Growth Hormone Is Necessary for the p53-Mediated, Obesity-Induced Insulin Resistance in Male C57BL/6J × CBA Mice

Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpres- sion of suppressors of cytokine signal 1–3 and signal transducers and activators of transcrip- tion-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice

Steroid treatment in the management of destructive thyrotoxicosis induced by PD1 blockade

Objective: Destructive thyroiditis is the most common endocrine immune related adverse event (iRAEs) in patients treated with anti-PD1/PD-L1 agents. Given its self-limited course, current guidelines recommend no treatment for this iRAE. Nevertheless in patients with enlarged thyroid volume and a poor performance status, thyrotoxicosis may be particularly severe and harmful. Aim of the study is to evaluate if steroid treatment might be useful in improving thyrotoxicosis in subjects with a poor performance status. Methods: We conducted a retrospective study, comparing the course of thyrotoxicosis of 4 patients treated with oral prednisone at the dosage of 25 mg/d (tapered to discontinuation in three weeks) and an enlarged thyroid volume to that of 8 patients with similar thyroid volume who were left untreated. Results: The levels of thyroid hormones were lower in subjects treated compared to those untreated at time 7, 14, 21, 28, 35, 42, 60 and 90 days (P<0.05 at each time). The time to remission of thyrotoxicosis was 24 days in patients treated with steroids and 120 days in untreated patients (P<0.001). At 6 months, the rate of evolution to hypothyroidism was similar in the 2 groups (4/4 in steroid group vs 7/8 in untreated group, P=0.74) and no difference was found in tumor progression (P=0.89). Conclusions: Our preliminary data suggest that in patients with a poor performance status experiencing a severe destructive thyrotoxicosis induced by PD-1 blockade, a short period of administration of oral prednisone is effective in obtaining a quick reduction of the levels of thyroid hormones

Comparison of the effects of primary somatostatin analogue therapy and pituitary adenomectomy on survival in patients with acromegaly: a retrospective cohort study

Objective: Acromegalic patients have an increased risk of mortality. The objective of this study was to compare the effect of different therapies for acromegaly on mortality. Design and methods: The mortality rate of 438 consecutive acromegalic patients was compared with that of the general population using the standardized mortality ratio (SMR); the effect of different therapies on survival was evaluated using Cox regression analysis. Results: Twenty patients (4.5%) died between 1999 and 2009. Age- and sex-adjusted SMR was 0.70 (95% CI 0.43–1.08). The Cox regression analysis revealed that, in the whole population, both general risk factors (age and physical status) and specific factors for acromegaly (macroadenoma, hypopituitarism and uncontrolled disease) were associated with death. The most compromised patients at diagnosis had a higher mortality rate (PZ0.001), which also occurred in patients with controlled acromegaly. Death occurred in 2.4% (adenomectomy), 2.6% (adenomectomy followed by somatostatin analogue (SSA) therapy) and 11.4% (SSA therapy as the primary therapy) of the patients. The risk of death was higher in patients receiving SSA therapy as the primary therapy (hazard ratio (HR) 5.52, 95% CI 1.06–28.77, PZ0.043) than in all patients submitted to adenomectomy; however, a higher risk of death occurred only in diabetic patients treated with SSAs alone (HR 21.94, 95% CI 1.56–309.04, PZ0.022). Radiotherapy was associated with an increased risk of mortality, which occurred in patients with the more locally advanced disease. Conclusions: Therapies for acromegaly and comorbidities have lowered the risk of mortality to the level of the general population; the effect of SSA therapy alone or that following pituitary adenomectomy was comparable to that of curative neurosurgery on survival in non-diabetic patients; on the contrary, SSA therapy as the primary therapy may be less effective than adenomectomy in reducing mortality rate in diabetic patients

Firm mass in thyroid of an elderly patient: not always cancer

Summary In elderly patients presenting with a solid thyroid mass, the differential diagnosis between benign and malignant lesion is not always straightforward. We present the case of an 85-year-old woman with fever and an enlarged, firm and painful thyroid mass. Blood exams documented a mild thyrotoxicosis with a moderate inflammatory status. Thyroid scintiscan showed an absent uptake of 131I. Ultrasound and CT scan documented a 3 cm hypoechoic nodule with infiltration of the sternocleidomastoid muscle, very suspicious for neoplastic nature. Fine-needle aspiration and tru-cut biopsy were performed. During biopsy, the lesion was partially drained and a brownish fluid was extracted. The culture resulted positive for Klebsiella pneumoniae whereas the pathological analysis of the specimen was not conclusive due to the presence of an intense inflammatory response. A targeted oral antibiotic therapy was then initiated, obtaining only a partial response thus, in order to achieve a definite diagnosis, a minimally invasive hemithyroidectomy was performed. The pathological analysis documented acute suppurative thyroiditis and the clinical conditions of the patient significantly improved after surgical removal of thyroid abscess. In elderly patients with a solid thyroid mass, although neoplastic origin is quite frequent, acute suppurative thyroiditis should be considered as a differential diagnosis. Learning points: A solid and rapidly growing thyroid mass in elderly patients can hide a multifaceted variety of diseases, both benign and malign. A multidisciplinary team (endocrinologist, surgeon, radiologist and pathologist) could be necessary in order to perform a correct differential diagnosis and therapeutic approach. Surgery can be decisive not only to clarify a clinically uncertain diagnosis, but also to rapidly improve the clinical conditions of the patient

Fine particle concentrations in buses and taxis in Florence, Italy

On October 2004, a sampling survey was carried out in Florence to estimate urban fine particle exposure concentrations inside commuting vehicles during workdays characterized by heavy traffic. Portable samplers were positioned inside four regularly scheduled diesel-powered buses and four taxis during eight weekdays. Each sampler consisted of a 2.5 μm size pre-separator cyclone, a direct-reading data logging photometer (pDR-1200), and a 4 L min−1 filter sampler for the determination of PM2.5 mass concentration. Based on reflectance analysis measurements, a PM2.5 Black Smoke Index was determined for each filter, and the elemental composition of the PM2.5 was analyzed by Particle Induced X-ray Emission (PIXE). PM2.5 mass concentrations inside the vehicles correlated well with the urban ambient air PM2.5 concentrations measured at the fixed-site monitoring stations. The PM2.5 excess above the urban ambient level was on average 32 μg m−3 (range: 22–52 μg m−3) and 20 μg m−3 (range: 11–29 μg m−3) in buses and taxis, respectively. The PM2.5-bound sulfur concentration was also higher in the buses than in the taxis. Based on daily Time-Microenvironment-Activity-Diary (TMAD) data, the Florentines spend on average 9.7% of their day in traffic, and the corresponding average exposure is approximately 12% of their daily PM2.5 personal exposure. The obtained data could be used to plan interventions to minimize the PM2.5 citizen exposures in commuting.This work is a part of the EU 5-FP funded and WHO/ECEH coordinated HEARTS-project.Peer reviewe

Pituitary and systemic autoimmunity in a case of intrasellar germinoma

Germinomas arising in the sella turcica are difficult to differentiate from autoimmune hypophysitis because of similar clinical and pathological features. This differentiation, nevertheless, is critical for patient care due to different treatments of the two diseases. We report the case of an 11-year-old girl who presented with diabetes insipidus and growth retardation, and was found to have an intra- and supra-sellar mass. Initial examination of the pituitary biopsy showed diffuse lymphocytic infiltration of the adenohypophysis and absent placental alkaline phosphatase expression, leading to a diagnosis of hypophysitis and glucocorticoid treatment. Because of the lack of clinical and radiological response, the pituitary specimen was re-examined, revealing this time the presence of scattered c-kit and Oct4 positive germinoma cells. The revised diagnosis prompted the initiation of radiotherapy, which induced disappearance of the pituitary mass. Immunological studies showed that the patient’s serum recognized antigens expressed by the patient’s own germinoma cells, as well as pituitary antigens like growth hormone and systemic antigens like the Sjögren syndrome antigen B and alpha-enolase. The study first reports the presence of pituitary and systemic antibodies in a patient with intrasellar germinoma, and reminds us that diffuse lymphocytic infiltration of the pituitary gland and pituitary antibodies does not always indicate a diagnosis of autoimmune hypophysitis

Autoimmune hypophysitis: mouse and human studies

Pituitary autoimmunity encompasses a spectrum of conditions ranging from histologically proven autoimmune hypophysitis to the presence of pituitary antibodies in apparently healhy subjects. Autoimmune hypophysitis (AH) is a rare but increasingly recognized disease of the pituitary gland that still needs a full characterization. The autoantigens target of the autoimmune attack are unknown. The diagnosis of AH is difficult because it is often misdiagnosed as a nonsecreting pituitary adenoma. Pituitary antibodies, a marker of pituitary autoimmunity, are measured by non-antigen specific methods so that their determination has limited clinical value. Moreover, a reliable mouse model of AH has not been established. Aims of the study were: 1) to establish a new mouse model of AH 2) to determine the prevalence of pituitary autoimmunity in endocrine patients and in healthy subjects 2) to search for novel antigens in AH using human sera. By immunizing female SJL/J mice with mouse pituitary extracts, we established a new mouse model of experimental AH. Immunized mice developed severe lymphocytic infiltration in the anterior pituitary that closely mimicked the human pathology. In the florid phase of the disease hypopituitarism developed, whereas in later stages of the disease the pituitary gland became atrophic as also demonstrated by the MRI finding of “empty sella”. By measuring pituitary antibodies using indirect immunofluorescence we found that pituitary autoimmunity prevalence is low in normal subjects, is moderately increased in normal pregnancies and in pituitary adenoma patients, and is significantly increased in patients with autoimmune thyroid diseases and in postpartum thyroiditis. By testing the pituitary function in patients with the combination of autoimmune thyroid diseases and pituitary autoimmunity we found a certain grade of GH deficiency in 35% of the patients. By measuring pituitary antibodies in a large cohort of patients with AH, using immunoblotting and a proteomic approach, we were able to identify several proteins that could act as autoantigens in AH. Of these, the most interesting candidate is the chorionic somatomammotropin, that need to be confirmated with further studies. Finally we found that immunoblotting has slighter greater sensitivity and specificity than immunofluorescence in predicting histologically proven AH