Growth And The Growth Hormone-Insulin Like Growth Factor 1 Axis In Children With Chronic Inflammation:Current Evidence, Gaps In Knowledge And Future Directions

Growth failure is frequently encountered in children with chronic inflammatory conditions like juvenile idiopathic arthritis, inflammatory bowel disease and cystic fibrosis. Delayed puberty and attenuated pubertal growth spurt is often seen during adolescence. The underlying inflammatory state mediated by pro-inflammatory cytokines, prolonged use of glucocorticoid and suboptimal nutrition contribute to growth failure and pubertal abnormalities. These factors can impair growth by their effects on the growth hormone-insulin like growth factor axis and also directly at the level of the growth plate via alterations in chondrogenesis and local growth factor signaling. Recent studies on the impact of cytokines and glucocorticoid on the growth plate studies further advanced our understanding of growth failure in chronic disease and provided a biological rationale of growth promotion. Targeting cytokines using biologic therapy may lead to improvement of growth in some of these children but approximately one third continue to grow slowly. There is increasing evidence that the use of relatively high dose recombinant human growth hormone may lead to partial catch up growth in chronic inflammatory conditions, although long term follow-up data is currently limited. In this review, we comprehensively review the growth abnormalities in children with juvenile idiopathic arthritis, inflammatory bowel disease and cystic fibrosis, systemic abnormalities of the growth hormone-insulin like growth factor axis and growth plate perturbations. We also systematically reviewed all the current published studies of recombinant human growth hormone in these conditions and discuss the role of recombinant human insulin like growth factor-1

Central neuropathic pain in MS results from distinct upper thoracic spinal cord lesions

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.There is central pain complaint of burning cold pain common to patients with multiple sclerosis. Approximately 30‐40% of patients with multiple sclerosis (MS) suffer from central neuropathic pain, usually focused symmetrically in both feet and legs and often accompanied by cold allodynia and deep hyperesthesia [Osterberg et al 2005]. This condition resembles thalamic central pain, which also presents with dysfunctional pain and temperature sensations; however, thalamic pain is strictly contralateral [Craig 2007]. A distinct explanation for bilateral MS central pain likely involves a spinal lesion, yet a correlation has not been found [Svendson et al 2011]. We hypothesized that ascending projections from lumbosacral lamina I neurons to bilateral midthoracic autonomic nuclei are mirrored by descending projections [Craig 2002]; thus, a midthoracic lesion that damaged bilateral autonomic descending projections to lumbosacral lamina I neurons might underlie bilateral central pain in MS. Sympathetic interneurons in the midthoracic IMM/IML project to the brainstem but not the thalamus, implying they could be involved in homeostatic sensory integration at both brainstem and spinal levels. The lower extremity pain could be due to a lesion in the upper thoracic cord, interrupting the homeostatic integration pathway between the parabrachial nucleus in the brainstem, the (intermediomedial) and intermediolateral (IMM/IML) region of T2‐6 segments of the spinal cord, and lumbar lamina 1. To prove the existence of bilateral propriospinal projections between upper thoracic sympathetic interneurons and lumbosacral sensory (“pain”) neurons, anterograde and retrograde labeling with CTb and fluorescent tracers were performed in three animal species. In parallel, MRI analysis of MS patients with bilateral burning cold pain in the lower extremities tested the theory by examining for spinal lesions in the upper thoracic level. We tested this hypothesis with parallel clinical and neuroanatomical studies and identified a striking correspondence; MS patients with central neuropathic pain are distinguished by the presence of a lesion focused in the center of the mid‐thoracic spinal cord, and in three mammalian species neurons with bilateral descending projections to the lumbosacral superficial dorsal horn are concentrated in the autonomic intermediomedial nucleus surrounding the mid‐thoracic central canal. These findings will allow us to devise future treatments based on the newly understood neuroanatomical mechanisms.This item is part of the College of Medicine - Phoenix Scholarly Projects 2013 collection. For more information, contact the Phoenix Biomedical Campus Library at [email protected]

Central neuropathic pain in MS is due to distinct thoracic spinal cord lesions.

OBJECTIVE: To determine a neuro-anatomic cause for central neuropathic pain (CNP) observed in multiple sclerosis (MS) patients. METHODS: Parallel clinical and neuro-anatomical studies were performed. A clinical investigation of consecutively acquired MS patients with and without CNP (i.e. cold allodynia or deep hyperesthesia) within a single MS center was pursued. A multivariate logistic regression model was used to assess the relationship between an upper central thoracic spinal cord focus to central pain complaints. To identify the hypothesized autonomic interneurons with bilateral descending projections to lumbosacral sensory neurons, retrograde single- and double-labeling experiments with CTb and fluorescent tracers were performed in three animal species (i.e. rat, cat, and monkey). RESULTS: Clinical data were available in MS patients with (n = 32; F:23; median age: 34.6 years (interquartile range [IQR]: 27.4-45.5)) and without (n = 30; F:22; median age: 36.6 years [IQR: 31.6-47.1]) CNP. The value of a central focus between T1-T6 in relation to CNP demonstrated a sensitivity of 96.9% (95% confidence interval [CI]: 83.8-99.9) and specificity of 83.3% (95% CI: 65.3-94.4). A significant relationship between CNP and a centrally located focus within the thoracic spine was also observed (odds ratio [OR]: 155.0 [95% CI lower limit: 16.0]; P < 0.0001, two-tailed Fisher exact test). In all animal models, neurons with bilateral descending projections to the lumbosacral superficial dorsal horn were concentrated in the autonomic intermediomedial nucleus surrounding the mid-thoracic central canal. INTERPRETATION: Our observations provide the first evidence for the etiology of CNP. These data may assist with the development of refined symptomatic therapies and allow for insights into unique pain syndromes observed in other demyelinating subtypes

Epilepsy and COVID 2021

Coronavirus 19 (COVID-19) has infected over 400 million people worldwide. Although COVID-19 causes predominantly respiratory symptoms, it can affect other organs including the brain, producing neurological symptoms. People with epilepsy (PWE) have been particularly impacted during the pandemic with decreased access to care, increased stress, and worsening seizures in up to 22% of them probably due to multiple factors. COVID-19 vaccines were produced in a record short time and have yielded outstanding protection with very rare serious side effects. Studies have found that COVID-19 vaccination does not increase seizures in the majority of PWE. COVID-19 does not produce a pathognomonic EEG or seizure phenotype, but rather 1 that can be seen in other types of encephalopathy. COVID-19 infection and its complications can lead to seizures, status epilepticus and post-COVID inflammatory syndrome with potential multi-organ damage in people without pre-existing epilepsy. The lack of access to care during the pandemic has forced patients and doctors to rapidly implement telemedicine. The use of phone videos and smart telemedicine are helping to treat patients during this pandemic and are becoming standard of care. Investment in infrastructure is important to make sure patients can have access to care even during a pandemic

Hemorrhagic stroke and anticoagulation in COVID-19

© 2020 Elsevier Inc. Background and Purpose: Patients with the Coronavirus Disease of 2019 (COVID-19) are at increased risk for thrombotic events and mortality. Various anticoagulation regimens are now being considered for these patients. Anticoagulation is known to increase the risk for adverse bleeding events, of which intracranial hemorrhage (ICH) is one of the most feared. We present a retrospective study of 33 patients positive for COVID-19 with neuroimaging-documented ICH and examine anticoagulation use in this population. Methods: Patients over the age of 18 with confirmed COVID-19 and radiographic evidence of ICH were included in this study. Evidence of hemorrhage was confirmed and categorized by a fellowship trained neuroradiologist. Electronic health records were analyzed for patient information including demographic data, medical history, hospital course, laboratory values, and medications. Results: We identified 33 COVID-19 positive patients with ICH, mean age 61.6 years (range 37–83 years), 21.2% of whom were female. Parenchymal hemorrhages with mass effect and herniation occurred in 5 (15.2%) patients, with a 100% mortality rate. Of the remaining 28 patients with ICH, 7 (25%) had punctate hemorrhages, 17 (60.7%) had small- moderate size hemorrhages, and 4 (14.3%) had a large single site of hemorrhage without evidence of herniation. Almost all patients received either therapeutic dose anticoagulation (in 22 [66.7%] patients) or prophylactic dose (in 3 [9.1] patients) prior to ICH discovery. Conclusions: Anticoagulation therapy may be considered in patients with COVID-19 though the risk of ICH should be taken into account when developing a treatment regimen

Prevalence and Predictors of Prolonged Cognitive and Psychological Symptoms Following COVID-19 in the United States

BACKGROUND/OBJECTIVES: Little is known regarding the prevalence and predictors of prolonged cognitive and psychological symptoms of COVID-19 among community-dwellers. We aimed to quantitatively measure self-reported metrics of fatigue, cognitive dysfunction, anxiety, depression, and sleep and identify factors associated with these metrics among United States residents with or without COVID-19. METHODS: We solicited 1000 adult United States residents for an online survey conducted February 3–5, 2021 utilizing a commercial crowdsourcing community research platform. The platform curates eligible participants to approximate United States demographics by age, sex, and race proportions. COVID-19 was diagnosed by laboratory testing and/or by exposure to a known positive contact with subsequent typical symptoms. Prolonged COVID-19 was self-reported and coded for those with symptoms ≥ 1 month following initial diagnosis. The primary outcomes were NIH PROMIS/Neuro-QoL short-form T-scores for fatigue, cognitive dysfunction, anxiety, depression, and sleep compared among those with prolonged COVID-19 symptoms, COVID-19 without prolonged symptoms and COVID-19 negative subjects. Multivariable backwards step-wise logistic regression models were constructed to predict abnormal Neuro-QoL metrics. RESULTS: Among 999 respondents, the average age was 45 years (range 18–84), 49% were male, 76 (7.6%) had a history of COVID-19 and 19/76 (25%) COVID-19 positive participants reported prolonged symptoms lasting a median of 4 months (range 1–13). Prolonged COVID-19 participants were more often younger, female, Hispanic, and had a history of depression/mood/thought disorder (all P < 0.05). They experienced significantly higher rates of unemployment and financial insecurity, and their symptoms created greater interference with work and household activities compared to other COVID-19 status groups (all P < 0.05). After adjusting for demographics, past medical history and stressor covariates in multivariable logistic regression analysis, COVID-19 status was independently predictive of worse Neuro-QoL cognitive dysfunction scores (adjusted OR 11.52, 95% CI 1.01–2.28, P = 0.047), but there were no significant differences in quantitative measures of anxiety, depression, fatigue, or sleep. CONCLUSION: Prolonged symptoms occurred in 25% of COVID-19 positive participants, and NeuroQoL cognitive dysfunction scores were significantly worse among COVID-19 positive subjects, even after accounting for demographic and stressor covariates. Fatigue, anxiety, depression, and sleep scores did not differ between COVID-19 positive and negative respondents

Assessing Cerebrovascular Hemodynamics Using Transcranial Doppler in Patients with Mechanical Circulatory Support Devices

BACKGROUND AND PURPOSE Mechanical circulatory support (MCS) devices are commonly used in heart failure patients. These devices carry risk for presumably embolic and additionally hemorrhagic stroke. Alterations in blood flow play a key role in stroke pathophysiology, and we aimed to learn more about hemodynamic compromise. In this study, we used transcranial Doppler (TCD) ultrasound to define hemodynamics of commonly used nonpulsatile MCS devices, as well as pulsatile devices, with special attention to the total artificial heart (TAH). METHODS From 2/2013 through 12/2016, we prospectively enrolled patients with MCS who underwent TCD imaging. We analyzed TCD parameters, including peak systolic velocity, end-diastolic velocity, pulsatility indices (PIs), and number of high-intensity transient signals. Waveform morphologies were compared between various MCS devices. RESULTS We performed 132 TCD studies in 86 MCS patients. Waveforms in patients supported by venoarterial-extracorporeal membrane oxygenation demonstrated continuous flow without clear systolic peaks with an average (+/- SD) PI of .43 (+/-.2). PIs were low in patients with continuous-flow left ventricular assist devices with a mean PI of .32 (+/-.13). Impella patients had morphologically distinct pulsatile waveforms and a higher mean PI of .65 (+/-.24). In intra-arterial balloon pump patients, mean PI was 1.01 (+/-.16) and diastolic upstrokes were pronounced. In TAH patients, mean middle cerebral artery velocity of 79.69 (+/- 32.33) cm/seconds and PI of .74 (+/-.14) approached normal values. CONCLUSION TCD can detect characteristic waveforms in patients supported by various MCS devices. These device-specific TCD patterns are recognizable and reproducible.12 month embargo; published online: 10 February 2020This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Risk factors for intracerebral hemorrhage in patients with COVID-19

© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Intracerebral hemorrhage (ICH) can be a devastating complication of coronavirus disease (COVID-19). We aimed to assess risk factors associated with ICH in this population. We performed a retrospective cohort study of adult patients admitted to NYU Langone Health system between March 1 and April 27 2020 with a positive nasopharyngeal swab polymerase chain reaction test result and presence of primary nontraumatic intracranial hemorrhage or hemorrhagic conversion of ischemic stroke on neuroimaging. Patients with intracranial procedures, malignancy, or vascular malformation were excluded. We used regression models to estimate odds ratios and 95% confidence intervals (OR, 95% CI) of the association between ICH and covariates. We also used regression models to determine association between ICH and mortality. Among 3824 patients admitted with COVID-19, 755 patients had neuroimaging and 416 patients were identified after exclusion criteria were applied. The mean (standard deviation) age was 69.3 (16.2), 35.8% were women, and 34.9% were on therapeutic anticoagulation. ICH occurred in 33 (7.9%) patients. Older age, non-Caucasian race, respiratory failure requiring mechanical ventilation, and therapeutic anticoagulation were associated with ICH on univariate analysis (p \u3c 0.01 for each variable). In adjusted regression models, anticoagulation use was associated with a five-fold increased risk of ICH (OR 5.26, 95% CI 2.33–12.24, p \u3c 0.001). ICH was associated with increased mortality (adjusted OR 2.6, 95 % CI 1.2–5.9). Anticoagulation use is associated with increased risk of ICH in patients with COVID-19. Further investigation is required to elucidate underlying mechanisms and prevention strategies in this population