Immunoglobulin free light chains in severe asthma patient: Could they be a new biomarker?

BACKGROUND: Increasing evidence is available about the presence of increased serum concentration of immunoglobulin (Ig) free light chains (FLCs) in both atopic and non-atopic inflammatory diseases, including severe asthma, providing a possible new biomarker of disease. METHODS: We analyzed clinical and laboratory data, including FLCs, obtained from a cohort of 79 asthmatic subjects, clinically classified into different GINA steps. A control group of 40 age-matched healthy donors (HD) was considered. Particularly, HD have been selected according to the absence of monoclonal components (in order to exclude paraproteinemias), were tested for total IgE (that were in the normal ranges) and were negative for aeroallergens specific IgE. Moreover, no abnormality of common inflammatory markers (i.e., erythrocyte sedimentation rate and C-reactive protein) was detectable. RESULTS: FLC-k levels were significantly increased in the asthmatic population, compared to the control group. Despite the absence of statistically significant differences in FLC-λ levels, the FLC-k/FLC-λ ratio displayed remarkable differences between the two groups. A positive correlation between FLC-κ and FLC-λ levels was found. FLC- λ level displayed a significant negative correlation with the FEV1 value. Moreover, the FLC-κ /FLC- λ ratio was negatively correlated with the SNOT-22 score and a positive correlation was observed between FLCs and Staphylococcus Aureus IgE enterotoxins sensitization. CONCLUSIONS: Our findings confirmed the role of FLCs in asthma as a potential biomarker in an inflammatory disease characterized by different endotypes and phenotypes. In particular, FLC-κ and FLC-k/FLC-λ ratio could be a qualitative indicator for asthma, while FLC-λ levels could be a quantitative indicator for clinical severity parameters.

IgG4 serum levels in Graves' orbitopathy.

OBJECTIVE: IgG4-related disease (IgG4-RD) can involve many organs, including thyroid and orbital tissues. A link between IgG4, Graves' disease (GD) and Graves' orbitopathy (GO) has been proposed, but results are conflicting. Here we investigated the possible association between IgG4 and GO. METHODS: Retrospective investigation in 297 patients with Graves' disease (GD), 152 with GO. PRIMARY OUTCOME: prevalence of IgG4 ≥ 135 mg/dL (cut-off for IgG4-RD). SECONDARY OBJECTIVES: (1) serum IgG4 concentrations; (2) IgG4/IgG ratio; (3) prevalence of IgG4/IgG ratio ≥ 8.0%; (4) relationship between IgG4 and eye features; (5) relationship between IgG4 and anti-TSH receptor antibodies (TRAbs). RESULTS: Because GO patients had lower FT3 concentrations, we evaluated the main objectives in the second and third FT3 quartiles subpopulation, in which there were no relevant differences between patients with (n = 81) or without GO (n = 67) for baseline parameters. Within this population, the prevalence of IgG4 levels ≥ 135 mg/dL did not differ between patients without and with GO (17.9% vs 17.3%). No difference was observed concerning IgG4 concentrations, prevalence of IgG4/IgG ≥ 8.0%, and IgG4/IgG ratio. There was no relationship between IgG4 and eye features and no correlation between IgG4 levels and TRAb was found. CONCLUSIONS: Our results suggest that, within GD, there is no relationship between serum IgG4 and GO.

In Graves' disease, thyroid autoantibodies and ultrasound features correlate with distinctive histological features.

PURPOSE: Laboratory, imaging, and pathological features of Graves' disease (GD), although well characterized, have been barely correlated each other. Aim of the study was to link laboratory and ultrasound characteristics of GD with its pathological features. METHODS: We correlated laboratory and ultrasound data at the time of diagnosis in 28 consecutive GD patients who underwent thyroidectomy with their pathological features, i.e., lymphocytic infiltration and follicular hyperplasia (both classified as mild or severe). RESULTS: Thyroid volume correlated positively with the levels of FT4 (P = 0.002, r2 = 0.42), FT3 (P = 0.011, r2 = 0.22), autoantibodies to thyroglobulin (TgAbs) (P = 0.016, r2 = 0.32), autoantibodies to thyroid peroxidase (TPOAbs) (P = 0.011, r2 = 0.34) and the extent of lymphocytic infiltration (P = 0.006 comparing mild to severe lymphocytic infiltration) but not with the levels of autoantibodies to the thyrotropin receptor (TRAbs) and to follicular hyperplasia. Compared to subjects with mild lymphocytic infiltration, those with severe lymphocytic infiltration showed higher levels of TgAbs (316 vs 0.0 IU/mL, P < 0.0001) and TPOAbs (295 IU/mL vs 14 IU/mL, P < 0.0001) and similar levels of TRAbs (7.5 vs 13 IU/mL, P = 0.68). Compared to patients with mild, those with severe follicular hyperplasia had similar levels of TgAbs (76 vs 30 IU/mL, P = 0.31) and TPOAbs (251 IU/mL vs 45 IU/mL, P = 0.26) but higher levels of TRAbs (39 vs 7.2 IU/mL, P < 0.001). CONCLUSION: In GD, TgAbs and TPOAbs levels correlate with the extent of lymphocytic infiltration, TRAbs levels with the degree of follicular hyperplasia. Thyroid volume, the main factor influencing the severity of hyperthyroidism, is related to lymphocytic infiltration and not to follicular hyperplasia.

Anti-nuclear autoantibodies in Graves' disease and Graves' orbitopathy.

OBJECTIVE: A relationship between thyroid and non-organ-specific autoimmunity could be relevant for Graves' orbitopathy (GO), which affects connective tissue. We investigated the association between GO and anti-nuclear antibodies (ANAs). METHODS: Retrospective investigation was conducted in 265 patients with Graves' disease (GD), 158 with and 107 without GO. Primary outcome was: prevalence of ANAs in GO vs no-GO. Secondary outcomes were: (1) relationship between ANAs and GO features; (2) prevalence of ANAs in GD compared with non-autoimmune hyperthyroidism [(78 patients with toxic nodular goiter (TNG)]; (3) distribution of ANA patterns. RESULTS: ANAs were detected in 212 (80%) GD patients, but prevalence did not differ between GO (79.7%) and no-GO (80.3%). Higher ANA titers (1:160) were more common in GO (51.5 vs 38.3%), but only nearly significantly (OR 0.5; 95% CI: 0.3-1; P = 0.059). Proptosis was lower in ANA-positive patients (mean difference: - 1.4 mm; 95% CI from - 2.5 to - 0.3; P = 0.011), in whom nearly significantly lower CAS (Mann-Whitney U: 1.5; P = 0.077) and eyelid aperture (mean difference: - 0.9 mm; 95% CI from - 2 to 0; P = 0.062) were observed. Prevalence of ANAs in GD was lower than in TNG (80 vs 91%; OR 0.3; 95% CI: 0.1-0.9; P = 0.028), but nuclear speckled pattern was more frequent (OR 22.9; 95% CI 1.3-381.3; P = 0.028). CONCLUSIONS: Although ANAs are not more frequent in GO, they seem to exert a protective role on its severity and on development of GD. A switch of T cell population in ANA-positive patients, resulting in a different phenotype, may be responsible. Further studies are needed to investigate the mechanisms.

Sirolimus as a second-line treatment for Graves' orbitopathy.

OBJECTIVES: A beneficial effect of sirolimus in Graves' orbitopathy (GO) was reported, suggesting a possible use in clinical practice. We conducted an observational, single-centre, no-profit, clinical study to investigate the efficacy of sirolimus as a second-line treatment for moderate-to-severe, active GO compared with methylprednisolone. METHODS: Data from consecutive patients given sirolimus (2 mg orally on first day, followed by 0.5 mg/day for 12 weeks) or methylprednisolone [500 mg iv/weekly (6 weeks), 250 mg/weekly (6 weeks)] as a second-line treatment were collected and compared. PRIMARY OBJECTIVE: overall GO outcome at 24 weeks, based on a composite evaluation. Secondary objectives at 24 weeks: (1) improvement in quality of life, evaluated using a specific uestionnaire (GO-QoL); (2) reduction in proptosis; (3) reduction in the clinical activity score (CAS); (4) improvement of eye ductions; and (5) reduction in eyelid aperture. RESULTS: Data from 30 patients (15 per group) treated between January 15, 2020, and June 15, 2021, were analysed. Proportion of GO responders (primary outcome) at 24 weeks was significantly greater in sirolimus group compared with methylprednisolone group (86.6% vs 26.6%; OR: 17.8; 95% CI from 2.7 to 116.8; P = 0.0026). GO-quality of life (GO-QoL) score was greater in sirolimus group. Proportion of proptosis responders was greater in sirolimus group, as well as proportion of clinical activity score (CAS) responders. No serious adverse events were observed, with no differences between groups. CONCLUSIONS: Sirolimus seems to be an effective second-line treatment for GO. Further randomized clinical trials are needed to confirm our observations.

Role of the mononuclear cell infiltrate in Graves' orbitopathy (GO): results of a large cohort study.

OBJECTIVE: The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves' orbitopathy (GO) is not completely defined. Here we investigated the relationship between the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients. METHODS: We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological evaluation was performed in all patients, as well as immunohistochemistry for CD3, CD4, CD8, CD56 (T-cell markers), CD25 (T and B-cell marker), CD20, CD19 (B-cell markers), and CD138 (plasmacell marker) in specimens collected at decompressive surgery. RESULTS: Having established cutoff values for each marker, cell infiltrates were found in 60 patients (78.9%; CD3: 39.4%, CD4 55.2%, CD8 50%, CD56: 0%, CD25: 28.9%, CD20: 51.3%, CD19: 25%, CD138: 26.3%). Eleven (14.4%) stained exclusively for CD138 (plasmacells). Patients with CD4-positive mononuclear cells had a significantly greater GO clinical activity score (CAS) (mean difference 1.07, 95% CI - 0.33 to - 1.82, P = 0.004 by univariate, P = 0.05 by multivariate analysis). CAS as well as the remaining GO features were not affected significantly by the mononuclear cell subpopulations in multivariate analyses. CONCLUSIONS: Mononuclear cell infiltrates are present in the majority of GO patients, with a small percentage represented exclusively by plasmacells. CD4 cells exert a major role on GO activity. These findings may represent a further advancement in the comprehension of GO pathogenesis.

Prediction of heparin binding of mutated short sequences of rat thyroglobulin.

BACKGROUND: Binding of thyroglobulin (Tg) to heparin is involved in Tg transcytosis via megalin. Rat Tg (rTg) binds to heparin through an exposed carboxyl terminal region (RELPSRRLKRPLPVK, Arg2489-Lys2503) rich in positively charged residues. This region is not entirely conserved in human Tg (hTg) (Arg2489-Glu2503, REPPARALKRSLWVE), resulting in lower affinity binding. Here, we developed a score to predict to what extent secondary structure modifications affect the heparin-binding ability of rTg. METHODS: We designed eight synthetic peptides, including one with the Arg2489-Lys2503 sequence of rTg (rTgP), one with the corresponding sequence of hTg (hTgP), and six "mutant" peptides, each carrying a point mutation obtained by replacing one amino acid residue of rTgP with the corresponding residue of hTgP. Heparin binding was assessed in solid-phase assays. The Bmax and the constants of dissociation (Kd) were calculated. RESULTS: Using a no-fee online service, we obtained predictions of peptide secondary structures and developed a scoring system to estimate to what extent mutations are expected to modify rTg secondary structure. The score was designated as Probability of Secondary Structure Change (PSSC) and it significantly correlated with the BMax (R = 0.942, P < 0.001) and the Kds (R = - 0.744, P < 0.01) of heparin binding of hTgP and of the "mutant" peptides. CONCLUSIONS: The PSSC score allows predicting to what extent point mutations are likely to affect the heparin-binding ability of short sequences of proteins: in this case rTg, regardless of whether mutations affect charge of the sequence. The secondary structure of Tg is likely to play a role in heparin binding.

Correlation between serum anti-TSH receptor autoantibodies (TRAbs) and the clinical feature of Graves' orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Several studies support the involvement of TSH receptor autoantibodies (TRAbs) in the pathogenesis of GO, and a correlation between GO features and TRAbs has been reported, but not confirmed by all studies. Thus, we conducted a cross-sectional investigation to determine whether there is a correlation between TRAbs and the clinical features of GO in an initial phase of the eye disease. METHODS: Ninety consecutive patients with untreated GO (67 women and 23 men, age 48.9 ± 12.6 years) were included. Patients who had received treatments other than anti-thyroid drugs for hyperthyroidism or lubricants for GO were excluded. All patients underwent an endocrinological and ophthalmological evaluation, the latter including exophthalmometry, measurement of eyelid width, clinical activity score (CAS), visual acuity, assessment of diplopia, and NOSPECS score. TRAb levels were measured by a third-generation competitive immunoassay. RESULTS: There was a statistically significant, direct correlation between serum TRAb levels and CAS by linear regression analysis (R = 0.278, P = 0.007). The correlation was confirmed by a multiple regression analysis (R = 0.285; P = 0.006) including age and FT3 levels, which also correlated with CAS. There were no relationships between TRAbs and exophthalmometry, eyelid aperture, degree of diplopia, visual acuity, and NOSPECS score. CONCLUSIONS: The levels of TRAb in subjects with a recent-onset, untreated GO are directly correlated with the clinical activity of the disease, confirming a possible role of these antibodies in the pathogenesis of GO.

Three weeks of passive and intervallic heat at high temperatures (100±2 °C) in a sauna improve acclimation to external heat (42±2 °C) in untrained males.

Currently, the effect of passive heat acclimation on aerobic performance is still controversial. Therefore, this study aimed to observe the effect of passive and intervallic exposure to high temperatures (100 ± 2 °C) in untrained males. Forty healthy untrained men participated in this investigation. They were randomised into a Control Group (CG; n = 18) and an Experimental Group (EG; n = 22). Both groups performed maximum incremental tests until exhaustion in normothermia (GXT1; 22 ± 2 °C), and 48h afterwards, in hyperthermia (GXT2; 42 ± 2 °C). The EG performed 9 sessions of intervallic exposure to heat (100 ± 2 °C) over 3 weeks. Subsequently, both groups performed two maximal incremental trials in normothermia (GXT3; 22 ± 2 °C) and 48h later, in hyperthermia (GXT4; 42 ± 2 °C). In each test, the maximal ergospirometric parameters and the aerobic (VT1), anaerobic (VT2) and recovery ventilatory thresholds were recorded. The Wilcoxon Test was used for intra-group comparisons and the Mann-Whitney U for inter-group comparisons. There were improvements in absolute VO2max (p = 0.049), W (p = 0.005) and O2pulse (p = 0.006) in hyperthermia. In VT1 there was an increase in W (p = 0.046), in VO2 in absolute (p = 0.025) and relative (p = 0.013) values, O2pulse (p = 0.006) and VE (p = 0.028) in hyperthermia. While W increased in hyperthermia (p = 0.022) at VT2. The results suggest that passive and intervallic acclimation at high temperatures improves performance in hyperthermia. This protocol could be implemented in athletes when they have to compete in hot environments.

3-Week passive acclimation to extreme environmental heat (100± 3 °C) in dry sauna increases physical and physiological performance among young semi-professional football players.

This manuscript aims to evaluate the influence of a novel passive heat acclimation program among human participants in the physical performance, as well as in several physiological parameters. 36 male football players were acclimated using a dry sauna bath to extreme hot (100 ± 3 °C), performing a total of nine sauna sessions with a weekly frequency of three sessions. The players were randomly into the sauna group (SG; n = 18; age: 20.69 ± 2.09 years) and the control group (CG; n = 18; age: 20.23 ± 1.98 years). All participants performed maximal effort test until exhaustion as well as hamstring flexibility test before and after the acclimation program. Anthropometric, respiratory, circulatory, hematological and physiological variables were evaluated at the beginning and at the end of the survey. Statistical analysis consisted of a Mann-Whitney U test to determine differences between groups at the beginning and at the end of the survey and a Wilcoxon test for paired samples to compare the differences for each group separately. Additionally, size effects of the pre-post acclimation changes were calculated. After the acclimation program SG participants experienced a diminution in body weight (p < 0.01), body mass index (p < 0.01), body fat (p < 0.05) and fat percentage (p < 0.05) decreased. Hamstring flexibility (p < 0.05) and work capacity (p < 0.05) increased. External basal temperature decreased (p < 0.05) as well as post-exercise systolic and diastolic blood pressures (p < 0.05). Finally, maximal oxygen uptake (ml Kg-1 min-1) (p < 0.05), maximal minute ventilation (p < 0.05) and maximal breath frequency (p < 0.05) increased at the end of the intervention. There were no significant changes in the CG in any variable. Favorable adaptations have been observed in this survey, suggesting a beneficial effect of extreme heat acclimation on physical performance. Several of the observed responses seem interesting for sport performance and health promotion as well. However, this is a novel, extreme protocol which requires further research.

Pervasive refusal syndrome or anorexia nervosa: a case report with a successful behavioural treatment.

PURPOSE: Pervasive refusal syndrome (PRS) is a rare psychiatric disease that affects children. It was first described by Lask in 1991 (Arch Dis Child 66:866-869, 1991). Recently, Otasowie and Collaborators reported a systematic review about PRS. Despite this, PRS has not yet been classified in DSM-5 and ICD-11 and the lack of evidence-based treatment makes this syndrome a real challenge for clinicians. The aim of this paper is to present our experience through the description of a case report and its treatment. METHODS AND RESULTS: The case reported is a girl aged 11 years that fits the clinical picture described in the literature of PRS. In previous reports, behavioural treatment was not used or appreciated; our case adds new knowledge regarding the PRS diagnosis and the successful behavioural treatment during hospitalization, which we describe in all its phases. CONCLUSION: PRS is a rare, life-threatening syndrome; it would be extremely important to have an official and evidence-based treatment guide. LEVEL OF EVIDENCE: Level V, case report.

Serum immunoglobulin free light chain levels in systemic autoimmune rheumatic diseases.

Several reports have highlighted the abnormal increments of serum immunoglobulin free light chains (FLCs) in the course of systemic autoimmune rheumatic diseases (SARD), but a comparative analysis among different conditions is still lacking. A strong association between elevated FLC and hepatitis C virus (HCV)-related mixed cryoglobulinaemia (HCVMC) has been well established. Here, we aimed to analyse serum FLC levels in patients with four different SARD in comparison with HCVMC. Using a turbidimetric assay, free κ and λ chains were quantified in sera from 198 SARD patients (37 rheumatoid arthritis, RA; 47 systemic lupus erythematosus, SLE; 52 anti-phospholipid syndrome, APS; 62 primary Sjogren's syndrome, pSS), 62 HCVMC and 50 healthy blood donors (HD). All patient groups showed increased κ levels when compared to HD: 33·5 ± 2·6 mg/l in HCVMC, 26·7 ± 2·3 mg/l in RA, 29·7 ± 1·9 mg/l in SLE, 23·8 ± 1·1 mg/l in APS, 24·2 ± 1·1 mg/l in pSS; 10·1 ± 0·6 mg/l in HD. Free λ levels displayed a significant increase only for HCVMC (20·4 ± 1·4 mg/l) and SLE (18·4 ± 1·0 mg/l) compared to HD (13·6 ± 0·9 mg/l). The increase of κ compared to λ takes into account a κ /λ ratio of 1·6 for all groups. Our results substantially analyse and strengthen the association between FLC and SARD focusing the questions regarding their role in the pathogenesis and diagnosis of human diseases. Unfortunately, the biochemical differences distinguishing normal from pathological FLC have not been identified. Production of different isotypes is probably connected to still-unknown pathways.

Orbital diseases mimicking graves' orbitopathy: a long-standing challenge in differential diagnosis.

Graves' orbitopathy (GO) is the most common cause of orbital tissue inflammation, accounting for ~ 60% of all orbital inflammatory conditions in the population aged 21-60 years, and for ~ 40% in the population aged > 60 year. GO is observed in 25-30% of patients with Graves' hyperthyroidism and more rarely in association with hypothyroid autoimmune thyroiditis. In addition, a small proportion of GO patients (1-2%) do not have a clinically overt thyroid dysfunction. Clinically, GO is characterized by proptosis, inflammation involving the eyelids and the conjunctiva, extraocular muscle hypertrophy, with consequent reduction of ocular motility and diplopia, and in the most severe cases, compression of the optic nerves at the orbital apex, with reduction of visual acuity. At CT scan or MRI, a muscle increase involving the superior, medial and inferior rectus is quite typical. In the most severe forms, compression of the optic nerves at the orbital apex can be observed. Euthyroid GO is usually an early sign of a full-blown Graves' disease; however, in some cases, the orbital disease can remain isolated. Moreover, euthyroid GO can rarely be unilateral, which makes the picture even more confusing. Under those circumstances, the diagnostic process becomes obviously quite difficult, having other conditions mimicking GO been excluded. A number of inflammatory conditions affecting orbital tissue can mimic GO, thereby requiring an accurate evaluation for a proper differential diagnosis. The majority of these conditions are immune mediated. Most of them are benign, but they can be rather aggressive and some can cause visual loss. The most common inflammatory condition affecting orbital tissues and mimicking GO is idiopathic orbital inflammation. Other, more rare, orbital diseases that should be considered in the differential diagnosis are infections, orbital manifestations of systemic diseases, primitive and secondary orbital neoplasms, and orbital vascular alterations. In most instances, when an orbitopathy occurs in the absence of hyperthyroidism, the diagnosis of the disease underlying the ocular symptoms and signs is based on exclusion of the other conditions. Here we review the conditions that can mimic GO and how to distinguish them from this obnoxious eye disease.

Putative protective role of autoantibodies against the insulin-like growth factor-1 receptor in Graves' Disease: results of a pilot study.

BACKGROUND: The insulin-like growth factor-1 receptor (IGF-1R) is a key element in the pathogenesis of Graves' Orbitopathy (GO), but the role of IGF-1R autoantibodies (IGF-1RAbs) has not been established. METHODS: We designed a cross-sectional investigation to measure IGF-1RAbs in patients with Graves' disease (GD), with or without GO, who underwent radioiodine therapy followed by glucocorticoids (GC). Twenty-nine patients were included, 15 of which with GO. Patients were evaluated at baseline and three and 6 months after radioiodine. The primary objective was the prevalence of positive tests for IGF-1RAbs. The secondary objectives were: (1) IGF-1RAbs concentrations and their variations; (2) relationship between IGF-1RAbs and the features of GO; (3) relationship between IGF-1RAbs and anti-thyroid autoantibodies. RESULTS: IGF-1RAbs above the cut-off value were found only in one patient with GD without GO. IGF-1RAb levels were greater in patients with GD without GO, at baseline (P < 0.0001), and after three (P < 0.0001) and six (P = 0.0001) months. No correlations were observed between IGF-1RAbs and the features of GO, nor between IGF-1RAbs and anti-thyroglobulin or anti-thyroperoxidase autoantibodies. There was an inverse correlation between anti-TSH receptor autoantibodies (TRAbs) and IGF-1RAb levels in GD patients with GO at 6 months (P = 0.03). CONCLUSIONS: IGF-1RAbs appear to be greater in patients with GD without GO compared with those with GO, suggesting a putative protective role of IGF-1RAbs on the development of GO, in line with the beneficial effects of Teprotumumab on GO. The inverse correlation between IGF-1RAbs and TRAbs 6 months after radioiodine may reflect antigen spreading and/or GC treatment.

Asymmetry indicates more severe and active disease in Graves' orbitopathy: results from a prospective cross-sectional multicentre study.

PURPOSE: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy. METHODS: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented. RESULTS: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]. CONCLUSION: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

Visceral and subcutaneous adipose tissue as markers of local and systemic inflammation: a comparison between celiac and obese patients using MRI.

BACKGROUND: Celiac disease (CD) is a systemic inflammatory disease, which primarily affects the gastrointestinal tract. It has been recently demonstrated that adipose-tissue infiltration by proinflammatory immune cells causes a chronic low-grade inflammation in obese patients. Magnetic resonance imaging (MRI) has already proved to be useful in evaluation of inflammatory states. The aim of the present study was to determine whether alterations of visceral and subcutaneous adipose tissue, identified with MRI, could serve as markers of local and systemic inflammation in patients with CD. METHODS: A pilot study was conducted comparing alterations in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in CD patients vs obese patients and healthy controls. Fifty patients were enrolled and assigned to one of the following groups: Group A: 11 active CD patients; Group B: 11 CD patients in remission; Group C: 16 obese patients; Group D: 12 healthy controls. A 3-T MRI unit was used and T2-weighted TSE images of VAT and SAT were obtained in specific regions of interest. Serum cytokine concentrations (TNF-α, IL-6, adiponectin, leptin, IL-2, IFN-γ) were determined. RESULTS: There was a significant difference in VAT T2 relaxation time between Group A and B (p < 0.001), A and D (p < 0.01), B and C (p < 0.001). There was a statistically significant difference in SAT T2 relaxation time between Group A and B (p < 0.001), A and C (p < 0.05), A and D (p < 0.001), B and C (p < 0.01). In addition, VAT/SAT T2 relaxation time ratio showed a statistically significant difference between Group A and C (p < 0.05) and between Group B and C (p < 0.01). Only TNF-α and IL-6 significantly correlated with both VAT and VAT/SAT ratio in active CD. CONCLUSIONS: MRI showed similar increased visceral inflammatory signals in patients with active CD and obese patients. However, subcutaneous inflammatory signals were higher in active CD than in all the other groups. These data show that there is a systemic inflammatory state in active CD, whereas chronic inflammation appears confined to VAT in obesity. These data were only partially confirmed by serological cytokine profiles, which showed less specificity than MRI.

Effects of exposure to high temperatures on serum, urine and sweat concentrations of iron and copper.

The objective of this research was to determine the acute effect of a maximum test until exhaustion in normothermia and hyperthermia, and after repeated exposure to heat at high temperatures on the homeostasis of Fe and Cu. The sample was composed of twenty-nine male university students. The participants were divided into a control group (CG) and an experimental group (EG). All of them underwent an incremental test until exhaustion in normothermia and hyperthermia before and after the repeated exposure of EG to heat at high temperatures, consisting of 9 heat acclimatisation sessions in the sauna. Samples of urine and blood were taken before and after each test. Additionally, sweat samples were collected in the hyperthermia test. The samples were frozen at -80 °C for further analysis by ICP-MS. None of the metal concentrations in serum were affected by hyperthermia or exposure to heat. Urinary Fe increased in CG in the hyperthermia test before Heat exposure at High Temperature (HEHT)(p < 0.05) and in both groups after HEHT (p < 0.05). In EG there was an increase in the urinary excretion of Cu after HEHT (p < 0.01) in both trials. Fe suffered a decrease in sweat in EG after exposure to heat (p < 0.05). The concentrations of Fe and Cu in serum were not affected by acute exercise and exposure to high temperatures. However, there was a decrease in excretion of Fe in sweat due to HEHT, and an increase in urinary excretion in both. Therefore, we think that in conditions of high temperatures for long periods of time, attention should be paid to the body levels of these metals.

Effect of exposure to high temperatures in the excretion of cadmium and lead.

OBJECTIVE: This study aims to observe the effect on urine and sweat excretion levels of cadmium (Cd) and lead (Pb) in healthy men in a maximum incremental test until exhaustion and repeated exposure to heat. METHODS: twenty-nine adult men divided into control group (CG; n = 14) and experimental group (EG; n = 15) performing two maximum tests until exhaustion in normothermia (22 °C) and hyperthermia (42 °C). EG experienced 9 sessions of heat exposure at high temperatures (100 °C) (HEHT). After the nine sessions, the initial tests were repeated in both groups. Urine samples were collected before and after each test. After the hyperthermia tests, sweat samples were gathered. RESULTS: Urinary Cd increased after initial tests in GC and in hyperthermia in EG (p < 0.05). Urinary excretion of Pb rose after HEHT (p < 0.05). Pb in sweat was higher in EG than in CG after HEHT (p < 0.05). CONCLUSION: Heat exercise and constant exposure to heat can be a valid method to increase the excretion of toxic metals.

Influence of a high-temperature programme on serum, urinary and sweat levels of selenium and zinc.

INTRODUCTION: The effect of hyperthermia on the antioxidant system in the human organism is well known. AIM: The objective of this study was to observe the effects of heat on the concentration of Se and Zn, elements related to antioxidant systems. METHODS: Twenty-nine subjects voluntarily participated in this study. They were divided into a control group (CG; n = 14) and an experimental group (EG; n = 15). All of them underwent two incremental tests until exhaustion in normothermia (22 °C, 20-40%RH) and hyperthermia (42 °C, 20-40%RH). EG experienced nine sessions of repeated heat exposure at high temperatures (100 °C, 20%RH) for three weeks (HEHT). After the intervention, the initial measurements were repeated. Urine and blood samples were collected before and after each test. Additionally, sweat samples were collected after tests in hyperthermia. RESULTS: There were no significant changes in serum. An increase in the elimination of Zn and Se in EG was observed in urine after HEHT (p < .05). The elimination of Zn by sweating decreased after HEHT in EG (p < .05). CONCLUSIONS: Exposure to heat at high temperatures increases the urinary excretion of Se and Zn.

New Limit on the Permanent Electric Dipole Moment of

We report results of a new technique to measure the electric dipole moment of ^{129}Xe with ^{3}He comagnetometry. Both species are polarized using spin-exchange optical pumping, transferred to a measurement cell, and transported into a magnetically shielded room, where SQUID magnetometers detect free precession in applied electric and magnetic fields. The result from a one week measurement campaign in 2017 and a 2.5 week campaign in 2018, combined with detailed study of systematic effects, is d_{A}(^{129}Xe)=(1.4±6.6_{stat}±2.0_{syst})×10^{-28} e cm. This corresponds to an upper limit of |d_{A}(^{129}Xe)|<1.4×10^{-27} e cm (95% C.L.), a factor of 5 more sensitive than the limit set in 2001.