Clinicopathological characteristics of low-dose methotrexate-induced epidermal dysmaturation: A study of 22 patients.

BACKGROUND AND OBJECTIVE: Erosions of the skin and mucous membranes with epidermal dysmaturation are a known side effect of cytostatic chemotherapy regimens and can also be observed during low-dose methotrexate (MTX) therapy. The study aimed to delineate the clinical and histopathological alterations. PATIENTS AND METHODS: A database search of the archive for dermatopathology was conducted, identifying 22 patients who developed epidermal dysmaturation on low-dose MTX. Clinical and laboratory changes, along with an array of histologic parameters were analyzed and statistically evaluated using SPSS. RESULTS: Patients were predominantly female with a mean age of 69.1 years. The main indications were psoriasis vulgaris and rheumatoid arthritis. Clinically, patients mostly presented erosive plaques at the injection site, on mucosal surfaces, and disseminated lesions. Most patients showed normal laboratory values. Histopathologically, key findings included enlarged keratinocytes with pale cytoplasm and enlarged nuclei with prominent nucleoli, along with the degeneration of the basal layer. Consistent observations in the dermal compartment included infiltration of neutrophilic granulocytes, lymphocytes, and histiocytes. CONCLUSIONS: This study proposes clinicopathological criteria for the diagnosis of MTX-associated skin toxicity, aiming to increase awareness among clinicians and pathologists for early diagnosis. Early recognition can prevent potentially life-threatening progression.

Dysmaturation of sleep state and electroencephalographic activity after hypoxia-ischaemia in preterm fetal sheep.

Antenatal hypoxia-ischaemia (HI) in preterm fetal sheep can trigger delayed evolution of severe, cystic white matter injury (WMI), in a similar timecourse to WMI in preterm infants. We therefore examined how severe hypoxia-ischaemia affects recovery of electroencephalographic (EEG) activity. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 min of complete umbilical cord occlusion (UCO, n = 9) or sham occlusion (controls, n = 9), and recovered for 21 days. HI was associated with a shift to lower frequency EEG activity for the first 5 days with persisting loss of EEG power in the delta and theta bands, and initial loss of power in the alpha and beta bands in the first 14 days of recovery. In the final 3 days of recovery, there was a marked rhythmic shift towards higher frequency EEG activity after UCO. The UCO group spent less time in high-voltage sleep, and in the early evening (7:02 pm ± 47 min) abruptly stopped cycling between sleep states, with a shift to a high frequency state for 2 h 48 min ± 40 min, with tonic electromyographic activity. These findings demonstrate persisting EEG and sleep state dysmaturation after severe hypoxia-ischaemia. Loss of fetal or neonatal sleep state cycling in the early evening may be a useful biomarker for evolving cystic WMI.

Melatonin as a Therapy for Preterm Brain Injury: What Is the Evidence?

Despite significant improvements in survival following preterm birth in recent years, the neurodevelopmental burden of prematurity, with its long-term cognitive and behavioral consequences, remains a significant challenge in neonatology. Neuroprotective treatment options to improve neurodevelopmental outcomes in preterm infants are therefore urgently needed. Alleviating inflammatory and oxidative stress (OS), melatonin might modify important triggers of preterm brain injury, a complex combination of destructive and developmental abnormalities termed encephalopathy of prematurity (EoP). Preliminary data also suggests that melatonin has a direct neurotrophic impact, emphasizing its therapeutic potential with a favorable safety profile in the preterm setting. The current review outlines the most important pathomechanisms underlying preterm brain injury and correlates them with melatonin's neuroprotective potential, while underlining significant pharmacokinetic/pharmacodynamic uncertainties that need to be addressed in future studies.

Clinical factors associated with microstructural connectome related brain dysmaturation in term neonates with congenital heart disease.

Objective: Term congenital heart disease (CHD) neonates display abnormalities of brain structure and maturation, which are possibly related to underlying patient factors, abnormal physiology and perioperative insults. Our primary goal was to delineate associations between clinical factors and postnatal brain microstructure in term CHD neonates using diffusion tensor imaging (DTI) magnetic resonance (MR) acquisition combined with complementary data-driven connectome and seed-based tractography quantitative analyses. Our secondary goal was to delineate associations between mild dysplastic structural brain abnormalities and connectome and seed-base tractography quantitative analyses. These mild dysplastic structural abnormalities have been derived from prior human infant CHD MR studies and neonatal mouse models of CHD that were collectively used to calculate to calculate a brain dysplasia score (BDS) that included assessment of subcortical structures including the olfactory bulb, the cerebellum and the hippocampus. Methods: Neonates undergoing cardiac surgery for CHD were prospectively recruited from two large centers. Both pre- and postoperative MR brain scans were obtained. DTI in 42 directions was segmented into 90 regions using a neonatal brain template and three weighted methods. Clinical data collection included 18 patient-specific and 9 preoperative variables associated with preoperative scan and 6 intraoperative (e.g., cardiopulmonary bypass and deep hypothermic circulatory arrest times) and 12 postoperative variables associated with postoperative scan. We compared patient specific and preoperative clinical factors to network topology and tractography alterations on a preoperative neonatal brain MRI, and intra and postoperative clinical factors to network topology alterations on postoperative neonatal brain MRI. A composite BDS was created to score abnormal findings involving the cerebellar hemispheres and vermis, supratentorial extra-axial fluid, olfactory bulbs and sulci, hippocampus, choroid plexus, corpus callosum, and brainstem. The neuroimaging outcomes of this study included (1) connectome metrics: cost (number of connections) and global/nodal efficiency (network integration); (2) seed based tractography methods of fractional anisotropy (FA), radial diffusivity, and axial diffusivity. Statistics consisted of multiple regression with false discovery rate correction (FDR) comparing the clinical risk factors and BDS (including subcortical components) as predictors/exposures and the global connectome metrics, nodal efficiency, and seed based- tractography (FA, radial diffusivity, and axial diffusivity) as neuroimaging outcome measures. Results: A total of 133 term neonates with complex CHD were prospectively enrolled and 110 had analyzable DTI. Multiple patient-specific factors including d-transposition of the great arteries (d-TGA) physiology and severity of impairment of fetal cerebral substrate delivery (i.e., how much the CHD lesion alters typical fetal circulation such that the highest oxygen and nutrient rich blood from the placenta are not directed toward the fetal brain) were predictive of preoperative reduced cost (p < 0.0073) and reduced global/nodal efficiency (p < 0.03). Cardiopulmonary bypass time predicted postoperative reduced cost (p < 0.04) and multiple postoperative factors [extracorporeal membrane oxygenation (ECMO), seizures and cardiopulmonary resuscitation (CPR)] were predictive of postoperative reduced cost and reduced global/nodal efficiency (p < 0.05). Anthropometric measurements (weight, length, and head size) predicted tractography outcomes. Total BDS was not predictive of brain network topology. However, key subcortical components of the BDS score did predict key global and nodal network topology: abnormalities of the cerebellum predicted reduced cost (p < 0.0417) and of the hippocampus predicted reduced global efficiency (p < 0.0126). All three subcortical structures predicted unique alterations of nodal efficiency (p < 0.05), including hippocampal abnormalities predicting widespread reduced nodal efficiency in all lobes of the brain, cerebellar abnormalities predicting increased prefrontal nodal efficiency, and olfactory bulb abnormalities predicting posterior parietal-occipital nodal efficiency. Conclusion: Patient-specific (d-TGA anatomy, preoperative impairment of fetal cerebral substrate delivery) and postoperative (e.g., seizures, need for ECMO, or CPR) clinical factors were most predictive of diffuse postnatal microstructural dysmaturation in term CHD neonates. Anthropometric measurements (weight, length, and head size) predicted tractography outcomes. In contrast, subcortical components (cerebellum, hippocampus, olfactory) of a structurally based BDS (derived from CHD mouse mutants), predicted more localized and regional postnatal microstructural differences. Collectively, these findings suggest that brain DTI connectome and seed-based tractography are complementary techniques which may facilitate deciphering the mechanistic relative contribution of clinical and genetic risk factors related to poor neurodevelopmental outcomes in CHD.

Human Milk and Preterm Infant Brain Development: A Narrative Review.

PURPOSE: To review and synthesize the literature on human milk and structural brain development and injury in preterm infants, focusing on the application of quantitative brain magnetic resonance imaging (MRI) in this field. METHODS: For this narrative review, we searched PubMed for articles published from 1990 to 2021 that reported observational or interventional studies of maternal milk or donor milk in relation to brain development and/or injury in preterm infants assessed with quantitative MRI at term equivalent age. Studies were characterized with respect to key aspects of study design, milk exposure definition, and MRI outcomes. FINDINGS: We identified 7 relevant studies, all of which were observational in design and published between 2013 and 2021. Included preterm infants were born at or below 33 weeks' gestation. Sample sizes ranged from 22 to 377 infants. Exposure to human milk included both maternal and donor milk. No study included a full-term comparison group. Main MRI outcome domains were white matter integrity (assessed with diffusion tensor imaging, resting state functional connectivity, or semiautomated segmentation of white matter abnormality) and total and regional brain volumes. Studies revealed that greater exposure to human milk versus formula was associated with favorable outcomes, including more mature and connected cerebral white matter with less injury and larger regional brain volumes, notably in the deep nuclear gray matter, amygdala-hippocampus, and cerebellum. No consistent signature effect of human milk exposure was found; instead, the beneficial associations were regional and tissue-specific neuroprotective effects on the areas of known vulnerability in the preterm infant. IMPLICATIONS: Evidence to date suggests that human milk may protect the preterm infant from the white matter injury and dysmaturation to which this population is vulnerable. Brain MRI at term equivalent age is emerging as a useful tool to investigate the effects of human milk on the preterm brain. When grounded in neurobiological knowledge about preterm brain injury and development, this approach holds promise for allowing further insight into the mechanisms and pathways underlying beneficial associations of human milk with neurodevelopmental outcomes in this population and in the investigation of specific milk bioactive components with neuroprotective or neurorestorative potential.

Dysmaturational Longitudinal Epigenetic Aging During Transition to Psychosis.

Psychosis frequently occurs during adolescence and young adulthood, possibly as a result of gene-environment interactions, mediated by epigenetic mechanisms such as DNA methylation. Methylation patterns can be leveraged to predict epigenetic age in order to identify anomalies in aging trajectories that may be associated with the emergence of psychosis. Thus, epigenetic age may provide a measurable surrogate of psychotic risk or psychosis' emergence, and shed light on the neurodevelopmental model of psychosis. In this study, we present the first longitudinal analysis of epigenetic age trajectory during conversion to psychosis in a population at ultra-high-risk, with available genome-wide methylation DNA at two time points, at baseline and after one year of follow-up (N = 38 × 2). After predicting epigenetic age, we computed epigenetic age gap as the cross-sectional difference between real age and predicted age, and (longitudinal) epigenetic age acceleration as the derivative of predicted age with respect to time. At baseline, future converters were 2.7 years younger than nonconverters and this difference disappeared at follow-up, when some converted to psychosis. This is because during conversion to psychosis, the epigenetic age of converters accelerated by 2.8 years/year compared to nonconverters. This acceleration was robust with a strictly positive 95% confidence interval, and held its significance after adjustment for age, sex, and cannabis intake. The methylation sites most associated with aging were on genes also linked with schizophrenia and neurodevelopmental disorders. This accelerated age trajectory, following a previous deceleration, may therefore reflect dysmaturational processes.

Dysmaturation Observed as Altered Hippocampal Functional Connectivity at Rest Is Associated With the Emergence of Positive Psychotic Symptoms in Patients With 22q11 Deletion Syndrome.

BACKGROUND: Hippocampal alterations are among the most replicated neuroimaging findings across the psychosis spectrum. Moreover, there is strong translational evidence that preserving the maturation of hippocampal networks in mice models prevents the progression of cognitive deficits. However, the developmental trajectory of hippocampal functional connectivity (HFC) and its contribution to psychosis is not well characterized in the human population. 22q11 deletion syndrome (22q11DS) offers a unique model for characterizing early neural correlates of schizophrenia. METHODS: We acquired resting-state functional magnetic resonance imaging in 242 longitudinally repeated scans from 84 patients with 22q11DS (30 with moderate to severe positive psychotic symptoms) and 94 healthy control subjects in the age span of 6 to 32 years. We obtained bilateral hippocampus to whole-brain functional connectivity and employed a novel longitudinal multivariate approach by means of partial least squares correlation to evaluate the developmental trajectory of HFC across groups. RESULTS: Relative to control subjects, patients with 22q11DS failed to increase HFC with frontal regions such as the dorsal part of the anterior cingulate cortex, prefrontal cortex, and supplementary motor area. Concurrently, carriers of the deletion had abnormally higher HFC with subcortical dopaminergic areas. Remarkably, this aberrant maturation of HFC was more prominent during midadolescence and was mainly driven by patients exhibiting subthreshold positive psychotic symptoms. CONCLUSIONS: Our findings suggest a critical period of prefrontal cortex-hippocampal-striatal circuit dysmaturation, particularly during late adolescence, which in light of current translation evidence could be a target for short-term interventions to potentially achieve long-lasting rescue of circuit dysfunctions associated with psychosis.

Chapter for antenatal steroids - Treatment drift for a potent therapy with unknown long-term safety seminars in fetal and neonatal medicine.

This chapter on therapeutic drift with antenatal steroids will make the case that this pilar of treatment to improve the outcomes of preterm infants, despite multiple Randomized Control Trials (RCTs) and meta-analysis, has multiple gaps in solid clinical data to support any expanded use of Antenatal Corticosteroids (ACS). A basic problem is that agents used for ACS have never been evaluated to minimize fetal exposures. Based on the premise that all drug exposure to the fetus should be minimized and only used when necessary, ACS is a potent developmental modulator that has never been evaluated to minimize the dose and duration of fetal exposure. The use of ACS is expanding to late preterm infants where the benefit is modest, to elective C-sections, and periviable fetuses, with minimal RCT data of long-term benefit. Relevant animal experiments demonstrate that much lower doses will induce lung maturation in sheep and primates. Another area of drift in the use of ACS is based on the assumption that the old RCT data accurately predict the magnitude of benefit when ACS is used today with entirely different OB and neonatal care strategies to improve outcomes. We do not have data that demonstrate the effectiveness of ACS in very low resource environments, where most of the preterm mortality occurs. The final concern is the risk of ACS to the infant and child. Short-term risks are minimal but dysmaturation effects of ACS on multiple organ systems (lung, heart, brain, and kidney) may result in disease presentation in later life.

Preterm brain Injury: White matter injury.

Despite the advances in neonatal intensive care, the preterm brain remains vulnerable to white matter injury (WMI) and disruption of normal brain development (i.e., dysmaturation). Compared to severe cystic WMI encountered in the past decades, contemporary cohorts of preterm neonates experience milder WMIs. More than destructive lesions, disruption of the normal developmental trajectory of cellular elements of the white and the gray matter occurs. In the acute phase, in response to hypoxia-ischemia and/or infection and inflammation, multifocal areas of necrosis within the periventricular white matter involve all cellular elements. Later, chronic WMI is characterized by diffuse WMI with aberrant regeneration of oligodendrocytes, which fail to mature to myelinating oligodendrocytes, leading to myelination disturbances. Complete neuronal degeneration classically accompanies necrotic white matter lesions, while altered neurogenesis, represented by a reduction of the dendritic arbor and synapse formation, is observed in response to diffuse WMI. Neuroimaging studies now provide more insight in assessing both injury and dysmaturation of both gray and white matter. Preterm brain injury remains an important cause of neurodevelopmental disabilities, which are still observed in up to 50% of the preterm survivors and take the form of a complex combination of motor, cognitive, and behavioral concerns.

Neuroprotection of the preterm brain.

Despite notable advances in the care and survival of preterm infants, a significant proportion of preterm neonates will have life-long cognitive, behavioral, and motor deficits, and robustly effective neuroprotective strategies are still missing. These therapies must target the pathophysiologic mechanisms observed in contemporaneous infants and rely on modern epidemiology, imaging, and experimental models and assessment techniques. Two drugs, magnesium sulfate and caffeine, are already in use in several units, and although their targets are apnea of prematurity and myometrial contractility (respectively), they do offer improved odds of positive outcomes. Nevertheless, these drugs have limited efficacy, and NICU-to-NICU administration varies greatly. As such, there is an obvious need for additional specific neurotherapeutic strategies to further enhance the outcome of this very fragile population of neonates. The chapter reviews these issues, highlights bottlenecks that need to be solved for meaningful progress in the field, and proposes future innovative avenues for intervention, including delayed interventions.

Hypergranulotic dyscornification: 30 cases of a striking epithelial reaction pattern.

BACKGROUND: Hypergranulotic dyscornification (HD) is a rarely reported histological reaction pattern that may be observed in solitary benign keratoses. OBJECTIVE AND METHODS: We retrospectively reviewed all cases described as displaying "hypergranulotic dyscornification" at our institution between January 1st 1990 to September 1st 2018. We excluded cases that on retrospective review displayed changes of epidermolytic hyperkeratosis. We conducted electron microscopy (EM) of two lesions. RESULTS: Thirty cases were identified in our search. Eleven patients were men and 19 were women. Their mean age was 56.9 ± 21.2 years. In contrast to previous reports, we found that HD does not spare the head and neck area. Frequent clinical impressions were inflamed seborrheic keratosis, Bowen disease or inflamed verruca. The most distinctive histopathologic finding was the presence of a prominent granular layer with clumped perinuclear keratohyaline granules. Some cases had mounds of rounded, anucleate glassy eosinophilic corneocytes in the stratum corneum. We observed one case of incidental HD occurring in an epidermoid cyst. EM of HD showed dense perinuclear bands which appeared to match areas of positive staining by keratin immunohistochemistry, without evidence of pale cytoplasmic areas devoid of keratin filaments, characteristic of epidermolytic hyperkeratosis. CONCLUSION: HD is a reproducible finding in some benign keratoses, probably because of abnormal keratinization. Awareness of this unique reaction pattern will help prevent misdiagnosis.

Dysmaturation of Premature Brain: Importance, Cellular Mechanisms, and Potential Interventions.

Prematurity, especially preterm birth (less than 32 weeks' gestation), is common and associated with high rates of both survival and neurodevelopmental disability, especially apparent in cognitive spheres. The neuropathological substrate of this disability is now recognized to be related to a variety of dysmaturational disturbances of the brain. These disturbances follow initial brain injury, particularly cerebral white matter injury, and involve many of the extraordinary array of developmental events active in cerebral white and gray matter structures during the premature period. This review delineates these developmental events and the dysmaturational disturbances that occur in premature infants. The cellular mechanisms involved in the genesis of the dysmaturation are emphasized, with particular focus on the preoligodendrocyte. A central role for the diffusely distributed activated microglia and reactive astrocytes in the dysmaturation is now apparent. As these dysmaturational cellular mechanisms appear to occur over a relatively long time window, interventions to prevent or ameliorate the dysmaturation, that is, neurorestorative interventions, seem possible. Such interventions include pharmacologic agents, especially erythropoietin, and particular attention has also been paid to such nutritional factors as quality and source of milk, breastfeeding, polyunsaturated fatty acids, iron, and zinc. Recent studies also suggest a potent role for interventions directed at various experiential factors in the neonatal period and infancy, i.e., provision of optimal auditory and visual exposures, minimization of pain and stress, and a variety of other means of environmental behavioral enrichment, in enhancing brain development.

Jugular Bulb Dysmaturation in Torcular Dural Sinus Malformation: Clinical Images and Review of Literature.

We present unique clinical images of jugular bulb dysmaturation (JBD) in an infant with torcular dural sinus malformation (tDSM). Lasjaunias et al hypothesized that the former possess a pivoting role for development of the latter. However, reports about tDSM are extremely rare and lack focus on JBD presence. In this paper we focused on JBD depiction. The combination of magnetic resonance imaging angiography, computed tomography angiography, and digital subtraction angiography imaging of JBD is unique. Moreover, we reviewed current tDSM literature and showed that the presence of JBD in tDSMs correlates significantly with a higher mortality.

White matter injury in the preterm infant: pathology and mechanisms.

The human preterm brain is particularly susceptible to cerebral white matter injury (WMI) that disrupts the normal progression of developmental myelination. Advances in the care of preterm infants have resulted in a sustained reduction in the severity of WMI that has shifted from more severe focal necrotic lesions to milder diffuse WMI. Nevertheless, WMI remains a global health problem and the most common cause of chronic neurological morbidity from cerebral palsy and diverse neurobehavioral disabilities. Diffuse WMI involves maturation-dependent vulnerability of the oligodendrocyte (OL) lineage with selective degeneration of late oligodendrocyte progenitors (preOLs) triggered by oxidative stress and other insults. The magnitude and distribution of diffuse WMI are related to both the timing of appearance and regional distribution of susceptible preOLs. Diffuse WMI disrupts the normal progression of OL lineage maturation and myelination through aberrant mechanisms of regeneration and repair. PreOL degeneration is accompanied by early robust proliferation of OL progenitors that regenerate and augment the preOL pool available to generate myelinating OLs. However, newly generated preOLs fail to differentiate and initiate myelination along their normal developmental trajectory despite the presence of numerous intact-appearing axons. Disrupted preOL maturation is accompanied by diffuse gliosis and disturbances in the composition of the extracellular matrix and is mediated in part by inhibitory factors derived from reactive astrocytes. Signaling pathways implicated in disrupted myelination include those mediated by Notch, WNT-beta catenin, and hyaluronan. Hence, there exists a potentially broad but still poorly defined developmental window for interventions to promote white matter repair and myelination and potentially reverses the widespread disturbances in cerebral gray matter growth that accompanies WMI.

Clinical Factors Associated with Cerebral Metabolism in Term Neonates with Congenital Heart Disease.

OBJECTIVE: To determine associations between patient and clinical factors with postnatal brain metabolism in term neonates with congenital heart disease (CHD) via the use of quantitative magnetic resonance spectroscopy. STUDY DESIGN: Neonates with CHD were enrolled prospectively to undergo pre- and postoperative 3T brain magnetic resonance imaging. Short-echo single-voxel magnetic resonance spectroscopy of parietal white matter was used to quantify metabolites related to brain maturation (n-acetyl aspartate, choline, myo- inositol), neurotransmitters (glutamate and gamma-aminobutyric acid), energy metabolism (glutamine, citrate, glucose, and phosphocreatine), and injury/apoptosis (lactate and lipids). Multivariable regression was performed to search for associations between (1) patient-specific/prenatal/preoperative factors with concurrent brain metabolism and (2) intraoperative and postoperative factors with postoperative brain metabolism. RESULTS: A total of 83 magnetic resonance images were obtained on 55 subjects. No patient-specific, prenatal, or preoperative factors associated with concurrent metabolic brain dysmaturation or elevated lactate could be identified. Chromosome 22q11 microdeletion and age at surgery were predictive of altered concurrent white matter phosphocreatine (P < .0055). The only significant intraoperative association found was increased deep hypothermic circulatory arrest time with reduced postoperative white matter glutamate and gamma-aminobutyric acid (P < .0072). Multiple postoperative factors, including increased number of extracorporeal membrane oxygenation days (P < .0067), intensive care unit, length of stay (P < .0047), seizures in the intensive care unit (P < .0009), and home antiepileptic use (P < .0002), were associated with reduced postoperative white matter n-acetyl aspartate. CONCLUSION: Multiple postoperative factors were found to be associated with altered brain metabolism in term infants with CHD, but not patient-specific, preoperative, or intraoperative factors.