Socioeconomic Disparities in Pediatric Scoliosis Surgery

Multiple studies have been published which investigate the effects of patient demographics on elective orthopedic operations. While this research demonstrates disparities in health care delivery in other states and in single center practices, there are large administrative databases that can be used to examine patient demographics and their influence on health care delivery. We queried the State of California Office of Statewide Health Planning and Development (OSHPD) database to compare the proportions of patients undergoing surgery for scoliosis by gender, race, and ethnicity and to determine if there were underlying differences in social determinants of health as measured by the child opportunity index (COI), social deprivation index (SDI), and insurance type among these patients in order to create a foundation of knowledge for future research on health disparities in the realm of orthopaedic surgery

HIV-1 mRNA knockdown with CRISPR/CAS9 enhances neurocognitive function

Mixed glia are infiltrated with HIV-1 virus early in the course of infection leading to the development of a persistent viral reservoir in the central nervous system. Modification of the HIV-1 genome using gene editing techniques, including CRISPR/Cas9, has shown great promise towards eliminating HIV-1 viral reservoirs; whether these techniques are capable of removing HIV-1 viral proteins from mixed glia, however, has not been systematically evaluated. Herein, the efficacy of adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing for eliminating HIV-1 messenger RNA (mRNA) from cortical mixed glia was evaluated in vitro and in vivo. In vitro, a within-subjects experimental design was utilized to treat mixed glia isolated from neonatal HIV-1 transgenic (Tg) rats with varying doses (0, 0.9, 1.8, 2.7, 3.6, 4.5, or 5.4 μL corresponding to a physical titer of 0, 4.23 × 109, 8.46 × 109, 1.269 × 1010, 1.692 × 1010, 2.115 × 1010, and 2.538 × 1010 gc/μL) of CRISPR/Cas9 for 72 h. Dose-dependent decreases in the number of HIV-1 mRNA, quantified using an innovative in situ hybridization technique, were observed in a subset (i.e., n = 5 out of 8) of primary mixed glia. In vivo, HIV-1 Tg rats were retro-orbitally inoculated with CRISPR/Cas9 for two weeks, whereby treatment resulted in profound excision (i.e., approximately 53.2%) of HIV-1 mRNA from the medial prefrontal cortex. Given incomplete excision of the HIV-1 viral genome, the clinical relevance of HIV-1 mRNA knockdown for eliminating neurocognitive impairments was evaluated via examination of temporal processing, a putative neurobehavioral mechanism underlying HIV-1-associated neurocognitive disorders (HAND). Indeed, treatment with CRISPR/Cas9 protractedly, albeit not permanently, restored the developmental trajectory of temporal processing. Proof-of-concept studies, therefore, support the susceptibility of mixed glia to gene editing and the potential of CRISPR/Cas9 to serve as a novel therapeutic strategy for HAND, even in the absence of full viral eradication

Endogenous amyloidogenesis in long-term rat hippocampal cell cultures

<p>Abstract</p> <p>Background</p> <p>Long-term primary neuronal cultures are a useful tool for the investigation of biochemical processes associated with neuronal senescence. Improvements in available technology make it possible to observe maturation of neural cells isolated from different regions of the rodent brain over a prolonged period <it>in vitro</it>. Existing experimental evidence suggests that cellular aging occurs in mature, long-term, primary neuronal cell cultures. However, detailed studies of neuronal development <it>in vitro </it>are needed to demonstrate the validity of long-term cell culture-based models for investigation of the biochemical mechanisms of <it>in vitro </it>neuronal development and senescence.</p> <p>Results</p> <p>In the current study, neuron-enriched hippocampal cell cultures were used to analyze the differentiation and degeneration of hippocampal neurons over a two month time period. The expression of different neuronal and astroglial biomarkers was used to determine the cytochemical characteristics of hippocampal cells in long-term cultures of varying ages. It was observed that the expression of the intermediate filament nestin was absent from cultures older than 21 days in vitro (DIV), and the expression of neuronal or astrocytic markers appeared to replace nestin. Additionally, morphological evaluations of neuronal integrity and Hoescht staining were used to assess the cellular conditions in the process of hippocampal culture development and aging. It was found that there was an increase in endogenous production of Aβ_1-42and an increase in the accumulation of Congo Red-binding amyloidal aggregates associated with the aging of neurons in primary culture. <it>In vitro </it>changes in the morphology of co-existing astrocytes and cell culture age-dependent degeneration of neurodendritic network resemble features of <it>in vivo </it>brain aging at the cellular level.</p> <p>Conclusion</p> <p>In conclusion, this study suggests that long-term primary CNS culture is a viable model for the study of basic mechanisms and effective methods to decelerate the process of neuronal senescence.</p

Prenatal IV Cocaine: Alterations in Auditory Information Processing

One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants’ startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the auditory startle response (ASR), habituation, and prepulse inhibition (PPI) in the offspring. Nulliparous Long–Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC) from gestation day (GD) 8–20 (1×/day-GD8–14, 2×/day-GD15–20). COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18–20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg). When reassessed in adulthood (D90–100), a linear dose–response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval and induced significant sex-dependent changes in response latency. Idazoxan, an α2-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses

Prenatal cocaine exposure alters alpha2 receptor expression in adolescent rats

BACKGROUND: Prenatal cocaine exposure produces attentional deficits which to persist through early childhood. Given the role of norepinephrine (NE) in attentional processes, we examined the forebrain NE systems from prenatal cocaine exposed rats. Cocaine was administered during pregnancy via the clinically relevant intravenous route of administration. Specifically, we measured α(2)-adrenergic receptor (α(2)-AR) density in adolescent (35-days-old) rats, using [(3)H]RX821002 (5 nM). RESULTS: Sex-specific alterations of α(2)-AR were found in the hippocampus and amygdala of the cocaine-exposed animals, as well as an upregulation of α(2)-AR in parietal cortex. CONCLUSION: These data suggest that prenatal cocaine exposure results in a persistent alteration in forebrain NE systems as indicated by alterations in receptor density. These neurochemical changes may underlie behavioral abnormalities observed in offspring attentional processes following prenatal exposure to cocaine

Gonadal steroids differentially modulate neurotoxicity of HIV and cocaine: testosterone and ICI 182,780 sensitive mechanism

BACKGROUND: HIV Associated Dementia (HAD) is a common complication of human immunodeficiency virus (HIV) infection that erodes the quality of life for patients and burdens health care providers. Intravenous drug use is a major route of HIV transmission, and drug use is associated with increased HAD. Specific proteins released as a consequence of HIV infection (e.g., gp120, the HIV envelope protein and Tat, the nuclear transactivating protein) have been implicated in the pathogenesis of HAD. In primary cultures of human fetal brain tissue, subtoxic doses of gp120 and Tat are capable of interacting with a physiologically relevant dose of cocaine, to produce a significant synergistic neurotoxicity. Using this model system, the neuroprotective potential of gonadal steroids was investigated. RESULTS: 17β-Estradiol (17β-E(2)), but not 17α-estradiol (17α-E(2)), was protective against this combined neurotoxicity. Progesterone (PROG) afforded limited neuroprotection, as did dihydrotestosterone (DHT). The efficacy of 5α-testosterone (T)-mediated neuroprotection was robust, similar to that provided by 17β-E(2. )In the presence of the specific estrogen receptor (ER) antagonist, ICI-182,780, T's neuroprotection was completely blocked. Thus, T acts through the ER to provide neuroprotection against HIV proteins and cocaine. Interestingly, cholesterol also demonstrated concentration-dependent neuroprotection, possibly attributable to cholesterol's serving as a steroid hormone precursor in neurons. CONCLUSION: Collectively, the present data indicate that cocaine has a robust interaction with the HIV proteins gp120 and Tat that produces severe neurotoxicity, and this toxicity can be blocked through pretreatment with ER agonists

Neurodevelopmental Processes in the Prefrontal Cortex Derailed by Chronic HIV-1 Viral Protein Exposure

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remain understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC) in HIV-1 transgenic (Tg) and control animals. Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations and progressive synaptodendritic dysfunction, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. From a neurodevelopmental perspective, HIV-1 Tg rats exhibited prominent deficits in dendritic and synaptic pruning. With regards to progressive synaptodendritic dysfunction, HIV-1 Tg animals exhibited an age-related population shift towards dendritic spines with decreased volume, increased backbone length, and decreased head diameter; parameters associated with a more immature dendritic spine phenotype. There was no compelling evidence for neuroinflammation in the mPFC during early development. Collectively, progressive neuronal and dendritic spine dysmorphology herald synaptodendritic dysfunction as a key neural mechanism underlying chronic neurocognitive impairments in pALHIV

Estrogen protects against the synergistic toxicity by HIV proteins, methamphetamine and cocaine

BACKGROUND: Human immunodeficiency virus (HIV) infection continues to increase at alarming rates in drug abusers, especially in women. Drugs of abuse can cause long-lasting damage to the brain and HIV infection frequently leads to a dementing illness.To determine how these drugs interact with HIV to cause CNS damage, we used an in vitro human neuronal culture characterized for the presence of dopaminergic receptors, transporters and estrogen receptors. We determined the combined effects of dopaminergic drugs, methamphetamine, or cocaine with neurotoxic HIV proteins, gp120 and Tat. RESULTS: Acute exposure to these substances resulted in synergistic neurotoxic responses as measured by changes in mitochondrial membrane potential and neuronal cell death. Neurotoxicity occurred in a sub-population of neurons. Importantly, the presence of 17beta-estradiol prevented these synergistic neurotoxicities and the neuroprotective effects were partly mediated by estrogen receptors. CONCLUSION: Our observations suggest that methamphetamine and cocaine may affect the course of HIV dementia, and additionally suggest that estrogens modify the HIV-drug interactions

Elevated Blood Lead Concentrations in Essential Tremor: A Case–Control Study in Mersin, Turkey

Essential tremor (ET) is one of the most common neurologic disorders. Aside from underlying susceptibility genes, recent studies have also begun to focus on environmental toxic factors. Yet there remains a paucity of information on such factors, making studies of environmental factors important. A recent study in New York City found blood lead concentrations to be elevated in ET cases compared with matched controls. Chronic exposure to lead produces cerebellar damage, and this could predispose individuals to develop ET