Fungal microbiota in newborn infants with and without respiratory distress syndrome.

BACKGROUND: Pneumocytis jirovecii infection in preterm newborns has recently been associated with neonatal respiratory distress syndrome and bronchopulmonary dysplasia. Changes in the bacterial microbiota of the airways have also been described in infants with bronchopulmonary dysplasia. However, until now there has been no information on the airway mycobiota in newborns. The purpose of this study was to describe the airway mycobiota in term and preterm newborns and its possible association with respiratory distress syndrome. METHODS: Twenty-six matched preterm newborns with and without respiratory distress syndrome were studied, as well as 13 term babies. The identification of the fungal microbiota was carried out using molecular procedures in aspirated nasal samples at birth. RESULTS: The ascomycota phylum was identified in 89.7% of newborns, while the basidiomycota phylum was found in 33.3%. Cladosporium was the predominant genus in both term and preterm infants 38.4% vs. 73% without statistical differences. Candida sake and Pneumocystis jirovecii were only found in preterm infants, suggesting a potential relationship with the risk of prematurity. CONCLUSIONS: This is the first report to describe the fungal microbiota of the airways in term and preterm infants with and without respiratory distress syndrome. Although no differences have been observed, the number of cases analyzed could be small to obtain conclusive results, and more studies are needed to understand the role of the fungal microbiota of the airways in neonatal respiratory pathology.

Racial disparity in the genomics of precision oncology of prostate cancer.

BACKGROUND: Significant racial disparities in prostate cancer incidence and mortality have been reported between African American Men (AAM), who are at increased risk for prostate cancer, and European American Men (EAM). In most of the studies carried out on prostate cancer, this population is underrepresented. With the advancement of genome-wide association studies, several genetic predictor models of prostate cancer risk have been elaborated, as well as numerous studies that identify both germline and somatic mutations with clinical utility. RECENT FINDINGS: Despite significant advances, the AAM population continues to be underrepresented in genomic studies, which can limit generalizability and potentially widen disparities. Here we outline racial disparities in currently available genomic applications that are used to estimate the risk of individuals developing prostate cancer and to identify personalized oncology treatment strategies. While the incidence and mortality of prostate cancer are different between AAM and EAM, samples from AAM remain to be unrepresented in different studies. CONCLUSION: This disparity impacts the available genomic data on prostate cancer. As a result, the disparity can limit the predictive utility of the genomic applications and may lead to the widening of the existing disparities. More studies with substantially higher recruitment and engagement of African American patients are necessary to overcome this disparity.

Alzheimer's disease: a continuum with visual involvements.

Introduction: Alzheimer's disease (AD) is the most common form of dementia affecting the central nervous system, and alteration of several visual structures has been reported. Structural retinal changes are usually accompanied by changes in visual function in this disease. The aim of this study was to analyse the differences in visual function at different stages of the pathology (family history group (FH+), mild cognitive impairment (MCI), mild AD and moderate AD) in comparison with a control group of subjects with no cognitive decline and no family history of AD. Methods: We included 53 controls, 13 subjects with FH+, 23 patients with MCI, 25 patients with mild AD and, 21 patients with moderate AD. All were ophthalmologically healthy. Visual acuity (VA), contrast sensitivity (CS), colour perception, visual integration, and fundus examination were performed. Results: The analysis showed a statistically significant decrease in VA, CS and visual integration score between the MCI, mild AD and moderate AD groups compared to the control group. In the CS higher frequencies and in the colour perception test (total errors number), statistically significant differences were also observed in the MCI, mild AD and moderate AD groups with respect to the FH+ group and also between the control and AD groups. The FH+ group showed no statistically significant difference in visual functions compared to the control group. All the test correlated with the Mini Mental State Examination score and showed good predictive value when memory decline was present, with better values when AD was at a more advanced stage. Conclusion: Alterations in visual function appear in subjects with MCI and evolve when AD is established, being stable in the initial stages of the disease (mild AD and moderate AD). Therefore, visual psychophysical tests are a useful, simple and complementary tool to neuropsychological tests to facilitate diagnosis in the preclinical and early stages of AD.

Retinal Vascular Study Using OCTA in Subjects at High Genetic Risk of Developing Alzheimer's Disease and Cardiovascular Risk Factors.

In 103 subjects with a high genetic risk of developing Alzheimer's disease (AD), family history (FH) of AD and ApoE ɛ4 characterization (ApoE ɛ4) were analyzed for changes in the retinal vascular network by OCTA (optical coherence tomography angiography), and AngioTool and Erlangen-Angio-Tool (EA-Tool) as imaging analysis software. Retinal vascularization was analyzed by measuring hypercholesterolemia (HCL) and high blood pressure (HBP). Angio-Tool showed a statistically significant higher percentage of area occupied by vessels in the FH+ ApoE ɛ4- group vs. in the FH+ ApoE ɛ4+ group, and EA-Tool showed statistically significant higher vascular densities in the C3 ring in the FH+ ApoE ɛ4+ group when compared with: i)FH- ApoE ɛ4- in sectors H3, H4, H10 and H11; and ii) FH+ ApoE ɛ4- in sectors H4 and H12. In participants with HCL and HBP, statistically significant changes were found, in particular using EA-Tool, both in the macular area, mainly in the deep plexus, and in the peripapillary area. In conclusion, OCTA in subjects with genetic risk factors for the development of AD showed an apparent increase in vascular density in some sectors of the retina, which was one of the first vascular changes detectable. These changes constitute a promising biomarker for monitoring the progression of pathological neuronal degeneration.

Therapeutic impact and routine application of next-generation sequencing: A single institute study.

Genomic sequencing of tumor tissues provides information on actionable gene aberrations that have diagnostic and therapeutic significance and may guide clinical management through the use of targeted therapies. The indications for these techniques and their possible limitations for application in daily practice should be established as a priority. In the present study, a group of patients with few suitable therapeutic options who were eligible for a next-generation sequencing (NGS) analysis were analyzed, and the molecular targets identified and their therapeutic impact are described. A series of 26 patients treated at the Virgen Macarena Hospital for whom an NGS study was requested between January 2017 and December 2019 were reviewed. Actionable molecular alterations were identified in 20 of the cases, and 4 patients received NGS-guided treatment. NGS techniques represent a novel opportunity for guiding treatment in cancer patients. Patients with few therapeutic alternatives, either due to diagnosis, atypical evolution or resistance to standard therapy, may be suitable candidates.

Neuro-Ophthalmological Findings in Friedreich's Ataxia.

Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a severe autosomal recessive genetic disorder of the central nervous (CNS) and peripheral nervous system (PNS), affecting children and young adults. Its onset is before 25 years of age, with mean ages of onset and death between 11 and 38 years, respectively. The incidence is 1 in 30,000-50,000 persons. It is caused, in 97% of cases, by a homozygous guanine-adenine-adenine (GAA) trinucleotide mutation in the first intron of the frataxin (FXN) gene on chromosome 9 (9q13-q1.1). The mutation of this gene causes a deficiency of frataxin, which induces an altered inflow of iron into the mitochondria, increasing the nervous system's vulnerability to oxidative stress. The main clinical signs include spinocerebellar ataxia with sensory loss and disappearance of deep tendon reflexes, cerebellar dysarthria, cardiomyopathy, and scoliosis. Diabetes, hearing loss, and pes cavus may also occur, and although most patients with FRDA do not present with symptomatic visual impairment, 73% present with clinical neuro-ophthalmological alterations such as optic atrophy and altered eye movement, among others. This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.

Retinal Ganglion Cell Loss and Microglial Activation in a SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

The neurodegenerative disease amyotrophic lateral sclerosis (ALS) affects the spinal cord, brain stem, and cerebral cortex. In this pathology, both neurons and glial cells are affected. However, few studies have analyzed retinal microglia in ALS models. In this study, we quantified the signs of microglial activation and the number of retinal ganglion cells (RGCs) in an SOD1G93A transgenic mouse model at 120 days (advanced stage of the disease) in retinal whole-mounts. For SOD1G93A animals (compared to the wild-type), we found, in microglial cells, (i) a significant increase in the area occupied by each microglial cell in the total area of the retina; (ii) a significant increase in the arbor area in the outer plexiform layer (OPL) inferior sector; (iii) the presence of cells with retracted processes; (iv) areas of cell groupings in some sectors; (v) no significant increase in the number of microglial cells; (vi) the expression of IFN-γ and IL-1ß; and (vii) the non-expression of IL-10 and arginase-I. For the RGCs, we found a decrease in their number. In conclusion, in the SOD1G93A model (at 120 days), retinal microglial activation occurred, taking a pro-inflammatory phenotype M1, which affected the OPL and inner retinal layers and could be related to RGC loss.

Ocular Vascular Changes in Mild Alzheimer's Disease Patients: Foveal Avascular Zone, Choroidal Thickness, and ONH Hemoglobin Analysis.

In Alzheimer's disease (AD), vascular changes could be caused by amyloid beta (Aß) aggregates replacing the contractile smooth musculature of the arteriole walls. These changes happen in the brain vascular network, but also in the eye, and are related to decreased vascular density and low blood flow. In patients with Alzheimer's disease, thinning of the choroid and the retina has been shown. The aim of this prospective study was to assess the retinal and choroidal vascular systems, analyzing the choroidal thickness with optical coherence tomography (OCT), the foveal avascular zone (FAZ) with OCT-angiography (OCTA), and the optic nerve head (ONH) hemoglobin with the Laguna ONhE program, to evaluate which of the two ocular vascular systems shows earlier changes in mild AD patients. These patients, compared to controls, showed a significantly thinner choroid at all the analyzed points, with the exception of the temporal macula (at 1000 and 1500 µm from the fovea). On the other hand, the FAZ and ONH hemoglobin did not show significant differences. In conclusion, a thinner choroid was the main ocular vascular change observed in mild AD patients, while the retinal vessels were not yet affected. Therefore, choroidal thickness could be used an early biomarker in AD.

Amyotrophic Lateral Sclerosis: A Neurodegenerative Motor Neuron Disease With Ocular Involvement.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes degeneration of the lower and upper motor neurons and is the most prevalent motor neuron disease. This disease is characterized by muscle weakness, stiffness, and hyperreflexia. Patients survive for a short period from the onset of the disease. Most cases are sporadic, with only 10% of the cases being genetic. Many genes are now known to be involved in familial ALS cases, including some of the sporadic cases. It has also been observed that, in addition to genetic factors, there are numerous molecular mechanisms involved in these pathologies, such as excitotoxicity, mitochondrial disorders, alterations in axonal transport, oxidative stress, accumulation of misfolded proteins, and neuroinflammation. This pathology affects the motor neurons, the spinal cord, the cerebellum, and the brain, but recently, it has been shown that it also affects the visual system. This impact occurs not only at the level of the oculomotor system but also at the retinal level, which is why the retina is being proposed as a possible biomarker of this pathology. The current review discusses the main aspects mentioned above related to ALS, such as the main genes involved, the most important molecular mechanisms that affect this pathology, its ocular involvement, and the possible usefulness of the retina as a biomarker.

Microglial changes in the early aging stage in a healthy retina and an experimental glaucoma model.

Glaucoma is an age-related neurodegenerative disease that begins at the onset of aging. In this disease, there is an involvement of the immune system and therefore of the microglia. The purpose of this study is to evaluate the microglial activation using a mouse model of ocular hypertension (OHT) at the onset of aging. For this purpose, we used both naive and ocular hypertensives of 15-month-old mice (early stage of aging). In the latter, we analyzed the OHT eyes and the eyes contralateral to them to compare them with their aged controls. In the eyes of aged naive, aged OHT and aged contralateral eyes, microglial changes were observed compared to the young mice, including: (i) aged naive vs young naive: An increased soma size and vertical processes; (ii) aged OHT eyes vs young OHT eyes: A decrease in the area of the retina occupied by Iba-1 cells and in vertical processes; and (iii) aged contralateral vs young contralateral: A decrease in the soma size and arbor area and an increase in the number of microglia in the outer segment layer. Aged OHT eyes and the eyes contralateral to them showed an up-regulation of the CD68 expression in the branched microglia and a down-regulation in the MHCII and P2RY12 expression with respect to the eyes of young OHT mice. Conclusion: in the early phase of aging, morphological microglial changes along with changes in the expression of MHCII, CD68 and P2RY12, in both naive and OHT mice. These changes appear in aged OHT eyes and the eyes contralateral to them eyes.

Macular Thickness Decrease in Asymptomatic Subjects at High Genetic Risk of Developing Alzheimer's Disease: An OCT Study.

In this case control study, we examined the retinal thickness of the different layers in the macular region and peripapillary retinal nerve fiber layer (RNFL) with optical coherence tomography (OCT) in healthy cognitive subjects (from 51 to 74 years old) at high genetic risk for developing Alzheimer's disease (AD). Thirty-five subjects with a family history of Alzheimer disease (AD) (FH+) and ApoE ɛ4 carriers and 29 age-matched control subjects without a family history of AD (FH-) and ApoE ɛ4 non-carriers were included. Compared to FH- ApoE ɛ4 non-carriers, in FH+ ApoE ɛ4 carriers, there were statistically significant decreases (p < 0.05) in (i) the foveal area of mRNFL; (ii) the inferior and nasal sectors in the outer and inner macular ring in the inner plexiform layer (IPL); (iii) the foveal area and the inferior sector in the outer macular ring in the inner nuclear layer (INL); and (iv) the inferior sector of the outer macular ring in the outer plexiform layer (OPL). However, no statistically significant differences were found in the peripapillary thickness of RNFL between both study groups. In subjects with cognitive health and high genetic risk for the development of AD, initial changes appeared in the macular area. OCT could be a promising, cost-effective and non-invasive test useful in early AD, before the onset of clinical symptoms.

Ocular Involvement in Friedreich Ataxia Patients and its Relationship with Neurological Disability, a Follow-up Study.

: Background: This study compared functional and structural visual changes in Friedreich ataxia (FRDA) patients with healthy controls (HC) and correlated these changes with neurological disability. METHODS: Eight FRDA Spanish patients and eight HC were selected from 2014 to 2018. Best corrected visual acuity (BCVA), visual field (VF), optic coherence tomography (OCT), and neurological disability measured by "scale for the assessment and rating of ataxia" (SARA) were taken in a basal exploration and repeated after 6 months. A linear mixed analysis and Bonferroni p-value correction were performed. RESULTS: FRDA baseline and follow-up patients showed statistically significant decreases in BCVA, VF, and OCT parameters compared with the HC. Some of the VF measurements and most of the OCT parameters had an inverse mild-to-strong correlation with SARA. Moreover, the analysis of the ROC curve demonstrated that the peripapillary retinal nerve fiber layer (pRNFL) average thickness was the best parameter to discriminate between FRDA patients and HC. CONCLUSIONS: The follow-up study showed a progression in OCT parameters. Findings showed a sequential effect in pRNFL, ganglion cell complex (GCC), and macula. The VF and the OCT could be useful biomarkers in FRDA, both for their correlation with neurological disease as well as for their ability to evaluate disease progression.

Changes in Retinal OCT and Their Correlations with Neurological Disability in Early ALS Patients, a Follow-Up Study.

BACKGROUND: To compare early visual changes in amyotrophic lateral sclerosis (ALS) patients with healthy controls in a baseline exploration, to follow-up the patients after 6 months, and to correlate these visual changes with neurological disability. METHODS: All patients underwent a comprehensive neurological and ophthalmological examination. A linear mixed analysis and Bonferroni p-value correction were performed, testing four comparisons as follows: Control baseline vs. control follow-up, control baseline vs. ALS baseline, control follow-up vs. ALS follow-up, and ALS baseline vs. ALS follow-up. RESULTS: The mean time from the diagnosis was 10.80 ± 5.5 months. The analysis of the optical coherence tomography (OCT) showed: (1) In ALS baseline vs. control baseline, a macular significantly increased thickness of the inner macular ring temporal and inferior areas; (2) in ALS follow-up vs. ALS baseline, a significant macular thinning in the inner and outer macular ring inferior areas; (3) in ALS follow-up vs. ALS baseline, a significant peripapillary retinal nerve fiber layer (pRNFL) thinning in the superior and inferior quadrants; and (4) ALS patients showed a moderate correlation between some OCT pRNFL parameters and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score. CONCLUSION: The OCT showed retinal changes in patients with motoneuron disease and could serve as a complementary tool for studying ALS.

Changes in visual function and retinal structure in the progression of Alzheimer's disease.

BACKGROUND: Alzheimer's Disease (AD) can cause degeneration in the retina and optic nerve either directly, as a result of amyloid beta deposits, or secondarily, as a result of the degradation of the visual cortex. These effects raise the possibility that tracking ophthalmologic changes in the retina can be used to assess neurodegeneration in AD. This study aimed to detect retinal changes and associated functional changes in three groups of patients consisting of AD patients with mild disease, AD patients with moderate disease and healthy controls by using non-invasive psychophysical ophthalmological tests and optical coherence tomography (OCT). METHODS: We included 39 patients with mild AD, 21 patients with moderate AD and 40 age-matched healthy controls. Both patients and controls were ophthalmologically healthy. Visual acuity, contrast sensitivity, colour perception, visual integration, and choroidal thicknesses were measured. In addition, OCT and OCT angiography (OCTA) were applied. FINDINGS: Visual acuity, contrast sensitivity, colour perception, and visual integration were significantly lower in AD patients than in healthy controls. Compared to healthy controls, macular thinning in the central region was significant in the mild AD patients, while macular thickening in the central region was found in the moderate AD group. The analysis of macular layers revealed significant thinning of the retinal nerve fibre layer, the ganglion cell layer and the outer plexiform layer in AD patients relative to controls. Conversely, significant thickening was observed in the outer nuclear layer of the patients. However, mild AD was associated with significant thinning of the subfovea and the nasal and inferior sectors of the choroid. Significant superonasal and inferotemporal peripapillary thinning was observed in patients with moderate disease. CONCLUSIONS: The first changes in the mild AD patients appear in the psychophysical tests and in the central macula with a decrease in the central retinal thickness. When there was a disease progression to moderate AD, psychophysical tests remained stable with respect to the decrease in mild AD, but significant thinning in the peripapillary retina and thickening in the central retina appeared. The presence of AD is best indicated based on contrast sensitivity.

The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma.

Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aß) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aß, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The aim of the present review is to describe the contribution in retina to microglial-mediated neuroinflammation in AD, PD, and glaucomatous neurodegeneration.

Early Acquisition of Pneumocystis jirovecii Colonization and Potential Association With Respiratory Distress Syndrome in Preterm Newborn Infants.

BACKGROUND: Pneumocystis pneumonia is a well-recognized lung disease of premature and malnourished babies. Even though serologic studies have shown that children are exposed to Pneumocystis jirovecii early in life, the epidemiology of human P. jirovecii infection and the host-microorganism relationship in infancy remain poorly understood. The aim of the present study was to investigate the prevalence of P. jirovecii colonization in preterm infants and its possible association with medical complications. METHODS: A prospective observational study of preterm infants (birth weight <1500 g and/or gestational age <32 weeks) was carried out. Identification of P. jirovecii colonization was performed by means of molecular techniques in nasal aspirated samples at birth. RESULTS: A total of 128 preterm infants were included during the study period. Pneumocystis DNA was identified in 25.7% (95% confidence interval [CI], 17.8%-33.7%) of newborns studied. A significant increase of respiratory distress syndrome in colonized group, even after adjusting for confounding factors (odds ratio, 2.7 [95% CI, 1.0-7.5]; P = .04), was observed. No differences were observed in other medical conditions between the 2 groups. CONCLUSIONS: Pneumocystis jirovecii colonization is frequent in preterm births and could be a risk factor to develop respiratory distress syndrome among preterm infants.

Bilateral superior oblique palsy: etiology and therapeutic options.

PURPOSE: To study the causes of bilateral superior oblique palsy (BSOP), treatment with botulinum toxin and/or surgery, and outcome of treatment. METHODS: This was an 11-year retrospective study of patients with BSOP treated with injections of botulinum toxin (Botox), surgery, or both. Treatment was considered successful when anomalous head turn and diplopia in primary gaze position and downgaze resolved. RESULTS: Bilateral superior oblique palsy was diagnosed in 12 patients (8 male; mean age, 29.5 years). Palsy was secondary to a neoplasm in 3 cases and to head trauma in 2. In 2 cases, it was ischemic, in 2 it was congenital; the remaining cases were iatrogenic (hydrocephalus secondary to meningitis, 1), hemorrhagic (1), and idiopathic (1). The clinical manifestations recorded were diplopia (10), anomalous head posture (9), V pattern (12), subjective excyclotorsion (8), and objective excyclotorsion (6). Recovery was spontaneous in 1 case with neoplastic disease. Botox was injected in 8 cases (inferior oblique and/or inferior rectus muscles [successful in 2]), and subsequent surgery was required in 6. Two patients underwent surgery without prior injection of Botox. The most common surgical technique was recession of the inferior oblique muscle (6 patients), either as the only operation or associated with other procedures. The final result was good in 72.72% (8/11). Mean follow-up was 62.6 months (range 9-99 months). CONCLUSIONS: Causes of BSOP were varied (most frequently neoplastic). Botox was effective as the only treatment in 25% (2/8). Outcome was good in a high percentage of cases with Botox, surgery, or both.