Recent reviews question current animal models of depression and emphasise the need for ethological models of mood disorders based on animals living under natural conditions. Domestic horses encounter ...chronic stress, including potential stress at work, which can induce behavioural disorders (e.g. "apathy"). Our pioneering study evaluated the potential of domestic horses in their usual environment to become an ethological model of depression by testing this models' face validity (i.e. behavioural similarity with descriptions of human depressive states).
We observed the spontaneous behaviour of 59 working horses in their home environment, focusing on immobility bouts of apparent unresponsiveness when horses displayed an atypical posture (termed withdrawn hereafter), evaluated their responsiveness to their environment and their anxiety levels, and analysed cortisol levels. Twenty-four percent of the horses presented the withdrawn posture, also characterized by gaze, head and ears fixity, a profile that suggests a spontaneous expression of "behavioural despair". When compared with control "non-withdrawn" horses from the same stable, withdrawn horses appeared more indifferent to environmental stimuli in their home environment but reacted more emotionally in more challenging situations. They exhibited lower plasma cortisol levels. Withdrawn horses all belonged to the same breed and females were over-represented.
Horse might be a useful potential candidate for an animal model of depression. Face validity of this model appeared good, and potential genetic input and high prevalence of these disorders in females add to the convergence. At a time when current animal models of depression are questioned and the need for novel models is expressed, this study suggests that novel models and biomarkers could emerge from ethological approaches in home environments.
Abstract Background Pneumocystis jiroveci pneumonia in human immunodeficiency virus (HIV)-negative immunocompromised patients is associated with high mortality rates. Although ...trimethoprim-sulfamethoxazole provides a very effective prophylaxis, pneumocystosis still occurs and may even be emerging due to suboptimal characterization of patients most at risk, hence precluding targeted prophylaxis. Methods We retrospectively analyzed all cases of documented pneumocystosis in HIV-negative patients admitted in our institution, a referral center in the area, from January 1990 to June 2010, and extracted data on their underlying condition(s). To estimate incidence rates within each condition, we estimated the number of patients followed-up in our area for each condition by measuring the number of patients admitted with the corresponding international classification diagnostic code, through the national hospital discharge database (Program of Medicalization of the Information System PMSI). Results From 1990 to 2010, 293 cases of pneumocystosis were documented, of which 154 (52.6%) tested negative for HIV. The main underlying conditions were hematological malignancies (32.5%), solid tumors (18.2%), inflammatory diseases (14.9%), solid organ transplant (12.3%), and vasculitis (9.7%). Estimated incidence rates could be ranked in 3 categories: 1) high risk (incidence rates >45 cases per 100,000 patient-year): polyarteritis nodosa, granulomatosis with polyangiitis, polymyositis/dermatopolymyositis, acute leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma; 2) intermediate risk (25-45 cases per 100,000 patient-year): Waldenström macroglobulinemia, multiple myeloma, and central nervous system cancer; and 3) low risk (<25 cases per 100,000 patient-year): other solid tumors, inflammatory diseases, and Hodgkin lymphoma. Conclusions These estimates may be used as a guide to better target pneumocystosis prophylaxis in the groups most at risk.
Objective
To compare microvascular damages on nailfold capillaroscopy (NFC) with macrovascular manifestations evaluated by hand power Doppler ultrasonography (PDUS) in systemic sclerosis (SSc) ...patients, and to assess the associations of these damages with the main digital manifestations of the disease: digital ulcers, acroosteolysis, and calcinosis.
Methods
NFC, hand radiographs, and PDUS were systematically performed in 64 unselected SSc patients. PDUS evaluation with assessment of ulnar artery occlusion (UAO) and finger pulp blood flow (FPBF) were performed blinded for the results of radiographs and NFC.
Results
UAO and pathologic FPBF were associated with severe capillary loss (<4 capillaries/mm) on NFC (odds ratio OR 4.04 95% confidence interval (95% CI) 1.23–13.29; P < 0.05, and OR 3.38 95% CI 1.03–11.05; P < 0.05, respectively). Digital ulcer history was associated with UAO (OR 10.71 95% CI 3.36–34.13; P < 0.0001), pathologic FPBF (OR 7.67 95% CI 2.52–23.28; P < 0.0001), late NFC pattern (OR 6.33 95% CI 2.03–19.68; P = 0.001), and severe capillary loss (OR 8.52 95% CI 2.15–33.78; P = 0.001). Acroosteolysis was also associated with UAO (OR 15.83 95% CI 3.95–63.54; P < 0.0001), pathologic FPBF (OR 5.52 95% CI 1.71–17.90; P = 0.003), late NFC pattern (OR 6.86 95% CI 2.18–21.53; P = 0.001), and severe capillary loss (OR 7.20 95% CI 2.16–24.02; P = 0.001). Calcinosis on radiographs was associated with late NFC pattern (OR 5.41 95% CI 1.82–16.12; P = 0.002), severe capillary loss (OR 12.69 95% CI 3.14–51.26; P < 0.0001), and UAO (OR 3.19 95% CI 1.14–8.92; P = 0.025). Combination of UAO and severe capillary loss in the same patient was especially associated with digital ulcer history (OR 18.60 95% CI 2.24–154.34; P = 0.001) and acroosteolysis (OR 10.83 95% CI 2.56–45.88; P = 0.001).
Conclusion
Microvascular damages evaluated by NFC and macrovascular features like UAO assessed by PDUS show concordant associations with the main digital manifestations of the disease.
Inhalation of crystalline silica (SiO
) is a risk factor of systemic autoimmune diseases such as systemic sclerosis (SSc) and fibrotic pulmonary disorders such as silicosis. A defect of apoptotic ...cell clearance (i.e., efferocytosis, a key process in the resolution of inflammation) is reported in macrophages from patients with fibrotic or autoimmune diseases. However, the precise links between SiO
exposure and efferocytosis impairment remain to be determined. Answering to this question may help to better link innate immunity and fibrosis. In this study, we first aim to determine whether SiO
might alter efferocytosis capacities of human and mouse macrophages. We secondly explore possible mechanisms explaining efferocytosis impairment, with a specific focus on macrophage polarization and on the RhoA/ROCK pathway, a key regulator of cytoskeleton remodeling and phagocytosis. Human monocyte-derived macrophages (MDM) and C57BL/6J mice exposed to SiO
and to CFSE-positive apoptotic Jurkat cells were analyzed by flow cytometry to determine their efferocytosis index (EI). The effects of ROCK inhibitors (Y27632 and Fasudil) on EI of SiO
-exposed MDM and MDM from SSc patients were evaluated
. Our results demonstrated that SiO
significantly decreased EI of human MDM
and mouse alveolar macrophages
. In human MDM, this SiO
-associated impairment of efferocytosis, required the expression of the membrane receptor SR-B1 and was associated with a decreased expression of M2 polarization markers (CD206, CD204, and CD163). F-actin staining, RhoA activation and impairment of efferocytosis, all induced by SiO
, were reversed by ROCK inhibitors. Moreover, the EI of MDM from SSc patients was similar to the EI of
- SiO
-exposed MDM and Y27632 significantly increased SSc MDM efferocytosis capacities, suggesting a likewise activation of the RhoA/ROCK pathway in SSc. Altogether, our results demonstrate that SiO
exposure may contribute to the impairment of efferocytosis capacities of mouse and human macrophages but also of MDM in SiO
-associated autoimmune diseases and fibrotic disorders such as SSc; in this context, the silica/RhoA/ROCK pathway may constitute a relevant therapeutic target.
Sarcoidosis is a systemic granulomatous disease which carries variable outcomes. Serum protein electrophoresis is an easily accessible and routinely performed examination at diagnosis, in order to ...search for hypergammaglobulinemia, which is frequently found, and to rule out other granulomatous diseases such as common variable immunodeficiency. We aimed to assess the impact of baseline immunoglobulin level on the outcome of sarcoidosis.
We conducted a retrospective cohort-study, at Rennes University Hospital, in which all newly diagnosed patients for whom a serum protein electrophoresis had been performed at baseline were enrolled, from 2006 to 2014. The main outcome was the need for corticosteroid treatment within 2 years from diagnosis, the secondary outcome was the occurrence of relapse among treated patients.
Eighty patients were included in the study, and 41.25% of them exhibited an elevated globulins rate. In univariate analysis, an elevated ACE level >70 U/l, Afro-Caribbean origin, and extra-pulmonary involvement, were associated with the need for corticosteroid treatment. In multivariate analysis, only ACE elevation (OR = 1.03, IC95% 1.01-1.05, p = 0.009) and extra-pulmonary involvement (OR = 5.8, IC95% 1.4-24, p = 0.015) were significant. Immunoglobulin level was not associated with the main outcome. Regarding the secondary outcome, none of the studied features were predictive of relapse among the 34 treated patients followed for two years.
There was no relation between the immunoglobulin level at diagnosis and the evolution of sarcoidosis. An elevated ACE level and the presence of initial extra-pulmonary involvement were both associated with a more severe course of the disease necessitating a corticosteroid treatment.
Objective
To define a semiquantitative classification of finger pulp blood flow (FPBF) and to evaluate whether this classification could be used to assess FPBF in healthy controls and in systemic ...sclerosis (SSc) patients.
Methods
Thirty controls and 86 SSc patients were consecutively included. A classification of FPBF including 5 grades (from grade 0 no signal to 4 signal detected on the entire finger pulp, including the subepidermal vascular network) was evaluated. This classification was explored in basal conditions and after hand baths in hot and cold water in controls. Its relevance was also assessed at room temperature in SSc patients.
Results
In controls, power Doppler ultrasonography (PDUS) of FPBF was improved after hot challenge (P = 0.024), whereas cold challenge decreased FPBF (P = 0.001). FPBF correlated with the vasodilation status assessed by the resistivity index of radial arteries (Spearman's correlation coefficient = –0.50, P = 0.0049). Grade 0 was more frequent in SSc patients than in controls (22.1% versus 3.3%; P < 0.05). In SSc patients, grade 0 was associated with severity markers of the digital vasculopathy such as digital ulcers (DUs) (current or past) (P < 0.05) or ulnar artery occlusion (P < 0.05). On the other hand, DUs were less frequent in patients with grade 4 (P < 0.05). A pathologic threshold of <2 (grade 0 or 1) was significantly associated with DUs (odds ratio 6.67 95% confidence interval 2.31–19.21, P < 0.0001).
Conclusion
PDUS allowed a semiquantitative evaluation of FBPF in SSc patients and controls. Further studies are warranted to validate these results in independent SSc populations and to compare PDUS to existing tools assessing digital blood flow.
Objective
To evaluate the association of ulnar artery occlusion (UAO) assessed using Doppler ultrasound (DUS) with the severity markers of systemic sclerosis (SSc).
Methods
Two hundred four ...unselected patients fulfilling the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria for SSc were included in this cross‐sectional multicenter study. All patients underwent bilateral hand DUS to evaluate the presence of UAO and clinical/paraclinical visceral evaluation according to current guidelines. Univariable and multivariable ordinal regression models were applied, grading the severity of UAO as “no UAO,” “only one UAO,” and “UAO on both hands,” and assessing its association with clinical features of SSc. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
Results
UAO was found in 76 patients (37.3%) and was bilateral in 49 patients (24%). UAO as an ordinal event was significantly associated with disease duration, history of fingertip ulcers, telangiectasia, higher modified Rodnan skin thickness score (MRSS), worse diffusing capacity for carbon monoxide (DLco) values, higher tricuspid jet velocity, late capillaroscopic pattern, and positivity for anticentromere antibodies (ACAs) (univariable analysis). In the adjusted multivariable ordinal model, UAO was less frequent in women (OR 0.35 95% CI 0.15–0.83, P = 0.017) and in patients receiving steroids (OR 0.24 95% CI 0.09–0.62, P = 0.0034). In multivariable analyses, significant association with UAO was retained for history of fingertip ulcers (OR 2.55 95% CI 1.24–5.21, P = 0.011), higher MRSS (OR 1.65 95% CI 1.06–2.56, P =0.025), lower DLco values (OR 0.85 95% CI 0.78–0.94, P = 0.0015), and ACA positivity (OR 2.89 95% CI 1.36–6.11, P = 0.0056).
Conclusion
UAO may represent a relevant severity marker of vasculopathy in SSc. Its predictive value for the onset of severe vascular manifestations such as pulmonary arterial hypertension, and its association with mortality, remain to be determined in longitudinal studies.
Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a ...limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.
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