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1.
Alcohol ; 118: 45-55, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38705312

RESUMEN

Prenatal alcohol exposure can have persistent effects on learning, memory, and synaptic plasticity. Previous work from our group demonstrated deficits in long-term potentiation (LTP) of excitatory synapses on dentate gyrus granule cells in adult offspring of rat dams that consumed moderate levels of alcohol during pregnancy. At present, there are no pharmacotherapeutic agents approved for these deficits. Prior work established that systemic administration of the histaminergic H3R inverse agonist ABT-239 reversed deficits in LTP observed following moderate PAE. The present study examines the effect of a second H3R inverse agonist, SAR-152954, on LTP deficits following moderate PAE. We demonstrate that systemic administration of 1 mg/kg of SAR-152954 reverses deficits in potentiation of field excitatory post-synaptic potentials (fEPSPs) in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses revealed PAE-related reductions in power during the fEPSP, and increased power during later components of evoked responses which are associated with feedback circuitry that are typically not assessed with traditional amplitude-based measures. Both effects were reversed by SAR-152954. These findings provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE.


Asunto(s)
Potenciación a Largo Plazo , Efectos Tardíos de la Exposición Prenatal , Receptores Histamínicos H3 , Animales , Potenciación a Largo Plazo/efectos de los fármacos , Femenino , Masculino , Ratas , Embarazo , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos H3/efectos de los fármacos , Agonistas de los Receptores Histamínicos/farmacología , Ratas Sprague-Dawley , Etanol/farmacología , Agonismo Inverso de Drogas , Potenciales Postsinápticos Excitadores/efectos de los fármacos
2.
Behav Neurosci ; 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38635177

RESUMEN

Prenatal alcohol exposure can produce disruptions in a wide range of cognitive functions, but it is especially detrimental to spatial navigation. In open environments, rodents organize their spatial behaviors around centralized locations, termed home bases, from which they make circuitous and slow locomotor trips (progressions) into the rest of the environment. Open-field behaviors are organized even under darkened test conditions, suggesting a role for self-motion cues (vestibular, motor, etc.). The impact of moderate prenatal alcohol exposure (mPAE) on the organization of spontaneous open-field behaviors under darkened conditions has not been investigated. Here we tested adult female and male rats with mPAE or saccharin control exposure in a circular open field for 30 min in a testing room that was made completely dark. While general locomotion, as measured by reductions in travel distance and increased stop duration, decreased across the test session, the organization of these behaviors, as measured by stop duration, home base establishment, home base stability, progression accuracy, and scaling of peak speeds with progression length, did not differ between mPAE and saccharin control rats. Together, the findings strongly suggest that spontaneous movement organization in relation to self-motion cues remains intact in adult mPAE rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

3.
Alcohol Clin Exp Res (Hoboken) ; 48(4): 640-652, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38302722

RESUMEN

BACKGROUND: Prenatal alcohol exposure (PAE) continues to be a worldwide problem. Affected offspring display impaired neurodevelopment, including difficulties with executive control. Although PAE has also been associated with decreased blood flow to fetuses, the relationship between PAE and altered blood flow is not well understood. METHODS: We used preclinical models of PAE, transient systemic hypoxia ischemia (TSHI), and PAE + TSHI combined to assess the effects on neurodevelopmental outcomes using translationally relevant touchscreen operant platform testing. Twenty-eight Long-Evans (Blue Spruce, Strain HsdBlu:LE) dams were randomly assigned to one of four experimental groups: Saccharin Control (Sham), 5% Ethanol (PAE), TSHI, or 5% Ethanol and TSHI (PAE + TSHI). Dams consumed either saccharin or 5% ethanol during gestation. TSHI was induced on Embryonic Day 19 (E19) during an open laparotomy where the uterine arteries were transiently occluded for 1 h. Pups were born normally and, after weaning, were separated by sex. A total of 80 offspring, 40 males and 40 females, were tested on the 5-Choice Continuous Performance paradigm (5C-CPT). RESULTS: Female offspring were significantly impacted by TSHI, but not PAE, with an increase in false alarms and a decrease in hit rates, omissions, accuracy, and correct choice latencies. In contrast, male offspring were mildly affected by PAE, but not TSHI, showing decreases in premature responses and increases in accuracy. No significant interactions between PAE and TSHI were detected on any measure. CONCLUSION: Transient systemic hypoxia ischemia impaired performance on the 5C-CPT in females, leading to a bias toward stimulus responsivity regardless of stimulus type. In contrast, TSHI did not affect male offspring, and only slight effects of PAE were seen. Together, these data suggest that TSHI in females may cause alterations in cortical structures that override alterations caused by moderate PAE.

4.
Curr Opin Ophthalmol ; 35(1): 34-43, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-37820078

RESUMEN

PURPOSE OF REVIEW: There is an ever-growing body of research regarding intraocular lens (IOL) power calculations following photorefractive keratectomy (PRK), laser-assisted in-situ keratomileusis (LASIK), and small-incision lenticule extraction (SMILE). This review intends to summarize recent data and offer updated recommendations. RECENT FINDINGS: Postmyopic LASIK/PRK eyes have the best refractive outcomes when multiple methods are averaged, or when Barrett True-K is used. Posthyperopic LASIK/PRK eyes also seem to do best when Barrett True-K is used, but with more variable results. With both aforementioned methods, using measured total corneal power incrementally improves results. For post-SMILE eyes, the first nontheoretical data favors raytracing. SUMMARY: Refractive outcomes after cataract surgery in eyes with prior laser refractive surgery are less accurate and more variable compared to virgin eyes. Surgeons may simplify their approach to IOL power calculations in postmyopic and posthyperopic LASIK/PRK by using Barrett True-K, and employing measured total corneal power when available. For post-SMILE eyes, ray tracing seems to work well, but lack of accessibility may hamper its adoption.


Asunto(s)
Queratomileusis por Láser In Situ , Lentes Intraoculares , Miopía , Queratectomía Fotorrefractiva , Humanos , Láseres de Excímeros/uso terapéutico , Miopía/cirugía , Queratomileusis por Láser In Situ/métodos , Refracción Ocular , Estudios Retrospectivos
5.
Alcohol Clin Exp Res (Hoboken) ; 47(12): 2262-2277, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38151779

RESUMEN

BACKGROUND: Neuroimmune dysregulation from prenatal alcohol exposure (PAE) may contribute to neurological deficits associated with fetal alcohol spectrum disorders (FASD). PAE is a risk factor for developing peripheral immune and spinal glial sensitization and release of the proinflammatory cytokine IL-1ß, which lead to neuropathic pain (allodynia) from minor nerve injury. Although morphine acts on µ-opioid receptors, it also activates immune receptors, TLR4, and the NLRP3 inflammasome that induces IL-1ß. We hypothesized that PAE induces NLRP3 sensitization by morphine following nerve injury in adult mice. METHODS: We used an established moderate PAE paradigm, in which adult PAE and non-PAE control female mice were exposed to a minor sciatic nerve injury, and subsequent allodynia was measured using the von Frey fiber test. In control mice with standard sciatic damage or PAE mice with minor sciatic damage, the effects of the NLRP3 inhibitor, MCC950, were examined during chronic allodynia. Additionally, minor nerve-injured mice were treated with morphine, with or without MCC950. In vitro studies examined the TLR4-NLRP3-dependent proinflammatory response of peripheral macrophages to morphine and/or lipopolysaccharide, with or without MCC950. RESULTS: Mice with standard sciatic damage or PAE mice with minor sciatic damage developed robust allodynia. Blocking NLRP3 activation fully reversed allodynia in both control and PAE mice. Morphine paradoxically prolonged allodynia in PAE mice, while control mice with minor nerve injury remained stably non-allodynic. Allodynia resolved sooner in nerve-injured PAE mice without morphine treatment than in morphine-treated mice. MCC950 treatment significantly shortened allodynia in morphine-treated PAE mice. Morphine potentiated IL-1ß release from TLR4-activated PAE immune cells, while MCC950 treatment greatly reduced it. CONCLUSIONS: In female mice, PAE prolongs allodynia following morphine treatment through NLRP3 activation. TLR4-activated PAE immune cells showed enhanced IL-1ß release with morphine via NLRP3 actions. Similar studies are needed to examine the adverse impact of morphine in males with PAE. These results are predictive of adverse responses to opioid pain therapeutics in individuals with FASD.

6.
Int J Mol Sci ; 24(17)2023 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-37686296

RESUMEN

Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician's difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta-cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic "placenta-cortex" signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ "placenta-cortex" signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta-cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein-protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that "intercellular communication" was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand-receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta-cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.


Asunto(s)
Trastornos del Espectro Alcohólico Fetal , Efectos Tardíos de la Exposición Prenatal , Embarazo , Lactante , Femenino , Humanos , Animales , Ratones , Transcriptoma , Trastornos del Espectro Alcohólico Fetal/genética , Ligandos , Placenta , Efectos Tardíos de la Exposición Prenatal/genética
7.
J Appl Crystallogr ; 56(Pt 4): 1277-1286, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37555231

RESUMEN

Modern diffraction experiments (e.g. in situ parametric studies) present scientists with many diffraction patterns to analyze. Interactive analyses via graphical user interfaces tend to slow down obtaining quantitative results such as lattice parameters and phase fractions. Furthermore, Rietveld refinement strategies (i.e. the parameter turn-on-off sequences) tend to be instrument specific or even specific to a given dataset, such that selection of strategies can become a bottleneck for efficient data analysis. Managing multi-histogram datasets such as from multi-bank neutron diffractometers or caked 2D synchrotron data presents additional challenges due to the large number of histogram-specific parameters. To overcome these challenges in the Rietveld software Material Analysis Using Diffraction (MAUD), the MAUD Interface Language Kit (MILK) is developed along with an updated text batch interface for MAUD. The open-source software MILK is computer-platform independent and is packaged as a Python library that interfaces with MAUD. Using MILK, model selection (e.g. various texture or peak-broadening models), Rietveld parameter manipulation and distributed parallel batch computing can be performed through a high-level Python interface. A high-level interface enables analysis workflows to be easily programmed, shared and applied to large datasets, and external tools to be integrated with MAUD. Through modification to the MAUD batch interface, plot and data exports have been improved. The resulting hierarchical folders from Rietveld refinements with MILK are compatible with Cinema: Debye-Scherrer, a tool for visualizing and inspecting the results of multi-parameter analyses of large quantities of diffraction data. In this manuscript, the combined Python scripting and visualization capability of MILK is demonstrated with a quantitative texture and phase analysis of data collected at the HIPPO neutron diffractometer.

8.
Front Neurosci ; 17: 1203557, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37425005

RESUMEN

Background: The amygdala, hippocampus and hypothalamus are critical stress regulatory areas that undergo functional maturation for stress responding initially established during gestational and early postnatal brain development. Fetal alcohol spectrum disorder (FASD), a consequence of prenatal alcohol exposure (PAE), results in cognitive, mood and behavioral disorders. Prenatal alcohol exposure negatively impacts components of the brain stress response system, including stress-associated brain neuropeptides and glucocorticoid receptors in the amygdala, hippocampus and hypothalamus. While PAE generates a unique brain cytokine expression pattern, little is known about the role of Toll-like receptor 4 (TLR4) and related proinflammatory signaling factors, as well as anti-inflammatory cytokines in PAE brain stress-responsive regions. We hypothesized that PAE sensitizes the early brain stress response system resulting in dysregulated neuroendocrine and neuroimmune activation. Methods: A single, 4-h exposure of maternal separation stress in male and female postnatal day 10 (PND10) C57Bl/6 offspring was utilized. Offspring were from either prenatal control exposure (saccharin) or a limited access (4 h) drinking-in-the-dark model of PAE. Immediately after stress on PND10, the hippocampus, amygdala and hypothalamus were collected, and mRNA expression was analyzed for stress-associated factors (CRH and AVP), glucocorticoid receptor signaling regulators (GAS5, FKBP51 and FKBP52), astrocyte and microglial activation, and factors associated with TLR4 activation including proinflammatory interleukin-1ß (IL-1ß), along with additional pro- and anti-inflammatory cytokines. Select protein expression analysis of CRH, FKBP and factors associated with the TLR4 signaling cascade from male and female amygdala was conducted. Results: The female amygdala revealed increased mRNA expression in stress-associated factors, glucocorticoid receptor signaling regulators and all of the factors critical in the TLR4 activation cascade, while the hypothalamus revealed blunted mRNA expression of all of these factors in PAE following stress. Conversely, far fewer mRNA changes were observed in males, notably in the hippocampus and hypothalamus, but not the amygdala. Statistically significant increases in CRH protein, and a strong trend in increased IL-1ß were observed in male offspring with PAE independent of stressor exposure. Conclusion: Prenatal alcohol exposure creates stress-related factors and TLR-4 neuroimmune pathway sensitization observed predominantly in females, that is unmasked in early postnatal life by a stress challenge.

9.
Front Neurosci ; 17: 1192096, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37449267

RESUMEN

We have reported that prenatal alcohol exposure (PAE) elevates histamine H3 receptor (H3R) agonist-mediated inhibition of glutamatergic neurotransmission in the dentate gyrus. Here, we hypothesized that PAE alters the expression of two prominent H3R isoforms namely, the rH3A and rH3C isoforms, which have differing intrinsic activities for H3R agonists, in a manner that may contribute to heightened H3R function in PAE rats. In contrast to our predictions, we found different effects of sex and PAE in various brain regions with significant interactions between sex and PAE in dentate gyrus and entorhinal cortex for both isoforms. Subsequently, to confirm the PAE-and sex-induced differences on H3R isoform mRNA expression, we developed a polyclonal antibody selective for the rH3A inform. Western blots of rH3A mRNA-transfected HEK-293 cells identified a ~ 48 kDa band of binding consistent with the molecular weight of rH3A, thus confirming antibody sensitivity for rH3A protein. In parallel, we also established a pan-H3R knockout mice line to confirm antibody specificity in rodent brain membranes. Both qRT-PCR and H3R agonist-stimulated [35S]-GTPγS binding confirmed the absence of mH3A mRNA and H3 receptor-effector coupling in H3R knockout (KO) mice. Subsequent western blotting studies in both rat and mouse brain membranes were unable to detect rH3A antibody binding at ~48 kDa. Rather, the H3RA antibody bound to a ~ 55 kDa band in both rat and mouse membranes, including H3R KO mice, suggesting H3RA binding was not specific for H3Rs in rodent membranes. Subsequent LC/MS analysis of the ~55 kDa band in frontal cortical membranes identified the highly abundant beta subunit of ATPase in both WT and KO mice. Finally, LC/MS analysis of the ~48 kDa band from rH3A mRNA-transfected HEK-293 cell membranes was able to detect rH3A protein, but its presence was below the limits of quantitative reliability. We conclude that PAE alters rH3A and rH3C mRNA expression in some of the same brain regions where we have previously reported PAE-induced alterations in H3R-effector coupling. However, interpreting the functional consequences of altered H3R isoform expression was limited given the technical challenges of measuring the relatively low abundance of rH3A protein in native membrane preparations.

10.
Front Neurosci ; 17: 1180308, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37360167

RESUMEN

Alcohol consumption during pregnancy is associated with Fetal Alcohol Spectrum Disorders (FASD) that results in a continuum of central nervous system (CNS) deficits. Emerging evidence from both preclinical and clinical studies indicate that the biological vulnerability to chronic CNS disease in FASD populations is driven by aberrant neuroimmune actions. Our prior studies suggest that, following minor nerve injury, prenatal alcohol exposure (PAE) is a risk factor for developing adult-onset chronic pathological touch sensitivity or allodynia. Allodynia in PAE rats occurs concurrently with heightened proinflammatory peripheral and spinal glial-immune activation. However, minor nerve-injured control rats remain non-allodynic, and corresponding proinflammatory factors are unaltered. A comprehensive molecular understanding of the mechanism(s) that underlie PAE-induced proinflammatory bias during adulthood remains elusive. Non-coding circular RNAs (circRNAs) are emerging as novel modulators of gene expression. Here, we hypothesized that PAE induces dysregulation of circRNAs that are linked to immune function under basal and nerve-injured conditions during adulthood. Utilizing a microarray platform, we carried out the first systematic profiling of circRNAs in adult PAE rats, prior to and after minor nerve injury. The results demonstrate a unique circRNA profile in adult PAE rats without injury; 18 circRNAs in blood and 32 spinal circRNAs were differentially regulated. Following minor nerve injury, more than 100 differentially regulated spinal circRNAs were observed in allodynic PAE rats. Bioinformatic analysis identified that the parental genes of these circRNAs are linked to the NF-κB complex, a central transcription factor for pain-relevant proinflammatory cytokines. Quantitative real-time PCR was employed to measure levels of selected circRNAs and linear mRNA isoforms. We have validated that circVopp1 was significantly downregulated in blood leukocytes in PAE rats, concurrent with downregulation of Vopp1 mRNA levels. Spinal circVopp1 levels were upregulated in PAE rats, regardless of nerve injury. Additionally, PAE downregulated levels of circItch and circRps6ka3, which are linked to immune regulation. These results demonstrate that PAE exerts long-lasting dysregulation of circRNA expression in blood leukocytes and the spinal cord. Moreover, the spinal circRNA expression profile following peripheral nerve injury is differentially modulated by PAE, potentially contributing to PAE-induced neuroimmune dysregulation.

11.
Alcohol ; 111: 39-49, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37225109

RESUMEN

Recent studies report varying levels of ethanol consumption by rodents maintained on different commercially available laboratory diets. As varied ethanol consumption by dams may impact offspring outcome measures in prenatal ethanol exposure paradigms, we compared ethanol consumption by rats maintained on the Envigo 2920 diet, used in our vivarium, with an isocalorically equivalent PicoLab 5L0D diet used in some alcohol consumption studies. Compared to 5L0D diet, female rats maintained on 2920 diet consumed 14% less ethanol during daily 4-h drinking sessions prior to pregnancy and 28% less ethanol during gestation. Rat dams consuming 5L0D diet gained significantly less weight during pregnancy. However, their pup birth weights were significantly higher. A subsequent study revealed that hourly ethanol consumption was not different between diets during the first 2 h, but was significantly lower on 2920 diet at the end of the third and fourth hours. The mean serum ethanol concentration in 5L0D dams after the first 2 h of drinking was 46 mg/dL compared to 25 mg/dL in 2920 dams. Further, ethanol consumption at the 2-h blood sampling time point was more variable in 2920 dams compared to 5L0D dams. An in vitro analysis mixing each powdered diet with 5% ethanol in acidified saline revealed that a 2920 diet suspension adsorbed more aqueous medium than the 5L0D diet suspension. The total ethanol remaining in aqueous supernatant of 5L0D mixtures was nearly twice the amount of ethanol in supernatants of the 2920 mixtures. These results suggest that the 2920 diet expands to a greater extent in aqueous medium than the 5L0D diet. We speculate that increasing adsorption of water and ethanol by the 2920 diet may reduce or delay the amount of ethanol absorbed and may decrease serum ethanol concentration to a greater extent than would be predicted from the amount of ethanol consumed.


Asunto(s)
Etanol , Efectos Tardíos de la Exposición Prenatal , Embarazo , Ratas , Femenino , Animales , Humanos , Resultado del Embarazo , Roedores , Dieta
12.
Case Rep Ophthalmol ; 13(2): 550-555, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36160482

RESUMEN

Bacterial keratitis (corneal infection) caused by more than one organism is rare and exceedingly difficult to treat due to variable antibiotic susceptibilities. Intrastromal injections of antibiotics may be necessary to achieve higher drug concentrations at the site of infection, particularly in the case of deep stromal disease refractory to topical therapy. However, while this approach is increasingly used for fungal keratitis, there is a paucity of the literature regarding the use of intrastromal antibiotics bacterial keratitis. In the current case, an 86-year-old patient presented with a left corneal ulcer with corresponding microbiologic cultures positive for Staphylococcus epidermidis, Staphylococcus aureus, and Achromobacter species. The ulcer continued to progress despite maximal topical antibiotic treatment yet demonstrated marked improvement after two intrastromal injections of moxifloxacin administered 2 weeks apart. Polymicrobial keratitis can be particularly challenging to eradicate despite maximal topical antibiotic therapeutics. Intrastromal corneal injections provide a mechanism for drug delivery directly to the site of infection and thus may represent an important alternative in refractory cases.

13.
Biomed Opt Express ; 13(4): 2346-2363, 2022 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-35519279

RESUMEN

Laser-induced refractive index change (LIRIC) is being developed as a non-invasive way to alter optical properties of transparent, ophthalmic materials including corneas ex vivo and in vivo. This study examined the optical and biological effects of blue-LIRIC (wavelengths 400-405 nm) of ex-vivo rabbit corneas. Following LIRIC treatment at low and high repetition rates (8.3 MHz and 80 MHz, respectively), we interferometrically measured optical phase change, obtained transmission electron microscopy (TEM) micrographs, and stained histological sections with collagen hybridizing peptides (CHP) to assess the structural and organizational changes caused by LIRIC at different repetition rates. Finally, we performed power and scan speed scaling experiments at three different repetition rates (1 MHz, 8.3 MHz, and 80 MHz) to study their impact on LIRIC efficacy. Histologic co-localization of CHP and LIRIC-generated green autofluorescence signals suggested that collagen denaturation had occurred in the laser-irradiated region. TEM imaging showed different ultrastructural modifications for low and high repetition rate writing, with discrete homogenization of collagen fibrils at 80 MHz, as opposed to contiguous homogenization at 8.3 MHz. Overall, this study confirmed that LIRIC efficacy can be dramatically increased, while still avoiding tissue ablation, by lowering the repetition rate from 80 MHz to 8.3 MHz. Modeling suggests that this is due to a higher, single-pulse, energy density deposition at given laser powers during 8.3 MHz LIRIC.

14.
Alcohol Clin Exp Res ; 46(5): 861-875, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35315075

RESUMEN

BACKGROUND: Prenatal alcohol exposure (PAE) can produce deficits in a wide range of cognitive functions but is especially detrimental to behaviors requiring accurate spatial information processing. In open field environments, spatial behavior is organized such that animals establish "home bases" marked by long stops focused around one location. Progressions away from the home base are circuitous and slow, while progressions directed toward the home base are non-circuitous and fast. The impact of PAE on the organization of open field behavior has not been experimentally investigated. METHODS: In the present study, adult female and male rats with moderate PAE or saccharin exposure locomoted a circular high walled open field for 30 minutes under lighted conditions. RESULTS: The findings indicate that PAE and sex influence the organization of open field behavior. Consistent with previous literature, PAE rats exhibited greater locomotion in the open field. Novel findings from the current study indicate that PAE and sex also impact open field measures specific to spatial orientation. While all rats established a home base on the periphery of the open field, PAE rats, particularly males, exhibited significantly less clustered home base stopping with smaller changes in heading between stops. PAE also impaired progression measures specific to distance estimation, while sex alone impacted progression measures specific to direction estimation. CONCLUSIONS: These findings support the conclusion that adult male rats have an increased susceptibility to the effects of PAE on the organization of open field behavior.


Asunto(s)
Etanol , Efectos Tardíos de la Exposición Prenatal , Animales , Etanol/toxicidad , Conducta Exploratoria , Femenino , Humanos , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Percepción Espacial
15.
Alcohol Clin Exp Res ; 45(9): 1775-1789, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34342371

RESUMEN

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a significant public health problem that is associated with a broad range of physical, neurocognitive, and behavioral effects resulting from prenatal alcohol exposure (PAE). Magnetic resonance imaging (MRI) has been an important tool for advancing our knowledge of abnormal brain structure and function in individuals with FASD. However, whereas only a small number of studies have applied graph theory-based network analysis to resting-state functional MRI (fMRI) data in individuals with FASD additional research in this area is needed. METHODS: Resting-state fMRI data were collected from adolescent and young adult participants (ages 12-22) with fetal alcohol syndrome (FAS) or alcohol-related neurodevelopmental disorder (ARND) and neurotypically developing controls (CNTRL) from previous studies. Group independent components analysis (gICA) was applied to fMRI data to extract components representing functional brain networks. Functional network connectivity (FNC), measured by Pearson correlation of the average independent component (IC) time series, was analyzed under a graph theory framework to compare network modularity, the average clustering coefficient, characteristic path length, and global efficiency between groups. Cognitive intelligence, measured by the Wechsler Abbreviated Scale of Intelligence (WASI), was compared and correlated to global network measures. RESULTS: Group comparisons revealed significant differences in the average clustering coefficient, characteristic path length, and global efficiency. Modularity was not significantly different between groups. The FAS and ARND groups scored significantly lower than the CNTRL group on Full Scale IQ (FS-IQ) and the Vocabulary subtest, but not the Matrix Reasoning subtest. No significant associations between intelligence and graph theory measures were detected. CONCLUSION: Our results partially agree with previous studies examining global graph theory metrics in children and adolescents with FASD and suggest that the exposure to alcohol during prenatal development leads to disruptions in aspects of functional network segregation and integration.


Asunto(s)
Trastornos del Espectro Alcohólico Fetal/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Adolescente , Adulto , Niño , Femenino , Trastornos del Espectro Alcohólico Fetal/psicología , Humanos , Inteligencia , Pruebas del Lenguaje , Imagen por Resonancia Magnética , Masculino , Trastornos del Neurodesarrollo/inducido químicamente , Trastornos del Neurodesarrollo/diagnóstico por imagen , Trastornos del Neurodesarrollo/psicología , Pruebas Neuropsicológicas , Embarazo , Efectos Tardíos de la Exposición Prenatal , Análisis de Componente Principal , Escalas de Wechsler , Adulto Joven
16.
Alcohol ; 93: 25-34, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33716098

RESUMEN

Fetal Alcohol Spectrum Disorder (FASD), a wide range of physical and neurobehavioral abnormalities associated with prenatal alcohol exposure (PAE), is recognized as a significant public health concern. Advancements in the diagnosis of FASD have been hindered by a lack of consensus in diagnostic criteria and limited use of objective biomarkers. Previous research from our group utilized resting-state functional magnetic resonance imaging (fMRI) to measure functional network connectivity (FNC), which revealed several sex- and region-dependent alterations in FNC as a result of moderate PAE relative to controls. Considering that FNC is sensitive to moderate PAE, this study explored the use of FNC data and machine learning methods to detect PAE among a sample of rodents exposed to alcohol prenatally and controls. We utilized previously acquired resting state fMRI data collected from adult rats exposed to moderate levels of prenatal alcohol (PAE) or a saccharin control solution (SAC) to assess FNC of resting state networks extracted by spatial group independent component analysis (GICA). FNC data were subjected to binary classification using support vector machine (SVM) -based algorithms and leave-one-out-cross validation (LOOCV) in an aggregated sample of males and females (n = 48; 12 male PAE, 12 female PAE, 12 male SAC, 12 female SAC), a males-only sample (n = 24; 12 PAE, 12 SAC), and a females-only sample (n = 24; 12 PAE, 12 SAC). Results revealed that a quadratic SVM (QSVM) kernel was significantly effective for PAE detection in females. QSVM kernel-based classification resulted in accuracy rates of 62.5% for all animals, 58.3% for males, and 79.2% for females. Additionally, qualitative evaluation of QSVM weights implicates an overarching theme of several hippocampal and cortical networks in contributing to the formation of correct classification decisions by QSVM. Our results suggest that binary classification using QSVM and adult female FNC data is a potential candidate for the translational development of novel and non-invasive techniques for the identification of FASD.


Asunto(s)
Aprendizaje Automático , Efectos Tardíos de la Exposición Prenatal , Animales , Etanol , Femenino , Trastornos del Espectro Alcohólico Fetal , Imagen por Resonancia Magnética , Masculino , Embarazo , Ratas
17.
J Am Coll Emerg Physicians Open ; 2(1): e12355, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33532756

RESUMEN

OBJECTIVES: The purpose of this study is to determine the sensitivity and specificity of novice emergency physician-performed point-of-care ultrasound diagnosis of papilledema using optic nerve sheath diameter (ONSD) against ophthalmologist-performed dilated fundoscopy. This observational study retrospectively analyzed results of ultrasound-measured ONSD of emergency department (ED) patients with suspected intracranial hypertension from a period spanning June 2014 to October 2017. METHODS: This study concerns a population of ED patients at a large, tertiary-care urban academic medical center from June 2014 to October 2017 over the age of 18 years with primary vision complaints evaluated for papilledema both by an emergency physician-performed ultrasound and an ophthalmologist-performed fundoscopic examination during their ED stay. Sensitivity and specificity of emergency physician-performed ultrasound measurement of optic nerve sheath diameter in the diagnosis of papilledema were primary outcomes for this study. RESULTS: A total of 206 individual patients (male 49%, female 51%; median age 45 years) were included in the study with a total of 212 patient encounters. Calculated sensitivity for the ocular ultrasound examination performed by emergency physicians to diagnose papilledema was 46.9% (95% confidence interval [CI], 32.5% to 61.7%), and specificity was 87.0% (95% CI, 82.8% to 90.5%). Positive predictive value and negative predictive value were calculated to be 35.4% (95% CI, 23.9% to 48.2%) and 91.5% (95% CI, 87.8% to 94.4%), respectively. CONCLUSIONS: Sonographic measurement of ONSD by emergency physicians has low sensitivity but high specificity for detection of papilledema compared to ophthalmologist-conducted fundoscopy.

18.
Ann Pediatr Res ; 4(1)2020.
Artículo en Inglés | MEDLINE | ID: mdl-33073262

RESUMEN

BACKGROUND: Prenatal Alcohol Exposure (PAE) impacts 2% to 5% of infants born in the United States yearly. Women who consume alcohol during pregnancy have a five-fold increased rate of Chorioamnionitis (CHORIO). Both PAE and CHORIO cause microstructural injury to multiple brain regions including major white matter tracts. OBJECTIVE: Utilizing two previously established animal models, we hypothesized that the combination of PAE+CHORIO would result in greater deficits in myelination and structural integrity than PAE alone. MATERIAL AND METHODS: Pregnant Long-Evans rats voluntarily drank 5% ethanol or saccharin until Gestational Day 19 (GD). On GD19, CHORIO was induced in one group of PAE dams by a 30 min uterine artery occlusion and injection of Lipopolysaccharide (LPS) into each amniotic sac. The remaining PAE dams and saccharin controls underwent sham surgery. Pups were born on GD22 and weaned on Postnatal Day 24 (PD). On PD28, offspring were sacrificed, and their brains examined using ex-vivo Diffusion Tensor Imaging (DTI). RESULTS: Compared to control, PAE alone did not affect offspring birth weights, mortality or any DTI measures. In contrast, PAE+CHORIO significantly reduced offspring survival and, in surviving pups, increased Radial Diffusivity (RD) in medial frontal cortex and decreased Fractional Anisotropy (FA) in medial and ventral frontal cortex and within capsular regions. CONCLUSION: The combination of moderate PAE+CHORIO results in an increased mortality, concomitant with diffuse microstructural brain injury noted in young adolescent offspring at PD28. Future studies should examine the extent to which PAE exacerbates the damage caused by CHORIO alone and whether these deficits persist into adulthood.

19.
Front Neurosci ; 14: 519, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32655346

RESUMEN

Jegou et al. (2012) have reported prenatal alcohol exposure (PAE)-induced reductions of angiogenesis-related proteins in mouse placenta. These effects were associated with striking alterations in microvascular development in neonatal cerebral cortex. Here, we employed a rat model of moderate PAE to search for additional proteins whose placental and fetal cortical expression is altered by PAE, along with a subsequent examination of fetal cerebral cortical alterations associated with altered protein expression. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 h each day throughout gestation. Daily ethanol consumption, which resulted in a mean peak maternal serum ethanol concentration of 60.8 mg/dL, did not affect maternal weight gain, litter size, or placental or fetal body weight. On gestational day 20, rat placental: fetal units were removed by Caesarian section. Placental protein expression, analyzed by 2D-PAGE - tandem mass spectroscopy, identified a total of 1,117 protein spots, 20 of which were significantly altered by PAE. To date, 14 of these PAE-altered proteins have been identified. Western blotting confirmed the alterations of two of these placental proteins, namely, annexin-A4 (ANX-A4) and cerebral cavernous malformation protein 3 (CCM-3). Specifically, PAE elevated ANX-A4 and decreased CCM-3 in placenta. Subsequently, these two proteins were measured in fetal cerebral cortex, along with radiohistochemical studies of VEGF binding and histofluorescence studies of microvascular density in fetal cerebral cortex. PAE elevated ANX-A4 and decreased CCM-3 in fetal cerebral cortex, in a pattern similar to the alterations observed in placenta. Further, both VEGF receptor binding and microvascular density and orientation, measures that are sensitive to reduced CCM-3 expression in developing brain, were significantly reduced in the ventricular zone of fetal cerebral cortex. These results suggest that the expression angiogenesis-related proteins in placenta might serve as a biomarker of ethanol-induced alterations in microvascular development in fetal brain.

20.
Curr Biol ; 30(18): 3556-3569.e5, 2020 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-32707066

RESUMEN

Prenatal alcohol exposure (PAE) leads to profound deficits in spatial memory and synaptic and cellular alterations to the hippocampus that last into adulthood. Neurons in the hippocampus called place cells discharge as an animal enters specific places in an environment, establish distinct ensemble codes for familiar and novel places, and are modulated by local theta rhythms. Spatial memory is thought to critically depend on the integrity of hippocampal place cell firing. Therefore, we tested the hypothesis that hippocampal place cell firing is impaired after PAE by performing in vivo recordings from the hippocampi (CA1 and CA3) of moderate PAE and control adult rats. Our results show that hippocampal CA3 neurons from PAE rats have reduced spatial tuning. Second, CA1 and CA3 neurons from PAE rats are less likely to orthogonalize their firing between directions of travel on a linear track and between changes in contextual stimuli in an open arena compared to control neurons. Lastly, reductions in the number of hippocampal place cells exhibiting significant theta rhythmicity and phase precession were observed, which may suggest changes to hippocampal microcircuit function. Together, the reduced spatial tuning and sensitivity to contextual changes provide a neural systems-level mechanism to explain spatial memory impairment after moderate PAE.


Asunto(s)
Potenciales de Acción , Consumo de Bebidas Alcohólicas/efectos adversos , Región CA1 Hipocampal/patología , Región CA3 Hipocampal/patología , Exposición Materna/efectos adversos , Efectos Tardíos de la Exposición Prenatal/patología , Ritmo Teta/efectos de los fármacos , Animales , Región CA1 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/efectos de los fármacos , Femenino , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Ratas , Ratas Long-Evans , Memoria Espacial
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