ABSTRACT
Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments. This study identified transcriptional signatures in keratinocytes and sub-basal CD4+ and CD8+ T lymphocytes from patients with psoriasis and AD. In silico prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, etc.). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases. Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.
Subject(s)
Biomarkers , Dermatitis, Atopic , Psoriasis , Transcriptome , Humans , Dermatitis, Atopic/genetics , Dermatitis, Atopic/blood , Dermatitis, Atopic/immunology , Psoriasis/genetics , Psoriasis/blood , Biomarkers/blood , Male , Female , Adult , Keratinocytes/metabolism , Middle Aged , Gene Expression Profiling/methods , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Young AdultABSTRACT
OBJECTIVE: In this review, we have highlighted the advances over the past year in genetics, genomics and epigenetics in the ï¬eld of osteoarthritis (OA). METHODS: A literature search of PubMed was performed using the criteria: "osteoarthritis" and one of the following terms "genetic(s), genomic(s), epigenetic(s), polymorphism, noncoding ribonucleic acid (RNA), microRNA, long noncoding RNA, lncRNA, circular RNA, RNA sequencing (RNA-seq), single cell sequencing, transcriptomics, or deoxyribonucleic acid (DNA) methylation between April 01, 2020 and April 30, 2021. RESULTS: In total we identiï¬ed 765 unique publications, which eventually reduced to 380 of relevance to the field as judged by two assessors. Many of these studies included multiple search terms. We summarised advances relating to genetics, functional genetics, genomics and epigenetics, focusing on our personal key papers during the year. CONCLUSIONS: This year few studies have identiï¬ed new genetic variants contributing to OA susceptibility, but a focus has been on refining risk loci or their functional validation. The use of new technologies together with investigating the cross-talk between multiple tissue types, greater sample sizes and/or better patient classification (OA subtypes) will continue to increase our knowledge of disease mechanisms and progress towards understanding and treating OA.
Subject(s)
Epigenomics , Osteoarthritis/genetics , Genomics , HumansABSTRACT
BACKGROUND: To evaluate the feasibility of a protocol using combined magnetic resonance imaging (MRI), clinical data, and electroencephalogram (EEG) to identify neonates with mild neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH) who are eligible for "early exit". METHODS: Retrospective chart review of TH cases at a single Level III NICU over a 5-year period was used to describe the demographic, clinical, and outcome data in neonates that received early exit in contrast to 72 hour TH treatment. RESULTS: Two hundred and eight TH cases, including 18 early exit cases (9%) and 9 cases (4%) evaluated for early exit with MRI but continued on 72 hours of TH, were identified. Early exit and 72 hour treatment groups did not differ in demographics or cord gas measures, although early exit neonates had a shorter length of stay (pâ<â0.05). Consistent with the early exit protocol, no early exit infants had evidence of moderate or severe encephalopathy on EEG or evidence of hypoxic ischemic injury on MRI at 24 hours of life. Neurology follow up between age 1 and 18 months was available for 10 early exit infants, 8 of whom had a normal examination. CONCLUSIONS: Early MRI at 24 hours of age, alongside clinical and EEG criteria, is feasible as part of a protocol to identify neonates eligible for early exit from therapeutic hypothermia.
Subject(s)
Duration of Therapy , Electroencephalography/methods , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain , Magnetic Resonance Imaging/methods , Clinical Decision-Making , Clinical Protocols , Female , Humans , Hypoxia-Ischemia, Brain/diagnosis , Hypoxia-Ischemia, Brain/therapy , Infant , Infant, Newborn , Length of Stay , Male , Neurologic Examination/methods , Outcome Assessment, Health Care , Severity of Illness IndexABSTRACT
OBJECTIVE: Long intergenic non-coding RNAs (lincRNAs) are emerging as key regulators in gene expression; however, little is known about the lincRNA expression changes that occur in osteoarthritis (OA). Here we aimed to define a transcriptome of lncRNAs in OA cartilage, specifically comparing the lincRNA transcriptome of knee and hip cartilage. METHOD: RNA-seq was performed on nucleic acid extracted from hip cartilage from patients undergoing joint replacement surgery because of either OA (n = 10) or because of a neck of femur fracture (NOF; n = 6). After transcript alignment, counts were performed using Salmon and differential expression for ENSEMBL lincRNAs determined using DESeq2. Hip RNA-seq lincRNA expression was compared to a knee dataset (ArrayExpress; E-MTAB-4304). ChIP-seq data from ENCODE was used to determine whether lincRNAs were associated with promoters (plncRNA) or unidirectional enhancer-like regulatory elements (elncRNAs). RESULTS: Our analysis of the hip transcriptome identified 1692 expressed Transcripts Per Million (TPM ≥1) Ensembl lincRNAs, of which 198 were significantly (FDR ≤0.05) differentially expressed in OA vs normal (NOF) cartilage. Similar analysis of knee cartilage transcriptome identified 648 Emsembl lincRNAs with 93 significantly (FDR ≤0.05) differentially expressed in intact vs damaged cartilage. In total, 1834 lincRNAs were expressed in both hip and knee cartilage, with a highly significant correlation in expression between the two cartilages. CONCLUSION: This is the first study to use RNA-seq to map and compare the lincRNA transcriptomes of hip and knee cartilage. We propose that lincRNAs expressed selectively in cartilage, or showing differential expression in OA, will play a role in cartilage homoeostasis.
Subject(s)
Cartilage, Articular/metabolism , Gene Expression Regulation , Osteoarthritis, Hip/genetics , Osteoarthritis, Knee/genetics , RNA, Long Noncoding/genetics , Transcriptome/genetics , Aged , Biomarkers/metabolism , Cartilage, Articular/diagnostic imaging , Female , Humans , Male , Osteoarthritis, Hip/diagnosis , Osteoarthritis, Hip/metabolism , Osteoarthritis, Knee/diagnosis , Osteoarthritis, Knee/metabolism , RNA/genetics , RNA, Long Noncoding/biosynthesisABSTRACT
Background: Elucidating developmental trajectories of white matter (WM) microstructure is critically important for understanding normal development and regional vulnerabilities in several brain disorders. Diffusion Weighted Imaging (DWI) is currently the method of choice for in-vivo white matter assessment. A majority of neonatal studies use the standard Diffusion Tensor Imaging (DTI) model although more advanced models such as the Neurite Orientation Dispersion and Density Imaging (NODDI) model and the Gaussian Mixture Model (GMM) have been used in adult population. In this study, we compare the ability of these three diffusion models to detect regional white matter maturation in typically developing control (TDC) neonates and regional abnormalities in neonates with congenital heart disease (CHD). Methods: Multiple b-value diffusion Magnetic Resonance Imaging (dMRI) data were acquired from TDC neonates (Nâ¯=â¯16) at 38 to 47 gestational weeks (GW) and CHD neonates (Nâ¯=â¯19) aged 37â¯weeks to 41â¯weeks. Measures calculated from the diffusion signal included not only Mean Diffusivity (MD) and Fractional Anisotropy (FA) derived from the standard DTI model, but also three advanced diffusion measures, namely, the fiber Orientation Dispersion Index (ODI), the isotropic volume fraction (Viso), and the intracellular volume fraction (Vic) derived from the NODDI model. Further, we used two novel measures from a non-parametric GMM, namely the Return-to-Origin Probability (RTOP) and Return-to-Axis Probability (RTAP), which are sensitive to axonal/cellular volume and density respectively. Using atlas-based registration, 22 white matter regions (6 projection, 4 association, and 1 callosal pathways bilaterally in each hemisphere) were selected and the mean value of all 7 measures were calculated in each region. These values were used as dependent variables, with GW as the independent variable in a linear regression model. Finally, we compared CHD and TDC groups on these measures in each ROI after removing age-related trends from both the groups. Results: Linear analysis in the TDC population revealed significant correlations with GW (age) in 12 projection pathways for MD, Vic, RTAP, and 11 pathways for RTOP. Several association pathways were also significantly correlated with GW for MD, Vic, RTAP, and RTOP. The right callosal pathway was significantly correlated with GW for Vic. Consistent with the pathophysiology of altered development in CHD, diffusion measures demonstrated differences in the association pathways involved in language systems, namely the Uncinate Fasciculus (UF), the Inferior Fronto-occipital Fasciculus (IFOF), and the Superior Longitudinal Fasciculus (SLF). Overall, the group comparison between CHD and TDC revealed lower FA, Vic, RTAP, and RTOP for CHD bilaterally in the a) UF, b) Corpus Callosum (CC), and c) Superior Fronto-Occipital Fasciculus (SFOF). Moreover, FA was lower for CHD in the a) left SLF, b) bilateral Anterior Corona Radiata (ACR) and left Retrolenticular part of the Internal Capsule (RIC). Vic was also lower for CHD in the left Posterior Limb of the Internal Capsule (PLIC). ODI was higher for CHD in the left CC. RTAP was lower for CHD in the left IFOF, while RTOP was lower in CHD in the: a) left ACR, b) left IFOF and c) right Anterior Limb of the Internal Capsule (ALIC). Conclusion: In this study, all three methods revealed the expected changes in the WM regions during the early postnatal weeks; however, GMM outperformed DTI and NODDI as it showed significantly larger effect sizes while detecting differences between the TDC and CHD neonates. Future studies based on a larger sample are needed to confirm these results and to explore clinical correlates.
Subject(s)
Brain/diagnostic imaging , Heart Defects, Congenital/diagnostic imaging , White Matter/diagnostic imaging , Cross-Sectional Studies , Diffusion Magnetic Resonance Imaging , Female , Humans , Infant, Newborn , Male , Nerve Net/diagnostic imagingABSTRACT
OBJECTIVES: Joint degeneration in osteoarthritis (OA) is characterised by damage and loss of articular cartilage. The pattern of loss is consistent with damage occurring only where the mechanical loading is high. We have investigated using RNA-sequencing (RNA-seq) and systems analyses the changes that occur in damaged OA cartilage by comparing it with intact cartilage from the same joint. METHODS: Cartilage was obtained from eight OA patients undergoing total knee replacement. RNA was extracted from cartilage on the damaged distal medial condyle (DMC) and the intact posterior lateral condyle (PLC). RNA-seq was performed to identify differentially expressed genes (DEGs) and systems analyses applied to identify dysregulated pathways. RESULTS: In the damaged OA cartilage, there was decreased expression of chondrogenic genes SOX9, SOX6, COL11A2, COL9A1/2/3, ACAN and HAPLN1; increases in non-chondrogenic genes COL1A1, COMP and FN1; an altered pattern of secreted proteinase expression; but no expression of major inflammatory cytokines. Systems analyses by PhenomeExpress revealed significant sub-networks of DEGs including mitotic cell cycle, Wnt signalling, apoptosis and matrix organisation that were influenced by a core of altered transcription factors (TFs), FOSL1, AHR, E2F1 and FOXM1. CONCLUSIONS: Gene expression changes in damaged cartilage suggested a signature non-chondrogenic response of altered matrix protein and secreted proteinase expression. There was evidence of a damage response in this late OA cartilage, which surprisingly showed features detected experimentally in the early response of cartilage to mechanical overload. PhenomeExpress analysis identified a hub of DEGs linked by a core of four differentially regulated TFs.
Subject(s)
Osteoarthritis, Knee , Arthroplasty, Replacement, Knee , Cartilage, Articular , Gene Expression , Gene Expression Profiling , HumansABSTRACT
BACKGROUND: The measurement of brain perfusion may provide valuable information for assessment and treatment of newborns with hypoxic-ischemic encephalopathy (HIE). While arterial spin labeled perfusion (ASL) magnetic resonance imaging (MRI) provides noninvasive and direct measurements of regional cerebral blood flow (CBF) values, it is logistically challenging to obtain. Near-infrared spectroscopy (NIRS) might be an alternative, as it permits noninvasive and continuous monitoring of cerebral hemodynamics and oxygenation at the bedside. OBJECTIVE: The purpose of this study is to determine the correlation between measurements of brain perfusion by NIRS and by MRI in term newborns with HIE treated with hypothermia. DESIGN/METHODS: In this prospective cohort study, ASL-MRI and NIRS performed during hypothermia were used to assess brain perfusion in these newborns. Regional cerebral blood flow (CBF) values, measured from 1-2 MRI scans for each patient, were compared to mixed venous saturation values (SctO2) recorded by NIRS just before and after each MRI. Analysis included groupings into moderate versus severe HIE based on their initial background pattern of amplitude-integrated electroencephalogram. RESULTS: Twelve concomitant recordings were obtained of seven neonates. Strong correlation was found between SctO2 and CBF in asphyxiated newborns with severe HIE (r=0.88; p value=0.0085). Moreover, newborns with severe HIE had lower CBF (likely lower oxygen supply) and extracted less oxygen (likely lower oxygen demand or utilization) when comparing SctO2 and CBF to those with moderate HIE. CONCLUSIONS: NIRS is an effective bedside tool to monitor and understand brain perfusion changes in term asphyxiated newborns, which in conjunction with precise measurements of CBF obtained by MRI at particular times, may help tailor neuroprotective strategies in term newborns with HIE.
Subject(s)
Asphyxia Neonatorum/diagnosis , Asphyxia Neonatorum/therapy , Cerebrovascular Circulation/physiology , Functional Neuroimaging/methods , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/diagnosis , Hypoxia-Ischemia, Brain/therapy , Magnetic Resonance Imaging/methods , Spectroscopy, Near-Infrared/methods , Cohort Studies , Electroencephalography , Female , Humans , Image Processing, Computer-Assisted , Infant, Newborn , Male , Oxygen/blood , Oxygen Consumption/physiology , Perfusion , Prospective Studies , Reproducibility of ResultsABSTRACT
OBJECTIVE: To evaluate the efficacy and safety of passive cooling during transport of asphyxiated newborns. STUDY DESIGN: Retrospective medical record review of newborns with perinatal asphyxia transported for hypothermia between July 2007 and June 2010. RESULT: Of 43 newborns transported, 27 were passively cooled without significant adverse events. Twenty (74%) passively cooled newborns arrived with temperature between 32.5 and 34.5 °C. One newborn arrived with a temperature <32.5, and 6 (22%) had temperatures >34.5 °C. Time from birth to hypothermia was significantly shorter among passively cooled newborns compared with newborns not cooled (215 vs 327 min, P<0.01), even though time from birth to admission to Boston Children's Hospital was similar (252 vs 259 min, P=0.77). Time from birth to admission was the only significant predictor of increased time to reach target temperature (P=0.001). CONCLUSION: Exclusive passive cooling achieves significantly earlier initiation of effective hypothermia for asphyxiated newborns but should not delay transport for active cooling.
Subject(s)
Asphyxia Neonatorum/therapy , Hypothermia, Induced/methods , Transportation of Patients , Apgar Score , Asphyxia Neonatorum/diagnosis , Birth Weight , Body Temperature , Electroencephalography , Female , Gestational Age , Humans , Hypoxia-Ischemia, Brain/prevention & control , Infant, Newborn , Intensive Care Units, Neonatal , Male , Neurologic Examination , Patient Outcome Assessment , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND AND PURPOSE: Induced hypothermia is thought to work partly by mitigating reperfusion injury in asphyxiated term neonates. The purpose of this study was to assess brain perfusion in the first week of life in these neonates. MATERIALS AND METHODS: In this prospective cohort study, MR imaging and ASL-PI were used to assess brain perfusion in these neonates. We measured regional CBF values on 1-2 MR images obtained during the first week of life and compared these with values obtained in control term neonates. The same or later MR imaging scans were obtained to define the extent of brain injury. RESULTS: Eighteen asphyxiated and 4 control term neonates were enrolled; 11 asphyxiated neonates were treated with hypothermia. Those developing brain injury despite being treated with induced hypothermia usually displayed hypoperfusion on DOL 1 and then hyperperfusion on DOL 2-3 in brain areas subsequently exhibiting injury. Asphyxiated neonates not treated with hypothermia who developed brain injury also displayed hyperperfusion on DOL 1-6 in brain areas displaying injury. CONCLUSIONS: Our data show that ASL-PI may be useful for identifying asphyxiated neonates at risk of developing brain injury, whether or not hypothermia is administered. Because hypothermia for 72 hours may not prevent brain injury when hyperperfusion is found early in the course of neonatal hypoxic-ischemic encephalopathy, such neonates may be candidates for adjustments in their hypothermia therapy or for adjunctive neuroprotective therapies.
Subject(s)
Asphyxia Neonatorum/physiopathology , Asphyxia Neonatorum/therapy , Brain/physiopathology , Cerebrovascular Circulation , Hypothermia, Induced/methods , Magnetic Resonance Angiography/methods , Blood Flow Velocity , Brain/pathology , Female , Humans , Infant, Newborn , Male , Reproducibility of Results , Sensitivity and Specificity , Treatment OutcomeABSTRACT
OBJECTIVE: To characterize the delivery and postnatal neurodevelopmental outcomes of fetuses referred for ventriculomegaly (VM). METHODS: Under an internal review board-approved protocol, pregnant women were referred for magnetic resonance imaging (MRI) after sonographic diagnosis of VM and classified into one of four diagnostic groups: Group 1, normal central nervous system (CNS); Group 2, isolated mild VM (10-12 mm); Group 3, isolated VM > 12 mm; and Group 4, other CNS findings. Pregnancy outcome was obtained. Follow-up visits were offered with assessment of neurodevelopmental, adaptive and neurological functioning at 6 months and 1 year and/or 2 years of age. Atrial diameter and VM group differences in developmental outcomes were evaluated using repeated measures logistic regression and Fishers exact test, respectively. RESULTS: Of 314 fetuses, 253 (81%) were liveborn and survived the neonatal period. Fetuses in Groups 4 and 3 were less likely to progress to live delivery and to survive the neonatal period (60% and 84%, respectively) than were those in Groups 2 or 1 (93% and 100%, respectively, P < 0.001). Of the 143 fetuses followed postnatally, between 41% and 61% had a Bayley Scales of Infant Development (BSID-II) psychomotor developmental index score in the delayed range (< 85) at the follow-up visits, whereas the BSID-II mental developmental index and Vineland Adaptive Behavior composite scores were generally in line with normative expectations. Among those that were liveborn, neither VM group nor prenatal atrial diameter was related to postnatal developmental outcome. CONCLUSIONS: Diagnostic category and degree of fetal VM based on ultrasound and MRI measurements are associated with the incidence of live births and thus abnormal outcome. Among those undergoing formal postnatal testing, VM grade is not associated with postnatal developmental outcome, but motor functioning is more delayed than is cognitive or adaptive functioning.
Subject(s)
Cerebral Ventricles/pathology , Child Development/physiology , Developmental Disabilities , Adolescent , Adult , Cerebral Ventricles/diagnostic imaging , Developmental Disabilities/etiology , Developmental Disabilities/pathology , Dilatation, Pathologic/diagnostic imaging , Dilatation, Pathologic/pathology , Female , Follow-Up Studies , Humans , Infant, Newborn , Magnetic Resonance Imaging/methods , Pregnancy , Pregnancy Outcome , Prospective Studies , Reproducibility of Results , Ultrasonography, Prenatal/methods , Young AdultABSTRACT
BACKGROUND: Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities. PATIENTS: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children's Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository. RESULTS: We report the clinical features of five patients with a BP4-BP5 deletion, three with a BP4-BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4-BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4-BP5 covers approximately 1.5 Mb (chr15:28.719-30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover approximately 500 kb (chr15:28.902-29.404 Mb) and contain three reference genes and one miRNA gene. The BP4-BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG. CONCLUSIONS: The phenotype of chromosome 15q13.2q13.3 BP4-BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.
Subject(s)
Autistic Disorder/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 15/genetics , Intellectual Disability/genetics , Adolescent , Autistic Disorder/pathology , Child , Child, Preschool , Chromosome Deletion , Comparative Genomic Hybridization , Female , Gene Duplication , Humans , Infant , Intellectual Disability/pathology , Male , Phenotype , Young AdultABSTRACT
The onset and duration of hypoxic-ischemic (HI) insults rarely can be determined precisely in perinatal asphyxia. The need to establish the timing of HI insults will be critical for the successful application of evolving neuroprotective therapies that may be administered to the asphyxiated newborn. Diffusion-weighted magnetic resonance imaging has emerged as an imaging technique that can be used to identify HI brain injury before the detection of abnormalities by conventional magnetic resonance imaging. This case illustrates the early changes in diffusion-weighted and conventional magnetic resonance imaging studies and in quantitative values of the apparent diffusion coefficient in a unique case of neonatal asphyxia in which the onset and duration of the HI insult were known.hypoxia-ischemia, newborn brain, perinatal asphyxia, diffusion-weighted imaging, proton magnetic resonance spectroscopy.
Subject(s)
Brain/pathology , Heart Arrest/pathology , Hypoxia-Ischemia, Brain/pathology , Magnetic Resonance Imaging/methods , Basal Ganglia/pathology , Brain Stem/pathology , Fatal Outcome , Heart Arrest/therapy , Humans , Hypoxia-Ischemia, Brain/therapy , Infant, Newborn , Magnetic Resonance Spectroscopy , Male , Resuscitation/methods , Thalamus/pathology , Time FactorsABSTRACT
Menkes' disease is an X-linked disorder caused by impaired intracellular transport of copper. Currently, no therapy effectively arrests the relentless neurodegeneration of Menkes' disease. Previous neuroimaging reports of patients with Menkes' disease describe a range of abnormalities, including intracranial vessel tortuosity and cerebral white matter changes. We report two infants with Menkes' disease who developed ischemic cerebrovascular disease early in infancy. Magnetic resonance studies, including diffusion-weighted imaging and proton magnetic resonance spectroscopy, demonstrated bilateral infarctions of deep gray matter nuclei, a finding not previously described in Menkes' disease. Potential mechanisms for these cerebrovascular lesions in Menkes' disease include the susceptibility to free radical attack and inadequate energy supply from oxidative phosphorylation. These infarctions may play an unrecognized but important role in the neurodegeneration of children with Menkes' disease. The development of effective therapeutic agents against this disease will require a more detailed understanding of such underlying mechanisms.
Subject(s)
Cerebral Infarction/diagnosis , Menkes Kinky Hair Syndrome/diagnosis , Cerebral Infarction/etiology , Humans , Infant , Magnetic Resonance Imaging , Male , Menkes Kinky Hair Syndrome/complicationsABSTRACT
Formulation of rational interventions in infantile hydrocephalus is limited by the inability to monitor cerebral hemodynamics quantitatively, continuously, and noninvasively. Near-infrared spectroscopy (NIRS) measures changes in cerebral concentration of oxygenated and deoxygenated hemoglobin (HbO(2) and Hb); HbD is the derived difference between HbO(2) and Hb. Our previous work showed that HbD reflected cerebral blood flow (CBF) measured by radioactive microspheres in a piglet model of systemic hypotension. This study was designed to determine whether NIRS detected important changes in cerebral perfusion and oxygenation in a piglet model of hydrocephalus and whether changes in HbD accurately reflected changes in CBF. Acute hydrocephalus was produced in neonatal piglets by intraventricular infusion of "mock cerebrospinal fluid." Intracranial pressure (ICP) was maintained for several minutes at approximately 10, 20, and 30 mm Hg above the baseline ICP. CBF was measured in cerebral cortex, white matter, and basal ganglia at each ICP by radioactive microspheres. Changes in HbO(2) and Hb were measured continuously by NIRS. Cerebral perfusion pressure declined with increasing ICP, and this decline was accompanied by significant decreases in HbD measured by NIRS and CBF measured by radioactive microspheres. There was a strong correlation between changes in HbD and individual changes in CBF in cerebral cortex, white matter, and basal ganglia (all p < 0.0001). This study demonstrates that changes in HbD reflect changes in CBF over a wide range of ICP in a model of acute hydrocephalus. This reproducible and easily obtained measurement by NIRS could facilitate considerably decisions concerning therapeutic interventions.
Subject(s)
Animals, Newborn , Brain/blood supply , Disease Models, Animal , Hydrocephalus/physiopathology , Spectroscopy, Near-Infrared , Animals , Blood Flow Velocity , Hemoglobins/analysis , Intracranial Pressure , Isotope Labeling , Microspheres , Oxyhemoglobins/analysis , SwineABSTRACT
Near-infrared spectroscopy (NIRS) is a relatively new technology that offers the enormous advantage of making measurements in vivo of changes in cerebral hemodynamics and oxygenation. Because NIRS is noninvasive and portable, it can provide real-time measurements of these changes at the bedside. Thus NIRS is ideally suited to the study of many physiological and pathological processes affecting the brain, particularly in the infant or young child in the intensive care unit or operating room. This review outlines the basic principles, advantages, and limitations of the current state of NIRS technology. An emphasis is placed on the animal and clinical studies that are relevant to the field of child neurology, with an eye to the future evolution and potential applications of this promising technique.
Subject(s)
Brain Diseases/diagnosis , Brain/blood supply , Cerebrovascular Circulation , Infant, Newborn, Diseases/diagnosis , Spectroscopy, Near-Infrared/methods , Brain Diseases/physiopathology , Brain Diseases/prevention & control , Child , Female , Humans , Infant, Newborn , Infant, Newborn, Diseases/physiopathology , Infant, Newborn, Diseases/prevention & control , Infant, Premature, Diseases/diagnosis , Spectroscopy, Near-Infrared/trendsABSTRACT
BACKGROUND AND PURPOSE: Sonographic identification of communicating and noncommunicating forms of posthemorrhagic hydrocephalus can be difficult. This study evaluates the feasibility of using sonographic contrast agents to determine ventricular patency in a newborn animal model. METHODS: A craniotomy was performed and a catheter was placed under sonographic guidance into the lateral ventricle in five anesthetized newborn piglets. Sonograms were obtained before and after intraventricular injection of 0.01 mL of a sonographic contrast agent (Imagent, formulation AF0150; Alliance Pharmaceutical Corp, San Diego, CA) diluted in 1 mL normal saline, and images were assessed for presence and location of echogenic contrast material. RESULTS: Flow of contrast material was identifiable from the ipsilateral lateral ventricle into the contralateral lateral ventricle, and through the third and fourth ventricles into the basal cisterns during real-time sonography in every animal. Ventricular and cistern echogenicity remained increased for approximately 4 minutes after injection. CONCLUSION: Contrast-enhanced sonographic ventriculography has the potential to identify patency of CSF pathways in newborns with hydrocephalus and an indwelling ventricular catheter.
Subject(s)
Cerebral Ventricles/diagnostic imaging , Contrast Media , Echoencephalography , Hydrocephalus/diagnostic imaging , Animals , Animals, Newborn , SwineABSTRACT
A patient with a carcinoid tumour of the oesophagus developed widespread metastases within three years of a successful local resection. Of the seven patients with oesophageal carcinoid tumours so far reported, four have died with widespread metastases.
Subject(s)
Carcinoid Tumor/pathology , Esophageal Neoplasms/pathology , Aged , Female , Follow-Up Studies , Humans , Neoplasm MetastasisSubject(s)
Eye Movements , Psychomotor Performance/physiology , Saccades , Vestibule, Labyrinth/physiology , Adult , Cognition/physiology , Darkness , Fixation, Ocular , Humans , Middle AgedABSTRACT
Multiplication-stimulating activity (125I-MSA) has been shown to bind to isolated rabbit chondrocytes, the binding being dependent on time, temperature, and cell density. Nonspecific binding was approximately 15%. Unlabelled MSA at 100 ng/ml inhibited 125I-MSA binding by 50%. Porcine insulin (0.5-10 micrograms/ml) did not compete with MSA but resulted in a 10-15% increase in 125I-MSA binding. The data suggest that normal chondrocytes carry IGF2-type receptors as well as the IGF1 type previously described.