Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis

Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited in scalability of injury severity. We describe a scalable blunt-force TBI model that exhibits a wide range of human clinical pathologies and allows for the study of both injury pathology/progression and mechanisms of regenerative recovery. We modified the Marmarou weight drop model for adult zebrafish, which delivers a scalable injury spanning mild, moderate, and severe phenotypes. Following injury, zebrafish display a wide range of severity-dependent, injury-induced pathologies, including seizures, blood–brain barrier disruption, neuroinflammation, edema, vascular injury, decreased recovery rate, neuronal cell death, sensorimotor difficulties, and cognitive deficits. Injury-induced pathologies rapidly dissipate 4–7 days post-injury as robust cell proliferation is observed across the neuroaxis. In the cerebellum, proliferating nestin:GFP-positive cells originated from the cerebellar crest by 60 h post-injury, which then infiltrated into the granule cell layer and differentiated into neurons. Shh pathway genes increased in expression shortly following injury. Injection of the Shh agonist purmorphamine in undamaged fish induced a significant proliferative response, while the proliferative response was inhibited in injured fish treated with cyclopamine, a Shh antagonist. Collectively, these data demonstrate that a scalable blunt-force TBI to adult zebrafish results in many pathologies similar to human TBI, followed by recovery, and neuronal regeneration in a Shh-dependent manner

Follow-up of health-related quality of life and pain in a cohort of patients with rheumatoid arthritis before and after COVID-19

The foot is one of the anatomical structures of the body most affected in rheumatoid arthritis (RA), associated with the disability of patients, even more during COVID-19. The aim of this study was to analyse whether the period of physical inactivity during COVID-19 is an influential factor on health-related quality of life and foot pain in patients with RA. Methods: 162 patients with foot pain and RA, recruited from the Hospital Virgen de las Nieves, Granada (Spain) were included. Data was collected during two different periods: January - December 2018 in person and June - September 2021 by phone. Patients were asked to complete the Spanish adapted version of the 12-Item Short Form Survey (SF-12) and the Visual Analogue Scale (VAS). Results: The results from the SF-12 questionnaires were divided between its two subscales (i.e., mental, and physical component). The physical component shows an improvement between 2018 and 2021, from 32.05in 2018–35.18 in 2021 (p < 0.05). The opposite happened with the mental component, showing a dete- rioration, from 39.69 in 2018–34.48 in 2021 (p < 0.05). Regarding pain, VAS shows higher levels of pain with statistically significant differences, both in general pain (from 6 in 2018–7 in 2012) and in foot pain (from 5 to 7), (p < 0.05). Conclusion: Mental quality of life and pain, both general and foot pain, are influenced by the period of physical inactivity during COVID-19.Funding for open access charge: Universidad de Málaga / CBU

Exploring the Frequency, Intensity, and Duration of Loneliness: A Latent Class Analysis of Data from the BBC Loneliness Experiment

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-12, pub-electronic 2021-11-16Publication status: PublishedFunder: Wellcome Trust; Grant(s): 209625/Z/17/ZAlmost all measures of loneliness have been developed without discussing how to best conceptualize and assess the severity of loneliness. In the current study, we adapted the four-item UCLA, so that it continued to measure frequency of loneliness, but also assessed intensity and duration, providing a measure of other aspects of loneliness severity. Using data from participants resident in the UK who completed the BBC Loneliness Experiment (N = 36,767; F = 69.6%) and Latent Class Profile Analyses, we identified four groups of people who scored high on loneliness on at least one of the three severity measures. Duration of loneliness often over months or years seemed to be particularly important in distinguishing groups. Further, group membership was predicted by important demographic and psychological variables. We discuss the findings in terms of implications for research and practice. We highlight the need to explore these profiles longitudinally to investigate how membership predicts later mental and physical health, and well-being

Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has potential tumour-suppressive activity in human lung cancer

Insulin-like growth binding protein-related protein 1 (IGFBP-rP1) has decreased expression in various tumors, but the role of IGFBP-rP1 in lung cancer has not yet been elucidated. In this study, we evaluated the IGFBP-rP1 expression in lung cancer cell lines and we found a reduced expression of IGFBP-rP1 at both mRNA and protein levels. In a tissue microarray containing 138 primary tumors analyzed by immunohistochemistry, 58 cases (42%) exhibited no expression of IGFBP-rP1, additionally, an association between IGFBP-rP1 expression and tumor gradings was found in squamous cell lung cancer. Neither deletion or gene rearrangement nor loss of heterozigosity was responsible for the inactivation of IGFBP-rP1. However, 5-aza-2'-deoxycytidine treatment restored the expression of IGFBP-rP1 in 3 out of 4 lung cancer cell lines. Sequencing of sodium bisulfite?treated genomic DNA from these 3 lung cancer cell lines revealed a heterogeneous methylation pattern in the region of exon 1 and intron 1. Stable transfection of IGFBP-rP1 full-length cDNA into a lung cancer cell line H2170 led to an increased protein expression of IGFBP-rP1. IGFBP-rP1 positive transfectants remarkably reduced the ability of colony formation in soft agar, suppressed the tumor growth rate in nude mice and increased the number of apoptotic cells as well as the expression level of casepase-3 compared to controls. Moreover, treatment with differentiation modulating agent 5-bromodeoxyuridine (BrdU) led to an enhanced expression of IGFBP-rP1 in lung cancer cells. Out data suggest that IGFBP-rP1 is a tumor suppressor possibly via DNA methylation and induction of apoptosis in human lung cancer

Introducing a pole concept for nodule growth in the thyroid gland: taller-than-wide shape, frequency, location and risk of malignancy of thyroid nodules in an area with iodine deficiency

Purpose : (i) To examine the criterion taller-than-wide (TTW) for the sonographic assessment of thyroid nodules in areas of iodine deficiency in terms of frequency, anatomical distribution within the thyroid gland and risk of malignancy. (ii) To develop a model for nodule growth in the thyroid gland. Methods: German multicenter study consisting of two parts. In the prospective part, thyroid nodules were sonographically measured in all three dimensions, location within the thyroid gland and contact to a protrusion-like formation (horn) in the dorsal position of thyroid gland was noted. In addition, further sonographic features such as the composition, echogenity, margins and calcifications were investigated. All nodules from the prospective part were assessed for malignancy as part of clinical routine at the decision of the treating physician adhering to institutionally based algorithms. In the retrospective part, only nodules with fine needle aspiration and/or histology were included. The risk of malignancy in TTW nodules was determined by correlating them with cyotological and histological results. Results: Prospective part: out of 441 consecutively evaluated thyroid nodules, 6 were found to be malignant (1.4%, 95% CI 0.6–2.7%). Among the 74 TTW nodules (17%), 1 was malignant (1%, 95% CI 0–4%). TTW nodules were more often located in the dorsal half of the thyroid than non-TTW nodules (factor 2.3, p = 0.01, 95% CI 2.1–2.5) and more often located in close proximity to a horn than non-TTW nodules (factor 3.0, p = 0.01, 95% CI 2.4–3.8). Retrospective part: out of 1315 histologically and/or cytologically confirmed thyroid nodules, 163 TTW nodules were retrieved and retrospectively analyzed. A TTW nodule was 1.7 times more often benign when it was dorsal (95% CI 1.1–2.5) and 2.5 times more often benign when it was associated with a horn (95% CI 1.2–5.3). The overall probability of malignancy for TTW nodules was 38% (95% CI 30–46%) in this highly preselected patient group. Conclusion: TTW nodules are common in iodine deficient areas. They are often located in the dorsal half of the thyroid gland and are frequently associated with a dorsal protrusion-like formation (horn) of the thyroid. Obviously, the shape of benign nodules follows distinct anatomical preconditions within the thyroid gland. The frequency of TTW nodules and their predominant benignity can be explained by a pole concept of goiter growth. The difference between the low malignancy risk of TTW nodules found on a prospective basis and the high risk found retrospectively may be the result of a positive preselection in the latter

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis