Human microglial state dynamics in Alzheimer's disease progression.

Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects and diverse Alzheimer's disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.

Dysregulation of persistent inward and outward currents in spinal motoneurons of symptomatic SOD1-G93A mice.

Persistent inward currents (PICs) and persistent outward currents (POCs) regulate the excitability and firing behaviours of spinal motoneurons (MNs). Given their potential role in MN excitability dysfunction in amyotrophic lateral sclerosis (ALS), PICs have been previously studied in superoxide dismutase 1 (SOD1)-G93A mice (the standard animal model of ALS); however, conflicting results have been reported on how the net PIC changes during disease progression. Also, individual PICs and POCs have never been examined before in symptomatic ALS. To fill this gap, we measured the net and individual PIC and POC components of wild-type (WT) and SOD MNs in current clamp and voltage clamp during disease progression (assessed by neuroscores). We show that SOD MNs of symptomatic mice experience a much larger net PIC, relative to WT cells from age-matched littermates. Specifically, the Na+ and Ca2+ PICs are larger, whereas the lasting SK-mediated (SKL) POC is smaller than WT (Na+ PIC is the largest and SKL POC is the smallest components in SOD MNs). We also show that PIC dysregulation is present at symptom onset, is sustained throughout advanced disease stages and is proportional to SOD MN cell size (largest dysregulation is in the largest SOD cells, the most vulnerable in ALS). Additionally, we show that studying disease progression using neuroscores is more accurate than using SOD mouse age, which could lead to misleading statistics and age-based trends. Collectively, this study contributes novel PIC and POC data, reveals ionic mechanisms contributing to the vulnerability differential among MN types/sizes, and provides insights on the roles PIC and POC mechanisms play in MN excitability dysfunction in ALS. KEY POINTS: Individual persistent inward currents (PICs) and persistent outward currents (POCs) have never been examined before in spinal motoneurons (MNs) of symptomatic amyotrophic lateral sclerosis (ALS) mice. Thus, we contribute novel PIC and POC data to the ALS literature. Male SOD MNs of symptomatic mice have elevated net PIC, with larger Na+ and Ca2+ PICs but reduced SKL POC vs. wild-type littermates. Na+ PIC is the largest and SKL POC is the smallest current in SOD cells. The PIC/POC dysregulation is present at symptom onset. PIC dysregulation is sustained throughout advanced disease, and is proportional to SOD MN size (largest dysregulation is in the largest cells, the most vulnerable in ALS). Thus, we reveal ionic mechanisms contributing to the vulnerability differential among MN types/sizes in ALS. Studying disease progression using SOD mice neuroscores is more accurate than using age, which could distort the statistical differences between SOD and WT PIC/POC data and the trends during disease progression.

The impact of the COVID-19 pandemic on renal cancer care.

PURPOSE: To evaluate the impact of the COVID-19 pandemic on renal cell carcinoma (RCC) care in the Netherlands. METHODS: Newly diagnosed RCCs between 2018 and 2021 were selected from the Netherlands Cancer Registry; 2020-2021 was defined as COVID period and 2018-2019 as reference period. Numbers of RCCs were evaluated using 3-week-moving averages, overall and by disease stage and age. Changes in treatment were evaluated with logistic regression analyses. To evaluate possible delays in care, time to start of treatment was assessed. The cumulative number of metastatic RCC (mRCC) over time was assessed to evaluate stage shift. RESULTS: During the 1st COVID wave (weeks 9-22, 2020), the number of new RCC diagnoses decreased with 15%. Numbers restored partially in 2020, but remained 10% lower compared to 2018/2019. The decline was mostly due to a drop in T1a/T1b RCCs and in age > 70 years. 2021 showed similar numbers of new RCC diagnoses compared to 2018/2019 without an increase due to previously missed RCCs. Treatment-related changes during the 1st COVID wave were limited and temporarily; less surgery in T1a RCCs in favor of more active surveillance, and in mRCC targeted therapy was preferred over immunotherapy. Time to start of firstline treatment was not prolonged during the 1st COVID wave. No increase in mRCC was found until the end of 2021. CONCLUSIONS: The COVID-19 pandemic resulted in fewer RCC diagnoses, especially T1a/T1b tumors. Treatment-related changes appeared to be limited, temporarily and in accordance with the adapted guidelines. The diagnostic delay could lead to more advanced RCCs in later years but there are no indications for this yet.

Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study.

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

Comparisons of postural control, proprioception, muscle strength, pain and disability between individuals with acute, subacute and chronic low back pain.

PURPOSE/AIM: Postural control, proprioception and lower extremity muscle strength are affected in individuals with low back pain (LBP). However, it is yet unknown whether these variables differentiate between acute, subacute and chronic stages of LBP. The aim was to investigate if there were any differences in postural control, proprioception, lower extremity muscle strength, pain intensity and disability between individuals in the different stages of LBP. MATERIALS AND METHODS: In this cross-sectional study, 124 individuals with LBP were grouped as acute LBP (ALBP) (n = 38), subacute LBP (SLBP) (n = 30) and chronic LBP (CLBP) (n = 56) groups. Postural control was assessed via computerised technology. Lumbar proprioception, lower extremity muscle strength, pain intensity and disability were assessed using Joint Repositioning Error Test, hand-held dynamometer, Numeric Rating Scale and Oswestry Disability Index (ODI), respectively. Kruskal-Wallis Tests, ANCOVA and post hoc Mann-Whitney U-Test with Bonferroni correction were performed. RESULTS: While there were no significant differences in terms of postural control, proprioception and pain intensity (p > 0.05), significant differences were found in terms of lower extremity muscle strength and ODI scores between groups when adjusted for age (p < 0.05). Individuals with CLBP demonstrated poorer lower extremity muscle strength than those with ALBP and SLBP, and higher disability than those with ALBP (p < 0.017). CONCLUSIONS: Although postural control, proprioception and pain intensity were similar between individuals with acute, subacute and chronic LBP, muscle strength and disability seem to worsen stepwise as the pain becomes chronic. Muscle strength and disability should be taken into account while evaluating and/or managing individuals with acute and subacute stages of LBP.

The generalized order statistics arising from three populations with the lower truncated proportional hazard rate models and its application to the sensitivity to the early disease stage.

In this paper, we present some results to make inference about the parameters of lower truncated proportional hazard rate models with the same baseline distributions based on three independent generalized order statistics samples. Then, especially by considering the results of the diagnostic tests for the non-diseased, early-diseased stage and fully diseased populations, we make inference about sensitivity to the early disease stage parameter. The maximum likelihood estimator, a generalized pivotal estimator and some Bayes estimators are obtained for different structures of prior distributions. The percentile bootstrap confidence interval, a generalized pivotal confidence interval and some Bayesian credible intervals are also presented. A Monte Carlo simulation study is used to evaluate the performances of the obtained point estimators and confidence/credible intervals and two competitors. We use two real datasets to illustrate the proposed methods.

Socioeconomic position and the pre-diagnostic interval among patients diagnosed with head and neck squamous cell carcinoma - a population-based study from DAHANCA.

BACKGROUND: The socioeconomic differences in survival are pronounced for patients diagnosed with head and neck cancer; disease stage at diagnosis is suggested to be a main driver of this association. This nationwide, population-based study investigates socioeconomic differences in the pre-diagnostic interval and disease stage at diagnosis. MATERIAL AND METHODS: Information on patient-reported symptoms, symptom onset and disease-specific factors was obtained from the nationwide population-based Danish Head and Neck Cancer Group (DAHANCA) database for patients diagnosed with head and neck squamous cell carcinoma between 2008 and 2019 in Denmark. Socioeconomic position (SEP) was measured by individual-level education, income and cohabitation status obtained from administrative registers. Socioeconomic differences in the interval from symptom onset to diagnosis were investigated in general linear models with 95% confidence intervals (CIs); overall and by subsite, symptom and comorbidity score. Consultation patterns prior to diagnosis were examined using methods for change-point detection. Associations with advanced-stage disease were estimated in logistic regression models. RESULTS: Patients with low, medium and high SEP had a similar interval from patient-reported symptom onset to diagnosis of 10 weeks. Although this interval varied according to primary symptom and anatomical subsite, no apparent socioeconomic differences were observed within these subgroups. Aligned with the patient-reported symptom onset, a distinct increase in consultation rates was observed at 9 weeks (95% CI [7.3; 10.7]) for patients with low SEP and 7 weeks (95% CI [4.8; 9.2]) for patients with high SEP, with overlapping CIs. Patients with low compared to high SEP had increased odds for advanced-stage glottic and oral cavity squamous cell carcinoma. For the remaining subsites the association varied according to SEP-indicator and TNM-edition. CONCLUSION: The interval from symptom onset to diagnosis and consultation patterns were similar across SEP groups. Still, socioeconomic differences in stage at diagnosis were observed for some - but not all - subsites.

Kidney biopsy diagnosis in childhood in the Norwegian Kidney Biopsy Registry and the long-term risk of kidney replacement therapy: a 25-year follow-up.

BACKGROUND: There is scarce information on biopsy-verified kidney disease in childhood and its progression to chronic kidney disease stage 5 (CKD 5). This study aims to review biopsy findings in children, and to investigate risk of kidney replacement therapy (KRT). METHODS: We conducted a retrospective long-term follow-up study of children included in the Norwegian Kidney Biopsy Registry (NKBR) and in the Norwegian Renal Registry (NRR) from 1988 to 2021. RESULTS: In total, 575 children with a median (interquartile range, IQR) age of 10.7 (6.1 to 14.1) years were included, and median follow-up time (IQR) after kidney biopsy was 14.3 (range 8.9 to 21.6) years. The most common biopsy diagnoses were minimal change disease (MCD; n = 92), IgA vasculitis nephritis (IgAVN; n = 76), IgA nephropathy (n = 63), and focal and segmental glomerulosclerosis (FSGS; n = 47). In total, 118 (20.5%) of the biopsied children reached CKD 5, median (IQR) time to KRT 2.3 years (7 months to 8.4 years). Most frequently, nephronophthisis (NPHP; n = 16), FSGS (n = 30), IgA nephropathy (n = 9), and membranoproliferative glomerulonephritis (MPGN; n = 9) led to KRT. CONCLUSIONS: The risk of KRT after a kidney biopsy diagnosis is highly dependent on the diagnosis. None of the children with MCD commenced KRT, while 63.8% with FSGS and 100% with NPHP reached KRT. Combining data from kidney biopsy registries with registries on KRT allows for detailed information concerning the risk for later CKD 5 after biopsy-verified kidney disease in childhood. A higher resolution version of the Graphical abstract is available as Supplementary information.

A morphometric analysis of hepatitis B subviral particles shows no correlation of filament proportion and length with clinical stage and genotype.

It was recently suggested that the composition of circulating hepatitis B subviral particles (SVPs) could be used to differentiate the various stages in chronic hepatitis B virus (HBV) infection, with significantly lower proportions of L and M proteins in inactive carriers than in individuals with chronic hepatitis. L protein is abundant in virions and filamentous SVPs but almost absent from spherical SVPs. We, therefore, performed a morphometric analysis of SVPs in these two groups of patients, by conducting a retrospective analysis on sera from 15 inactive carriers and 11 patients with chronic hepatitis infected with various HBV genotypes. Subviral particles were concentrated by centrifugation on a sucrose cushion, with monitoring by transmission electron microscopy. The percentage of filamentous SVPs and filament length for 100 SVPs was determined with a digital camera. The L protein PreS1 promoter was sequenced from viral genomes by the Sanger method. No marked differences were found between patients, some of whom had only spherical SVPs, whereas others had variable percentages of filamentous SVPs (up to 28%), of highly variable length. High filament percentages were not associated with a particular sequence of the L protein promoter, HBV genotype or even disease stage. High levels of circulating filamentous SVPs are probably more strongly related to individual host factors than to viral strain characteristics or disease stage.

Effect of predictors on incidence rate of pregnancy among reproductive age women on antiretroviral therapy at public hospitals of Jigjiga and Harar Towns, Eastern Ethiopia: a retrospective cohort study.

BACKGROUND: Globally, Human Immunodeficiency Virus (HIV) is the leading cause of death in women of reproductive age and accountable for a quarter of deaths during pregnancy in sub-Saharan Africa including Ethiopia. Introduction of antiretroviral therapy to women living with HIV highly improves lifestyle and the desire to have children. A comprehensive understanding of baseline predictors of pregnancy among women receiving ART essential to reduces unintended pregnancies, appropriate care, and preventing transmission from mother to child. OBJECTIVE: To determine the effect of baseline predictors on incidence rate of pregnancy among reproductive age women on antiretroviral therapy at public hospitals of Jigjiga and Harar town, Eastern Ethiopia from February 15 to march 15, 2020. METHODS: Retrospective cohort study was conducted on randomly selected 420 HIV-infected women using data recorded from September 11, 2014, to September 10, 2019 in Jigjiga and Harar town in Eastern Ethiopia. Simple random sampling was used to select study subjects from each hospital. Data were entered to Epi data version 3.2 and exported to Stata version 14.2 for analysis. Kaplan-Meier failure, and Cox proportional hazards model were used to estimate the incidence, and to identify predictors of pregnancy respectively. Variables which were significant (P value < 0.05) in the multivariate analysis were considered independent predictors of pregnancy. RESULTS: The overall incidence rate of pregnancy was 9.1 per 100 person-years (95% CI 7.19, 11.76). Being unadvanced HIV disease stage (AHR: 2.50; 95% CI 1.46, 4.19), having less than two children (AHR: 2.93; 95% CI 1.59, 5.40), and disclosed HIV status (AHR: 2.25; 95% CI 1.34, 3.79) were independent predictors of pregnancy. CONCLUSION: The incidence rate of pregnancy among reproductive age women on ART was found to be considerable. Being unadvanced HIV disease stage, having less than two children, and disclosed HIV status were independent predictors of pregnancy. Thus, tailoring counseling have to be designed to enhance better pregnancy planning and consecutive health outcomes.

Empirical likelihood confidence interval for sensitivity to the early disease stage.

Disease status can naturally be classified into three or more ordinal stages rather than just being binary stages. Many works have been done for the estimation and inference procedure regarding three ordinal disease stages, which are non-disease, early disease, and full disease stages. The early disease stage can be very important for therapeutic intervention and prevention potentiality. As a diagnostic measure, sensitivity to the early disease stage is often used. In this article, we propose confidence intervals for the sensitivity to early disease stage based on given target specificity for non-disease stage and target sensitivity to full disease stage using both empirical likelihood (EL) and adjusted EL procedures. We compare the performance of the proposed EL confidence intervals with other procedures in our simulation study. The proposed procedures are further applied to Alzheimer's Disease Neuroimaging Initiative data set.

Disease Progression in CNGA3 and CNGB3 Retinopathy; Characteristics of Slovenian Cohort and Proposed OCT Staging Based on Pooled Data from 126 Patients from 7 Studies.

Achromatopsia has been proposed to be a morphologically predominately stable retinopathy with rare reports of progression of structural changes in the macula. A five-grade system of optical coherence tomography (OCT) features has been used for the classification of structural macular changes. However, their association with age remains questionable. We characterized the Slovenian cohort of 12 patients with pathogenic variants in CNGA3 or CNGB3 who had been followed up with OCT for up to 9 years. Based on observed structural changes in association with age, the following four-stage classification of retinal morphological changes was proposed: (I) preserved inner segment ellipsoid band (Ise), (II) disrupted ISe, (III) ISe loss and (IV) ISe and RPE loss. Data from six previously published studies reporting OCT morphology in CNGA3 and CNGB3 patients were additionally collected, forming the largest CNGA3/CNGB3 cohort to date, comprising 126 patients aged 1-71 years. Multiple regression analysis showed a significant correlation of OCT stage with age (p < 0.001) and no correlation with gene (p > 0.05). The median ages of patients with stages I-IV were 12 years, 23 years, 27 years and 48 years, respectively, and no patient older than 50 years had continuous ISe. Our findings suggest that achromatopsia presents with slowly but steadily progressive structural changes of the macular outer retinal layers. However, whether morphological changes in time follow the proposed four-stage linear pattern needs to be confirmed in a long-term study.

Interleukin-34 expression in ovarian cancer: a possible correlation with disease progression.

Ovarian cancer is the second-most lethal gynecological malignancy and the seventh-commonest cause of cancer-related death in women around the world. Most of the ovarian cancer patients are diagnosed at advanced stages and suffer from recurrence after primary cytoreductive surgery and standard first-line chemotherapy. Thus, the successful management of ovarian cancer patients requires the identification of factors that contribute to progression and relapse. Interleukin-34 (IL-34) is a novel cytokine that acts as a tissue-specific ligand of colony-stimulating factor-1 receptor (CSF-1R). In cancer, IL-34 exerts pro-tumorigenic functions that promote tumor growth, metastasis, angiogenesis, immune suppression and therapeutic resistance. In this study, we evaluate the impact of IL-34 on progression and survival of ovarian cancer patients. First, IL-34 was found to be expressed in several human ovarian cancer cell lines and cancer tissues from patients. The expression of IL-34 was enhanced by cytotoxic chemotherapy in ovarian cancer cell lines and cancer tissues from chemotherapy-treated ovarian cancer patients. Importantly, high IL-34 expression correlated with worse progression-free survival (PFS) and overall survival in different cohorts. The assessment of PFS based on a combination between IL34 expression and other related genes such as CSF1R and CD163 helped further to reach more statistical significance compared with IL34 alone. Furthermore, in the murine ovarian cancer cell HM-1 in vivo model, it was suggested that IL-34-derived tumor cells was correlated with tumor progression and survival by modulating the immune environment. Collectively, these findings indicate a possible correlation between IL-34 expression and disease progression in ovarian cancer patients and the mouse model.

A Comparison of Erectile Dysfunction Improvement Between Patients With Regular Hemodialysis and Patients With Continuous Ambulatory Peritoneal Dialysis.

BACKGROUND: Erectile dysfunction (ED) is one of the sexual dysfunctions that are often encountered as a complication of male patients with stage 5 chronic kidney disease (stage 5 CKD). ED can be caused by psychological factors in patients with regular dialysis therapy. Currently, Hemodialysis (HD) therapy is the first choice in dialysis therapy and only 2% of stage 5 CKD patients are using Continuous Ambulatory Peritoneal Dialysis (CAPD) as a dialysis therapy. ED in stage 5 CKD patients should become a part of the treatment of patients with dialysis, which hopefully will improve the quality of life of patients. This study aims to compare the improvement in ED degree in patients with HD and CAPD. METHOD: This study is an observational analytic comparative study involving 44 male patients with stage 5 CKD; 22 of whom underwent HD and the remaining 22 patients underwent CAPD. The differences evaluated were changes in the ED degree before and after dialysis, which were assessed using the International Index of Erectile Function-5 (IIEF-5). RESULT: There were significant differences in the improvement in ED degree and IIEF-5 scores in CAPD group. In the HD group, no significant difference was obtained in the improvement in ED degree and IIEF-5 score. A significant difference was obtained in the improvement in ED degree between the HD and CAPD groups by comparing the improvement in IIEF-5 score. CONCLUSION: Patients with CAPD have a better improvement in ED degree than patients with HD. Duarsa GWK, Kandarini Y, Winarta GK, et al. A Comparison of Erectile Dysfunction Improvement Between Patients With Regular Hemodialysis and Patients With Continuous Ambulatory Peritoneal Dialysis. J Sex Med Rev 2021;18:920-925.

Risk factors for Lyme disease stage and manifestation using electronic health records.

BACKGROUND: Little is known about risk factors for early (e.g., erythema migrans) and disseminated Lyme disease manifestations, such as arthritis, neurological complications, and carditis. No study has used both diagnoses and free text to classify Lyme disease by disease stage and manifestation. METHODS: We identified Lyme disease cases in 2012-2016 in the electronic health record (EHR) of a large, integrated health system in Pennsylvania. We developed a rule-based text-matching algorithm using regular expressions to extract clinical data from free text. Lyme disease cases were then classified by stage and manifestation using data from both diagnoses and free text. Among cases classified by stage, we evaluated individual, community, and health care variables as predictors of disseminated stage (vs. early) disease using Poisson regression models with robust errors. Final models adjusted for sociodemographic factors, receipt of Medical Assistance (i.e., Medicaid, a proxy for low socioeconomic status), primary care contact, setting of diagnosis, season of diagnosis, and urban/rural status. RESULTS: Among 7310 cases of Lyme disease, we classified 62% by stage. Overall, 23% were classified using both diagnoses and text, 26% were classified using diagnoses only, and 13% were classified using text only. Among the staged diagnoses (n = 4530), 30% were disseminated stage (762 arthritis, 426 neurological manifestations, 76 carditis, 95 secondary erythema migrans, and 76 other manifestations). In adjusted models, we found that persons on Medical Assistance at least 50% of time under observation, compared to never users, had a higher risk (risk ratio [95% confidence interval]) of disseminated Lyme disease (1.20 [1.05, 1.37]). Primary care contact (0.59 [0.54, 0.64]) and diagnosis in the urgent care (0.22 [0.17, 0.29]), compared to the outpatient setting, were associated with lower risk of disseminated Lyme disease. CONCLUSIONS: The associations between insurance payor, primary care status, and diagnostic setting with disseminated Lyme disease suggest that lower socioeconomic status and less health care access could be linked with disseminated stage Lyme disease. Intervening on these factors could reduce the individual and health care burden of disseminated Lyme disease. Our findings demonstrate the value of both diagnostic and narrative text data to identify Lyme disease manifestations in the EHR.

Cytoskeletal tubulin competes with actin to increase deformability of metastatic melanoma cells.

The formation of membrane protrusions during migration is reliant upon the cells' cytoskeletal structure and stiffness. It has been reported that actin disruption blocks protrusion and decreases cell stiffness whereas microtubule disruption blocks protrusion but increases stiffness in several cell types. In melanoma, cell migration is of concern as this cancer spreads unusually rapidly during early tumour development. The aim of this study was to characterise motility, structural properties and stiffness of human melanoma cells at radial growth phase (RGP), vertical growth phase (VGP), and metastatic stage (MET) in two-dimensional in vitro environments. Wound assays, western blotting and mitochondrial particle tracking were used to assess cell migration, cytoskeletal content and intracellular fluidity. Our results indicate that cell motility increase with increasing disease stage. Despite their different motility, RGP and VGP cells exhibit similar fluidity, actin and tubulin levels. MET cells, however, display increased fluidity which was associated with increased actin and tubulin content. Our findings demonstrate an interplay between actin and microtubule activity and their role in increasing motility of cells while minimizing cell stiffness at advanced disease stage. In earlier disease stages, cell stiffness may however not serve as an indicator of migratory capabilities.

Study on different pathogenic factors in different disease stages of patients with Wilson disease.

OBJECTIVE: To investigate in different stages of patients with Wilson disease (WD), there are different pathogenic factors such as metal deposition, oxidative stress, and inflammatory response in the brain. METHODS: A total of 32 untreated WD patients and 10 normal controls were enrolled in the study. The neurological symptoms were evaluated using the modified Young scale. Liver function, metal metabolism, susceptibility-weighted imaging (SWI), diffusion tensor imaging (DTI), and magnetic resonance spectroscopy (MRS) examination were done. The clinical disease stages were divided into metal deposition period, fiber damage period, and neuronal necrosis period according to the imaging results. The content of 24-h urine copper, serum copper, and serum iron; and the levels of catalase (CAT), glutathione peroxidase (GSH-PX), malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD), interleukin (IL-1), and tumor necrosis factor alpha (TNF-α) were detected. RESULTS: The contents of urinary copper in WD patients at neuronal necrosis stage were lower than those in patients at the metal deposition stage (P = 0.011) and fiber injury stage (P = 0.023). The contents of NOS (P = 0.039) and NO (P = 0.047) in WD patients at the stage of fiber injury were higher than those of the normal control, while GSH-PX (P = 0.025) and CAT (P = 0.041) were lower in the neuronal necrosis stage. In the stage of neuronal necrosis, the levels of IL-1 (P = 0.030) and TNF-α were higher than those of the normal control (P = 0.042). The neurological symptom scores in patients with fiber injury (P = 0.013) and neuron injury were higher than those with metal deposition (P = 0.026). CONCLUSION: There are different pathogenic factors in different stages of WD. At the neuronal necrosis stage, copper deposition was decreased in WD patients. In the stage of fiber injury and neuronal necrosis, there is oxidative stress injury in WD patients. In the neuronal necrosis phase, WD patients have an inflammatory response.

Decrease of choriocapillary vascular density measured by optical coherence tomography angiography in Vogt-Koyanagi-Harada disease.

PURPOSE: Changes of choroidal circulation throughout the disease course of Vogt-Koyanagi-Harada (VKH) disease and the clinical significance remain unclear. Choriocapillary vascular density (CC VD) measured by optical coherence tomography angiography (OCTA) were compared in different disease stages of VKH and its correlation with other parameters was analyzed, aiming to explore their clinical relevance. METHODS: This is a retrospective case series. One hundred and fourteen VKH patients and 47 normal controls (NCs) were included. Patients were grouped into the acute uveitic, convalescent, and chronic recurrent stages (only anterior recurrent cases included), and OCTA images were obtained from VKH patients in these stages. Best corrected visual acuity (BCVA), CC VD, and subfoveal choroidal thickness (SFCT) were recorded and compared. RESULTS: CC VD in acute (58.26% ± 0.84%), convalescent (64.85% ± 0.33%), and chronic recurrent (62.78% ± 0.70%) stage of VKH patients were all significantly lower than that in NCs (66.37% ± 0.41%) (p < 0.001, p = 0.017, and p < 0.001, respectively). CC VD increased by 6.59% ± 0.91% with resolution of acute inflammation (p < 0.001) and decreased by 2.07% ± 0.74% during anterior uveitis relapse (p = 0.009). Patients with a positive history of anterior recurrence had lower CC VD (- 2.43% ± 0.75%, p = 0.003) in the convalescent stage than those without. CC VD was negatively correlated with logMAR BCVA in VKH (r = - 0.261, p < 0.001). CONCLUSION: CC VD was decreased in every stage of VKH. CC VD has the potential to reflect the status of uveitis and might be promising in monitoring the disease activity. OCTA is a convenient and straightforward tool to evaluate choroidal vascularity, and CC VD provides supplemental quantitative information of the choriocapillaris. Further studies are needed to explore the values of OCTA quantitative parameters in monitoring VKH progression, predicting visual prognosis, and guiding clinical decisions.

[Immunotherapy and personalized treatment of multiple sclerosis]. / Immuntherapie und personalisierte Behandlung bei Multipler Sklerose.

Personalized medicine requires a patient-oriented approach with the exact classification of the disease being determined by the underlying pathophysiological processes. In particular, the optimal treatment of multiple sclerosis (MS) requires personalized treatment that goes beyond the pure concept of precision medicine; however, due to the lack of robust biomarkers beyond cranial magnetic resonance imaging and a lacking detailed understanding of some aspects of MS pathogenesis, this approach is not yet fully implemented. Important questions for a better therapeutic stratification of MS patients are: (1) when does MS start? (2) Does the spectrum of MS really span multiple diseases? (3) When does the progressive phase of the disease begin? (4) In which phase of the disease is there a therapeutic window for immunotherapy? Recent findings indicate that MS represents a spectrum of diseases and that there is a therapeutic delay of several years, on which the optimal treatment effect of a disease-modifying treatment depends. For a personalized treatment of MS it is important to determine the exact disease stage of the patient and to react to the development or increase of focal inflammatory activity in a timely manner.

Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium.

Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I-IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I-IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.