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ELife Nov 2023The structure and function of the vertebrate retina have been extensively studied across species with an isolated, ex vivo preparation. Retinal function in vivo,...
The structure and function of the vertebrate retina have been extensively studied across species with an isolated, ex vivo preparation. Retinal function in vivo, however, remains elusive, especially in awake animals. Here, we performed single-unit extracellular recordings in the optic tract of head-fixed mice to compare the output of awake, anesthetized, and ex vivo retinas. While the visual response properties were overall similar across conditions, we found that awake retinal output had in general (1) faster kinetics with less variability in the response latencies; (2) a larger dynamic range; and (3) higher firing activity, by ~20 Hz on average, for both baseline and visually evoked responses. Our modeling analyses further showed that such awake response patterns convey comparable total information but less efficiently, and allow for a linear population decoder to perform significantly better than the anesthetized or ex vivo responses. These results highlight distinct retinal behavior in awake states, in particular suggesting that the retina employs dense coding in vivo, rather than sparse efficient coding as has been often assumed from ex vivo studies.
Topics: Mice; Animals; Wakefulness; Retina
PubMed: 37922200
DOI: 10.7554/eLife.78005 -
Frontiers in Endocrinology 2023Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of...
BACKGROUND
Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 () gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel variant.
CASES
The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript.
CONCLUSION
Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of variants in this phenotype raise the question of whether should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.
Topics: Humans; Male; Mutation; Optic Nerve; Osteopetrosis; Osteosclerosis; Protein Serine-Threonine Kinases; Ribs; Sclerosis; Vision Disorders; Child
PubMed: 37920250
DOI: 10.3389/fendo.2023.1258340 -
Cancer Cell Dec 2023Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152...
Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception.
Topics: Humans; Stomach Neoplasms; Prospective Studies; Gastric Mucosa; Genomics; Metaplasia; Precancerous Conditions
PubMed: 37890493
DOI: 10.1016/j.ccell.2023.10.004 -
American Journal of Ophthalmology Case... Dec 2023To report the case of a pediatric patient with optic neuritis in whom changes in the retinal ganglion cell complex (GCC) and superficial retinal vessel density were...
PURPOSE
To report the case of a pediatric patient with optic neuritis in whom changes in the retinal ganglion cell complex (GCC) and superficial retinal vessel density were dissociated.
OBSERVATIONS
An 8-year-old girl had an upper respiratory tract infection in early February 2019, after which she began to experience oculomotor pain and vision loss in her left eye. She was diagnosed with optic neuritis of the left eye. Initial examination showed a visual acuity of 20/20 in her right eye and light perception in her left eye. After steroid pulse therapy, her left visual acuity improved to 20/20 in April 2019, with no further symptoms to date. The GCC in the affected eye continued to become thinner until November 2019. However, optical coherence tomography angiography carried out after improvement in her visual function showed no difference in vascular density of the superficial retinal capillary plexus between the right and left eyes.
CONCLUSIONS AND IMPORTANCE
In glaucoma, GCC thinning and vascular density loss occur almost simultaneously at an early stage. However, the current neuritis case showed changes in GCC but no corresponding changes in vascular density in the same area. This report suggests that optic neuritis and glaucoma involve different mechanisms of GCC thinning.
PubMed: 37860669
DOI: 10.1016/j.ajoc.2023.101937 -
Fa Yi Xue Za Zhi Aug 2023To investigate the characteristics and objective assessment method of visual field defects caused by optic chiasm and its posterior visual pathway injury.
OBJECTIVES
To investigate the characteristics and objective assessment method of visual field defects caused by optic chiasm and its posterior visual pathway injury.
METHODS
Typical cases of visual field defects caused by injuries to the optic chiasm, optic tracts, optic radiations, and visual cortex were selected. Visual field examinations, visual evoked potential (VEP) and multifocal visual evolved potential (mfVEP) measurements, craniocerebral CT/MRI, and retinal optical coherence tomography (OCT) were performed, respectively, and the aforementioned visual electrophysiological and neuroimaging indicators were analyzed comprehensively.
RESULTS
The electrophysiological manifestations of visual field defects caused by optic chiasm injuries were bitemporal hemianopsia mfVEP abnormalities. The visual field defects caused by optic tract, optic radiation, and visual cortex injuries were all manifested homonymous hemianopsia mfVEP abnormalities contralateral to the lesion. Mild relative afferent pupil disorder (RAPD) and characteristic optic nerve atrophy were observed in hemianopsia patients with optic tract injuries, but not in patients with optic radiation or visual cortex injuries. Neuroimaging could provide morphological evidence of damages to the optic chiasm and its posterior visual pathway.
CONCLUSIONS
Visual field defects caused by optic chiasm, optic tract, optic radiation, and visual cortex injuries have their respective characteristics. The combined application of mfVEP and static visual field measurements, in combination with neuroimaging, can maximize the assessment of the location and degree of visual pathway damage, providing an effective scheme for the identification of such injuries.
Topics: Humans; Optic Chiasm; Visual Pathways; Visual Fields; Evoked Potentials, Visual; Random Amplified Polymorphic DNA Technique; Hemianopsia; Vision Disorders; Optic Nerve Injuries; Brain Injuries, Traumatic
PubMed: 37859473
DOI: 10.12116/j.issn.1004-5619.2023.230309 -
Journal of Neurology, Neurosurgery, and... Mar 2024Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To...
BACKGROUND
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis rarely causes visible lesions in conventional MRI, yet advanced imaging detects extensive white matter damage. To improve prognostic capabilities, we evaluate the T1-weighted/T2-weighted (T1w/T2w) ratio, a measure of white matter integrity computable from clinical MRI sequences, in NMDAR encephalitis and examine its associations with cognitive impairment.
METHODS
T1-weighted and T2-weighted MRI were acquired cross-sectionally at 3 Tesla in 53 patients with NMDAR encephalitis (81% women, mean age 29 years) and 53 matched healthy controls. Quantitative and voxel-wise group differences in T1w/T2w ratios and associations with clinical and neuropsychological outcomes were assessed. P-values were false discovery rate (FDR) adjusted where multiple tests were conducted.
RESULTS
Patients with NMDAR encephalitis had significantly lower T1w/T2w ratios across normal appearing white matter (p=0.009, Hedges' g=-0.51), which was associated with worse verbal episodic memory performance (r=0.39, p=0.005, p(FDR)=0.026). White matter integrity loss was observed in the corticospinal tract, superior longitudinal fascicle, optic radiation and callosal body with medium to large effects (Cohen's d=[0.42-1.17]). In addition, patients showed decreased T1w/T2w ratios in the hippocampus (p=0.002, p(FDR)=0.005, Hedges' g=-0.62), amygdala (p=0.002, p(FDR)=0.005, Hedges' g=-0.63) and thalamus (p=0.010, p(FDR)=0.019, Hedges' g=-0.51).
CONCLUSIONS
The T1w/T2w ratio detects microstructural changes in grey and white matter of patients with NMDAR encephalitis that correlate with cognitive performance. Computable from conventional clinical MRI sequences, this measure shows promise in bridging the clinico-radiological dissociation in NMDAR encephalitis and could serve as an imaging outcome measure in clinical trials.
Topics: Humans; Female; Adult; Male; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Magnetic Resonance Imaging; White Matter; Hippocampus; Biomarkers
PubMed: 37798094
DOI: 10.1136/jnnp-2023-332069 -
Medicina (Kaunas, Lithuania) Sep 2023: Although ocular disorders can occasionally impact people with HIV over the course of their illness, HIV/AIDS is unmistakably a multisystem disorder. A physician can...
: Although ocular disorders can occasionally impact people with HIV over the course of their illness, HIV/AIDS is unmistakably a multisystem disorder. A physician can rule out a wide range of ophthalmic problems with the assistance of an ophthalmologist, from adnexal disorders to posterior segment diseases, including those affecting the optic tract and optic nerve. : Based on patient medical data from the "St. Parascheva" Clinical Hospital of Infectious Diseases in Iasi, we carried out a retrospective clinical investigation on patients with HIV/AIDS and ophthalmological conditions who were hospitalized in northeastern Romania. We seek to draw attention to the characteristics and ophthalmological comorbidities of HIV/AIDS patients. The studied period was between 1 January 1991 and 31 December 2022. : There were a total of 38 recorded cases of ophthalmological manifestations in the HIV-infected patients. The research group's average age was 37.31 years old (standard deviation 9.5693917). Males were primarily impacted, having lower total CD4+ T-lymphocyte levels based on sex and CD4+ T-lymphocyte levels overall. The HIV viral load was 999 268.13 copies/mL on average (standard deviation 1,653,722.9). Of all the patients, we found out that 17 had congenital eye diseases (44.73%) and the others (21, 55.26%) developed ophthalmological diseases. CMV Retinitis was found most frequently, in eight patients (21.05%), followed by Myopia in seven patients (18.42%). : The key to the management of HIV-positive patients is a multidisciplinary approach and access to antiretroviral therapy. Anyone who is HIV-positive and experiences ocular symptoms at any time should be directed to seek professional ophthalmologic treatment as soon as feasible. A therapeutic holdup could result in irreversible vision loss. Long-term coordination is required to combat this disease, improving communication between the ophthalmology and infectious disease fields.
PubMed: 37763724
DOI: 10.3390/medicina59091605 -
Scientific Reports Sep 2023Multiple Sclerosis (MS) is an autoimmune demyelinating disease characterised by changes in iron and myelin content. These biomarkers are detectable by Quantitative...
Multiple Sclerosis (MS) is an autoimmune demyelinating disease characterised by changes in iron and myelin content. These biomarkers are detectable by Quantitative Susceptibility Mapping (QSM), an advanced Magnetic Resonance Imaging technique detecting magnetic properties. When analysed with radiomic techniques that exploit its intrinsic quantitative nature, QSM may furnish biomarkers to facilitate early diagnosis of MS and timely assessment of progression. In this work, we explore the robustness of QSM radiomic features by varying the number of grey levels (GLs) and echo times (TEs), in a sample of healthy controls and patients with MS. We analysed the white matter in total and within six clinically relevant tracts, including the cortico-spinal tract and the optic radiation. After optimising the number of GLs (n = 64), at least 65% of features were robust for each Volume of Interest (VOI), with no difference (p > .05) between left and right hemispheres. Different outcomes in feature robustness among the VOIs depend on their characteristics, such as volume and variance of susceptibility values. This study validated the processing pipeline for robustness analysis and established the reliability of QSM-based radiomics features against GLs and TEs. Our results provide important insights for future radiomics studies using QSM in clinical applications.
Topics: Humans; Multiple Sclerosis; Reproducibility of Results; Autoimmune Diseases; Patients; Magnetic Resonance Imaging
PubMed: 37758804
DOI: 10.1038/s41598-023-42914-4 -
International Journal of Ophthalmology 2023To describe the clinical and radiologic features of retrolaminar migration silicone oil (SiO) and observe the dynamic position of ventricular oil accumulation in supine...
AIM
To describe the clinical and radiologic features of retrolaminar migration silicone oil (SiO) and observe the dynamic position of ventricular oil accumulation in supine and prone.
METHODS
For this retrospective study, 29 patients who had a history of SiO injection treatment and underwent unenhanced head computed tomography (CT) were included from January 2019 to October 2022. The patients were divided into migration-positive and negative groups. Clinical history and CT features were compared using Whitney and Fisher's exact tests. The dynamic position of SiO was observed within the ventricular system in supine and prone. CT images were visually assessed for SiO migration along the retrolaminar involving pathways for vision (optic nerve, chiasm, and tract) and ventricular system.
RESULTS
Intraocular SiO migration was found in 5 of the 29 patients (17.24%), with SiO at the optic nerve head (=1), optic nerve (=4), optic chiasm (=1), optic tract (=1), and within lateral ventricles (=1). The time interval between SiO injection and CT examination of migration-positive cases was significantly higher than that of migration-negative patients (22.8±16.5mo 13.1±2.6mo, <0.001). The hyperdense lesion located in the frontal horns of the right lateral ventricle migrated to the fourth ventricle when changing the position from supine to prone.
CONCLUSION
Although SiO retrolaminar migration is unusual, the clinician and radiologist should be aware of migration routes. The supine combined with prone examination is the first-choice method to confirm the presence of SiO in the ventricular system.
PubMed: 37724262
DOI: 10.18240/ijo.2023.09.20 -
Science Translational Medicine Sep 2023Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and...
Tau pathogenesis is a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD). Although the events leading to initial tau misfolding and subsequent tau spreading in patient brains are largely unknown, traumatic brain injury (TBI) may be a risk factor for tau-mediated neurodegeneration. Using a repetitive TBI (rTBI) paradigm, we report that rTBI induced somatic accumulation of phosphorylated and misfolded tau, as well as neurodegeneration across multiple brain areas in 7-month-old tau transgenic PS19 mice but not wild-type (WT) mice. rTBI accelerated somatic tau pathology in younger PS19 mice and WT mice only after inoculation with tau preformed fibrils and AD brain-derived pathological tau (AD-tau), respectively, suggesting that tau seeds are needed for rTBI-induced somatic tau pathology. rTBI further disrupted axonal microtubules and induced punctate tau and TAR DNA binding protein 43 (TDP-43) pathology in the optic tracts of WT mice. These changes in the optic tract were associated with a decline of visual function. Treatment with a brain-penetrant microtubule-stabilizing molecule reduced rTBI-induced tau, TDP-43 pathogenesis, and neurodegeneration in the optic tract as well as visual dysfunction. Treatment with the microtubule stabilizer also alleviated rTBI-induced tau pathology in the cortices of AD-tau-inoculated WT mice. These results indicate that rTBI facilitates abnormal microtubule organization, pathological tau formation, and neurodegeneration and suggest microtubule stabilization as a potential therapeutic avenue for TBI-induced neurodegeneration.
Topics: Animals; Mice; Brain Injuries, Traumatic; Microtubules; DNA-Binding Proteins; Brain; Alzheimer Disease; Disease Models, Animal; Excipients; Mice, Transgenic
PubMed: 37703352
DOI: 10.1126/scitranslmed.abo6889