Basal Status Research Articles

Seguridad y eficacia de un programa de ejercicio terapéutico en jóvenes intervenidos de hernia diafragmática congénita

Introduction and objectivePatients with congenital diaphragmatic hernia (CDH) can have up to 40 times more frequency of muskuloskeletal deformities and decreased perception of physical activity tan their pairs. The objective of this study is to evaluate the safety and efficacy of an individualized exercise program in late adolescents and young adults with repaired CDH, as well as a description of their basal status. Material and methodsNon randomized prospective trial of 13 patients with repaired CDH between 1997-2005. An initial physical exploration and a pre-post assessment of bioimpedance (BIA), dynamometry, maximal inspiratory and expiratory pressure (MIP/MEP), 6-minute walk test (6MWT), physical activity level (IPAQ) and quality of life (QoL) was made. The training program last for 4 weeks. For the statistical analysis, the Student's t test for paired samples and Wilcoxon test were used. Results77% (n=10) were male with a mean age of 19.23±2.13 years. In baseline BIA, 62% (n=8) had truncal sarcopenia that improved in −0.43±0.58, and P=.016. MIP, MEP, 6MWT and QoL tests increased by −7.27±8.26 cmH2O, P=.008; −11.91±10.20 cmH2O, P=.002; −70.63±17.88 m, P=.001; −42,19±26.79, P=.00 respectively. The IPAQ did not change significantly (P=0.86), however the time dedicated to muscle strengthening increased. No adverse effects were reported. ConclusionsA personalized rehabilitation program is safe and could improve the respiratory muscle strength and truncal sarcopenia as well as the submaximal effort capacity in late adolescents and young adults with repaired CDH.

Platelet Rich Plasma Therapy in Achilles and Patellar Tendinopathies: Outcomes in Subjects with Diabetes (A Retrospective Case-Control Study).

Introduction: Diabetes mellitus (DM) is associated with a high risk of chronic degenerative Achilles (AT) and Patellar (PT) tendinopathies and ruptures. Growth factors (GFs) synthesis in diabetics is substantially decreased in human connective tissues, including in tendons. Platelet Rich Plasma (PRP), which is enriched in GFs, might prove of great help in tendon healing. The aim of the study was to assess whether pre-existent DM or Impaired Glucose Tolerance (IGT) could influence the clinical outcome in subjects undergoing PRP treatment. Methods: Sixty subjects with diabetes/pre-diabetes and sixty euglycemic controls, matched for sex and age, were enrolled. Patients suffering from proximal insertional PT and mid-portion AT, treated with PRP therapy, were included in the study. To assess the basal status and the efficacy of the therapy after 3 and 6 months, the Victorian Institute of Sport Assessment (VISA) questionnaire and the Ultrasound methodology study were used. Patient satisfaction was assessed by means of the Likert Scale. Results: In the population study at 6 months, the mean VISA-score increased (8.92 ± 0.67; p-value < 0.001). The improvement in the diabetic group was less evident compared to the controls (-2.76 ± 0.95; p-value = 0.003). Even though the improvement was poor, it was still significant. MCID analysis revealed that diabetics had higher risk of therapeutic unsuccess. Logistic regression analysis was applied to assess factors associated with unsatisfactory results (Likert-scale) of PRP treatment: AT (O.R.: 3.05; 95%CI: 1.40-6.64; p-value = 0.005), higher BMI values (O.R.: 1.02; 95%CI: 1.01-1.04; p-value = 0.01), and lower VISA score values at baseline (O.R.: 0.95; 95%CI: 0.90-0.99; p-value = 0.04). Conclusions: PRP treatment in AT and PT chronic tendinopathies resulted in less favorable results in subjects with diabetes compared with euglycemic subjects. Moreover, the subjects with PT showed better results than those with AT.

The genetic link between anxiety and libido: libido as an anxiety conversion

Psychoanalysis in the study of the human psyche considers all processes in the psychodynamic paradigm. The term "psychodynamics" first appeared in the works of Freud. From the information given by Freud deduces the definition: psychodynamics is the mutual influence of unconscious (id, BSZ) and conscious (ego) processes in which BSZ is of priority importance [14]. The psychodynamic approach made it possible to reveal the economic features of mental processes. Psychic economism describes how psychic energy is involved in the processes of production/reproduction, distribution, transition and qualitative and quantitative changes. When describing psychodynamics and the economy of Freud focused on libido as the only psychic energy that can be invested in an object in a direct and sublimated form, and manifest itself in models of attraction or conversion, in symptoms. However, the study of mental processes in patients with borderline personality organization of psychogenic etiology with the help of hypnopsychoanalysis allowed us to change the view of libido as the primary and central mental energy. According to the data of psychocorrective work, we came to the conclusion that anxiety is a pre-libidinal energy that is first experienced by a child at the moment of birth and in the process of ontogenesis is able to convert into libido. This leads to the conclusion that libido is the result of the conversion of anxiety, or, in other words, the reactive formation of anxiety. For the first time, an attempt to give anxiety a basal status was made by Karen Horney [20]. However, her work describes the phenomenological aspects of anxiety. We find a broad study of anxiety in a phenomenological way both in early authors, among whom R. May is particularly noted [8], and in modern ones [5], [3], [7]. In turn, the report examines the economic aspect of anxiety in the psychodynamic approach, its genetic relationship with libido, and the ability of anxiety to convert into libido. The research methodology is based on the following: - analysis of sources that highlight the problem of anxiety; - philosophical justification of the singular and plural; - data obtained as a result of psychocorrective work using psychodynamic hypnotherapy

Lipopolysaccharide-responsive beige-like anchor is involved in regulating NF-κB activation in B cells.

Lipopolysaccharide-responsive and beige-like anchor (LRBA) is a scaffolding protein that interacts with proteins such as CTLA-4 and PKA, the importance of which has been determined in various cell types, including T regulatory cells, B cells, and renal cells. LRBA deficiency is associated with an inborn error in immunity characterized by immunodeficiency and autoimmunity. In addition to defects in T regulatory cells, patients with LRBA deficiency also exhibit B cell defects, such as reduced cell number, low memory B cells, hypogammaglobulinemia, impaired B cell proliferation, and increased autophagy. Although Lrba-/- mice do not exhibit the immunodeficiency observed in humans, responses to B cell receptors (BCR) in B cells have not been explored. Therefore, a murine model is for elucidating the mechanism of Lrba mechanism in B cells. To compare and evaluate spleen-derived B cell responses to BCR crosslinking in C57BL6 Lrba-/- and Lrba+/+ mice. Spleen-derived B cells were obtained from 8 to 12-week-old mice. Subpopulations were determined by immunostaining and flow cytometry. BCR crosslinking was assessed by the F(ab')2 anti-μ chain. Activation, proliferation and viability assays were performed using flow cytometry and protein phosphorylation was evaluated by immunoblotting. The nuclear localization of p65 was determined using confocal microscopy. Nur77 expression was evaluated by Western blot. Lrba-/- B cells showed an activated phenotype and a decreased proportion of transitional 1 B cells, and both proliferation and survival were affected after BCR crosslinking in the Lrba-/- mice. The NF-κB pathway exhibited a basal activation status of several components, resulting in increased activation of p50, p65, and IκBα, basal p50 activation was reduced by the Plcγ2 inhibitor U73122. BCR crosslinking in Lrba-/ - B cells resulted in poor p50 phosphorylation and p65 nuclear localization. Increased levels of Nur77 were detected. These results indicate the importance of Lrba in controlling NF-κB activation driven by BCR. Basal activation of NF-κB could impact cellular processes, such as, activation, differentiation, proliferation, and maintenance of B cells after antigen encounter.

P-788 Analysis of tissue regeneration after transplantation of bioengineered uterine grafts in a sheep model of uterine injury

Abstract Study question Can we regenerate a damaged uterus using decellularized (further repopulated with stem cells or not) uterine scaffolds in a sheep model? Summary answer Bioengineered uterine grafts can promote the regeneration of a damaged uterus, but this process is highly dependent on the basal immune status of the recipient. What is known already Uterus bioengineering aims to develop scaffolds to repair defective uterine tissue that may cause infertility. The remaining extracellular matrix after uterus decellularization has frequently been used as a scaffold material for preclinical treatment applications. So far, multiple in vivo studies using rodents have shown successful restoration of uterine tissue and even fertility when small grafts were used. Furthermore, this pro-regenerative effect is enhanced when repopulating the scaffolds with mesenchymal stem cells (MSCs). However, studies using larger animal models and larger scaffolds are still missing. Therefore, we investigated the therapeutic potential of transplanting these scaffolds in the sheep model. Study design, size, duration All experiments were performed in university facilities, including the sheep animal work. Uterine scaffold donor sheep (from a local abattoir) and recipient sheep (n = 10) were of the same mixed sheep breed (Swedish fin-ull and Dutch texel mixed breed) and age (8-12 months old). Recipient sheep were transplanted with uterine decellularized (either recellularized or not) grafts that were maintained for 6 weeks. Participants/materials, setting, methods We implemented our previously established decellularization protocol (2% sodium deoxycholate) for sheep uterine scaffold production, generating 3x2cm grafts; half of these were recellularized with sheep MSCs. Decellularized (DC; n = 7) and recellularized (RC; n = 8) grafts were transplanted as replacements for native uterine tissue. After six weeks, histological, immunohistochemistry (CD31, CD45), and gene expression (progesterone/estrogen receptors, HOXA10, VEGF, vWF, TNFA, IFNG) analysis were conducted. Simultaneously, we used cell sorting to monitor the systemic immune response over time. Main results and the role of chance Angiogenesis was increased in the RC group as more new blood vessels (CD31+ cells) were evidenced (P=0.0120). VEGF and vWF gene expression also indicated the presence of blood vessels in the grafts but without differences among the groups. Regarding the immune response, CD45 staining revealed leukocyte recruitment into both transplanted grafts, with an increased significance in the DC group (P=0.0071) compared to the RC (P=0.0181). Furthermore, the pro-inflammatory genes TNFA and IFNG expression remained invariable compared to the native tissue. Finally, hormone receptor gene levels were comparable to those in the native tissue, with HOXA10 presenting higher values in the RC group compared to the DC (P=0.0548). So, the RC group showed signs of better uterine regeneration, probably due to the MSC’s anti-inflammatory action. Still, differences were subtle between groups. So, we blindly analyzed the histology of all grafts and detected substantially but also poorly regenerated grafts in both DC and RC groups. The analysis of the systemic immune response likely answers this, as when segregating individuals in substantially and poorly regenerated grafts, there was a significant difference in the percentage of activated CD4+ T-cells, being higher (P&amp;lt;0.0001) in those with poorly regenerated grafts already at day 0. Limitations, reasons for caution Due to the lack of available sheep antibodies, we did not study specific subtypes of leukocytes by immunohistochemistry as we did for the cell sorting analysis. Also, despite experienced group members performing the blinded histological analysis of the grafts to detect substantially/poorly regenerated grafts, this method requires refinement. Wider implications of the findings Basal immune system status should be considered before transplanting uterine grafts, as inflammation seems crucial in tissue regeneration. Trial registration number Not applicable

Long‐term clinical, nutritional, and functional outcomes of COVID‐19 patients after hospital discharge

AbstractBackgroundLong‐term nutritional and functional status after hospitalization due to COVID‐19 has been poorly described. We show the physical and nutritional stata and the symptoms compatible with Long‐COVID in patients who survived after an episode of hospitalization due to COVID‐19 and the associated factors.MethodsSingle‐center prospective observational study. Clinical, nutritional, and physical function data were assessed in 345 subjects over 18 years of age hospitalized in an university hospital for a diagnosis of COVID‐19 in 2020 at three different times of follow‐up: 6 (n = 118), 9 (n = 115), and 15 months (n = 112) after discharge. All survivors discharged during each of those periods were called consecutively at the times of follow‐up in order to collect data about their nutritional and functional stata, and long‐COVID symptoms.ResultsThe mean age of the 345 subjects included in the present study was 62.8 years (SD 15.8), and 180 (52.2%) were men. The mean number of comorbidities was 2.6 (SD 2.1). After a mean follow‐up time of 10.2 ± 3.2 months, mean Barthel score showed a decrease of 2.00 (SD 0.12) points, that showed to be consistent disregarding the time after discharge (6 months: 1.71 ± 4.8; 9 months: 2.17 ± 5.97; 15 months: 2.20 ± 5.25). The risk factors associated with worsening in the Barthel index score were basal Barthel index [BI &lt; 95; odds ratio (OR): 3.34, 95% confidence interval (CI): 1.26–8.85], age (OR: 1.03, CI: 1.00–1.06, per year), having comorbidities (≥3 pathologies) (OR: 1.98, CI: 1.00–3.90), and female sex (OR: 2.68, CI: 1.47–4.90). Self‐reported Long‐COVID symptoms were frequent, mainly those related to functioning: fatigue/tiredness (39.4%), decreased mobility (16.2%), and subjective loss of muscle mass/strength (15.9%) plus mental complaints (depression/anxiety; 20.6%). Decreased mobility (OR 7.82, CI: 3.69–16.55), cognitive impairment (OR 6.76, CI: 2.22–20.58) and a score in SARC‐F ≥ 2 (OR: 3.89; CI: 2.03–7.49) at follow‐up were associated to the worsening in BI. BMI showed a modest, non‐significant decrease at 6 months (−0.3 ± 1.7 kg/m2), that was fully recovered in the longest follow‐up period (+0.4 ± 2.1).ConclusionsAdmission for COVID‐19 produces a significant functional loose, mainly in those who are older, female, and with a poor basal functional status and comorbidities. This impairment does not recover spontaneously and is a main component of the long‐term COVID‐19 symptoms.

Posttraumatic stress disorder is characterized by functional dysregulation of dermal fibroblasts

Incidence of mental health disorders are rising in modernity, with psychological stress linked to a propensity for developing various chronic diseases due to a relative inability of the body to counter the allostatic load on cellular level. Despite these high rates of comorbidities associated with posttraumatic stress disorder (PTSD), there is still a lack of understanding in terms of the peripheral effects of PTSD on tissue level. Therefore, the purpose of this study was to profile basal dermal fibroblast functional status in PTSD using a wide range of markers involved in the cell-to-cell communication facilitated by fibroblasts. Primary dermal fibroblasts derived from patients diagnosed with PTSD (n = 11) and matched trauma exposed controls (i.e. who did not develop PTSD, n = 10) were cultured using standard techniques. The patients and controls were matched based on age, sex, body-mass index (BMI) and lifestyle. The growth rate, population doubling time, cell surface marker expression (CD31, FNDC5) (flow cytometry), secretome (TIMP-2, MMP-9) (ELISAs), intracellular signalling capacity (Fluo-4 Ca2+ flux) and gene expression (IL-6, IL-10, PTX-3, iNOS, Arg1) were compared between groups. The data illustrated significant PTSD-associated fibroblast conditioning resulting in a blunted signalling capacity. This observation highlights the importance of including tissue-specific investigations in future studies focused on elucidating the association between PTSD and subsequent risk for somatic disease.

Severe PTSD is marked by reduced oxytocin and elevated vasopressin

Neuroendocrine analyses of posttraumatic stress disorder (PTSD) have generally focused on hypothalamic-pituitary-adrenal (HPA) axis alterations. In the present analyses, we examine two additional neuroendocrine factors that have been previously implicated in biological stress responses: oxytocin (OT) and arginine vasopressin (AVP). Here we examined basal neuropeptide status in military veterans clinically diagnosed with PTSD (n = 29) and in two non-traumatized comparison groups with previous stress exposure (n = 11 SWAT trainees and n = 21 ultramarathon runners). PTSD patients showed low levels of plasma OT and high levels of AVP. The ratio of AVP/OT robustly related to PTSD status, and emerged as a statistically plausible mediator of relationships between the number of personal traumatic experiences and subsequent PTSD symptom burden. Over the course of behavioral therapy for PTSD, measures of OT showed a significant but modest normalization. Plasma cortisol levels were not statistically different among the three groups. This study suggests that AVP/OT ratios may represent a neuroendocrine predictor of severe PTSD, as well as a potential treatment response biomarker.

Basal differentiation and expression status of SOX2 and KLF4 in basal layers are prognostic factors for disease-specific survival in oral squamous cell carcinoma.

Basal differentiation in oral squamous cell carcinoma is usually detected at invasive sites. However, its significance as a prognostic value has been poorly investigated. COL17 was selected as a basal differentiation marker because of its stable expression in the basal-like cells of oral squamous cell carcinoma. Sixty-five cases of oral squamous cell carcinoma were subclassified into COL17-high (30 cases) and -low (35 cases) types, and the prognostic value was analyzed by Cox regression analysis. In addition, the stem cell markers such as SOX2, KLF4, MYC as well as the stem cell-related markers BMI1, EZH2, and YAP and its paralog TAZ, were immunohistochemically analyzed. Their prognostic values were investigated along with their COL17 status by Cox regression analysis. No significant difference was observed between the COL17-high and -low groups in the disease-specific survival and recurrence-free survival in oral squamous cell carcinoma. When the COL17-high and -low categories were combined with the SOX2, KLF4, EZH2, or YAP/TAZ status in the basal layers, together with gender and age as covariates, the hazard ratios reached 3.3, 3.7, 2.8, and 3.1, respectively. In addition, multivariate analysis, including COL17, SOX2, and KLF4, with gender and age as covariates, showed a significantly poor prognosis for disease-specific survival. Based on the relatively high hazard ratios, it is indicated that basal differentiation and the expression status of SOX2 and KLF4 in the basal layers are prognostic factors for oral squamous cell carcinoma.

Elevated oxidative stress biomarkers in adults with segmented sleep patterns.

We investigated the association between different sleep patterns and inflammatory and oxidative stress biomarkers in adults. A total of 321 consented adults who fulfilled the inclusion criteria were recruited in this cross-sectional study. The inclusion criteria were mainly based on apparently healthy adults aged 18-59 years. To identify sleep patterns, participants were requested to wear the actigraph for 1 week for 24 hours a day. Fasting blood was collected from each participant at day 8. The blood serum was analyzed for inflammatory and oxidative stress biomarkers. Sleep patterns were defined as monophasic (1 episode of night sleep) biphasic (2 episodes of sleep; night and aternoon siesta), and polyphasic sleep pattern (3 or more sleep episodes). There was no correlation between night sleep duration, total sleep in 24 hours, and napping among inflammatory and oxidative stress biomarkers: high-sensitivity C-reactive protein, malondialdehyde, total glutathione, and basal oxidizability status. Actigraphy reports showed 3 sleep patterns in this cohort, monophasic (24.3%), biphasic-napping (45.2%) and polyphasic (30.5%). Individuals with segmented sleep patterns were significantly associated with oxidative stress biomarkers. A polyphasic sleep pattern was significantly associated with higher basal oxidizability status (P = .023), whereas a biphasic sleep pattern showed higher malondialdehyde (P = .036) as compared to a monophasic sleep pattern. Total glutathione was significantly higher in monophasic sleepers (P = .046). There was no difference in serum high-sensitivity C-reactive protein among all sleep patterns. Segmented sleep in polyphasic and biphasic sleep patterns is associated with higher serum malondialdehyde and basal oxidizability status in particular. Further studies are recommended on the cardiometabolic impact of oxidative stress biomarkers in individuals with segmented sleep. Al Lawati I, Zadjali F, Al-Abri MA. Elevated oxidative stress biomarkers in adults with segmented sleep patterns. J Clin Sleep Med. 2024;20(6):959-966.

Assessment of psychological status by a comprehensive approach in thyroid cancer patients undergoing radionuclide therapy: A feasibility study.

This feasibility study evaluated the psychological status of patients with differentiated thyroid cancer (DTC) before, during, and 40 days after administration of I-131 radionuclide therapy (RAI). We investigated the appropriateness of providing patient a comprehensive psychological assessment in an isolation ward. Thirty consecutive patients (Study Group; SG) who received RAI were enrolled. The tools used were the Hospital Anxiety and Depression Scale (HADS) at three different moments, and the Coping Responses Inventory (CRI) at baseline for each patient. A supportive approach was also implemented. Data were collected at the first specialist visit, at the day of admission, and at 40 days follow-up visit. A matched cohort of patients (Control Group; CG), who did not receive psycho-oncological counseling, was retrospectively studied only about their medical needs and requests. Staff exposure to radiation was also compared during SG and CG hospitalization, to assess a possible reduction of radiological risk for them. A significant difference between the basal, intermediate, and final psychological status was observed (p < 0.0001), which was found to be irrespective of the induced hypothyroidism. Patients showed a significant worsening of their status in terms of anxiety and depression after the consent, but it improved 40 days after treatment. Repeated measures analysis showed a similar trend in patients' psychological status over this period. At hospital discharge, patients showed indirect signs of increased well-being. CG required more nursing and medical interventions. Staff exposure was significantly lower during hospitalization of SG as compared to CG. This study demonstrates that timed psychological evaluation and appropriate support may help to reduce anxiety and depression of patients receiving a diagnosis of cancer and undergoing RAI. Moreover, an improvement of workplace safety was recorded.

Prognostic variables predict clinical outcome after decompressive craniectomy: A single institute experience; A retrospective study.

Decompressive craniectomy (DC) is a well-established neurosurgical intervention in patients with high intracranial pressure who fail to respond to medical treatment. Data on predictive factors for functional outcomes in patients with DC who have malignant middle cerebral artery (MCA) infarction as opposed to intracranial hemorrhage (ICH) are scarce. Eighty-four patients who underwent DC treatment for ICH and malignant MCA infarction were examined. All patients underwent surgery in the Bahrain Salmaniya Medical Complex Neurosurgery Unit between January 2017 and June 2021. To determine whether any of these demonstrated a link to the functional outcome, radiographic factors were compared with clinical data. The postsurgical midline shift (MLS) (ICH group) showed the strongest correlation (ρ = 0.434; P = .006), as in the MCA infarction group as well (ρ = 0.46; P = .005). Further analyses using binary logistic regression with postsurgical basal cistern status and ∆ MLS, and it was observed to be statistically significant (odds ratios: 0.067, 95% CI: 0.007, 0.67; P = .021). The initial Glasgow coma scale, postsurgical MLS, basal cistern status, and ∆ are Measurable variables that can be used to predict outcomes in the groups with ICH and MCA infarction.

PSVI-10 Effects of Poor Maternal Nutrition During Gestation on Offspring Basal Immune Status

Abstract Poor maternal nutrition during gestation affects offspring pre- and post-natal growth, decreasing muscularity and increasing adiposity. Chronic inflammation may be a potential mechanism for the alterations reported. The objective of this research was to determine the effects of poor maternal nutrition during gestation on offspring inflammatory status. We hypothesized that offspring of restricted- and over-fed ewes would have an altered inflammatory status which would be dependent on offspring sex. To test this hypothesis, multiparous Dorset ewes (n = 45) pregnant with twins were fed 100% (CON), 60% (RES), or 140% (OVER) of National Research Council requirements from d 30 of gestation until parturition. At parturition, all ewes were fed a control diet, such that the nutritional insult only occurred during gestation. At d 120, whole blood was collected from offspring and RNA was isolated to evaluate 86 genes related to the innate and adaptive immune responses. Data were analyzed in SAS 9.4 using PROC MIXED with fixed effects of offspring sex, maternal diet, and the interaction. Maternal diet affected 7 genes. Bovine major histocompatibility complex, a gene in the innate immune response, was downregulated by 27% and 37% in OVER compared with CON and RES, respectively (P = 0.001). Cluster of differentiation 86, a marker of T cell activation, was upregulated by 17% in OVER compared with CON (P = 0.04). Lymphocyte antigen 96, critical in the response to pathogens, expression was 48% greater in RES compared with CON (P = 0.04). A transcription factor in cytokine signaling, Signal transducer and activator of transcription 3 was upregulated in OVER and RES offspring by 19 and 21%, respectively, compared with CON (P = 0.02). Pattern recognition receptors Toll-like receptor-1 (TLR1), TLR4, and TLR8 were upregulated in RES and OVER compared with CON (P ≤ 0.04). The interaction of offspring sex and maternal diet significantly altered gene expression in 2 genes. A regulator of T cell differentiation, GATA Binding Protein 3 was downregulated in OVER females by 21 to 43% compared with all other offspring and was upregulated in OVER males by 26 to 76% compared with all female offspring (P = 0.04). A gene related to cytokine signaling, Janus Kinase 2 was upregulated in RES and OVER males by 29 to 64% compared with all other offspring (P = 0.05). Sex altered gene expression of 54 genes (P ≤ 0.05). Overall, maternal diet altered gene expression of the innate and adaptive immune responses in a sex-specific manner. Alterations in inflammatory status may contribute to altered body composition and may predispose offspring to impaired response to immune challenges. Future work should focus on the impacts of poor maternal nutrition during gestation on the response to an immune challenge.

Deep Characterization of Immune Dysfunction in Patients with Multiple Myeloma (MM) and Identification of Cellular Biomarkers for Tailored Vaccination Strategies

Background: Infection is the leading cause of death in MM. However, the extent of immune dysfunction compared to other B-cell lymphoproliferative disorders (B-CLPD) and healthy adults remains poorly studied. Greater knowledge is needed for tailored vaccination strategies and to improve outcomes upon new pathogens or breakthrough infections. Aim: Generate an atlas of the basal immune status and its response to vaccination in MM vs B-CLPD patients and age-matched health care practitioners (HCP), using the COVID-19 mRNA vaccines as a case study. Methods: A total of 1,099 blood and serum samples were collected from 177 individuals: 28 MM, 53 B-CLPD and 96 HCP older than 50. They were studied before COVID-19 mRNA vaccination, at days 7 and 14 after the first dose, at days 7 and 62 after the second dose, as well as before and at day 17 after the booster. Immune profiling was performed using multidimensional and computational flow cytometry that systematically analyzed 56 immune cell types per sample and time point: 17 B, 30 T, 6 antigen-presenting cell (APC) and 3 granulocytic subsets. Serum levels of IgM, IgG and IgA against the receptor-binding domain (RBD) of the spike (S) glycoprotein, S glycoprotein, nucleocapsid (N) and main protease were quantified using a multiplex-microsphere-based flow cytometry assay. SARS-CoV-2-specific CD8 T cells were quantified using a dextramer panel of S, N, membrane, and ORF3 proteins. Results: When compared to HCP and/or B-CLPD, MM patients showed abnormal distribution of 17/17 B, 22/30 T, 4/6 APC and 1/3 granulocytic cell subsets prior to vaccination. The most deviated cell types in MM were naïve CD21+ B-cells, naïve CD4 T-cells, PD1- and PD1+CD127low effector memory (EM) CD8 T cells, classical monocytes and neutrophils. The B cell compartment of MM patients showed impaired response to COVID-19 mRNA vaccination. While B-CLPD patients and HCP displayed significant expansions of naïve CD21-, IgM+IgD+CD27+CD21-, IgG+CD27-CD21-, and IgG+CD27+CD21- B-cell subsets, as well as of IgA+ circulating plasma cells, such expansions were not observed in MM patients. Accordingly, anti-RBD IgM, IgA and IgG titers were significantly reduced in MM compared to B-CLPD and HCP after the second dose ( P ≤.002). Importantly, the booster increased anti-RBD IgG levels in HCP (20,184 to 186,629 IU/mL, P &amp;lt;.001) but not in MM (1,991 to 5,998 IU/mL, P =.14) and B-CLPD (33,548 to 41,288 IU/mL, P =.19) patients. The immune response of the T-cell compartment was also altered in MM patients. The significant expansion of CD127lowPD1+ and CD127+CD25+ EM CD4, naïve CD4 and CD127lowPD1+ EM CD8 subsets observed in HCP was unnoted in MM and B-CLPD patients. Accordingly, the percentage of virus-specific CD8 T cells after the second dose did not increase in MM and B-CLPD patients. The booster increased virus-specific CD8 T cells in HCP (0.08 to 0.14%, P =.02), but not in MM (0.08 to 0.09%, P =.94) and B-CLPD (0.23 to 0.16%, P =.85). Furthermore, the booster induced virus-specific CD8 T cell differentiation into an EM phenotype in HCP but not in MM and B-CLPD patients. In addition to the dysfunctional B and T cell response to vaccination, MM patients showed abnormal kinetics of APC such as intermediateclassical and non-classical SLAN- and SLAN+ monocytes, as well as of granulocytic subsets such as basophils and neutrophils. Based on differences in immune-cell distribution using HCP as a reference, we calculated an immune dysregulation longitudinal cumulative score in each individual that included 48,496 immune parameters. Compared with HCP, up to 34% MM and 17% B-CLPD patients showed high immune dysregulation scores. Among them, 75% and 33%, respectively, had low seroconversion after the second dose. We found 7/30 T and 14/17 B-cell subsets associated with poor vaccine response in MM patients, namely CD127lowPD1+CXCR5+ EM CD8 T cells, as well as CD21- and CD21+ naïve, transitional, IgM+IgD+CD27+CD21+, IgM+CD27-CD21+, and IgG+CD27-CD21+ B cells. Conclusion: We provide an atlas of the immune dysfunction in MM patients and how it affects the efficacy of vaccination strategies such as for COVID-19. The schedule of vaccine doses may thus benefit from individualization according to patients' immune status, which could act as a surrogate of host, tumor and treatment-related immune dysfunction. Accordingly, we have identified key cell types for readily monitoring of patients' immune status using routinely available flow cytometry.

Effects of heat stress abatement on systemic and mammary inflammation in lactating dairy cows

To examine the effects of evaporative cooling on systemic and mammary inflammation of lactating dairy cows, 30 multiparous Holstein cows (parity = 2.4, 156 d in milk) were randomly assigned to 1 of 2 treatments: cooling (CL) with fans and misters or not (NC). The experiment was divided into a 10-d baseline when all cows were cooled, followed by a 36-d environmental challenge when cooling was terminated for NC cows. The onset of environmental challenge was considered as d 1. Temperature-humidity index averaged 78.4 during the environmental challenge. Milk yield and dry matter intake (DMI) were recorded daily. Blood and milk samples were collected from a subset of cows (n = 9/treatment) on d -3, 1, 3, 7, 14, and 28 of the experiment to measure cortisol, interleukin 10 (IL10), tumor necrosis factor-α (TNF-α), haptoglobin, and lipopolysaccharide binding protein (LBP). Mammary biopsies were collected from a second subset of cows (n = 6/treatment) on d -9, 2, 10, and 36 to analyze gene expression of cytokines and haptoglobin. A subset of cows (n = 7/treatment) who were not subjected to mammary biopsy collection received a bolus of lipopolysaccharides (LPS) in the left rear quarter on d 30 of the experiment. Blood was sampled from cows and milk samples from the LPS-infused quarter were collected at -4, 0, 3, 6, 12, 24, 48, and 96 h relative to infusion, for analyses of inflammatory products. Deprivation of cooling decreased milk yield and DMI. Compared with CL cows, plasma cortisol concentration of NC cows was higher on d 1 but lower on d 28 of the experiment (cooling × time). Deprivation of cooling did not affect circulating TNF-α, IL10, haptoglobin, or LBP. Compared with CL cows, NC cows tended to have higher milk IL10 concentrations but did not show effects in TNF-α, haptoglobin, or LBP. No differences were observed in mammary tissue gene expression of TNF-α, IL10, and haptoglobin. Milk yield declined after LPS infusion but was not affected by treatment. Compared with CL cows, NC cows had greater milk somatic cell count following intramammary LPS infusion. Non-cooled cows had lower circulating TNF-α and IL10 concentrations and tended to have lower circulating haptoglobin concentrations than CL cows. Milk IL10 and TNF-⍺ concentrations were higher 3 h after LPS infusion for NC cows compared with CL cows. Additionally, NC cows tended to have higher milk haptoglobin concentration after LPS infusion than CL cows. In conclusion, deprivation of evaporative cooling had minimal effects on lactating cows' basal inflammatory status, but upregulated mammary inflammatory responses after intramammary LPS infusion.

Effects of Intermittent Fasting on Regulation of Metabolic Homeostasis: A Systematic Review and Meta-Analysis in Health and Metabolic-Related Disorders.

Intermittent fasting (IF) is an emerging dietetic intervention that has been associated with improved metabolic parameters. Nowadays, the most common IF protocols are Alternate-Day Fasting (ADF) and Time-Restricted Fasting (TRF), but in this review and meta-analysis we have also considered Religious Fasting (RF), which is similar to TRF but against the circadian rhythm. The available studies usually include the analysis of a single specific IF protocol on different metabolic outcomes. Herein, we decided to go further and to conduct a systematic review and meta-analysis on the advantages of different IF protocols for metabolic homeostasis in individuals with different metabolic status, such as with obesity, diabetes mellitus type 2 (T2D) and metabolic syndrome (MetS). Systematic searches (PubMed, Scopus, Trip Database, Web of Knowledge and Embase, published before June 2022) of original articles in peer-review scientific journals focusing on IF and body composition outcomes were performed. Sixty-four reports met the eligibility criteria for the qualitative analysis and forty-seven for the quantitative analysis. Herein, we showed that ADF protocols promoted the major beneficial effects in the improvement of dysregulated metabolic conditions in comparison with TRF and RF protocols. Furthermore, obese and MetS individuals are the most benefited with the introduction of these interventions, through the improvement of adiposity, lipid homeostasis and blood pressure. For T2D individuals, IF impact was more limited, but associated with their major metabolic dysfunctions-insulin homeostasis. Importantly, through the integrated analysis of distinct metabolic-related diseases, we showed that IF seems to differently impact metabolic homeostasis depending on an individual's basal health status and type of metabolic disease.

Abstract 3994: Differential regulation of hormone receptors and Ki67 in luminal breast carcinomas and tumor-adjacent mammary glands by mifepristone treatment

Abstract Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB), we designed a window-of-opportunity trial (MIPRA; NCT02651844) to study the benefits of mifepristone (MFP) in luminal breast carcinomas from postmenopausal patients selected by their PR+ expression (&amp;gt;50%) and their PR isoform ratio (PRA/PRB&amp;gt;1.5; PRA-H). A decrease in the cell proliferation marker Ki67 was registered after treatment in 14 out of the 20 tumors evaluated. This inhibition was associated with a decrease in PR, estrogen receptor (ER) and pSer118ER evaluated by immunohistochemistry while no changes in pSer167ER expression were observed (PMID: 36269797). In selected tissues from these samples we observed that the staining intensity in trapped glands within the MFP-treated tumors did not follow a similar trend as that of tumor cells. Thus, the aim of this study was to evaluate the expression of hormone receptors and Ki67 in non-neoplastic human mammary glands (nnMG) adjacent to the PRA-H tumor tissue of postmenopausal patients, treated (n=8) or not (n=9) with MFP. No differences in PR, ER and pSer118ER expression were observed between MFP-treated nnMG and those from untreated patients. Notably, contrarily to what occurred in tumors, there was a significant decrease of pSer167ER expression (p=0.008) in the MFP-treated nnMG compared to the untreated glands, suggesting a selective modulation in the AKT-mediated activation of ER. Regarding the proliferative state of the nnMGs, there was a slight but significant increase (p=0.02) in Ki67 expression in MFP-treated vs. non-treated nnMG. Data regarding the effect of antiprogestins in normal mammary glands is limited and points, in premenopausal women, to a decrease in the Ki67 index after treatment. The basal quiescent status of nnMG in postmenopausal women may explain this slight stimulatory effect. In conclusion, our results show that MFP exerts a specific regulatory effect in PRA-H tumors that is not observed in the nnMG, probably due to the fact that nnMG have presumably equimolar levels of PRA and PRB. In addition, to counteract the possible stimulatory effect that MFP may induce on nnMG, the combination of MFP and tamoxifen treatment is suggested. Citation Format: Leo Saldain, Silvia Vanzulli, Paula Martinez Vazquez, Javier Burruchaga, Eunice Spengler, Claudia Lanari, Paola Rojas. Differential regulation of hormone receptors and Ki67 in luminal breast carcinomas and tumor-adjacent mammary glands by mifepristone treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3994.

PD35-11 EPITHELIAL DIFFERENTIATION IS ALTERED IN URETHRAL LICHEN SCLEROSUS

You have accessJournal of UrologyCME1 Apr 2023PD35-11 EPITHELIAL DIFFERENTIATION IS ALTERED IN URETHRAL LICHEN SCLEROSUS Ethan Richmond, Caleb Sokovich, Wei Huang, Chad Vezina, and Matthew D Grimes Ethan RichmondEthan Richmond More articles by this author , Caleb SokovichCaleb Sokovich More articles by this author , Wei HuangWei Huang More articles by this author , Chad VezinaChad Vezina More articles by this author , and Matthew D GrimesMatthew D Grimes More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003333.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lichen sclerosus (LS) is an idiopathic chronic inflammatory disease of the genital epithelium resulting in fibrosis and severe urethral stricture disease in affected men. Epithelia are subdivided into basal, intermediate, and superficial cell layers which are defined by protein expression patterns. Loss of basal cell differentiation is a feature of other fibrotic disorders but have not been studied in the urethra or LS. The proteins keratin 5 (KRT5) and p63 have been reliably established as basal cell markers in urothelium. Therefore, we hypothesized that urethral epithelium affected by LS would have decreased basal expression of KRT5 and p63. METHODS: Urethral tissue after urethral biopsy or urethroplasty was examined by a genitourinary pathologist to determine LS status. Using multiplexed fluorescent immunohistochemistry, KRT 5, CD45, p63, and DAPI were stained and three epithelial regions imaged per specimen. Using QuPath analysis software, the epithelium was segmented into basal and luminal compartments and relative abundance (RA) of each primary antibody was measured (number of positive cells/number of nucleated cells). RA was compared with respect to LS status and basal/luminal compartment using a Mann-Whitney U test. RESULTS: We analyzed 14 slides (n=7 LS, n=7 non-LS). The RA of KRT5 and p63 positive cells were similar with respect to epithelial versus basal compartment and LS status. However, we noted a change in patterning such that LS tissues displayed a shift of KRT5 and p63 expression from the basal to the luminal epithelium. To quantify this, we compared the ratio of basal to luminal KRT5 and p63 expression and dichotomized this as “basal predominant” (>1) or “luminal predominant” (<1). LS urethra were significantly more likely to have luminal predominant expression of p63 and KRT5 compared to non-LS (p=0.03, p=0.03) (Figure 1). CONCLUSIONS: We identified a change in expression pattern of basal epithelial markers (KRT5 and p63) in LS urethra. Altered epithelial differentiation is seen in other inflammatory diseases and may be implicated in the pathogenesis of LS. Source of Funding: K12DK100022NIH/NIDDK © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e978 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ethan Richmond More articles by this author Caleb Sokovich More articles by this author Wei Huang More articles by this author Chad Vezina More articles by this author Matthew D Grimes More articles by this author Expand All Advertisement PDF downloadLoading ...

Characteristics of inflammatory response and repair after experimental blast lung injury in rats.

Blast-induced lung injury is associated with inflammatory, which are characterised by disruption of the alveolar-capillary barrier, haemorrhage, pulmonary infiltrateration causing oedema formation, pro-inflammatory cytokine and chemokine release, and anti-inflammatory counter-regulation. The objective of the current study was to define sequence of such alterations in with establishing blast-induced lung injury in rats using an advanced blast generator. Rats underwent a standardized blast wave trauma and were euthanised at defined time points. Non-traumatised animals served as sham controls. Obtained samples from bronchoalveolar lavage fluid (BALF) at each time-point were assessed for histology, leukocyte infiltration and cytokine/chemokine profile. After blast lung injury, significant haemorrhage and neutrophil infiltration were observed. Similarly, protein accumulation, lactate dehydrogenase activity (LDH), alveolar eicosanoid release, matrix metalloproteinase (MMP)-2 and -9, pro-Inflammatory cytokines, including tumour necrosis factor (TNF) and interleukin (IL) -6 raised up. While declining in the level of anti-inflammatory cytokine IL-10 occurred. Ultimately, pulmonary oedema developed that increased to its maximum level within the first 1.5 h, then recovered within 24 h. Using a stablished model, can facilitate the study of inflammatory response to blast lung injury. Following the blast injury, alteration in cytokine/chemokine profile and activity of cells in the alveolar space occurs, which eventuates in alveolar epithelial barrier dysfunction and oedema formation. Most of these parameters exhibit time-dependent return to their basal status that is an indication to resilience of lungs to blast-induced lung injury.

The effect of exercise on cognitive function in people with multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.

A growing body of research examining the effect of exercise on cognitive function in people with multiple sclerosis (MS), while findings of available studies were conflicting. We aimed to explore the effect of exercise on cognitive function in MS patients. For this systematic review and meta-analysis, we searched PubMed, Web of Science, EBSCO, Cochrane, and Scopus electronic databases, through July 18, 2022. Cochrane risk assessment tool was used to evaluate the methodological quality of the included literature. Twenty-one studies with a total of 23 experimental groups and 21 control groups met the inclusion criteria. There was a significant effect of exercise on improving cognitive function in MS patients, while the effect size was small (Cohen's d = 0.20, 95% CI 0.06-0.34, p < 0.001, I2 = 39.31%). Subgroup analysis showed that exercise significantly improved memory (Cohen's d = 0.17, 95% CI 0.02-0.33, p = 0.03, I2 = 7.59%). In addition, multicomponent training, exercise conducted 8weeks and 10weeks, up to 60min per session, 3 times or more per week, 180min or more per week increased cognitive function significantly. Furthermore, a worse basal MS status (defined by the Expanded Disability Status Scale) and an older age were associated with greater improvement in cognitive function. MS patients are recommended to participate in at least three multicomponent training sessions per week, with each session lasting up to 60min, and the exercise goal of 180min per week can be achieved by increasing the frequency of exercise. Exercise lasting 8 or 10weeks is best for cognitive function improvement. Additionally, a worse basal MS status, or the older the age, the greater effect on cognitive function.