADRD are caused by multiple factors, such as genetic mutations, modifiable and non-modifiable risk factors, and lifestyle. Studies of postmortem brains have revealed multiple cellular changes implicated in AD and ADRD, including the accumulation of amyloid beta and phosphorylated tau, synaptic damage, inflammatory responses, hormonal imbalance, mitochondrial abnormalities, and neuronal loss. These changes occur in both early-onset familial and late-onset sporadic forms. Two-thirds of women and one-third of men are at life time risk for AD. A small proportion of total AD cases are caused by genetic mutations in amyloid precursor protein, presenilin 1, and presenilin 1 genes, and the APOE4 allele is a risk factor. Tremendous research on AD/ADRD, and other comorbidities such as diabetes, obesity, hypertension, and cancer has been done on almost all ethnic groups, however, very little biomedical research done on US Native Americans. AD/ADRD prevalence is high among all ethnic groups. In addition, US Native Americans have poorer access to healthcare and medical services and are less likely to receive a diagnosis once they begin to exhibit symptoms, which presents difficulties in treating Alzheimer's and other dementias. One in five US Native American people who are 45 years of age or older report having memory issues. Further, the impact of caregivers and other healthcare aspects on US Native Americans is not yet. In the current article, we discuss the history of Native Americans of United States (US) and health disparities, occurrence, and prevalence of AD/ADRD, and shedding light on the culturally sensitive caregiving practices in US Native Americans. This article is the first to discuss biomedical research and healthcare disparities in US Native Americans with a focus on AD and ADRD, we also discuss why US Native Americans are reluctant to participate in biomedical research.

Urgent needs of caregiving in ageing populations with Alzheimer's disease and other chronic conditions: Support our loved ones.

The ageing process begins at birth. It is a life-long process, and its exact origins are still unknown. Several hypotheses attempt to describe the normal ageing process, including hormonal imbalance, formation of reactive oxygen species, DNA methylation & DNA damage accumulation, loss of proteostasis, epigenetic alterations, mitochondrial dysfunction, senescence, inflammation, and stem cell depletion. With increased lifespan in elderly individuals, the prevalence of age-related diseases including, cancer, diabetes, obesity, hypertension, Alzheimer's, Alzheimer's disease and related dementias, Parkinson's, and other mental illnesses are increased. These increased age-related illnesses, put tremendous pressure & burden on caregivers, family members, and friends who are living with patients with age-related diseases. As medical needs evolve, the caregiver is expected to experience an increase in duties and challenges, which may result in stress on themselves, and impact their own family life. In the current article, we assess the biological mechanisms of ageing and its effect on body systems, exploring lifestyle and ageing, with a specific focus on age-related disorders. We also discussed the history of caregiving and specific challenges faced by caregivers in the presence of multiple comorbidities. We also assessed innovative approaches to funding caregiving, and efforts to improve the medical system to better organize chronic care efforts, while improving the skill and efficiency of both informal and formal caregivers. We also discussed the role of caregiving in end-of-life care. Our critical analysis strongly suggests that there is an urgent need for caregiving in aged populations and support from local, state, and federal agencies.

Fatty acids, esters, and biogenic oil disinfectants: novel agents against bacteria.

For hundreds of years, disinfectants have comprised a variety of active chemical agents that destroy microorganisms through a wide spectrum of mechanisms. In recent years, there has been growing interest in novel disinfectants. One novel method for disinfectant is aerosols. Since the beginning of the 20th century, aerosols produced by the volatilization and subsequent recondensation of oil vapors have been utilized as obscurants (smoke) screens during military operations. Specifically, a petroleum middle distillate, known as the FOG oil, has been used in the US military battlefield to create obscurant smoke screens. Biogenic oils are non-petroleum-based oils that resemble FOG oil in terms of their physical characteristics. Furthermore, FOG and biogenic oils have characteristics that make them preferable to other disinfectants that are frequently employed. In this review, we examine the antimicrobial activities of mineral oils and biogenic oil esters aerosols/vapors as novel disinfectants against bacteria and other microorganisms.

Optimum duration of hyperventilation during electroencephalography.

Hyperventilation (HV) is carried out for 3 minutes as a standard activation procedure in most routine electroencephalographic (EEG) procedures. The cerebral blood flow (CBF) reduction and the accompanying cerebral vasoconstriction caused by HV is believed to be the mechanism of EEG activation during HV. Some advocate for 5 minutes of HV, although the optimum duration is unknown. In this study, we measured the CBF continuously over the anterior temporal lobes using subdural probes, which use thermal diffusion flowmetry to measure CBF directly from the cerebral cortex. We sought to determine the duration of HV that produces the maximum reduction in CBF during routine HV in our epilepsy monitoring unit and prolonged the procedure for an additional 2 minutes for this study. Flowtronics® CBF probes were placed over the anterior temporal lobes in addition to the standard subdural strip placement for localization of their seizure focus in six patients who were candidates for epilepsy surgery. CBF was measured continuously for 2 minutes before and 5 minutes during HV for each patient. Time to reach maximum reduction of CBF for each attempt (11 temporal lobes) was computed. At 3 minutes, CBF reduction ranged from 11.6% to 40.0% from the pre-HV CBF level (mean 23.9%). At 5 minutes, CBF ranged from 14.3% to 42.0% (mean 25.7%). Six of the 11 measurements were steady or decreased slightly, and in the five other measurements, CBF showed a reverse trend after 3 minutes. A significant CBF reduction was attained in 3 minutes of HV in all trials. Continued HV after 3 minutes resulted in only a marginal (mean 1.8%) additional CBF reduction after 3 minutes. Thus, we propose that 3 minutes of HV is sufficient for EEG activation by the CBF criterion.

Anti-Pseudomonas aeruginosa Vaccines and Therapies: An Assessment of Clinical Trials.

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen that causes high morbidity and mortality in cystic fibrosis (CF) and immunocompromised patients, including patients with ventilator-associated pneumonia (VAP), severely burned patients, and patients with surgical wounds. Due to the intrinsic and extrinsic antibiotic resistance mechanisms, the ability to produce several cell-associated and extracellular virulence factors, and the capacity to adapt to several environmental conditions, eradicating P. aeruginosa within infected patients is difficult. Pseudomonas aeruginosa is one of the six multi-drug-resistant pathogens (ESKAPE) considered by the World Health Organization (WHO) as an entire group for which the development of novel antibiotics is urgently needed. In the United States (US) and within the last several years, P. aeruginosa caused 27% of deaths and approximately USD 767 million annually in health-care costs. Several P. aeruginosa therapies, including new antimicrobial agents, derivatives of existing antibiotics, novel antimicrobial agents such as bacteriophages and their chelators, potential vaccines targeting specific virulence factors, and immunotherapies have been developed. Within the last 2-3 decades, the efficacy of these different treatments was tested in clinical and preclinical trials. Despite these trials, no P. aeruginosa treatment is currently approved or available. In this review, we examined several of these clinicals, specifically those designed to combat P. aeruginosa infections in CF patients, patients with P. aeruginosa VAP, and P. aeruginosa-infected burn patients.

Two-muscle surgical treatment of a compensatory head tilt in an adult with acquired downbeat nystagmus.

Kestenbaum-Anderson-like operations have proven beneficial in treatment of compensatory head tilt in patients with infantile nystagmus. However, their use in acquired vertical nystagmus in adults with head tilt has rarely been reported. Presented here is a case of a 52-year-old woman with acquired downbeat nystagmus with a significant head tilt who responded to a simple two-muscle surgery involving the superior recti. Cyclovertical muscle surgery should be considered a viable option in such patients who are refractory to medical intervention. Additionally, it appears that four-muscle vertical muscle recessions (two muscles per eye) may not be necessary to dampen vertical nystagmus since good results can be obtained with a single muscle recession bilaterally.

The Role of Red Cell Distribution Width as a Prognostic Marker in Chronic Liver Disease: A Literature Review.

Liver disease is one of the leading public health problems faced by healthcare practitioners regularly. As such, there has been a search for an inexpensive, readily available, non-invasive marker to aid in monitoring and prognosticating hepatic disorders. Recently, red blood cell distribution width (RDW) has been found to be associated with various inflammatory conditions with implications for its use as a potential marker for assessing disease progression and prognosis in multiple conditions. Multiple factors effect red blood cell production whereby a dysfunction in any process can lead to anisocytosis. Furthermore, a chronic inflammatory state leads to increased oxidative stress and produces inflammatory cytokines causing dysregulation and increased intracellular uptake and use of both iron and vitamin B12, which leads to a reduction in erythropoiesis causing an increase in RDW. This literature review reviews in-depth pathophysiology that may lead to an increase in RDW and its potential correlation with chronic liver diseases, including hepatitis B, hepatitis C, hepatitis E, non-alcoholic fatty liver disease, autoimmune hepatitis, primary biliary cirrhosis, and hepatocellular carcinoma. In our review, we examine the use of RDW as a prognostic and predictive marker for hepatic injury and chronic liver disease.

The in vitro efficacy of betadine antiseptic solution and colloidal silver gel combination in inhibiting the growth of bacterial biofilms.

INTRODUCTION: Betadine (Povidone-Iodine) solution is a topically applied antiseptic, which has been used routinely used in wound care and general surgery to prevent skin and wound infections. However, several studies have documented the ineffectiveness of betadine. Other topical antimicrobial dressings, including those that contain silver, have been used in the management of infected wounds. The present study was undertaken to determine if the combination of 5% betadine solution and silver colloidal gel (Ag-gel) is more effective than either substance alone in inhibiting the growth gram-negative and gram-positive bacteria. METHODS: The effectiveness of 5% betadine solution and Ag-gel as anti-microbial agents were assessed using both colony forming unit (CFU) assay and confocal laser scanning microscopy (CLSM). RESULTS: Ag-gel showed complete inhibition on all the bacteria species examined except the Klebsiella pneumoniae clinical isolate (CL) strain while 5% betadine concentrations did not completely kill any of the tested bacteria. In contrast, K. pneumoniae was completely eliminated in the presence of both 5% betadine solution and Ag-gel together. The CLSM showed similar findings to the CFU results examining the 5% betadine solution and Ag-gel combination. CONCLUSIONS: This study demonstrated that while the individual treatments using either 5% betadine solution and Ag-gel alone were infective antimicrobial agents, the combination of 5% betadine solution and Ag-gel was superior at eliminating all tested bacteria, including K. pneumoniae CL.

The In Vivo and In Vitro Assessment of Pyocins in Treating Pseudomonas aeruginosa Infections.

Pseudomonas aeruginosa can cause several life-threatening infections among immunocompromised patients (e.g., cystic fibrosis) due to its ability to adapt and develop resistance to several antibiotics. In recent years, P. aeruginosa infections has become difficult to treat using conventional antibiotics due to the increase multidrug-resistant P. aeruginosa strains. Therefore, there is a growing interest to develop novel treatments against antibiotic-resistance P. aeruginosa strains. One novel method includes the application of antimicrobial peptides secreted by P. aeruginosa strains, known as pyocins. In this review, we will discuss the structure, function, and use of pyocins in the pathogenesis and treatment of P. aeruginosa infection.

Cerebral blood flow dynamics before, during, and after seizures from epilepsy and the periictal state.

Changes in cerebral blood flow (CBF) in the human cerebral cortex during surgery were reported by Penfield. However, data on continuous CBF during seizures were not available until Carter et al developed a subdural CBF probe for measuring continuous CBF. This probe used thermal resistor methodology and was developed to study patients with head trauma. With such a probe, changes in continuous CBF and electroencephalography during and after a seizure were reported by Oommen et al. Such changes were later confirmed examining the same phenomenon by using cerebral perfusion with laser Doppler methodology with epidural electroencephalography. This review details the evolution of our knowledge of CBF from observational reports to recordings from the animal and human cortices, by varying methodologies.

Binding of Citrate-Fe3+ to Plastic Culture Dishes, an Artefact Useful as a Simple Technique to Screen for New Iron Chelators.

NaCT mediates citrate uptake in the liver cell line HepG2. When these cells were exposed to iron (Fe3+), citrate uptake/binding as monitored by the association of [14C]-citrate with cells increased. However, there was no change in NaCT expression and function, indicating that NaCT was not responsible for this Fe3+-induced citrate uptake/binding. Interestingly however, the process exhibited substrate selectivity and saturability as if the process was mediated by a transporter. Notwithstanding these features, subsequent studies demonstrated that the iron-induced citrate uptake/binding did not involve citrate entry into cells; instead, the increase was due to the formation of citrate-Fe3+ chelate that adsorbed to the cell surface. Surprisingly, the same phenomenon was observed in culture wells without HepG2 cells, indicating the adsorption of the citrate-Fe3+ chelate to the plastic surface of culture wells. We used this interesting phenomenon as a simple screening technique for new iron chelators with the logic that if another iron chelator is present in the assay system, it would compete with citrate for binding to Fe3+ and prevent the formation and adsorption of citrate-Fe3+ to the culture well. This technique was validated with the known iron chelators deferiprone and deferoxamine, and with the bacterial siderophore 2,3-dihydroxybenzoic acid and the catechol carbidopa.

Effects of Dexamethasone on DNA Synthesis in Lens Epithelial Cells Are Dependent on Cell Type and Growth Factor.

PURPOSE: To determine the factors that influence the ability of dexamethasone (dex) to inhibit or stimulate the growth of lens epithelial cells. METHOD: Different growth factors with or without dex (10-6 M) were added to quiescent cultures of two clones of Nakano mouse lens epithelial cells (NK11) in serum-free medium. DNA synthesis was then measured after 8-12 hours by the incorporation of tritiated thymidine. RESULTS: Dex was found to both stimulate and inhibit mitogen-induced 3H-thymidine incorporation into the DNA of cultured mouse lens epithelial cells. Enhancement or repression by dex was found to depend on the growth factor used to stimulate the quiescent cell. EGF and insulin were consistently inhibited with dex. Basic fibroblast growth factor (bFGF) and retinoblastoma-derived growth factor (RbDGF) were both enhanced and inhibited by dex, depending on the growth factor concentration and the cell clone used for the experiment. Additionally, RbDGF protects against the dex inhibition of insulin stimulation, but not the inhibition of EGF stimulation. Progesterone, an inhibitor of the activation of the glucocorticoid receptor, blocks the dex inhibitory effect on the EGF and insulin stimulation of DNA synthesis. The ability of progesterone to affect the dex inhibition is consistent with the dex receptor modulating DNA synthesis. The dex effect on DNA synthesis, either stimulatory or inhibitory, was still seen if dex was added as late as 10 hours after the growth factor. CONCLUSIONS: The study demonstrated that dex reduces the overall growth and activity of lens epithelial cells in vitro. This result provides insight into the risk of developing posterior subcapsular cataracts (PSC) in patients on oral glucocorticoid therapy. Understanding the basic mechanisms by which steroids mediate lens cell growth may provide the ability to more accurately predict who will develop PSC. The present studies show the difference in the effect of dex from lens cell to lens cell, but, more importantly, suggest a pattern of dependent variables that might prove useful in such predictions.

Case report of recurrent fibromatosis with laryngeal involvement: Treatment based on network analyses of NGS data.

Aggressive fibromatosis (AF) is a rare, benign neoplasm originating from musculoaponeurotic stromal structures characterized by aggressive growth and infiltration of local tissues. To date, only six previous cases of AF involving the larynx have been reported. The present case was that of a 70-year-old female patient with a 5-year history of hoarseness and an enlarging neck mass consistent with aggressive recurrent fibromatosis. MRI displayed a large, solid mass arising from the left anterior cervical space displacing the trachea and upper airway to the right. At one year after the initial radical resection, the patient presented with recurrence. A second radical excision was performed not including a laryngectomy. Radiation therapy was considered for possible local treatment to prevent subsequent tumor recurrence. According to the literature, AF has recurrence rates of up to 40-70% within 18 months. There is only sparse literature to guide treatment. Using the mutations detected in the patient's AF tissue, an Ingenuity Pathway Analysis (IPA) was used to guide treatment of the recurrence. In the present case, the IPA analysis indicated the use of pazopanib to treat the patient's cancer. In general, surgery appears to be the treatment of choice for head and neck AF, but the management of recurrence is controversial.

Global Impact of COVID-19 on Colorectal Cancer Screening: Current Insights and Future Directions.

The coronavirus disease 2019 (COVID-19) pandemic has brought significant challenges to many aspects of healthcare delivery since the first reported case in early December 2019. Once in the body, SARS-CoV-2 can spread to other digestive organs, such as the liver, because of the presence of ACE2 receptors. Colorectal cancer (CRC) remains the second-leading cause of death in the United States (US). Therefore, individuals are routinely screened using either endoscopic methods (i.e., flexible sigmoidoscopy and colonoscopy) or stool-based tests, as per the published guidelines. At the beginning of the COVID-19 pandemic, the Centers for Medicare and Medicaid Services (CMS) recommended that all non-urgent surgical and medical procedures, including screening colonoscopies, be delayed until the pandemic stabilization. This article aims to review the impact of COVID-19 on CRC screening.

Anticancer Activity of Ω-6 Fatty Acids through Increased 4-HNE in Breast Cancer Cells.

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.

Scope of Artificial Intelligence in Gastrointestinal Oncology.

Gastrointestinal cancers are among the leading causes of death worldwide, with over 2.8 million deaths annually. Over the last few decades, advancements in artificial intelligence technologies have led to their application in medicine. The use of artificial intelligence in endoscopic procedures is a significant breakthrough in modern medicine. Currently, the diagnosis of various gastrointestinal cancer relies on the manual interpretation of radiographic images by radiologists and various endoscopic images by endoscopists. This can lead to diagnostic variabilities as it requires concentration and clinical experience in the field. Artificial intelligence using machine or deep learning algorithms can provide automatic and accurate image analysis and thus assist in diagnosis. In the field of gastroenterology, the application of artificial intelligence can be vast from diagnosis, predicting tumor histology, polyp characterization, metastatic potential, prognosis, and treatment response. It can also provide accurate prediction models to determine the need for intervention with computer-aided diagnosis. The number of research studies on artificial intelligence in gastrointestinal cancer has been increasing rapidly over the last decade due to immense interest in the field. This review aims to review the impact, limitations, and future potentials of artificial intelligence in screening, diagnosis, tumor staging, treatment modalities, and prediction models for the prognosis of various gastrointestinal cancers.

Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis.

We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or both alleles of the tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect tumor growth but significantly reduced the lung metastatic burden of breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2 breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated cancers, and our findings may yield novel methods for prevention or treatment of cancer in patients with HER2 mutations or tumor HER2 expression.

Emerging Role of Fascin-1 in the Pathogenesis, Diagnosis, and Treatment of the Gastrointestinal Cancers.

Gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, liver, and pancreatic cancers, remain as one of the leading causes of death worldwide, with a large proportion accounting for fatalities related to metastatic disease. Invasion of primary cancer occurs by the actin cytoskeleton remodeling, including the formation of the filopodia, stereocilia, and other finger-like membrane protrusions. The crucial step of actin remodeling in the malignant cells is mediated by the fascin protein family, with fascin-1 being the most active. Fascin-1 is an actin-binding protein that cross-links filamentous actin into tightly packed parallel bundles, giving rise to finger-like cell protrusions, thus equipping the cell with the machinery necessary for adhesion, motility, and invasion. Thus, fascin-1 has been noted to be a key component for determining patient diagnosis and treatment plan. Indeed, the overexpression of fascin-1 in GI tract cancers has been associated with a poor clinical prognosis and metastatic progression. Moreover, fascin-1 has received attention as a potential therapeutic target for metastatic GI tract cancers. In this review, we provide an up-to-date literature review of the role of fascin-1 in the initiation of GI tract cancers, metastatic progression, and patients' clinical outcomes.

Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood-brain barrier.

NaCT/SLC13A5 is a Na+-coupled transporter for citrate in hepatocytes, neurons, and testes. It is also called mINDY (mammalian ortholog of 'I'm Not Dead Yet' in Drosophila). Deletion of Slc13a5 in mice leads to an advantageous phenotype, protecting against diet-induced obesity, and diabetes. In contrast, loss-of-function mutations in SLC13A5 in humans cause a severe disease, EIEE25/DEE25 (early infantile epileptic encephalopathy-25/developmental epileptic encephalopathy-25). The difference between mice and humans in the consequences of the transporter deficiency is intriguing but probably explainable by the species-specific differences in the functional features of the transporter. Mouse Slc13a5 is a low-capacity transporter, whereas human SLC13A5 is a high-capacity transporter, thus leading to quantitative differences in citrate entry into cells via the transporter. These findings raise doubts as to the utility of mouse models to evaluate NaCT biology in humans. NaCT-mediated citrate entry in the liver impacts fatty acid and cholesterol synthesis, fatty acid oxidation, glycolysis, and gluconeogenesis; in neurons, this process is essential for the synthesis of the neurotransmitters glutamate, GABA, and acetylcholine. Thus, SLC13A5 deficiency protects against obesity and diabetes based on what the transporter does in hepatocytes, but leads to severe brain deficits based on what the transporter does in neurons. These beneficial versus detrimental effects of SLC13A5 deficiency are separable only by the blood-brain barrier. Can we harness the beneficial effects of SLC13A5 deficiency without the detrimental effects? In theory, this should be feasible with selective inhibitors of NaCT, which work only in the liver and do not get across the blood-brain barrier.