Browsing by Author "Yusuf, Kamran"

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    Cellular and molecular mechanisms underlying anesthetic-induced cytotoxicity, and their impact on learning and memory
    (2022-01) Jimenez Tellez, Nerea; Syed, Naweed; Rice, Tiffany; Shutt, Tim; Yusuf, Kamran
    Anesthetics are required for most – if not all – clinical procedures, ranging from surgery to dentistry practices. However, the precise mechanisms underlying anesthetic modes of action remain to be fully defined. Moreover, notwithstanding their essential requirements for all surgical procedures, recent animal studies have raised concerns regarding anesthetic’s long-term cytotoxic effects – especially on the nervous tissue. I designed this study to first, search for potential sites of anesthetic toxicity, and then aimed to decipher potential mitigating strategies accordingly. To achieve my objectives both in vitro and in vivo rodent models were used. For the in vitro studies, frontal cortical and hippocampal neurons were extracted from rat pups at postnatal day zero, and these were then exposed to various clinically relevant concentrations of sevoflurane and dexmedetomidine (DEX). Specifically, I tested sevoflurane, to determine its effects on cell viability, growth, synapse formation, mitochondrial function and morphology using a variety of morphological and molecular tools. All of the above-mentioned aspects examined in this study were compromised by sevoflurane. Furthermore, the sevoflurane-induced effects were then compared with DEX, which is thought to be less toxic and deemed potentially neuroprotective. I found that indeed DEX was not only safer, but it also exerted neuroprotective effects, rescuing neurons from sevoflurane-induced cytotoxicity. To test for the effects of these compounds on long-term effects on learning and memory, I used a battery of memory tests, which included open field, Morris water maze, novel object recognition testing and contextual fear-conditioning. I discovered that sevoflurane exposure of the neonates compromised learning and memory in the adult animals in several subtle, albeit important ways. Some, but not all aspects of sevoflurane-induced learning and memory deficits were however rescued by DEX pre-treatment. Moreover, the expression patterns of a host of genes were also found to be specifically perturbed by sevoflurane. These data were then correlated with the observed effects on cellular viability and learning and memory. This study thus underscores the importance of re-examining our position vis-à-vis the long-term effects of anesthetic exposure on the developing brain and invoking behavioural enrichment strategies in instances where anesthetic use becomes unavoidable.
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    Congenital tuberculosis in an extremely preterm infant conceived after in vitro fertilization: case report
    (2017-02-20) Samedi, Veronica; Field, Stephen K; Al Awad, Essa; Ratcliffe, Gregory; Yusuf, Kamran
    Abstract Background Congenital tuberculosis is a rare manifestation of tuberculosis. The diagnosis is often delayed, especially in preterm neonates because of the non-specific clinical presentation and the lack of awareness of maternal disease prior to pregnancy. Case Presentation We report a case of congenital tuberculosis in an infant born at 24 weeks of gestation to a mother who presented with uncontrolled seizures during preterm labor. Maternal diagnosis was initially made by placental pathology, and later confirmed by isolation of Mycobacterium tuberculosis in urine, gastric aspirates and sputum. Full screening was performed on the newborn infant, and both mother and infant were successfully treated for tuberculosis with a four drug regimen. Conclusion Pregnancy can exacerbate latent tuberculosis and women originating from endemic areas are especially susceptible. The best way to prevent congenital tuberculosis is to have a high index of suspicion and identify and treat tuberculosis in pregnant women.
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    Designing a novel 3-D in-Vitro scaffold to define mechanisms underlying neuronal myelination
    (2018-11-28) Shahidi, Sahar; Syed, Naweed I.; Sanati Nezhad, Amir; Ousman, Shalina S.; Yusuf, Kamran
    All nervous system functions in animals require neuronal assembly during development and the ensuing communications between large networks of neurons, which are often difficult to monitor in the intact brain. As such, most labs around the globe have opted to use and explore in vitro model systems where neurons are generally grown on two-dimensional, plane glass substrates, which limit the ability to decipher fundamental understanding of the mechanisms underlying neuronal growth, polarity and synapse specificity. Most approaches used today employ 2-D models where neurons are cultured on the Poly-D-lysine (PDL) coated substrate which does not mimic the 3-D configuration of the intact mammalian brain – thus limiting a direct comparison between in vivo and in vitro conditions. Assessing cellular and molecular mechanisms of neuronal myelination are critical to determine how myelination and demyelination processes occur in vertebrate models so as to understand developmental and neurodegenerative diseases such as multiple sclerosis. However, there are no suitable in vitro models available to date whereby the process of axon myelination could be studied directly at the level of individual central and peripheral neurons. In contrast to PDL, collagen offers a 3-D structure in which neurons can be suspended in a 3-D configuration, allowing glia to gain access to axonal membrane to exhibit myelination. However, we still lack a reliable 3-D model where mechanisms of neuronal polarity and myelination could be studied at the level of individual peripheral and central neurons. In this study, I designed a 3D substrate comprising of a gelatin base hydrogel with tunable chemical mechanical properties. Using rat Dorsal Root Ganglia Cells (DRG) and their corresponding Schwann cells (SC), I compared and contrasted the effectiveness of GelMA with PDL and Collagen substrates and provide the first direct evidence that the former is more conducive to studying myelination than the later two. Moreover, I also demonstrate that both DRG growth and SC behavior on GelMA resembles to what is seen in vivo thus validating further the usefulness of this substrate for future studies.
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    The mystery of persistent pulmonary hypertension: an idiopathic infantile arterial calcification
    (BioMed Central, 2013-07-16) Shaireen, Huma; Howlett, Alexandra; Amin, Harish; Yusuf, Kamran; Kamaluddeen, Majeeda; Lodha, Abhay
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    Temporal expression pattern of cytokines and other markers of brain injury in term infants with hypoxic ischemic injury
    (2018-09-13) Goswami, Ipsita Roy; Esser, Michael J.; Mineyko, Aleksandra; Pittman, Q. J.; Yusuf, Kamran; Khorshid, Mohammad
    Hypoxic Ischemic Encephalopathy (HIE) is the most common cause of perinatal brain injury. Treatment is available, therapeutic hypothermia (TH), but reliable tools are needed to determine early after birth who will benefit most. Cytokines, as indicators of brain injury, are potential biomarkers and are best studied by understanding network changes. This study sought to identify the cytokine molecular signatures associated with abnormal MRI or death in neonates with HIE. Multiplex immunoassay was used to quantify cytokine levels at multiple timepoints from birth to 96 hours of life. Machine learning algorithms were used for pattern identification to gain mechanistic insights. Cord blood levels of IL-6, IFNγ, IL-1ra, G-CSF, FGF-b and MCP-1 were significantly elevated in neonates with HIE compared to controls. Neonates with abnormal MRI or death had elevated cord blood IL-10 and MCP1 levels, high serum IL1ra and G-CSF levels at 24 hours, and low PDGF and IP10 levels at all time points. Further, in neonates with adverse outcomes IL-10, G-CSF, MCP1, IL-6, TNF-α, IL-8, and IL-1ra levels were elevated, while IL-4, PDGF, MIP1a, IL-15, IP10, and IFN-γ were lower at all time points. Conversely, the combinations of TNF-α levels < 74.4 pg/ml with IL8 levels > 0.85 pg/ml and IFN-γ levels > 0.04 pg/ml in cord blood predicted normal MRI (sensitivity 100%, specificity 37.5%). Similarly, IL-10 levels > 36.7 pg/ml or a combination of IL-6 levels < 8.46 pg/ml and IL-8 levels > 59.5 pg/ml at 24 hours were predictive of unfavorable outcome (sensitivity 95.2%, specificity of 62.5%). Regardless of the encephalopathy grading, TH shifted the cytokine balance towards neurotrophic factors (G-CSF) and Th2 cytokines (IL-4, IL-5, IL-10) around 24 hours of life followed by a reversal towards Th1 cytokines (IL-2, TNF-α and IFN-γ) after termination of TH. This general analysis of the peripheral cytokines in HIE delineates the principal drivers of the cytokine network that may serve as biomarkers. Upregulation of proinflammatory cytokines accompanied by active modulation of anti-inflammatory cytokines could account for the variations in patient-specific innate compensatory response that ultimately characterizes the short-term clinical outcome.