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.

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.

Costs of therapy with biologics in the treatment of moderate to severe plaque psoriasis in the context of the Italian health-care system.

AIM: Biologics were introduced as innovative and effective therapies for the treatment of moderate-to severe psoriasis. However, in the Italian context there are no comparative cost-effectiveness analyses of all biologics currently approved for psoriasis by the European Medicines Agency (EMA). This study estimates whether the cost of ustekinumab (meant as cost of drug therapies and monitoring) is lower, similar to or higher than that of anti-TNF-α. METHODS: The incremental cost-effectiveness ratio (ICER) and the cost-effectiveness ratio (CER) in terms of cost for patients achieving 75% improvement in PASI (PASI 75) were calculated. The analysis, both during the first 52 weeks, including induction and in maintenance period is based on efficacy data taken from single studies. The costs, based on official source, are calculated in the perspective of National Health Service (SSN). RESULTS: Ustekinumab has the lowest cost for responder, resulting always cost-effective and, in some case, cost saving in the baseline scenario at 52 weeks and in maintenance period. CONCLUSION: Ustekinumab seems to be the most favorable biologic in term of cost per PASI 75 responder for the treatment of psoriasis and it is cost-effective in all scenarios analyzed. Further cost-effectiveness evaluations based on data of use of long-term treatment with biologics in clinical practice, are necessary to support this results.

Dietary fat differentially modulate the mRNA expression levels of oxidative mitochondrial genes in skeletal muscle of healthy subjects.

BACKGROUND AND AIMS: Different types of dietary fats exert differential effects on glucose and lipid metabolism. Our aim was to evaluate the impact of different dietary fats on the expression of skeletal muscle genes regulating mitochondrial replication and function in healthy subjects. METHODS AND RESULTS: Ten healthy subjects (age 29 ± 3 years; BMI 25.0 ± 3 kg/m(2)) received in a random order a test meal with the same energy content but different composition in macronutrients and quality of fat: Mediterranean (MED) meal, SAFA meal (Lipid 66%, saturated 36%) and MUFA meal (Lipid 63%, monounsaturated 37%). At fast and after 180 min, a fine needle aspiration was performed from the vastus lateralis for determination of mitochondrial gene expression by quantitative PCR. No difference in glucose and triglyceride response was observed between the three meals, while NEFA levels were significantly higher following fat-rich meals compared to MED meal (p < 0.002-0.0001). MED meal was associated with an increased expression, albeit not statistically significant, of some genes regulating both replication and function. Following MUFA meal, a significant increase in the expression of PGC1ß (p = 0.02) and a reduction in the transcription factor PPARδ (p = 0.006) occurred with no change in the expression of COX and GLUT4 genes. In contrast, SAFA meal was associated with a marked reduction in the expression of COX (p < 0.001) PFK (p < 0.003), LPL (p = 0.002) and GLUT4 (p = 0.009) genes. CONCLUSION: Dietary fats differentially modulate gene transcriptional profile since saturated, but not monounsaturated fat, downregulate the expression of genes regulating muscle glucose transport and oxidation.

Microvesicle and tunneling nanotube mediated intercellular transfer of g-protein coupled receptors in cell cultures.

Recent evidence shows that cells exchange collections of signals via microvesicles (MVs) and tunneling nano-tubes (TNTs). In this paper we have investigated whether in cell cultures GPCRs can be transferred by means of MVs and TNTs from a source cell to target cells. Western blot, transmission electron microscopy and gene expression analyses demonstrate that A(2A) and D(2) receptors are present in released MVs. In order to further demonstrate the involvement of MVs in cell-to-cell communication we created two populations of cells (HEK293T and COS-7) transiently transfected with D(2)R-CFP or A(2A)R-YFP. These two types of cells were co-cultured, and FRET analysis demonstrated simultaneously positive cells to the D(2)R-CFP and A(2A)R-YFP. Fluorescence microscopy analysis also showed that GPCRs can move from one cell to another also by means of TNTs. Finally, recipient cells pre-incubated for 24 h with A(2A)R positive MVs were treated with the adenosine A(2A) receptor agonist CGS-21680. The significant increase in cAMP accumulation clearly demonstrated that A(2A)Rs were functionally competent in target cells. These findings demonstrate that A(2A) receptors capable of recognizing and decoding extracellular signals can be safely transferred via MVs from source to target cells.

Two weekly sessions of combined aerobic and resistance exercise are sufficient to provide beneficial effects in subjects with Type 2 diabetes mellitus and metabolic syndrome.

This study was performed to establish whether only 2 sessions per week of combined aerobic and resistance exercise are enough to reduce glycated hemoglobin (HbA(1c)) and to induce changes in skeletal muscle gene expression in Type 2 diabetes mellitus (DM2) subjects with metabolic syndrome. Eight DM2 subjects underwent a 1-yr exercise program consisting of 2 weekly sessions of 140 min that combined aerobic [at 55-70% of maximal oxygen uptake (VO(2max))] and resistance circuit training [at 60-80% of 1 repetition maximum (RM)]. The training significantly improved VO(2max) (from 33.5+/-3.8 ml/kg/min to 38.2+/-3.5 ml/kg/min, p=0.0085) and muscle strength (p<0.05). Changes over baseline were significant for HbA(1c), reduced by 0.45% (p=0.0084), fasting blood glucose (from 8.8+/-1.5 to 6.9+/-2.2 mmol/l, p=0.0132), waist circumference (from 98.9+/-4.8 to 95.9+/-4.6 cm, p=0.0054), body weight (from 87.5+/-10.7 to 85.7+/-10.1 kg, p=0.0375), systolic blood pressure (from 137+/-15 to 126+/-8 mmHg, p=0.0455), total cholesterol (from 220+/-24 to 184+/-13 mg/dl, p=0.0057), and LDL-cholesterol (from 150+/-16 to 105+/-15 mg/dl, p=0.0004). Mitochondrial DNA/nuclear DNA ratio at 6 and 12 months did not change. There was a significant increase of mRNA of peroxisome proliferator- activated receptor (PPAR)-gamma after 6 months of train - ing (p=0.024); PPARalpha mRNA levels were significantly increased at 6 (p=0.035) and 12 months (p=0.044). The mRNA quantification of other genes measured [mitochondrially encoded cytochrome c oxidase subunit II (MTCO2), cytochrome c oxidase subunit Vb (COX5b), PPARgamma coactivator 1alpha (PGC- 1alpha), glucose transporter 4 (GLUT 4), forkhead transcription factor BOX O1 (FOXO-1), carnitine palmitoyltransferase 1 (CPT-1), lipoprotein lipase (LPL), and insulin receptor substrate 1 (IRS-1)] did not show significant changes at 6 and 12 months. This study suggests that a twice-per-week frequency of exercise is sufficient to improve glucose control and the expression of skeletal muscle PPARgamma and PPARalpha in DM2 subjects with metabolic syndrome.

A protocol for the treatment of mandibular condylar fractures.

The authors suggest a protocol for the treatment of mandibular condylar fractures classified by fracture level: the condylar head, the condylar neck and subcondylar fractures. The protocol provides a guide to individualizing intervention according to the type of fracture, the patient's age, the degree of restriction of mandible movement and the possible presence of fractured condyle displacement, which is often associated with functional disorders. The age of the patient is a key factor in the choice of treatment. The therapeutic goal in adult patients differs from that in growing patients, since in children the condyle is a major growth center for the mandible. Management may be surgical or nonsurgical; surgical intervention may be conservative with or without immobilization with closed or open reduction and fixation.

Physiopathological aspects of body overweight in the female climacteric.

The correlation between overweight and the climacteric was studied in 550 menopause clinic patients by investigating certain clinical and sociocultural parameters (age, marital status, educational level, occupation and type of work, calorie intake, smoking habits, parity, blood pressure, previous hormonal therapy and climacteric symptoms), evaluating plasma levels of various hormones (17 beta-oestradiol, follicle-stimulating hormone (FSH), luteinizing (LH), testosterone, hydrocortisone, adrenocorticotrophic hormone (ACTH), triiodothyronine (T3), thyroxine (T4), growth hormone (GH) and insulin), glucose and various lipid fractions (total lipids, total cholesterol, nonesterified fatty acids (NEFA), triglycerides and phospholipids) and exploring the blood-clotting pattern ( Owren 's test, euglobulin lysis time, antithrombin III and prothrombin agglutination time (PAT). The subjects were classified as normal weight or overweight by reference to Broca's Index, as modified by Brusch , and the degree of overweight was determined by means of the Body Mass Index (BMI). Of the subjects examined, 49% were overweight and, in successive years following the menopause, there was a growing bipolarization of the weight increase. The correlation between overweight in the climacteric and the parameters considered was found to be significant only in regard to calorie intake, age and educational level. Post-menopausal gonadotrophin levels in blood were significantly lower in the overweight than in the normal-weight women. With the onset of menopause, the plasma level of testosterone fell in the normal-weight women, while it increased, along with that of hydrocortisone, in the overweight women. In the normal-weight women at menopause, it was found that there was a tendency towards a substantial increase in lipid fractions and glycaemia, as well as a state of hypercoagulability. In the overweight women, the tendency was towards an even more marked increase in both glycaemia and the various lipid fractions, and, besides the hypercoagulative state, there was an associated reduction in fibrinolytic activity. It is concluded that the menopause not only causes metabolic changes but also aggravates the metabolic and endocrine tendencies which characterize overweight subjects and thus, clinically, constitutes an obesity risk factor in those women who already demonstrate a tendency towards overweight in the pre-menopausal phase.