SACM - United States of America
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Item Restricted Neurocognitive Impairment and Oral Health Outcomes in Patients with HIV (PWH) On Antiretroviral Therapy (ART)(The University of Pennsylvania, School of Dental Medicine, 2024-08) Alamodi, Eman; Omolehinwa, Temitope; Akay-Espinoza, Cagla; Jordan-Sciutto, Kelly; Akintoye, SundayBackground The advent of antiretroviral medication (ART) led to a significant decline in HIV associated morbidity, including the more severe presentations of HIV-associated neurocognitive disorders (HAND). However, milder forms of neurocognitive impairment (NCI) persist. Neurocognitive deficits have also been independently associated with poor dental outcomes, especially in the elderly population. However, there is limited, if any, reports of dental health outcomes in people with HIV (PWH) with NCI. This study was designed to better understand oral health outcomes in PWH with NCI. Methods A cross-sectional pilot study was conducted on 40 participants, comprising 10 healthy controls and 30 PWH. Neurocognition and dental outcomes were assessed in all participants. Neurocognition was evaluated using a computerized neurobehavioral battery (CNB) test. Dental caries was assessed using the Decayed, Missing, and Filled Teeth (DMFT) index, the Decayed and Filled Teeth (DFT) index, and the Missing Teeth (MT) index. Periodontal status was measured through clinical attachment loss, periodontal pocket depth, and the percentage of sites with bleeding on probing (%BOP). Results Mean DMFT, DFT and MT were significantly higher among PWH (p < 0.001, p = 0.02, p = 0.048, respectively) than in control subjects. NCI was present in 4 PWH and 1 control subject. We also noted that among PWH, those with NCI had a higher DMFT index (20.8 versus 18.5) and a significantly higher mean DFT (12.3 versus 8.0) compared to PWH without NCI (p = 0.048). Conclusion Poor oral health, especially dental caries, is a challenge among PWH and moreso among PWH with NCI.51 0Item Restricted THE EFFECT OF ANTIRETROVIRAL THERAPY ON THE INTEGRATED STRESS RESPONSE IN THE CENTRAL NERVOUS SYSTEM: IN VIVO ASSESSMENT IN SIV-INFECTED RHESUS MACAQUES(University of Pennsylvania, 2024) AbedAlthaqafi, Razan; Jordan-Sciutto, Kelly; Akay-Espinoza, CaglaDespite the benefits of antiretroviral therapy (ART) in people with HIV (PWH), a large percentage of PWH still suffer from some form of neurocognitive impairment. Studies have shown that high degree of oxidative stress and inflammation remain present in the central nervous system of PWH, which can activate the integrated stress response (ISR) pathway. In our lab, studies showed that the levels of several markers for ISR activation, like phosphorylated eukaryotic initiation factor 2α (P-eIF2α), were elevated in neurons and astrocytes in the cortex in autopsy brain tissue of PWH. Phosphorylation of eIF2α is mediated by four kinases, which will result in ISR activation, which is reported in neurodegenerative conditions. In general, ISR is an adaptive pathway; however, chronically activated ISR may contribute to neuronal damage or death and to neurocognitive impairment in PWH. Recently, several studies showed that certain ART drugs contribute to the persistence of HIV-associated neurocognitive disorders and can induce ISR. The aim of the present study was to assess ISR activation in neurons, astrocytes, and oligodendrocytes in brain tissue samples of SIV-infected rhesus macaques. Methods We examined necropsy brain tissue specimens of 11 rhesus macaques, including SIV-infected/ART-untreated macaques (n = 3), SIV-infected/ART-treated macaques (n = 4), and uninfected/untreated (n = 4) macaques to determine if ART aggravated ISR activation in the CNS. Formalin-fixed/paraffin-embedded sections of cortical tissue were immunofluorescently stained using an antibody to p-eIF2α to detect the activation of ISR and antibodies against MAP2, GFAP, and ASPA to label neurons, astrocytes, and oligodendrocytes, respectively. Results By semiquantitative analysis of images of stained specimens obtained from the cortex of the frontal lobes of the treated rhesus macaques, we found that ISR activation in neurons was higher in the SIV-infected/ART-treated group compared to the SIV-infected/ART-untreated group, which was statistically significant. However, we did not observe differences in ISR activation in astrocytes and oligodendrocytes among the three groups. Conclusion In our study, we observed a significant increase in ISR activation in neurons in the gray matter of SIV-infected/ART-treated rhesus macaques compared to SIV-infected/ART-untreated rhesus macaques, which we did not observe in astrocytes and oligodendrocytes.11 0Item Restricted Optimal control frameworks for a class of epidemiological and oncological models(University of Texas at Arlington, 2024-05) Alghamdi, Asma; Roy, SouvikIn this thesis, we employ optimal control frameworks in two distinct contexts: Human immunodeficiency virus (HIV) and esophageal cancer. For HIV, we introduce a comprehensive data-driven nonlinear optimization framework designed for personalized therapies. This framework utilizes a deterministic in-host nonlinear ordinary differential equation (ODE) model and formulates two optimization problems using individual patient data. The first problem focuses on estimating patient-specific parameters through constrained optimization, while the second problem determines optimal combination therapies to reduce viral load to undetectable levels. Several numerical experiments suggest that our framework can provide robust and effective optimal dosages with lower toxicity levels to control HIV. In esophageal cancer, we present an innovative approach to model and control aberrant signaling pathways. This involves leveraging an It\^o stochastic process to capture signaling pathway dynamics governed by a degenerate Fokker-Planck partial differential equation. Our study proposes a refined treatment strategy targeting aberrant signaling pathways, specifically focusing on epidermal growth factor (EGF) pathways. This strategy includes developing a pharmacokinetic model considering pathway heterogeneities, preceded by constrained optimization to obtain model parameters from patient data. Subsequently, we propose a personalized optimal treatment strategy targeting aberrant EGF using a non-smooth open-loop control for a stochastic process modeled by the Fokker-Planck equation. The solution to these problems is characterized within the framework of Pontryagin's minimum principle (PMP), and the optimization problem is solved using a sequential quadratic Hamiltonian (SQH) method. Experimental results are presented to validate the proposed framework successfully.26 0Item Restricted Role of HIV-1 Nef in reduced migration of Macrophages in the Lung of HIV-Tg Mice(Saudi Digital Library, 2022-12) Alrajhi, Yousef; Jerebtsova, MarinaBackground: Past studies have shown that antiretroviral therapy significantly improved the longevity of HIV-infected patients. However, chronic long-term HIV-1 infection is complicated by the increased rates of age-associated chronic diseases, particularly non-infectious respiratory disorders. The mechanism of increased lung non-infectious lung diseases in people living with HIV is poorly understood. An HIV-transgenic mouse model was used to study LPS-induced lung injury. Reduced lung macrophage infiltration and increased lung neutrophil infiltrations with increased lung injury after LPS injection was demonstrated in HIV-transgenic (HIV-Tg) compared to wild-type mice (WT). Activated macrophages accumulated in the capillaries of HIV-Tg mice after LPS injection. The results further showed that Inhibition of HIV-1 transcription significantly increased macrophages' lung infiltration and reduced lung injury in HIV-Tg mice. Hypothesis: We, therefore, hypothesize that reduced LPS-induced lung macrophage migration in HIV-Tg mice is associated with the activation of Src kinase by HIV-1 Nef. We further hypothesize that inhibition of Src activation by PPi inhibitor will restore regular lung macrophage migration and reduces lung injury. Methods: HIV Tg mice and wild-type littermates (WT) were injected with LPS, and blood and lungs were collected 24h after injection. RT-PCR was used to detect the expression of proinflammatory cytokines (IL-1β and IL-18) and Nef in the lung. ELISAs were used to detect the plasma levels of pro-inflammatory cytokines (IL-6 and TNF-α). Levels of Src kinase and phosphorylated Src were determined by Western Blot and flow cytometry. Hematoxylin and eosin staining was used to evaluate lung injury—immunohistochemistry and immunofluorescence staining were used to assess lung macrophage infiltration. Results: Our results demonstrate higher levels of LPS-induced inflammation in HIV-Tg mice. Nef was not expressed in the lung of HIV-Tg mice but was detected in the infiltrated immune cells after LPS injection. Src was expressed and was highly phosphorylated in the lungs of both HIVTg and WT mice. LPS injection significantly reduced lung Src phosphorylation, but Src was highly phosphorylated in the capillary macrophages of HIV-Tg mice. PPI inhibitor of Src significantly reduces lung injury and increases macrophage migration in the lung of HIV Tg mice. Conclusion: Inhibition of Src with PPi improves migration of macrophages and reduces lung injury of HIV-Tg mice.13 0Item Restricted Synthesis and biological evaluation of novel borono-nucleoside analogs as anti- HIV agents(2023-03-21) Alhthlol, Latifah; Tomsho, JohnThe human immunodeficiency virus (HIV) has infected millions of people worldwide. This virus is still a global pandemic due to the continued emergence of viral resistance to current drugs. The nucleoside reverse transcriptase inhibitors (NRTIs) are one of the most used classes of drugs in antiretroviral therapy (ART). These NRTIs analogs can inhibit HIV replication since they are competitive inhibitors of the native nucleotide triphosphate (NTP) substrates of reverse transcriptase (RT). Because of the lack of 3’-hydroxyl group in the nucleoside reverse transcriptase inhibitors, incorporation causes termination of DNA chain elongation. Although these drugs have been proven effective clinically, they have several drawbacks when used in long-term treatment regimes. These drugs have relatively low bioavailability and require phosphorylation by human and/or viral kinases to become activated. Boronic acids and their derivatives have recently emerged as biologically interesting moieties, with increased attention in their use as pharmaceutical agents. It is hypothesized that the incorporation of the boronic acid moiety will improve cellular permeability and pharmacological properties due to their lower negative charge compared to the current nucleoside analogs which incorporate phosphonate moieties, e.g., tenofovir. In this research, we investigate nucleoside boronic acids and their derivatives as potential NRTIs useful for HIV treatment. Herein, we report on the synthesis of a novel borono-nucleoside analogs compounds that are rationally designed analog of Adefovir and tenofovir. Novel borono-nucleoside analogs compounds exhibit an anti- HIV activity when they evaluated against HIV replication. Moreover, structure activity relationship studies indicate that changing boron warhead, increasing carbon chain length, and including ether linker on the alkyl chain backbone, have importance effect on the borononucleoside analogs activity against HIV replication. In addition, cytotoxicity analysis also shows that the borono-nucleoside analogs are not toxic to the mammalian cells. However, the mechanism of action is still unclear although we suggest that borono-nucleoside analogs may act as competitive inhibition, metal chelator, and act as Lewis’s acids and bind to Lewis basic amino acids in the active side. These data will then be utilized in ongoing drug design efforts and allow us to further probe the structure activity relationships of this class compounds.28 0