Summary In patients with multiple sclerosis (MS), grey matter damage is widespread and might underlie many of the clinical symptoms, especially cognitive impairment. This relation between grey matter ...damage and cognitive impairment has been lent support by findings from clinical and MRI studies. However, many aspects of cognitive impairment in patients with MS still need to be characterised. Standardised neuropsychological tests that are easy to administer and sensitive to disease-related abnormalities are needed to gain a better understanding of the factors affecting cognitive performance in patients with MS than exists at present. Imaging measures of the grey matter are necessary, but not sufficient to fully characterise cognitive decline in MS. Imaging measures of both lesioned and normal-appearing white matter lend support to the hypothesis of the existence of an underlying disconnection syndrome that causes clinical symptoms to trigger. Findings on cortical reorganisation support the contribution of brain plasticity and cognitive reserve in limiting cognitive deficits. The development of clinical and imaging biomarkers that can monitor disease development and treatment response is crucial to allow early identification of patients with MS who are at risk of cognitive impairment.
The unique differentiation of IgE cells suggests unconventional mechanisms of IgE memory. IgE germinal centre cells are transient, most IgE cells are plasma cells, and high affinity IgE is produced ...by the switching of IgG1 cells to IgE. Here we investigate the function of subsets of IgG1 memory B cells in IgE production and find that two subsets of IgG1 memory B cells, CD80
CD73
and CD80
CD73
, contribute distinctively to the repertoires of high affinity pathogenic IgE and low affinity non-pathogenic IgE. Furthermore, repertoire analysis indicates that high affinity IgE and IgG1 plasma cells differentiate from rare CD80
CD73
high affinity memory clones without undergoing further mutagenesis. By identifying the cellular origin of high affinity IgE and the clonal selection of high affinity memory B cells into the plasma cell fate, our findings provide fundamental insights into the pathogenesis of allergies, and on the mechanisms of antibody production in memory B cell responses.IgE is an important mediator of protective immunity as well as allergic reaction, but how high affinity IgE antibodies are produced in memory responses is not clear. Here the authors show that IgE can be generated via class-switch recombination in IgG1 memory B cells without additional somatic hypermutation.
Patients with neuroblastoma received CAR-positive T cells targeting disialoganglioside. Of 63% with a response, 33% had a complete response (some durable). Cytokine release syndrome was common.
Proton Pump Inhibitors (PPIs) have been associated with chronic kidney disease (CKD). Our objective was to quantify the association between PPI use and incident CKD in a population-based cohort.
We ...used a population-based retrospective cohort, including people aged 15 years or over, between January 1, 2005 and December 31, 2012. PPI use was measured in a follow-up session by recording prescriptions. Incident CKD was defined as an estimated glomerular filtration rate < 60 ml/ min/1.73 m2 and/or urinary albumin level to creatinine level ≥ 30 mg/g, in two or more determinations over a period of at least 3 months of the follow-up. Proton Pump Inhibitor use was associated with incident CKD in analysis adjusted for different clinical variables (Hazard Ratio (HR) 1.18; 95% CI 1.04-1.51) in individuals who used PPI in the basal visit (HR 1.37; 95% CI 1.25-1.50) and in those who started to use PPI during the follow-up. High doses of PPI increased the risk of incident CKD (HR 1.92; 95%CI 1.00-6.19) for any type of exposure to PPIs (HR 2.40; 95%CI 1.65-3.46) and for individuals who used high doses throughout the follow-up. This risk of incident CKD increased after three months' exposure to PPIs, (HR1.78; 95% CI 1.39-2.25) between the third and sixth months and (HR 1.30; 95%CI 1.07-1.72) after the sixth month.
PPI use is associated with a higher risk of incident CKD. This association is greater for high doses and becomes apparent after three months' exposure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
How to manage patients with prostate cancer (PCa) with biochemical recurrence (BCR) following primary curative treatment is a controversial issue. Importantly, this prostate-specific antigen ...(PSA)-only recurrence is a surrogate neither of PCa-specific survival nor of overall survival. Physicians are therefore challenged with preventing or delaying the onset of clinical progression in those deemed at risk, while avoiding over-treating patients whose disease may never progress beyond PSA-only recurrence. Adjuvant therapy for radical prostatectomy (RP) or local radiotherapy (RT) has a role in certain at-risk patients, although it is not recommended in low-risk PCa owing to the significant side-effects associated with RT and androgen deprivation therapy (ADT). The recommendations for salvage therapy differ depending on whether BCR occurs after RP or primary RT, and in either case, definitive evidence regarding the best strategy is lacking. Options for treatment of BCR after RP are RT at least to the prostatic bed, complete or intermittent ADT, or observation; for BCR after RT, salvage RP, cryotherapy, complete or intermittent ADT, brachytherapy, high-intensity focused ultrasound (HIFU), or observation can be considered. Many patient- and cancer-specific factors need to be taken into account when deciding on the best strategy, and optimal management depends on the involvement of a multidisciplinary team, consultation with the patient themselves, and the adoption of an individualised approach. Improvements in imaging techniques may enable earlier detection of metastases, which will hopefully refine future management decisions.
Abstract Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, ...with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms. We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK−/− /TauVLW ). At 3 months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12 months old, plaques of murine β-amyloid in the hippocampus. Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK−/− /TauVLW phenotype. The treatment with trehalose of 3-month-old PK−/− /TauVLW mice for 2.5 months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK−/− /TauVLW and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4 months of 3-month-old PK−/− /TauVLW mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK−/− /TauVLW mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine β-amyloid plaques. Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.
Background
There is a lack of automated tools for the segmentation and quantification of neuromelanin (NM) and iron in the nigrosome‐1 (N1). Existing tools evaluate the N1 sign, i.e., the presence or ...absence of the “swallow‐tail” in iron‐sensitive MRI, or globally analyze the MRI signal in an area containing the N1, without providing a volumetric delineation.
Purpose
Present an automated method to segment the N1 and quantify differences in N1's NM and iron content between Parkinson's disease (PD) patients and healthy controls (HCs). Study whether N1 degeneration is clinically related to PD and could be used as a biomarker of the disease.
Study Type
Prospective.
Subjects
Seventy‐one PD (65.3 ± 10.3 years old, 34 female/37 male); 30
HC
(62.7 ± 7.8 years old, 17 female/13 male).
Field Strength/Sequence
3 T Anatomical T1‐weighted MPRAGE, NM‐MRI T1‐weighted gradient with magnetization transfer, susceptibility‐weighted imaging (SWI).
Assessment
N1 was automatically segmented in SWI images using a multi‐image atlas, populated with healthy N1 structures manually annotated by a neurologist. Relative NM and iron content were quantified and their diagnostic performance assessed and compared with the substantia nigra pars compacta (SNc). The association between image parameters and clinically relevant variables was studied.
Statistical Tests
Nonparametric tests were used (Mann–Whitney's
U
, chi‐square, and Friedman tests) at
P
= 0.05.
Results
N1's relative NM content decreased and relative iron content increased in PD patients compared with HCs (NM‐CR
HC
= 22.55 ± 1.49; NM‐CR
PD
= 19.79 ± 1.92; NM‐nVol
HC
= 2.69 × 10
−5
± 1.02 × 10
−5
; NM‐nVol
PD
= 1.18 × 10
−5
± 0.96 × 10
−5
; Iron‐CR
HC
= 10.51 ± 2.64; Iron‐CR
PD
= 19.35 ± 7.88; Iron‐nVol
HC
= 0.72 × 10
−5
± 0.81 × 10
−5
; Iron‐nVol
PD
= 2.82 × 10
−5
± 2.04 × 10
−5
). Binary logistic regression analyses combining N1 and SNc image parameters yielded a top AUC = 0.955. Significant correlation was found between most N1 parameters and both disease duration (
ρ
NM‐CR
= −0.31;
ρ
iron‐CR
= 0.43;
ρ
iron‐nVol
= 0.46) and the motor status (
ρ
NM‐nVol
= −0.27;
ρ
iron‐CR
= 0.33;
ρ
iron‐nVol
= 0.28), suggesting NM reduction along with iron accumulation in N1 as the disease progresses.
Data Conclusion
This method provides a fully automatic N1 segmentation, and the analyses performed reveal that N1 relative NM and iron quantification improves diagnostic performance and suggest a relative NM reduction along with a relative iron accumulation in N1 as the disease progresses.
Evidence Level
1
Technical Efficacy
Stage 1
Noninvasive ventilation (NIV) is an effective form of treatment in obesity hypoventilation syndrome (OHS) with severe OSA. However, there is paucity of evidence in patients with OHS without severe ...OSA phenotype.
Is NIV effective in OHS without severe OSA phenotype?
In this multicenter, open-label parallel group clinical trial performed at 16 sites in Spain, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnea-hypopnea index < 30 events/h (ie, no severe OSA) to NIV or lifestyle modification (control group) using simple randomization through an electronic database. The primary end point was hospitalization days per year. Secondary end points included other hospital resource utilization, incident cardiovascular events, mortality, respiratory functional tests, BP, quality of life, sleepiness, and other clinical symptoms. Both investigators and patients were aware of the treatment allocation; however, treating physicians from the routine care team were not aware of patients' enrollment in the clinical trial. The study was stopped early in its eighth year because of difficulty identifying patients with OHS without severe OSA. The analysis was performed according to intention-to-treat and per-protocol principles and by adherence subgroups.
Forty-nine patients in the NIV group and 49 in the control group were randomized, and 48 patients in each group were analyzed. During a median follow-up of 4.98 years (interquartile range, 2.98-6.62), the mean hospitalization days per year ± SD was 2.60 ± 5.31 in the control group and 2.71 ± 4.52 in the NIV group (adjusted rate ratio, 1.07; 95% CI, 0.44-2.59; P = .882). NIV therapy, in contrast with the control group, produced significant longitudinal improvement in Paco
, pH, bicarbonate, quality of life (Medical Outcome Survey Short Form 36 physical component), and daytime sleepiness. Moreover, per-protocol analysis showed a statistically significant difference for the time until the first ED visit favoring NIV. In the subgroup with high NIV adherence, the time until the first event of hospital admission, ED visit, and mortality was longer than in the low adherence subgroup. Adverse events were similar between arms.
In stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days per year. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS.
ClinicalTrials.gov; No.: NCT01405976; URL: www.clinicaltrials.gov.
Adaptive Foxp3
+CD4
+ regulatory T (iTreg) cells develop outside the thymus under subimmunogenic antigen presentation, during chronic inflammation, and during normal homeostasis of the gut. iTreg ...cells are essential in mucosal immune tolerance and in the control of severe chronic allergic inflammation, and most likely are one of the main barriers to the eradication of tumors. The Foxp3
+ iTreg cell repertoire is drawn from naive conventional CD4
+ T cells, whereas natural Treg (nTreg) cells are selected by high-avidity interactions in the thymus. The full extent of differences and similarities between iTreg and nTreg cells is yet to be defined. We speculate that iTreg cell development is driven by the need to maintain a noninflammatory environment in the gut, to suppress immune responses to environmental and food allergens, and to decrease chronic inflammation, whereas nTreg cells prevent autoimmunity and raise the activation threshold for all immune responses.
Scope
The aim is to assess the action of an aqueous extract from cocoa shell (CAE) and its main phenolic compounds to prevent the loss of obesity‐induced mitochondrial function and insulin ...sensitivity, targeting inflammation between macrophages‐adipocytes in vitro.
Methods and results
CAE (31–500 µg mL−1) inhibits 3T3‐L1 adipocytes lipid accumulation and induces browning during differentiation. LPS‐stimulated RAW264.7 macrophages show reduced inducible nitric oxide synthase and cyclooxygenase‐2 expression and lowered pro‐inflammatory cytokine production when treated with CAE and pure phenolics. Inflammatory crosstalk created by stimulating adipocytes with macrophage‐conditioned media (CM) is arrested; CAE diminishes tumor necrosis factor‐α (67%) and promotes adiponectin secretion (12.3‐fold). Mitochondrial function, measured by reactive oxygen species production, mitochondrial content, and activity, is preserved in CM‐treated adipocytes through up‐regulating peroxisome proliferator‐activated receptor gamma coactivator 1‐α expression. Increases in insulin receptor (9‐fold), phosphoinositide 3‐kinase (3‐fold), protein kinase B (4‐fold) phosphorylation, and a decrease in insulin receptor substrate 1 serine phosphorylation induce increased glucose uptake (34%) and glucose transporter 4 translocation (14‐fold) in CM‐induced adipocytes.
Conclusion
CAE phenolics promote a beige phenotype in adipocytes. Macrophages‐adipocytes inflammatory interaction is reduced preventing mitochondrial dysfunction and insulin resistance. For the first time, CAE shows a positive effect on adipogenesis and inflammation‐related disorders.
Obesity and diabetes are associated with low‐grade inflammation. In the adipose tissue, inflammation derives from the interaction between macrophages and adipocytes, and cocoa shell phenolic‐rich extract has an impact on this interaction. Inflammation markers are reduced in macrophages and adipocytes. Adipocytes show a reduction in fat accumulation and improve mitochondrial function and insulin sensitivity.
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