What factors have impact on glucocorticoid replacement in adrenal insufficiency: a real-life study.

PURPOSE: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. METHODS: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. RESULTS: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). CONCLUSIONS: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

ΔNp63 targets cytoglobin to inhibit oxidative stress-induced apoptosis in keratinocytes and lung cancer.

During physiological aerobic metabolism, the epidermis undergoes significant oxidative stress as a result of the production of reactive oxygen species (ROS). To maintain a balanced oxidative state, cells have developed protective antioxidant systems, and preliminary studies suggest that the transcriptional factor p63 is involved in cellular oxidative defence. Supporting this hypothesis, the ΔNp63α isoform of p63 is expressed at high levels in the proliferative basal layer of the epidermis. Here we identify the CYGB gene as a novel transcriptional target of ΔNp63 that is involved in maintaining epidermal oxidative defence. The CYGB gene encodes cytoglobin, a member of the globin protein family, which facilitates the diffusion of oxygen through tissues and acts as a scavenger for nitric oxide or other ROS. By performing promoter activity assays and chromatin immunoprecipitation, reverse transcriptase quantitative PCR and western blotting analyses, we confirm the direct regulation of CYGB by ΔNp63α. We also demonstrate that CYGB has a protective role in proliferating keratinocytes grown under normal conditions, as well as in cells treated with exogenous hydrogen peroxide. These results indicate that ΔNp63, through its target CYGB has an important role in the cellular antioxidant system and protects keratinocytes from oxidative stress-induced apoptosis. The ΔNp63-CYGB axis is also present in lung and breast cancer cell lines, indicating that CYGB-mediated ROS-scavenging activity may also have a role in epithelial tumours. In human lung cancer data sets, the p63-CYGB interaction significantly predicts reduction of patient survival.

Comparison of conventional L-thyroxine withdrawal and moderate hypothyroidism in preparation for whole-body 131-I scan and thyroglobulin testing.

PURPOSE: After thyroidectomy for thyroid cancer, patients often withdraw L-T4 for diagnostic or therapeutic purposes, showing signs and symptoms of hypothyroidism. A slighter hypothyroidism (reducing L-T4 to one-half) has been proposed to limit these inconveniences. We evaluated half-dose L-T4 protocol, in comparison to conventional L-T4 withdrawal, in terms of effectiveness and improvement of clinical and biochemical disorders. METHODS: We randomized 55 thyroid cancer patients into two groups: 29 patients underwent 5 weeks of half-dose of previous L-T4 treatment (HD group); 26 patients replaced L-T4 with L-T3 for 3 weeks followed by 2 weeks of withdrawal (TW group). Clinical features (Zulewsky clinical score) and biochemical parameters (lipids, liver, and muscle enzymes) were evaluated in all patients at baseline and after 5 weeks. RESULTS: Total cholesterol, creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase increased at 5 weeks in both groups, but significantly more in TW, but no difference was found by clinical score. Patients who achieved the thyroid-stimulating hormone (TSH) target value (25 µU/ml) were 92.3% in TW group and 48.3% in HD group (p < 0.001). In the HD group, only basal TSH statistically correlated with the achievement of the TSH target. Receiver operating characteristic curves indicated that a basal TSH ≥0.52 µU/ml is required to reach an adequate TSH level. CONCLUSIONS: Half-dose L-T4 protocol, compared to conventional L-T4 withdrawal, is associated with less biochemical disorders but no significant clinical advantage. Therefore, the half-dose protocol reaches an adequate TSH target in 48.3% of patients and is not effective unless basal serum TSH is ≥0.52 µU/ml.

Improving the prediction of malignancy in cytologically suspicious thyroid nodules.

BACKGROUND: Fine needle cytology aspirates (FNA) classified as THY4 are a heterogeneous group suspicious for malignancy [papillary thyroid cancer (PTC)], which is confirmed in 50-80% of cases after surgery. AIM: To better stratify THY4 FNA specimens for the relative risk of malignancy. METHODS: We retrospectively analyzed 78 thyroid nodules classified as THY4 because of the presence of atypical cells, hypercellular trabeculae and/or intranuclear inclusions (ICI), in the absence of papillae. Two subgroups were identified: group 1 (38 nodules), showing ICI with (no.=17) or without (no.=21) trabeculae and cellular atypia, and group 2 (40 nodules), showing trabeculae and atypia but without ICI. RESULTS: PTC was detected at histology in 56/78 of the patients (71.8%). Malignancy occurred in 36/38 (94.7%) of the patients in group 1 and in 20/40 (50.0%) of the patients in group 2. Therefore, the positive predictive value (PPV) for PTC was 97.3% in the ICI+ specimens (group 1), with a sensitivity of 64.3% and specificity of 95.2%. When only ICI was present, without atypia and trabeculae, the PPV and specificity were similar (95.0 and 95.2%, respectively), but the sensitivity was decreased (48.7%). In specimens without ICI (group 2), the PPV was only 50.0%; however, combined with young age (<40 yr) and male gender, it reached a value similar to that of group1. CONCLUSIONS: In ICI+ specimens compared to ICI-, the risk of PTC is nearly doubled, since PPV increases from 50.0% to 97.3%. This observation suggests that surgery should be considered mandatory in all lesions classified THY4 at FNA, although the relevant difference in terms of cancer risk between ICI- vs ICI+ nodules might be an useful information for both the clinician and the patient.

Radiometabolic treatment of hyperthyroidism with a calculated dose of 131-iodine: results of one-year follow-up.

Oral administration of radioactive iodine (131I) is a well-known and effective procedure for the treatment of hyperthyroidism. However, the optimal dose is still a matter of debate, as is the frequency of recurrence and hypothyroidism. The aim of our study was to evaluate the 1-yr outcome of a calculated dose of 131I activity in the treatment of hyperthyroidism, following the guidelines published jointly by the Italian Society of Endocrinology and the Italian Society of Nuclear Medicine.We studied 84 patients affected with hyperthyroidism (55 with Graves' disease and 29 with toxic adenoma), who were treated with a dose of 131I activity obtained by using the formula from the guidelines. In all patients serum free T4, free T3, and TSH were measured before, and 2, 6, and 12 months after radiometabolic therapy. A thyroid scan and thyroid uptake with 131I were also performed before treatment, and a thyroid ultrasound scan was obtained before and 1 yr after treatment. One year after treatment, 22 out of 55 patients with Graves' diseases (40.0%) had persistence/ recurrence of hyperthyroidism, whereas only 1 patient of the 29 with toxic adenoma (3.4%) was still in a hyperthyroid state. The frequency of hypothyroidism in patients responsive to therapy was higher in subjects with Graves' disease (45.5%), than in those with toxic adenoma (17.3%, p=0.02). Overall size reduction of the target lesion was 56.2+/-23.1%. In conclusion, the dose calculation suggested by the guidelines represents an effective method for treating thyroid toxic adenoma. In subjects with Graves' disease, we propose using a pre-determined 131I activity, which is higher than that derived from the guidelines. Such an approach would reduce the incidence of recurrent/persistent hyperthyroidism. On the other hand, an increase in post-131I hypothyroidism should not be regarded as a negative effect in these patients, since hypothyroidism is easily corrected, and the risk of worsening ophthalmopathy is reduced.

Healing of chronic necrobiosis lipoidica lesions in a type 1 diabetic patient after pancreas-kidney transplantation: a case report.

Necrobiosis lipoidica (NL) is a degenerative disease of dermal connective tissue of unknown etiology characterized by erythematous plaques preferentially localized to distal extremities. Skin lesions show a chronic relapsing nature. NL is often associated with diabetes mellitus and satisfactory treatment options are lacking. We describe the spontaneous healing of NL lesions after pancreas and kidney transplantation in a Type 1 diabetic patient with chronic NL recalcitrant to a variety of standard treatments. The 31-yr-old male patient had experienced NL lesions for more than 15 yr; despite various systemic and topical treatments, the skin lesions had pregressively enlarged. Because of end-stage renal disease, a simultaneous pancreas and kidney transplantation was performed and immunosuppressive therapy with tacrolimus (TAC), mycophenolate mofetil (MMF), and prednisone was started. Pancreatic transplantation maintained satisfactory metabolic control with no need of exogenous insulin. After transplantation, skin lesions slowly healed without any specific treatment, leaving residual areas of fibrotic scars. A skin biopsy confirmed the absence of typical NL lymphocytic and histiocytic inflammatory response. Clinical remission of NL lesions may probably be explained by the concomitant effect of multiple-drug regimen for immunosuppression (TAC, MMF, and prednisone) and improved skin microcirculation secondary to the good metabolic control provided by pancreas transplantation.

Vasopressin (DDAVP) therapy in chronic schizophrenia: effects on negative symptoms and memory.

Ten chronic undifferentiated schizophrenics, 6 men and 4 women, aged 28-63, with 6- to 31-year histories of the disease were given DDAVP to observe the effects of this neuropeptide on the prevalent negative symptoms of their illness. Patients were maintained on neuroleptic therapy and first given a 20-day course of placebo followed by 20 days of DDAVP i.m., 4 micrograms Andreasen Scale for assessment of negative symptoms, the Brief Psychiatric Rating Scale, the NOSIE Rating Scale and the Luria-Nebraska Rating Scale were administered to monitor negative symptomatology, behavior and memory before the study began, after placebo and after DDAVP administration. Patients were also given a growth hormone-clonidine test and in addition plasma basal concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) were measured at the same intervals. DDAVP therapy induced a significant improvement of negative symptomatology and a trend toward improvement of short- to medium-term memory. No changes in homovanillic acid, MHPG, 5-HIAA and DOPAC, nor of growth hormone response to clonidine stimulation were observed.