Objective Currently, our ability to treat intervertebral disc (IVD) degeneration is hampered by an incomplete understanding of disc development and aging. The specific function of matricellular proteins, including CCN2, during these processes remains an enigma. The aim of this study was to determine the tissue‐specific localization of CCN proteins and to characterize their role in IVD tissues during embryonic development and age‐related degeneration by using a mouse model of notochord‐specific CCN2 deletion. Methods Expression of CCN proteins was assessed in IVD tissues from wild‐type mice beginning on embryonic day 15.5 to 17 months of age. Given the enrichment of CCN2 in notochord‐derived tissues, we generated notochord‐specific CCN2–null mice to assess the impact on the IVD structure and extracellular matrix composition. Using a combination of histologic evaluation and magnetic resonance imaging (MRI), IVD health was assessed. Results Loss of the CCN2 gene in notochord‐derived cells disrupted the formation of IVDs in embryonic and newborn mice, resulting in decreased levels of aggrecan and type II collagen and concomitantly increased levels of type I collagen within the nucleus pulposus. CCN2‐knockout mice also had altered expression of CCN1 (Cyr61) and CCN3 (Nov). Mirroring its role during early development, notochord‐specific CCN2 deletion accelerated age‐associated degeneration of IVDs. Conclusion Using a notochord‐specific gene targeting strategy, this study demonstrates that CCN2 expression by nucleus pulposus cells is essential to the regulation of IVD development and age‐associated tissue maintenance. The ability of CCN2 to regulate the composition of the intervertebral disc suggests that it may represent an intriguing clinical target for the treatment of disc degeneration.
Tracheotomy and percutaneous endoscopic gastrostomy (PEG) are sometimes performed in critically ill hemorrhagic stroke patients in order to avoid complications associated with prolonged intubation and nasogastric feeding. However, there is a paucity of information regarding the optimal timing of these procedures. In this study, we aimed to evaluate the role of early tracheotomy and PEG in hemorrhagic stroke patients.
Methods
A series of patients treated at University of Kentucky for hemorrhagic stroke between June 1, 2011 and June 1, 2015 was retrospectively reviewed. Data regarding diagnosis, demographics, comorbidities, treatment, hospital course, and performance of tracheotomy and/or PEG were collected and then analyzed using logistic regression and multiple linear regression.
Results
Of 366 hemorrhagic stroke patients, 75 underwent tracheotomy and 86 received PEG. Factors significantly associated with tracheotomy and PEG included patient age (p < 0.01), pneumonia present on admission (p < 0.005), and subtype of hemorrhagic stroke (p < 0.05). Tracheotomy and PEG were not significantly associated with patient survival or development of complications. Earlier PEG placement was correlated significantly with shorter overall hospital stay in survivors (p < 0.001), but neither tracheotomy nor PEG was correlated with ICU length of stay.
Conclusions
Hemorrhagic stroke is a devastating neurovascular event that requires prompt intervention and vigilant management. Our study identified patient risk factors that may suggest candidacy for tracheotomy and PEG. Additionally, we found that timing of PEG may shape a patient's hospital course. Complication rates related to tracheostomy and PEG in this population were minimal. In conclusion, this retrospective data set supports some benefit to early PEG placement in this population, and justifies the need for further prospective study.
BACKGROUND The non-invasive imaging examinations of mammography (MG), low-dose CT for lung cancer screening (LCS) and CT colonography (CTC) play important roles in screening for the most common cancer types. Internet search data can be used to gauge public interest in screening techniques, assess common screening-related questions and concerns, and formulate public awareness strategies. OBJECTIVE To compare historical Google search volumes for MG, LCS, and CTC and to determine the most common search topics. METHODS Google Trends data were used to quantify relative Google search frequencies for these imaging screening modalities over the last two decades. A commercial search engine tracking product (keywordtool.io) was used to assess the content of related Google queries over the year from May 1, 2022 to April 30, 2023, and two authors used an iterative process to agree upon a list of thematic categories for these queries. Queries with at least 10 monthly instances were independently assigned to the most appropriate category by the two authors, with disagreements resolved by consensus. RESULTS The mean 20-year relative search volume for MG was approximately 10-fold higher than for LCS and 25-fold higher than for CTC. Search volumes for LCS have trended upward since the publication of the National Lung Screening Trial in 2011. The most common topics of MG-related searches included nearby screening locations (24%) and inquiries about procedural discomfort (11%). Most common LCS-related searches included CT-specific inquiries (48%) or general inquiries (16%), use of AI or deep learning (11%), and eligibility criteria (9%). For CTC, the most common searches were CT-specific inquiries (32%) or for procedural details (25%). CONCLUSIONS Over the past two decades, Google search volumes have been significantly higher for MG than for either LCS or CTC, although search volumes for LCS have trended upward since the publication of the National Lung Screening Trial in 2011. Knowledge of public interest and queries related to imaging-based screening techniques may help guide public awareness efforts.
Glycogen synthase kinase–3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by 2 genes, GSK3A and GSK3B. GSK-3 is thought to be involved in tissue repair and fibrogenesis, but its role in these processes is currently unknown. To investigate the function of GSK-3β in fibroblasts, we generated mice harboring a fibroblast-specific deletion of Gsk3b and evaluated their wound-healing and fibrogenic responses. We have shown that Gsk3b-conditional-KO mice (Gsk3b-CKO mice) exhibited accelerated wound closure, increased fibrogenesis, and excessive scarring compared with control mice. In addition, Gsk3b-CKO mice showed elevated collagen production, decreased cell apoptosis, elevated levels of profibrotic α-SMA, and increased myofibroblast formation during wound healing. In cultured Gsk3b-CKO fibroblasts, adhesion, spreading, migration, and contraction were enhanced. Both Gsk3b-CKO mice and fibroblasts showed elevated expression and production of endothelin-1 (ET-1) compared with control mice and cells. Antagonizing ET-1 reversed the phenotype of Gsk3b-CKO fibroblasts and mice. Thus, GSK-3β appears to control the progression of wound healing and fibrosis by modulating ET-1 levels. These results suggest that targeting the GSK-3β pathway or ET-1 may be of benefit in controlling tissue repair and fibrogenic responses in vivo.
Burn patients show a high variability and poor predictability in their length-of-stay (LOS) due to the complexity of burn injury itself and various complications. To focus care expectation and prognosis we aimed to identify key factors that contribute to prolonged LOS. A retrospective cohort-study was conducted in an adult burn-center between January 2006 and December 2016. We excluded patients that died during hospitalization and patients with <10% TBSA burn. Patients were then stratified into expected-LOS (<2days LOS/%TBSA) and longer-than-expected-LOS (>2days LOS/%TBSA). We assessed demographics, burn etiology, comorbidities, and in-hospital complications. Logistic regression and propensity matching (adjustment/matching for age, gender, inhalation injury, and TBSA% of 3rd degree burns) was utilized. There were 583 patients that met inclusion criteria; and of those, 477 showed an expected-LOS whereas 106 exceeded that time frame. Patients who exceeded their LOS were significantly older, had greater 3rd degree TBSA% burn, and a larger proportion of inhalation injuries (p<0.05). Additionally, there was a significantly greater proportion of these patients that had in-hospital complications of infection, sepsis, and organ failure (p<0.05). Interesting, exceeding LOS patients also had a higher number of pre-existing psychiatric conditions such as depression or schizophrenia. In-hospital complications have a high influence on exceeding the average LOS in burn patients. Burn patients also have a unique and complex set of pre-existing medical conditions such as mental health issues that further complicate their treatment and interferes with an early recovery and discharge. More studies are need to investigate how to modify these critical factors. Progress has been made to update the 1day/%TBSA convention to better aid health care providers in giving appropriate outcomes for patients and their families and to supply intensive care units with valuable data to assess the quality of their care and improve patient prognosis.
Abstract Visual discrimination improves with training, a phenomenon that is thought to reflect plastic changes in the responses of neurons in primary visual cortex (V1). However, the identity of the neurons that undergo change, the nature of the changes, and the consequences of these changes for other visual behaviors remain unclear. Using chronic in vivo 2-photon calcium imaging to monitor the responses of neurons in V1 of tree shrews learning a Go/No-Go fine orientation discrimination task, we find increases in neural population measures of discriminability for task-relevant stimuli that correlate with performance and depend on a select subset of neurons with preferred orientations that include the rewarded stimulus and nearby orientations biased away from the non-rewarded stimulus. Learning is accompanied by selective enhancement in the response of these neurons to the rewarded stimulus that further increases their ability to discriminate the task stimuli. These changes persist outside of the trained task and predict observed enhancement and impairment in performance of other discriminations, providing evidence for selective persistent learning-induced plasticity in V1 with significant consequences for perception.
Purpose/Aim: The intervertebral disc (IVD) is composed of cell types whose subtle phenotypic differences allow for the formation of distinct tissues. The role of the nucleus pulposus (NP) in the initiation and progression of IVD degeneration is well established; however, the genes and pathways associated with NP degeneration are poorly characterized. Materials and Methods: Using a genetic strategy for IVD lineage-specific fluorescent reporter expression to isolate cells, gene expression and bioinformatic analysis was conducted on the murine NP at 2.5, 6, and 21 months-of-age and the annulus fibrosus (AF) at 2.5 and 6 months-of-age. A subset of differentially regulated genes was validated by qRT-PCR. Results: Transcriptome analysis identified distinct profiles of NP and AF gene expression that were remarkably consistent at 2.5 and 6 months-of-age. Prg4, Cilp, Ibsp and Comp were increased >50-fold in the AF relative to NP. The most highly enriched NP genes included Dsc3 and Cdh6, members of the cadherin superfamily, and microRNAs mir218-1 and mir490. Changes in the NP between 2.5 and 6 months-of-age were associated with up-regulation of molecular functions linked to laminin and Bmp receptor binding (including up-regulation of Bmp5 & 7), with the most up-regulated genes being Mir703, Shh, and Sfrp5. NP degeneration was associated with molecular functions linked to alpha-actinin binding (including up-regulation of Ttn & Myot) and cytoskeletal protein binding, with the overall most up-regulated genes being Rnu3a, Snora2b and Mir669h. Conclusions: This study provided insight into the phenotypes of NP and AF cells, and identified candidate pathways that may regulate degeneration.
Existing literature supports benefits of early tracheostomy and percutaneous endoscopic gastrostomy (PEG) in certain patient populations. The aim of this study was to review tracheostomy and PEG placement data in patients with hemorrhagic stroke in order to identify factors associated with earlier placement and to evaluate outcomes.
