9 research outputs found
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
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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 30â40% 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 T2â6 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 (âpainâ) 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 midâthoracic 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 midâthoracic 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]
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 2.33â12.24, p \u3c 0.001). ICH was associated with increased mortality (adjusted OR 2.6, 95 % CI 1.2â5.9). 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
Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function
We have identified a lethal phenotype characterized by sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males [Online Mendelian Inheritance in Man (OMIM) accession no. 608800]. Twenty-one affected individuals with this autosomal recessive syndrome were ascertained in nine separate sibships among the Old Order Amish. High-density single-nucleotide polymorphism (SNP) genotyping arrays containing 11,555 single-nucleotide polymorphisms evenly distributed across the human genome were used to map the disease locus. A genome-wide autozygosity scan localized the disease gene to a 3.6-Mb interval on chromosome 6q22.1-q22.31. This interval contained 27 genes, including two testis-specific Y-like genes (TSPYL and TSPYL4) of unknown function. Sequence analysis of the TSPYL gene in affected individuals identified a homozygous frameshift mutation (457_458insG) at codon 153, resulting in truncation of translation at codon 169. Truncation leads to loss of a peptide domain with strong homology to the nucleosome assembly protein family. GFP-fusion expression constructs were constructed and illustrated loss of nuclear localization of truncated TSPYL, suggesting loss of a nuclear localization patch in addition to loss of the nucleosome assembly domain. These results shed light on the pathogenesis of a disorder of sexual differentiation and brainstem-mediated sudden death, as well as give insight into a mechanism of transcriptional regulation