Dysregulation In Patients Research Articles

Alterations of gut microbial pathways and virulence factors in hemodialysis patients.

Alterations in gut microbiota might contribute to uremic toxicity and immune dysregulation in patients with end-stage renal disease. Hemodialysis patients are prone to infection and higher mortality following sepsis. The virulence factors in the gut metagenome have not been well studied in hemodialysis patients, which could be employed by microorganisms to successfully thrive and flourish in their hosts. In this study, we performed shotgun metagenomics sequencing on fecal DNA collected from 16 control subjects and 24 hemodialysis patients. Our analysis shows that a number of microbial species, metabolic pathways, antibiotic resistance, and virulence factors were significantly altered in hemodialysis patients compared with controls. In particular, erythromycin resistance methylase, pyridoxamine 5-phosphate oxidase, and streptothricin-acetyl-transferase were significantly increased in hemodialysis patients. The findings in our study laid a valuable foundation to further elucidate the causative role of virulence factors in predisposing HD patients to infection and to develop treatment strategies to reduce the genetic capacities of antibiotic resistance and virulence factors in HD patients.

Abnormal brain oscillations and activation of patients with heroin use disorder during emotion regulation: The role of delta- and theta-band power

BackgroundEmotion dysregulation is a crucial component of substance use disorders in predisposition, maintenance, and relapse. Emotional regulation strategies are an important factor in emotion dysregulation. However, studies on heroin use disorder (HUD) patients' ability to use emotion regulation strategies are scarce. MethodsTime-frequency-based analyses were used to compare the power of 33 patients with HUD and 28 healthy controls to elucidate whether patients with HUD have abnormal neural oscillations during passive viewing and emotion regulation strategies. Using the standardized low-resolution brain electromagnetic tomography algorithm (sLORETA), we estimated the possible sources of the anomalous band power. ResultsCompared to patients with HUD, healthy controls showed a stronger decrease in the power of the delta/theta band across all task conditions. The effect peaked at approximately 1300–1900 ms after stimulus onset and varied by task condition. The estimation of sLORETA suggested the frontal, parietal, and limbic lobes as possible generators. LimitationsWe cannot exclude the potential influence of additional factors, such as sex, depression and anxiety levels, and polysubstance use, on the results. ConclusionsPatients with HUD have blunted arousal and impaired ability to use emotion regulation strategies. The abnormal patterns described above may be the underlying neurophysiological basis for this dysfunction. Future studies could combine different approaches to improve emotion dysregulation in patients with HUD to promote treatment outcomes.

Interleukin-6 level is a powerful predictor of risk for acute myeloid leukemia (AML) among Iraqi patients

Background: Several studies demonstrate the existence of cytokine dysregulation in patients with acute myeloid leukemia (AML), which may be associated with pathogenesis, disease progression, and patient survival. The aim of this study was to evaluate the association of IL-6 levels and the risk of AML among Iraqi patients. Methods: A case-control study was carried out to analyze IL-6 levels in the serum of 60 patients with AML and a healthy control group. In this study, AML patients were divided into two groups: 30 AML before receiving treatment and 30 AML after receiving treatment. A variety of biochemical and anthropometric measurements, such as sex and age, BMI, serum IL-6, ALT, AST, urea, and creatinine levels, were examined in this study. Results: With regard to the patient group, the BMI, RBC, WBC, Hb, Lymphocytes, neutrophils, platelets, serum ALT, AST, urea, and creatinine levels revealed a significant difference compared with the control group.

Systemic sclerosis patients with negative antinuclear antibodies have distinctive clinical manifestations: amulticenter CRDC cohort in China.

The presence of circulating antinuclear antibodies (ANAs) is ahallmark of immune dysregulation in patients with systemic sclerosis (SSc). Avariety of ANAs are associated with unique sets of disease manifestations and are widely used in clinical practice in SSc. This study aimed to investigate the clinical features of SSc patients negative for ANAs in aChinese Rheumatism Data Center (CRDC) multicenter cohort in China. Patients were prospectively recruited between April 2008 and June 2019 from 154 clinical centers nationwide, and all cases fulfilled the 2013 ACR/EULAR classification criteria for systemic sclerosis. Results for antinuclear antibodies were intensively collected. Demographic, clinical, and laboratory data were compared between ANA-positive SSc patients and those negative for ANAs. Antinuclear antibodies were detected in 2129 of 2809patients enrolled in the study; 4.2% of patients were negative. There were more males among ANA-negative SSc patients (29/60 vs. 294/1746, p < 0.001). The incidence of certain critical organ involvement, including gastroesophageal reflux (5.6% vs. 18.5%, p = 0.002), interstitial lung disease (65.2% vs. 77.9%, p = 0.015), and pulmonary arterial hypertension (11.5% vs. 29.0%, p = 0.006) was significantly lower in ANA-negative patients than in ANA-positive patients. The proportion of abnormal erythrocyte sedimentation rate (32.4% vs. 47.6%, p = 0.013) and IgG elevation (14.3% vs. 37.0%, p = 0.003), an indicator of disease activity, was significantly lower in ANA-negative patients than in ANA-positive patients. Antinuclear antibodies are strongly associated with the clinical manifestations of systemic sclerosis, with ANA-negative SSc patients tending to exhibit relatively milder disease.

Interleukin-7 regulates CD127 expression and promotes CD8+ T cell activity in patients with primary cutaneous melanoma

BackgroundInterleukin (IL)-7 signaling through CD127 is impaired in lymphocytes in cancers and chronic infections, resulting in CD8+ T cell exhaustion. The mechanisms underlying CD8+ T cell responses to IL-7 in melanoma remain not completely elucidated. We previously showed reduced IL-7 level in melanoma patients. Thus, the aim of this study was to investigate the effect of IL-7 regulation on CD127 expression and CD8+ T cell responses in melanoma.MethodsHealthy controls and primary cutaneous melanoma patients were enrolled. Membrane-bound CD127 (mCD127) expression on CD8+ T cells was determined by flow cytometry. Soluble CD127 (sCD127) protein level was measured by ELISA. Total CD127 and sCD127 mRNA level was measured by real-time PCR. CD8+ T cells were stimulated with recombinant human IL-7, along with signaling pathway inhibitors. CD8+ T cells were co-cultured with melanoma cell line, and the cytotoxicity of CD8+ T cells was assessed by measurement of lactate dehydrogenase expression.ResultsPlasma sCD127 was lower in melanoma patients compared with controls. The percentage of CD8+ T cells expressing mCD127 was higher, while sCD127 mRNA level was lower in peripheral and tumor-infiltrating CD8+ T cells from melanoma patients. There was no significant difference of total CD127 mRNA expression in CD8+ T cells between groups. IL-7 stimulation enhanced total CD127 and sCD127 mRNA expression and sCD127 release by CD8+ T cells. However, mCD127 mRNA expression on CD8+ T cells was not affected. This process was mainly mediated by phosphatidylinositol 3-kinase (PI3K) pathway. CD8+ T cells from melanoma patients exhibited decreased cytotoxicity. IL-7 stimulation promoted CD8+ T cell cytotoxicity, while inhibition of PI3K dampened IL-7-induced elevation of CD8+ T cell cytotoxicity.ConclusionThe current data suggested that insufficient IL-7 secretion might contribute to CD8+ T cell exhaustion and CD127 dysregulation in patients with primary cutaneous melanoma.

An Observational Study of Heart Rate Variability Using Wearable Sensors Provides a Target for Therapeutic Monitoring of Autonomic Dysregulation in Patients with Rett Syndrome.

Rett Syndrome (RTT) is a complex neurodevelopmental disorder that has multi-system involvement with co-occurring epilepsy, breathing problems and autonomic dysregulation. Autonomic dysregulation can increase the risk of cardiorespiratory vulnerability in this patient group. Assessment of heart rate variability (HRV) provides an overview of autonomic health in RTT and offers insight into how the sympathetic and parasympathetic components of the nervous system function. However, to our knowledge, no study has evaluated HRV in Rett patients to assess how the dynamics of autonomic function vary with age and changes during the day and/or night. Using non-invasive wearable sensors, we measured HRV in 45 patients with RTT and examined the time and frequency domain sympathetic and parasympathetic indices. Among the HRV indices assessed, heart rate decreases with age and is lower in the night across all ages studied. The sympathetic index (SDNN) and the parasympathetic indices (RMSSD and pNN50) are not seen to change with age. Nevertheless, these indices were all higher during the day when compared to the night. Our findings appear to show that Rett patients are less adaptable to autonomic changes during the night. In the clinical setting, this might be more relevant for patients with severe psychopathology.

P1640: SINGLE NUCLEOTIDE POLYMORPHISMS OF THE HIF1A GENE ARE ASSOCIATED WITH SENSITIVITY OF GLUCOCORTICOID TREATMENT IN PEDIATRIC ITP PATIENTS

Background: Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1α is associated with the inflammation and pathologic activities of autoimmune diseases，suggesting that HIF1α may be involved in immune dysregulation in patients with immune thrombocytopenia (ITP). Aims: The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to ITP and its clinical prognosis including incidence of chronic immune thrombocytopenia (CITP) and glucocorticoid sensitivity. Methods: This study involved 197 Chinese ITP pediatric patients (discovery cohort) and 220 healthy controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect three SNPs genotypes in the HIF1A gene: rs11549465, rs1957757 and rs2057482. We also employed another ITP cohort (N = 127) to validate the significant results of SNPs found in the discovery cohort. Results: The frequencies of the three SNPs did not show any significant differences between the ITP and healthy control groups. The CT genotype at rs11549465 was significantly higher in ITP patients sensitive to glucocorticoid-treatment than in those insensitive to glucocorticoid-treatment (P = .025). These results were validated using another ITP cohort (N =127, P = .033). Moreover, the CC genotype was a risk factor for insensitive to GT the OR (95% confidence interval) was 5.96(5.23-6.69) in standard prednisone (PDN) (P=.0069) and 6.35(5.33-7.37) in high-dose dexamethasone (HDD) (P=.04). Summary/Conclusion: Although HIF1A gene polymorphisms were not associated with susceptibility to ITP, the CT genotype at rs11549465 was associated with the sensitivity to glucocorticoid-treatment of ITP patients, suggesting that the rs11549465 SNP may contribute to the sensitivity of glucocorticoid treatment in pediatric ITP patients.

Impaired Kallikrein-Kinin System in COVID-19 Patients' Severity.

COVID-19 has emerged as a devastating disease in the last 2 years. Many authors appointed to the importance of kallikrein-kinin system (KKS) in COVID-19 pathophysiology as it is involved in inflammation, vascular homeostasis, and coagulation. We aim to study the bradykinin cascade and its involvement in severity of patients with COVID-19. This is an observational cohort study involving 63 consecutive patients with severe COVID-19 pneumonia and 27 healthy subjects as control group. Clinical laboratory findings and plasma protein concentration of KKS peptides [bradykinin (BK), BK1-8], KKS proteins [high–molecular weight kininogen (HK)], and KKS enzymes [carboxypeptidase N subunit 1 (CPN1), kallikrein B1 (KLKB1), angiotensin converting enzyme 2 (ACE2), and C1 esterase inhibitor (C1INH)] were analyzed. We detected dysregulated KKS in patients with COVID-19, characterized by an accumulation of BK1-8 in combination with decreased levels of BK. Accumulated BK1-8 was related to severity of patients with COVID-19. A multivariate logistic regression model retained BK1-8, BK, and D-dimer as independent predictor factors to intensive care unit (ICU) admission. A Youden’s optimal cutoff value of −0.352 was found for the multivariate model score with an accuracy of 92.9%. Multivariate model score-high group presented an odds ratio for ICU admission of 260.0. BK1-8 was related to inflammation, coagulation, and lymphopenia. Our data suggest that BK1-8/BK plasma concentration in combination with D-dimer levels might be retained as independent predictors for ICU admission in patients with COVID-19. Moreover, we reported KKS dysregulation in patients with COVID-19, which was related to disease severity by means of inflammation, hypercoagulation, and lymphopenia.

Network analysis to determine association between immuno-related toxicities and immune soluble profile in patients treated with anti–PD-1.

2553 Background: Immune checkpoint inhibitors (ICIs) have peculiar, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies by ICI class, administered dose and treatment schedule. The aim of the study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods: A prospective, multicenter study evaluating the IP of 79 patients with advanced cancer, treated with anti-PD-1drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. IDO levels were evaluated through a modified liquid chromatography–tandem mass spectrometry. Data were first pre-processed by performing logarithmic transformation and Shapiro-Wilk-test. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (23%). A positive and statistically significant correlation between the cumulative toxicity and IP10 and IL8, sLAG3, sPDL-2 sHEVM, sCD137, sCD27 and sICAM1 was found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern characterized by disruption of most of the paired connections between cytokines (all the connections of the cytokine IL8, most of the connections between the pro-inflammatory chemokines, or all the connections of CD137, CD27, and CD28), while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients with toxicity. Conclusions: A peculiar pattern of immune dysregulation in patients who develop irAEs was defined. This immune serological profile could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.

Leukocyte cytokine responses in adult patients with mitochondrial DNA defects.

Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.3243A > G mutation or single, large-scale mtDNA deletions, we examined (i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure and (ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose-response experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 74-79% lower responses for IL-6 and IL-1β (pIL-6 = 0.031, pIL-1β = 0.009). Moreover, whole blood from patients with mtDNA deletions (pIL-6 = 0.006), but not patients with the m.3243A > G mutation, showed greater sensitivity to the immunosuppressive effects of dexamethasone. Together, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and increase the sensitivity to immune cytokine suppression by glucocorticoids. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes. KEY MESSAGES: Little is known about leukocyte cytokine responses in patients with mitochondrial diseases. Leukocytes of patients with mtDNA deletions show blunted LPS sensitivity and cytokine responses. Leukocytes of patients with mtDNA deletions are more sensitive to glucocorticoid-mediated IL-6 suppression. Work in larger cohorts is needed to delineate potential immune alterations in mitochondrial diseases.

Single Nucleotide Polymorphisms of the HIF1A Gene are Associated With Sensitivity of Glucocorticoid Treatment in Pediatric ITP Patients.

Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1α is associated with the inflammation and pathologic activities of autoimmune diseases, suggesting that HIF1α may be involved in immune dysregulation in patients with immune thrombocytopenia (ITP). The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to ITP and its clinical prognosis including incidence of chronic ITP and glucocorticoid sensitivity. This study involved 197 Chinese ITP pediatric patients (discovery cohort) and 220 healthy controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect 3 SNPs genotypes in the HIF1A gene: rs11549465, rs1957757, and rs2057482. We also used another ITP cohort (N=127) to validate the significant results of SNPs found in the discovery cohort. The frequencies of the three SNPs did not show any significant differences between the ITP and healthy control groups. The CT genotype at rs11549465 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment ( P =0.025). These results were validated using another ITP cohort (N=127, P =0.033). Moreover, the CC genotype was a risk factor for insensitive to GT the odds ratio (95% confidence interval) was 5.96 (5.23-6.69) in standard prednisone ( P =0.0069) and 6.35 (5.33-7.37) in high-dose dexamethasone ( P =0.04). Although HIF1A gene polymorphisms were not associated with susceptibility to ITP, the CT genotype at rs11549465 was associated with the sensitivity to glucocorticoid treatment of ITP patients, suggesting that the rs11549465 SNP may contribute to the sensitivity of glucocorticoid treatment in pediatric ITP patients.

PcMSC Modulates Immune Dysregulation in Patients With COVID-19-Induced Refractory Acute Lung Injury.

Background and ObjectivesThe novel coronavirus disease 2019 (COVID-19) has been a pandemic health issue in 30 January 2020. The mortality rate is as high as 50% in critically ill patients. Stem cell therapy is effective for those who are refractory to standard treatments. However, the immune responses that underlie stem cell therapy have not been well reported, particularly, in patients associated with moderate to severe acute respiratory distress syndrome (ARDS).MethodsOn Days 0 and 4, an intravenous infusion of 2 × 107 placenta-derived mesenchymal stem cells (pcMSCs) (MatriPlax) were administered to five severe COVID-19 patients refractory to current standard therapies. Peripheral blood inflammatory markers and immune profiles were determined by multi-parameter flow cytometry and studied at Days 0, 4, and 8. Clinical outcomes were also observed.ResultsNone of the pc-MSC treated patients experienced 28-day mortality compared with the control group and showed a significant improvement in the PaO2/FiO2 ratio, Murray’s lung injury scores, reduction in serum ferritin, lactate dehydrogenase (LDH), and C-reactive protein (CRP) levels. The cytokine profiles also showed a reduction in IL-1β, IFN-γ, IL-2, and IL-6, and an increase in IL-13 and IL-5 type 2 cytokines within 7 days of therapy. Lymphopenia was also significantly improved after 7 days of treatment. Immune cell profiles showed an increase in the proportions of CD4+ T cells (namely, CD4+ naïve T cells and CD4+ memory T cell subtypes), Treg cells, CD19+ B cells (namely, CD19+ naïve B cells, CD27+ switched B cell subtypes) and dendritic cells, and a significant decrease in the proportion of CD14+ monocytes (namely, CD16- classical and CD16+ non-classical subtypes), and plasma/plasmablast cells. No adverse effects were seen at the serial follow-up visits for 2 months after initial therapy.Conclusionpc-MSCs therapy suppressed hyper-inflammatory states of the innate immune response to COVID-19 infection by increasing Treg cells, decreasing monocytes and plasma/plasmablast cells, and promoting CD4+ T cells and CD19+ B cells toward adaptive immune responses in severely critically ill COVID-19 patients with moderate to severe ARDS, especially those who were refractory to current standard care and immunosuppressive therapies.

Cerebrovascular Dysregulation in Patients with Glioma Assessed with Time-shifted BOLD fMRI.

Background Microscopic vascular events, such as neovascularization and neurovascular uncoupling, are common in cerebral glioma. Mapping the cerebrovascular network remodeling at the macroscopic level may provide an alternative approach to assess hemodynamic dysregulation in patients with glioma. Purpose To investigate cerebrovascular dynamics and their relevance to tumor aggressiveness by using time-shift analysis (TSA) of the systemic low-frequency oscillation (sLFO) of the resting-state blood oxygenation level-dependent signal and a decision tree model. Materials and Methods In this retrospective study, 96 patients with histologically confirmed cerebral glioma were consecutively included (March 2012 to February 2017). TSA was performed to quantify the temporal properties of sLFO signals. Alteration in the time-shift properties was assessed in the tumor region and the contralesional hemisphere relative to the brains of healthy controls by using the Mann-Whitney U test. A decision tree model based on time-shift features was developed to predict the World Health Organization (WHO) glioma grade. Results A total of 88 patients with glioma (WHO grade II, 45; grade III, 21; grade IV, 22; mean age, 42 years; age range, 20-73 years; 51 men) and 40 healthy individuals from the 1000 Functional Connectomes Project (mean age, 32 years; age range, 24-49 years; 19 men) were included. The sLFO of the brain tissues was characterized by increased time shift in the tumor region and enhanced correlation with the global reference signal in the contralesional hemisphere compared with healthy brains. The proportion of tumor voxels with negative correlation to the reference signal significantly increased with the glioma malignancy grade. The decision tree model achieved an accuracy of 91% (80 of 88 patients) in predicting the glioma malignancy grade at the individual level (P = .004) based on the time-shift features. Conclusion Gliomas induced grade-specific cerebrovascular dysregulation in the entire brain, with altered time-shift features of systemic low-frequency oscillation signals. © RSNA, 2022 Online supplemental material is available for this article.

Continuous monitoring with wearables in multiple sclerosis reveals an association of cardiac autonomic dysfunction with disease severity

BackgroundDysfunction of the autonomic nervous system is common in multiple sclerosis patients, and probably present years before diagnosis, but its role in the disease is poorly understood.ObjectivesTo study the autonomic nervous system in patients with multiple sclerosis using cardiac autonomic regulation measured with a wearable.MethodsIn a two-week study, we present a method to standardize the measurement of heart rate variability using a wearable sensor that allows the investigation of circadian trends. Using this method, we investigate the relationship of cardiac autonomic dysfunction with clinical hallmarks and subjective burden of fatigue and autonomic symptoms.ResultsIn 55 patients with multiple sclerosis and 24 healthy age- and gender-matched controls, we assessed the cumulative circadian heart-rate variability trend of two weeks. The trend analysis revealed an effect of inflammation (P = 0.0490, SMD = -0.5466) and progressive neurodegeneration (P = 0.0016, SMD = 1.1491) on cardiac autonomic function. No association with subjective symptoms could be found.ConclusionsTrend-based heart rate variability measured with a wearable provides the opportunity for unobtrusive long-term assessment of autonomic functions in patients with multiple sclerosis. It revealed a general dysregulation in patients with multiple sclerosis.

Ocular rigidity and neuroretinal damage in patients with vasospasticity: a pilot study

ObjectifIl existe des données selon lesquelles la dérégulation du débit sanguin oculaire chez des sujets qui présentent un trouble vasospastique découlerait de stimuli biomécaniques, d'où une sensibilité de la tête du nerf optique en présence de glaucome. Nous nous penchons ici sur le rôle du trouble vasospastique dans l'association entre la rigidité oculaire et les lésions neurorétiniennes, en posant comme hypothèse qu'il existe une corrélation entre une faible rigidité oculaire et l'apparition de lésions glaucomateuses plus importantes chez les patients qui présentent un trouble vasospastique. NatureÉtude transversale. ParticipantsPatients qui présentent un glaucome à angle ouvert (GAO), dont le disque optique a une allure suspecte ou qui n'ont pas de glaucome. MéthodesLa rigidité oculaire a été mesurée au moyen d'une méthode non invasive mise au point et validée par notre équipe. On a eu recours à la tomographie par cohérence optique en domaine spectral pour mesurer l’épaisseur des couches de fibres nerveuses rétiniennes (RNFL, pour retinal nerve fiber layer) et du complexe des cellules ganglionnaires. Le trouble vasospastique a été évalué grâce à un questionnaire standardisé créé à partir de questionnaires validés et adapté aux besoins de notre étude. L'athérosclérose a été évaluée d'après le score de maladie cardiovasculaire de Broadway et Drance (1998). On a recherché des corrélations entre la rigidité oculaire et les paramètres structuraux chez des patients présentant un trouble vasospastique de même que chez des patients présentant une athérosclérose. RésultatsSur les 118 patients – qui avaient un GAO (n = 67), dont le disque optique avait une allure suspecte (n = 26) ou qui ne présentaient pas de glaucome (n = 25) – recrutés de manière consécutive, 10 ont reçu un diagnostic de trouble vasospastique, et 37, d'athérosclérose. Dans le groupe trouble vasospastique, il a été possible d’établir des corrélations significatives entre la rigidité oculaire et le complexe des cellules ganglionnaires le plus mince (rs = 0,681; p = 0,030), l’épaisseur moyenne des RNFL (rs = 0,745; p = 0,013) et l’épaisseur des RNFL dans le quadrant temporal (rs = 0,772; p = 0,009), ce qui dénote un dommage accru à mesure que diminue la rigidité oculaire. Les tendances se sont maintenues, même après avoir réalisé une correction de tests multiples. Cependant, seule la huitième heure de l'horloge des RNFL correspondant au quadrant temporal inférieur de la région péripapillaire demeurait significativement corrélée avec la rigidité oculaire dans le groupe trouble vasospastique (p = 0,015). En revanche, aucune corrélation n'a pu être mise au jour dans le groupe athérosclérose (p > 0,05). ConclusionsLes résultats de la présente étude pilote révèlent une tendance selon laquelle les patients qui présentent un trouble vasospastique et dont la rigidité oculaire est moindre sont sujets à plus de lésions des structures neuronales. Il est donc possible que la rigidité oculaire joue un plus grand rôle dans le glaucome chez les patients qui présentent un trouble vasospastique que chez les patients qui présentent une athérosclérose. Si ces résultats jettent une lumière intéressante sur la physiopathologie du GAO, d'autres études devront étayer nos observations.

Sleep disturbances in the context of neurohormonal dysregulation in patients with bipolar disorder

BackgroundSleep dysfunction is a core symptom in bipolar disorder (BD), especially during major mood episodes. This study investigated the possible link between subjective and objective sleep disturbances in inter-episode BD, changes in melatonin and cortisol levels, and circadian melatonin alignment. The study included 21 euthymic BD patients and 24 healthy controls. Participants had to wear an actigraphy device, keep a weekly sleep diary and take salivary samples: five samples on the last evening to determine the dim light melatonin onset (DLMO) and one the following morning to measure rising cortisol. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) and Regensburg Insomnia Scale (RIS), and circadian alignment by the phase angle difference (PAD).ResultsIn comparison to healthy controls, BD patients had: (1) higher PSQI (5.52 ± 3.14 vs. 3.63 ± 2.18; p = 0.022) (significant after controlling for age and gender), and higher RIS scores (8.91 ± 5.43 vs. 5.83 ± 3.76; p = 0.031); (2) subjective a longer mean TST (p = 0.024) and TIB (p = 0.002) (both significant after controlling for age and gender), longer WASO (p = 0.019), and worse SE (p = 0.036) (significant after controlling for gender); (3) actigraphically validated earlier sleep onset (p = 0.002), less variation in sleep onset time (p = 0.005) and no longer TST (p = 0.176); (4) no differing melatonin levels (4.06 ± 2.77 vs. 3.35 ± 2.23 p = 0.352), an 1.65 h earlier DLMO (20.17 ± 1.63 vs. 21.82 ± 1.50; p = 0. 001) (significant after controlling for gender), and a phase advance of melatonin (6.35 ± 1.40 vs. 7.48 ± 1.53; p = 0.017) (significant after controlling for gender); and (5) no differing cortisol awakening response (16.97 ± 10.22 vs 17.06 ± 5.37 p = 0.969).ConclusionsPatients with BD, even in euthymic phase, have a significantly worse perception of their sleep. Advanced sleep phases in BD might be worth further investigation and could help to explain the therapeutic effects of mood stabilizers such as lithium and valproate.

Age and Injury Size Influence the Magnitude of Fecal Dysbiosis in Adult Burn Patients.

Clinical studies have demonstrated that age 50 years or older is an independent risk factor associated with poor prognosis after burn injury, the second leading cause of traumatic injuries in the aged population. While mechanisms driving age-dependent postburn mortality are perplexing, changes in the intestinal microbiome, may contribute to the heightened, dysregulated systemic response seen in aging burn patients. The fecal microbiome from 22 patients admitted to a verified burn center from July 2018 to February 2019 was stratified based on the age of 50 years and total burn surface area (TBSA) size of ≥10%. Significant differences (P = .014) in overall microbiota community composition (ie, beta diversity) were measured across the four patient groups: young <10% TBSA, young ≥10% TBSA, older <10% TBSA, and older ≥10% TBSA. Differences in beta diversity were driven by %TBSA (P = .013) and trended with age (P = .087). Alpha diversity components, richness, evenness, and Shannon diversity were measured. We observed significant differences in bacterial species evenness (P = .0023) and Shannon diversity (P = .0033) between the groups. There were significant correlations between individual bacterial species and levels of short-chain fatty acids. Specifically, levels of fecal butyrate correlated with the presence of Enterobacteriaceae, an opportunistic gut pathogen, when elevated in burn patients lead to worsen outcomes. Overall, our findings reveal that age-specific changes in the fecal microbiome following burn injuries may contribute to immune system dysregulation in patients with varying TBSA burns and potentially lead to worsened clinical outcomes with heightened morbidity and mortality.

A Systematic Review on HOX Genes as Potential Biomarkers in Colorectal Cancer: An Emerging Role of HOXB9.

Emerging evidence shows that Homeobox (HOX) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64–10.43, I2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

Rasagiline does not exacerbate autonomic blood pressure dysregulation in early or mild Parkinson’s disease

IntroductionOrthostatic hypotension (OH) and abnormal blood pressure (BP) fluctuations occur mainly due to noradrenergic dysfunction and are clinically important in patients with Parkinson’s disease (PD). They lead to impairments of cognition function, daily activities, and quality of life. Some monoamine oxidase (MAO)-B inhibitors have a sympathomimetic amine, which can be attributed to OH. Therefore, we determined whether rasagiline, a common MAO-B inhibitor used in PD treatment, can contribute to cardiovascular autonomic BP dysregulation in patients with early or mild PD. MethodsNineteen patients with early or mild PD were recruited, and tilt test and 24-h ambulatory BP monitoring (ABPM) were performed before and after rasagiline administration. Early or mild PD was defined as patients with de novo (n = 4), levodopa (n = 10), dopamine agonist (n = 1), levodopa and one dopamine agonist (n = 2), levodopa and droxidopa (n = 1), and levodopa and istradefylline (n = 1). Furthermore, patients with motor fluctuation and multiple dopamine agonists were excluded from our study. ResultsOH and BP frequency were not significantly exacerbated before or after rasagiline administration. No significant differences of type in BP fluctuation on ABPM and the degree of nocturnal BP falls were found before and after rasagiline administration. The Unified Parkinson’s Disease Rating Scale motor score in patients (post-rasagiline administration) was significantly improved compared with before. ConclusionRasagiline seems to be a suitable medication for Parkinsonian symptoms in patients with early and mild PD. It does not exacerbate cardiovascular autonomic responses, circadian rhythm of BP, or both.

Relationship Between Severity of T cell Lymphopenia and Immune Dysregulation in Patients With DiGeorge Syndrome (22q11.2 Deletions and/or Related TBX1 Mutations): A USIDNET Study

To evaluate if the severity of T-cell lymphopenia is associated with immune dysregulation, such as autoimmunity and asthma, in patients with DiGeorge syndrome (DGS) and/or TBX1 mutation.In this study, researchers included 415 patients with DGS and/or TBX1 mutations from the US Immunodeficiency Network registry. Patients with complete and atypical complete DGS were excluded. The median age was 4.6 years (range: 0–45 years).This was a retrospective analysis of 415 patients with DGS and/or TBX1 mutations from the US Immunodeficiency Network registry. Patients were stratified on the basis of severity of initial absolute CD3+ T cells. The rate of infections, autoimmunity, and atopic disease were compared by using χ2 tests and multivariate logistic regression.In this DGS cohort, the median absolute CD3+ T-cell count was 1424 (range: 85–6371 cells/μl). Among the 415 DGS patients, 25% reported congenital heart disease, 4.1% reported autoimmunity, and 6.7% reported asthma. Absolute CD3 counts were lower in those with cardiac disease (P < .001). Patients with absolute CD3+ T cells <50% of age-adjusted normal values were more likely to have reported autoimmunity (odds ratio: 7.56; 95% confidence interval: 1.58 to 36.17; P = .01) and asthma (odds ratio: 4.5; 95% confidence interval: 1.06 to 18.93; P = .04) when compared with those with normal T cell counts. The most commonly reported autoimmune conditions were thyroid disease and cytopenias. Patients with reported autoimmunity more frequently had low CD19+ B cells (P = .002) and low immunoglobulin G (P = .005), when compared with those without autoimmunity. There was no association noted between low CD3+ T cells and immunoglobulin levels or infection rates.Patients with DGS and absolute CD3+ T cells <50% of age-adjusted normal levels had a higher odds of developing autoimmunity and/or asthma, when compared with those with normal T cell counts.Although it is well known that DGS increases the risk for autoimmunity and atopy, in this study, the authors investigated the association between the severity of T-cell lymphopenia and odds of autoimmunity and atopy. Patients with absolute CD3+ T cells <50% of age-adjusted normal levels had a significantly higher odds of developing autoimmunity and/or asthma. This information is useful to providers because it helps us identify those at higher risk for developing autoimmunity and/or asthma and allows us to heighten our surveillance in this population, especially because autoimmunity and/or asthma had increasing frequency with advancing age. This was a large study of DGS patients nationally; however, it was limited by the nature of registry data, which had variable areas of missing data.