Modulating gut microbiota in a mouse model of Graves' orbitopathy and its impact on induced disease

BACKGROUND: Graves' disease (GD) is an autoimmune condition in which autoantibodies to the thyrotropin receptor (TSHR) cause hyperthyroidism. About 50% of GD patients also have Graves' orbitopathy (GO), an intractable disease in which expansion of the orbital contents causes diplopia, proptosis and even blindness. Murine models of GD/GO, developed in different centres, demonstrated significant variation in gut microbiota composition which correlated with TSHR-induced disease heterogeneity. To investigate whether correlation indicates causation, we modified the gut microbiota to determine whether it has a role in thyroid autoimmunity. Female BALB/c mice were treated with either vancomycin, probiotic bacteria, human fecal material transfer (hFMT) from patients with severe GO or ddH2O from birth to immunization with TSHR-A subunit or beta-galactosidase (βgal; age ~ 6 weeks). Incidence and severity of GD (TSHR autoantibodies, thyroid histology, thyroxine level) and GO (orbital fat and muscle histology), lymphocyte phenotype, cytokine profile and gut microbiota were analysed at sacrifice (~ 22 weeks). RESULTS: In ddH2O-TSHR mice, 84% had pathological autoantibodies, 67% elevated thyroxine, 77% hyperplastic thyroids and 70% orbital pathology. Firmicutes were increased, and Bacteroidetes reduced relative to ddH2O-βgal; CCL5 was increased. The random forest algorithm at the genus level predicted vancomycin treatment with 100% accuracy but 74% and 70% for hFMT and probiotic, respectively. Vancomycin significantly reduced gut microbiota richness and diversity compared with all other groups; the incidence and severity of both GD and GO also decreased; reduced orbital pathology correlated positively with Akkermansia spp. whilst IL-4 levels increased. Mice receiving hFMT initially inherited their GO donors' microbiota, and the severity of induced GD increased, as did the orbital brown adipose tissue volume in TSHR mice. Furthermore, genus Bacteroides, which is reduced in GD patients, was significantly increased by vancomycin but reduced in hFMT-treated mice. Probiotic treatment significantly increased CD25+ Treg cells in orbital draining lymph nodes but exacerbated induced autoimmune hyperthyroidism and GO. CONCLUSIONS: These results strongly support a role for the gut microbiota in TSHR-induced disease. Whilst changes to the gut microbiota have a profound effect on quantifiable GD endocrine and immune factors, the impact on GO cellular changes is more nuanced. The findings have translational potential for novel, improved treatments. Video abstract

Genetics of migraine in the age of genome-wide association studies

Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine

Stati vegetativo e di minima coscienza: risultati del progetto nazionale di ricerca.

L’articolo riporta i risultati della ricerca che ha condotto alla raccolta di dati relativi a 602 persone (566 adulti e 36 bambini), con diagnosi di stato vegetativo o stato di minima coscienza. Vengono riportati i valori rispetto alle caratteristiche del campione indagato (dati sociodemografici, tempo trascorso dall’evento acuto, condizione clinica, alimentazione e idratazione, respirazione , terapie eccetera) sulla base di una definizione di funzionamento e disabilità nell’ottica del modello biopsicosociale della classificazione ICF

Risk factors for mortality in 600 patients in vegetative and minimally conscious states.

A significant proportion of patients who survive traumatic or nontraumatic severe acquired brain injuries experiences disorders of consciousness. The vegetative state and the minimally conscious state may have different prognoses, and while some patients regain awareness, others have negative outcomes and die. The aim of this work is to identify age-related, medical and behavioural risk factors for mortality in those patients. Participants were enrolled from June 2009 to March 2012 in 107 Italian health care institutions. Univariate and multivariate Cox proportional hazard models were adopted to screen and test candidate risk factors. The study enrolled 600 subjects in vegetative and minimally conscious states for an overall mortality rate of 180.1 per 1,000 person-years. The following traits were associated with a significantly lower chance of survival: age at the acute event higher than 51 years, disease duration less than 1 year, post-anoxic aetiology, absence of visual fixation, and the presence of endocrine, nutritional, and metabolic diseases, and immunity disorders. Clinical history, behavioural assessment, and age-related factors provide important prognostic information on negative outcomes that helps clinicians and researchers to predict patients who are at higher risk of mortality. This knowledge has important clinical, managerial, and ethical implications

Personal and interpersonal changes in caregivers of patients in Vegetative State or Minimally Conscious State: a qualitative study

There are few studies on caregivers of patients in Vegetative State (VS) or Minimally Conscious State (MCS) which findings show high level of burden and worse general health of caregivers of these patients. To bring a better understanding about how caregivers themselves view and perceive their role and changes in family relationships after acute event a qualitative study was conducted. Fifteen caregivers of adult patients in VS or MCS were interviewed and main contents related to caregivers burden emerged. Caregivers reported some psychological difficulties and problems in integrating past and present inner representation of the patient: confusing past with present tense describing the patient and switching from ‘’adult-adult’’ to ‘’adult-child’’ attitude to the patient. They also reported actively avoiding thoughts about the future. Needs expressed by caregivers were mainly related to the patient: care-giving was the main role of their life. However, they reported to find new personal resources to deal with this situation. This study brings a better understanding about changes in family relationships and caregivers role in life. Targeted interventions aiming to empower their capabilities and personal new abilities, and to support a better integration between past and present, may be useful to promote their health

Physical and mental health, anxiety and depressive symptoms in caregivers of patients in vegetative state and minimally conscious state.

Caregivers of patients in vegetative state and minimally conscious state play a crucial role in the process of taking care and, as previous studies reported, they can suffer of high burden and negative health outcomes. The aim of this national cross-sectional study was to assess whether physical and mental health of caregivers, considering gender differences, is related to the presence of depressive symptoms, anxiety, age and patient’s disease duration. Four-hundred and eighteen caregivers, 294 women and 124 men, completed the State Trait Anxiety Inventory-Y, Beck Depression Inventory, second version and Short Form-12. Hierarchical multiple regression analyses were performed to evaluate to which extent depressive and anxiety symptoms predict physical and mental health. Men reported higher levels of mental health state, whereas physical health was not different across gender. High levels of anxiety symptoms were associated to negative mental health outcomes in both genders, whereas depressive symptoms were found to impact on female’s mental and physical health only. A comprehensive and cost-effective screening of anxiety and depressive symptoms may help to identify determinants of health worsening in order to plan, when necessary, caregivers’ support

Caregiver´s burden in disorders of consciousness: a longitudinal study

Objectives – To study the changes in the burden of informal caregivers of patients with disorders of consciousness (DOC) over time. Materials and methods – Short Form-12, Family Strain Questionnaire, Beck Depression Inventory and Coping Orientations to Problem Experiences were administered. Results – Data collected on 216 informal caregivers of patients with DOC (59.6% females, mean age 53.4 ` 12.7 years old) were analysed at two time-points (mean distance is 2.7 years). Results of the national study revealed that caregivers’ mental health improved (T0: M = 41.1, SD = 11.8; T1: M = 45.8, SD = 11.7), whereas the emotional burden (T0: M = 7.4, SD = 3.6; T1: M = 6.6, SD = 3.9) and the presence of depressive symptoms (T0: M = 14.3, SD = 9.3; T1: M = 11.7, SD = 10.2) as well as the need for information about the disease (T0: M = 2.7, SD = 1.2; T1: M = 2.2, SD = 1.4), thoughts of death (T0: M = 3.6, SD = 1.5; T1: M = 3.1, SD = 1.6) and the use of avoiding coping strategy (T0: M = 7.8, SD = 1.0; T1: M = 6.0, SD = 1.3) decreased at T1. Furthermore, depressive symptoms positively correlated with the emotional burden (0.580) and negatively with the mental health component of caregivers’ self-perceived health condition ( 0.473). Physical ( 0.308) and mental health ( 0.444) negatively correlated with emotional burden. Finally, the acute event and patients’ health condition still have a deep impact on the economic situation of the family. Conclusion – Although high level of burden was observed, it tends to decrease over time, except for financial burden. Hence, this study suggests the importance to plan strategies or targeted interventions in order to reduce the psychosocial and financial burden associated with caregiving