Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence ...of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer's disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.
Psychiatric syndromes in dementia are often derived from the Neuropsychiatric Inventory (NPI) using principal component analysis (PCA). The validity of this statistical approach can be questioned, ...since the excessive proportion of zeros and skewness of NPI items may distort the estimated relations between the items. We propose a novel version of PCA, ZIBP-PCA, where a zero-inflated bivariate Poisson (ZIBP) distribution models the pairwise covariance between the NPI items. We compared the performance of the method to classical PCA under zero-inflation using simulations, and in two dementia-cohorts (N = 830, N = 1349). Simulations showed that component loadings from PCA were biased due to zero-inflation, while the loadings of ZIBP-PCA remained unaffected. ZIBP-PCA obtained a simpler component structure of "psychosis," "mood" and "agitation" in both dementia-cohorts, compared to PCA. The principal components from ZIBP-PCA had component loadings as follows: First, the component interpreted as "psychosis" was loaded by the items delusions and hallucinations. Second, the "mood" component was loaded by depression and anxiety. Finally, the "agitation" component was loaded by irritability and aggression. In conclusion, PCA is not equipped to handle zero-inflation. Using the NPI, PCA fails to identify components with a valid interpretation, while ZIBP-PCA estimates simple and interpretable components to characterize the psychopathology of dementia.
Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to ...investigate whether mKP predict mortality in patients with heart failure.
The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5'phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments.
Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA HR 1.80, p = 0.013, HK HR 1.77, p = 0.005, HK/XA HR 1.67, p < 0.001 and KTR HR 1.55, p = 0.009 were associated with increased mortality in patients with heart failure, while XA HR 0.68-0.80, p = 0.013-0.037 were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls.
Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.
ObjectivesThe aim of this study was to explore determinants of psychosocial distress and pain in patients who have survived severe extremity amputation in Gaza.SettingThis study was conducted in a ...secondary care rehabilitation centre in Gaza, Palestine. The clinic is Gaza’s sole provider of artificial limbs.ParticipantsWe included 254 civilian Palestinians who had survived but lost one or more limb(s) during military incursions from 2006 to 2016. We included patients with surgically treated amputation injuries who attended physical rehabilitation at a specialist prosthesis centre in Gaza. Amputees with injuries prior to 2006 or non-military related injuries were excluded.We assessed their pain and psychological stress using the General Health Questionnaire (GHQ-12). We used income, amputation severity scored by proximity to torso, current employment status, loss of family members and loss of home as independent variables.ResultsThe amputees median age was 23 years at the time of trauma, while a median of 4.3 years had passed from trauma to study inclusion. Nine of 10 were male, while 43 were children when they were amputated (17%≤18 years). One hundred and ninety-one (75%) were unemployed and 112 (44%) reported unemployment caused by being amputated. Pain was the most frequent problem, and 80 amputees (32%) reported to suffer from daily pain. Family income was significantly correlated with the physical pain (OR=0.54, CI 0.36 to 0.80, p=0.002). Psychological distress was higher among unemployed amputees (OR=1.36, CI 1.07 to 1.72, p=0.011). We found no association between psychological distress (GHQ-scores) and the extent of the initial amputation.ConclusionPain and psychological distress following war-related extremity amputation of one or more limbs correlated stronger with deteriorated family economy and being unemployed than with the anatomical and medical severity of extremity amputations.
•Tryptophan and kynurenines are related to inflammation and may be neuroactive.•Experimental studies indicates a role for the rate limiting enzyme IDO in cognition.•We assessed potential associations ...between kynurenines and cognition in 2174 older adults.•Lower cognitive performance is seen with higher kynurenine-to-tryptophan ratio and neopterin.•Our study supports that kynurenines may play a role in human cognition.
Tryptophan, its downstream metabolites in the kynurenine pathway and neopterin have been associated with inflammation and dementia. We aimed to study the associations between plasma levels of these metabolites and cognitive function in community-dwelling, older adults.
This cross-sectional study included 2174 participants aged 70–72 years of the community-based Hordaland Health Study. Tryptophan, kynurenine, neopterin and eight downstream kynurenines were measured in plasma. Kendrick Object Learning Test (KOLT), Digit Symbol Test (DST) and the Controlled Oral Word Association Test (COWAT) were all outcomes in standardized Zellner’s regression. The Wald test of a composite linear hypothesis of an association with each metabolite was adjusted by the Bonferroni method. Age, body mass index, C-reactive protein, depressive symptoms, diabetes, education, glomerular filtration rate, hypertension, previous myocardial infarction, prior stroke, pyridoxal 5′phosphate, sex and smoking were considered as potential confounders.
Higher levels of the kynurenine-to-tryptophan ratio (KTR) and neopterin were significantly associated with poorer, overall cognitive performance (p < 0.002). Specifically, KTR was negatively associated with KOLT (β −0.08, p = 0.001) and COWAT (β −0.08, p = 0.001), but not with DST (β −0.03, p = 0.160). This pattern was also seen for neopterin (KOLT: β −0.07; p = 0.001; COWAT: β −0.06, p = 0.010; DST: β −0.01, p = 0.800). The associations were not confounded by the examined variables. No significant associations were found between the eight downstream kynurenines and cognition.
Higher KTR and neopterin levels, biomarkers of cellular immune activation, were associated with reduced cognitive performance, implying an association between the innate immune system, memory, and language.
Little data exist to describe the use and medical consequences of drone strikes on civilian populations in war and conflict zones. Gaza is a landstrip within the Palestinian territories and the home ...of 2 million people. The median age in Gaza is 17·2 years and almost half of the population is below the age of 14 years. We studied the prevalence and severity of extremity amputation injuries caused by drone strikes compared with those caused by other explosive weapons among patients with amputations attending the main physical prosthesis and rehabilitation centre in Gaza.
In this retrospective cross-sectional study, we recruited patients from the Artificial Limb and Polio Centre (ALPC) in Gaza city in the Gaza strip with conflict-related traumatic extremity amputations. Patients were eligible if they had one or more amputations sustained during a military incursion in Gaza during 2006–16 and had an available patient record. Each patient completed a self-reporting questionnaire of the time and mechanism of injury, subsequent surgeries, comorbidities, and their socioeconomic status, and we collected each patient's medical history, recorded the anatomical location of their amputation or amputations, and interviewed each patient to obtain a detailed description of the incursion or incursions that led to their amputation injury. We classified the severity of amputations and number of subsequent surgeries on ordinal scales and then we determined the associations between these outcomes and the mechanism of explosive weapon delivery (drone strike vs other) using ordinal logistical regression.
We collected data on 254 patients from APLC who had sustained an amputation injury. Of these patients, 234 (92%) were male and 43 (17%) were aged 18 years or younger at the time of injury. The age of participants was representative of the Gaza population, with a median age at inclusion was 28 years (IQR 23–33), and the median age at the time of injury was 23 years (IQR 20–29). 136 (54%) amputation injuries were caused by explosive weapons delivered by drone strikes, with explosives delivered by tanks being the next most common source of amputation injury (28 11%). Adjusted for age and sex, drone-delivered weapons caused significantly more severe injuries than explosives delivered by other mechanisms (eg, military jet airplanes, helicopters, tank shelling, and naval artillery; odds ratio OR 2·50, 95% CI 1·52–4·11; p=0·0003). Compared with all other types of weapons, the patients whose injuries were caused by drone strikes needed significantly more subsequent surgical operations to treat their amputation injuries than those injured by other weapons (OR 1·93, 1·19–3·14; p=0·008).
Drone strikes were the most commonly reported cause of amputation injury in our study population and were associated with more severe injuries and more additional surgeries than injuries caused by other explosive weapons. Limitations of our study include the self-reported nature of the mechanism of injury and number of subsequent surgeries and selection bias from not incorporating amputation injuries from individuals who died immediately or due to complications. The increasing use of drones needs to be addressed, rather than passively accepted, by the international community. This study fills a gap in our knowledge of the civilian consequences of modern warfare and we believe it is also relevant to the growing populations that are being exposed to drone warfare and for health-care personnel treating these people.
None.
More than 17.000 Palestinians were injured during different Israeli military incursions on the Gaza Strip from 2006 to 2014. Many suffered traumatic extremity amputations. We describe the injuries, ...complications, living conditions and health among a selection of traumatic amputees in the Gaza Strip.
We included 254 civilian Palestinians who had survived, but lost one or more limb(s) during military incursions from 2006 to 2016. All patients were receiving follow-up treatment at a physical rehabilitation center in Gaza at the time of inclusion. We measured and photographed anatomical location and length of extremity amputations and interviewed the amputees using standard questionnaires on self-reported health, socioeconomic status, mechanism of injury, physical status and medical history.
The amputees were young (median age 25,6 years at the time of trauma), well educated (37% above graduate level), males (92%), but also 43 children (17% ≤ 18 years). The greater part suffered major amputations (85% above wrist or ankle). Limb losses were unilateral (35% above-, 29·5% below knee), and bilateral (17%) lower extremity amputations. Pain was the most frequent long-term complaint (in joints; 34%, back; 33% or phantom pain; 40·6%). Sixty-three percent of amputees were their family's sole breadwinner, 75·2% were unemployed and 46% had lost their home. Only one in ten (11·6%) of the destroyed homes had been rebuilt.
The most frequently observed amputees in our study were young, well-educated male breadwinners and almost one in five were children. Conflict-related traumatic amputations have wide-ranging, serious consequences for the amputees and their families.
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