IL-1α, IL-1β, IL-6, and IL-8 secretion of human keratocytes following photodynamic inactivation (PDI) in vitro

Purpose

With increasing resistance of microorganisms to antibiotics, photodynamic inactivation (PDI) may also be a potential therapeutic option in infectious keratitis. As part of the inflammatory response in infectious keratitis, keratocytes produce various interleukins. The purpose of this study was to evaluate the potential anti-inflammatory effect of PDI, analyzing interleukin-1 alpha (IL-1α), interleukine-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) secretion of human keratocytes following PDI, in vitro.

Methods

Primary human keratocytes were isolated by digestion in collagenase A (1.0 mg/ml) from human corneal buttons, and cultured in DMEM/Ham’s F12 medium supplemented with 10 % FCS. Keratocyte cell cultures underwent illumination using red (670 nm) light for 13 min following exposure to 100 nM concentration of the photosensitizer chlorin e6 (Ce6) in the culture medium. Five and 24 hours after PDI, secretion of IL-1α, IL-1β, IL-6, and IL-8 was measured by enzyme-linked immunoabsorbent assay (ELISA).

Results

The secretion of IL-1α was under the measurement limit in treated and untreated cell cultures 5 and 24 h after PDI. Compared to untreated controls, IL-6 and IL-8 secretion of keratocytes decreased (p?<?0.05 and 0.0001) significantly 5 hours after PDI, whereas IL-1β secretion remained unchanged. Twenty-four hours after PDI, secretion of IL-1β, IL-6, and IL-8 did not differ significantly from untreated controls.

Conclusions

In the short term, PDI does not have an impact on IL-1α and IL-1β secretion of keratocytes, in vitro. Photodynamic inactivation inhibits IL-6 and IL-8 secretion of keratocytes transiently (5 h), which normalizes 24 h following treatment. Through the short-term impact of chlorine e6-PDI on IL-6 and IL-8 secretion, PDI may inhibit the inflammatory cascade in at least keratocyte cultures.     

Physiological instability is linked to mortality in primary central nervous system lymphoma: A case–control fMRI study

Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREG_BOLD) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age‐matched controls (median 63y; 73% females) were scanned for MREG_BOLD signal during 2018–2021. Motion effects were removed. Voxel‐by‐voxel Coefficient of Variation (CV) maps of MREG_BOLD signal was calculated to examine the stability of physiological brain pulsations. Group‐level differences in CV were examined using nonparametric covariate‐adjusted tests. Subject‐level CV alterations were examined against control population Z‐score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast‐enhanced, diffusion‐weighted, fluid‐attenuated inversion recovery (FLAIR) data]. Whole‐brain mean CV was linked to short‐term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values (n = 5, median 0.055) than surviving patients (n = 16, median 0.028) (p < .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories (p ≤ .001). Abnormal clusters (median 1.10 × 10⁵mm³) extended spatially beyond FLAIR lesions (median 0.62 × 10⁵mm³) with differences in volumes (p = .0055).     

Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection

OBJECTIVE: To evaluate neurodevelopmental status of children treated with intrauterine red blood cell and platelet transfusion for fetal hydrops caused by parvovirus B19. METHODS: Maternal and neonatal records of all intrauterine transfusions for congenital parvovirus B19 infection in our center between 1997 and 2005 were reviewed. Congenital B19 virus infection was confirmed by the presence of parvovirus B19-specific immunoglobulin M or parvovirus B19 DNA in fetal blood samples. All children underwent a general pediatric and neurological examination. Primary outcome measure was neurodevelopmental status (developmental index by Bayley Scales of Infant Development or Snijders-Oomen test). Secondary outcome measure was general health status of surviving children. RESULTS: A total of 25 intrauterine transfusions were performed in 24 hydropic fetuses. Median fetal hemoglobin concentration, platelet count, and blood pH before intrauterine transfusions were 4.5 g/dL (range 2.4-11.4 g/dL), 79x10(9)/L (range 37-238x10(9)/L) and 7.36 (range 7.31-7.51), respectively. Sixteen survivors aged 6 months to 8 years were included in the follow-up study. Eleven children (68%) were normal, and 5 children (32%) demonstrated a delayed psychomotor development with an suboptimal neurological examination (mild delay n=3, severe delay n=2). Neurodevelopmental status did not correlate with pre-intrauterine transfusion hemoglobin, platelet, or blood pH values. Growth and general health status were normal in all. Two children had minor congenital defects. CONCLUSION: Neurodevelopmental status was abnormal in 5 of 16 survivors and was not related to the severity of fetal anemia and acidemia. We hypothesize that fetal parvovirus B19 infection may induce central nervous system damage. LEVEL OF EVIDENCE: III.     

The Effect of a 2-Year Intervention Consisting of Diet,Physical Exercise,Cognitive Training,and Monitoring of Vascular Risk on Chronic Morbidity—the FINGER Randomized Controlled Trial

Objective

To verify whether a multidomain intervention lowers the risk of developing new chronic diseases in older adults.

Prediction of individual clinical outcome in MCI by means of genetic assessment and (18)F-FDG PET.

Patients with mild cognitive impairment (MCI) represent a risk population for progressing to dementia of the Alzheimer type (DAT). However, clinical criteria do not ensure reliable individual prognosis in these patients. The objective of this longitudinal, prospective study was to examine the value of (18)F-FDG PET of cerebral glucose metabolism and of genetic susceptibility, as defined by an APOEepsilon4-positive genotype, with regard to the early diagnosis of DAT in patients with MCI. METHODS: In 30 patients with the diagnosis of MCI (16 female, 14 male; age, 70 +/- 8 y), baseline and follow-up examinations (mean observation period, 16 mo) were performed. In all patients, the APOE genotype was assessed and cerebral glucose metabolism was evaluated at baseline using cranial (18)F-FDG PET. Individual PET data were screened for findings suggestive of Alzheimer's disease (AD), with the help of an automated computer program. After stereotactical normalization of the PET images, this program performs an observer-independent statistical comparison with an age-matched reference database (n = 22). RESULTS: In 43% of all MCI subjects, a PET scan suggestive of AD pathology according to our predefined criteria was observed at baseline (PET+); 57% of all MCI patients were carriers of the APOE epsilon4 allele (e4+). In 40% of all patients, progression of symptoms within the observation period justified the clinical diagnosis of probable DAT at the time of follow-up reevaluation. Statistical evaluation revealed the best results for PET with regard to early diagnosis of DAT in MCI patients (sensitivity, 92%; specificity, 89%). Classification according to the APOE genotype was significantly less successful (sensitivity, 75%; specificity, 56%). However, a combination of both diagnostic tests allowed early diagnosis with either very high specificity (PET+ AND e4+: sensitivity, 67%; specificity, 100%) or very high sensitivity (PET+ OR e4+: sensitivity, 100%; specificity, 44%). CONCLUSION: (18)F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients. Results are superior to the exclusive assessment of the APOE genotype. A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity. This may be valuable, for example, for patient selection in scientific studies.     

Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study

High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF-alpha gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P = 0.034). Subjects with both the A allele of the TNF-alpha gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF-alpha gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.     

The structure of the General Health Questionnaire (GHQ-12): two meta-analytic factor analyses

The General Health Questionnaire (GHQ-12) is a popular measure of psychological distress. Despite its widespread use, an ongoing controversy pertains to its internal structure. Although the GHQ-12 was originally constructed to capture a unitary construct, empirical studies identified different factor structures. Therefore, this study examined the dimensionality of the GHQ-12 in two independent meta-analyses. The first meta-analysis used summary data published in 38 primary studies (total N?=?76,473). Meta-analytic exploratory factor analyses identified two factors formed by negatively and positively worded items. The second meta-analysis included individual responses of 410,640 participants from 84 independent samples. Meta-analytic confirmatory factor analyses corroborated the two-dimensional structure of the GHQ-12. However, bifactor modelling showed that most of the variance was explained by a general factor. Therefore, subscale scores reflected rather limited unique variance. Overall, the two meta-analyses demonstrated that the GHQ-12 is essentially unidimensional. It is not recommended to use and interpret subscale scores because they primarily reflect general mental health rather than distinct constructs.