Improved overall survival in patients developing endocrine toxicity during treatment with nivolumab for advanced non-small cell lung cancer in a prospective study.

PURPOSE: Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC. METHODS: In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography. RESULTS: An impaired thyroid function was recorded in 23.4% of patients (n = 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p = 0.021) and multivariate analyses (p = 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p = 0.031). CONCLUSIONS: Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.

The impact of overweight on lipid phenotype in different forms of dyslipidemia: a retrospective cohort study.

PURPOSE: Dyslipidemia plays a pivotal role in increasing cardiovascular risk. In clinical practice the misleading association between altered lipid profile and obesity is common, therefore genetically inherited dyslipidemias may not completely be addressed among patients with overweight. Thus, we aim to investigate the influence of overweight and obesity on the lipid phenotype in a cohort of patients with different forms of dyslipidemia. METHODS: A retrospective analysis was conducted on patients with dyslipidemia from 2015 to 2022. Patients were stratified in familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), non-familial hyperlipidemia or polygenic hypercholesterolemia (PH). Clinical characteristics and lipid profile were evaluated. RESULTS: Of the total of 798 patients, 361 were affected by non-familial hyperlipidemia (45.2%), while FCHL, FH and PH was described in 19.9%, 14.0% and 20.9% of patients, respectively. Overweight prevalence was higher in FCHL and non-familial hyperlipidemia patients than FH and PH patients. Subjects with overweight and obesity were independently associated with lower levels of high-density lipoprotein cholesterol (HDL-C) compared to patients with normal weight (52.4 and 46.0 vs 58.1, respectively; p < 0.0001); levels of triglycerides (TG) and non-HDL-C were higher in patients with overweight and obesity than patients with normal weight (257.3 and 290.9 vs 194.8, and 221.5 and 219.6 vs 210.1, p < 0.0001 and p = 0.01, respectively), while no differences were observed between patients with overweight and obesity. CONCLUSION: While dyslipidemias can be influenced by various factors, an important determinant may lie in genetics, frequently acting as an underlying cause of altered lipid profiles, even in cases of overweight conditions.

Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.

BACKGROUND: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE: To evaluate gender differences in clinical presentation and outcome of CaS. METHODS: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.

Diabetic striatopathy: an updated overview of current knowledge and future perspectives.

PURPOSE: Diabetic striatopathy (DS) is a rare complication of poorly controlled diabetes mellitus (DM), characterized by hyperglycemia associated with chorea/ballism and characteristic reversible basal ganglia abnormalities on computed tomography (CT) and/or magnetic resonance imaging (MRI). We propose a narrative review of the literature on this topic, currently unknown to most, and about which physicians should be aware. We intend to summarize, critically review, and take to mean the evidence on this disorder, describing its typical features. METHODS: We searched Pubmed for English-language sources using the following keywords in the title and the abstract: diabetic striatopathy, hyperglycemic non-ketotic hemichorea/hemiballism, chorea/hemichorea associated with non-ketotic hyperglycemia, diabetic hemiballism/hemichorea, chorea, hyperglycemia, and basal ganglia syndrome. We collected scientific articles, including case reports, reviews, systematic reviews, and meta-analyses from the years 1975 to 2023. We eliminated duplicate, non-English language or non-related articles. RESULTS: Older Asian women are more frequently affected. Suddenly or insidiously hemichorea/hemiballism, mainly in the limbs, and high blood glucose with elevated HbA1c in the absence of ketone bodies have been observed. Furthermore, CT striatal hyperdensity and T1-weighted MRI hyperintensity have been observed. DS is often a treatable disease following proper hydration and insulin administration. Histopathological findings are variable, and no comprehensive hypothesis explains the atypical cases reported. CONCLUSION: DS is a rare neurological manifestation of DM. If adequately treated, although treatment guidelines are lacking, the prognosis is good and life-threatening complications may occur occasionally. During chorea/hemiballism, we recommend blood glucose and HbA1c evaluation. Further studies are needed to understand the pathogenesis.

Impact of microscopic extrathyroidal extension on differentiated thyroid cancer post-surgical risk of recurrence: a retrospective analysis.

PURPOSE: In the last edition of the American Joint Committee on Cancer (AJCC) staging system, differentiated thyroid cancers (DTC) showing microscopic extrathyroidal extension (mETE) are considered comparable to intrathyroidal cancers for their clinical behavior and prognosis. The aim of the study is to evaluate the impact of this updated assessment of T, when applied to the postoperative recurrence risk stratification, according to the American Thyroid Association Guidelines (ATA-RR). METHODS: One-hundred DTC patients who underwent total thyroidectomy were retrospectively evaluated. The downstaging of mETE was introduced in the definition of T, and the updated classification defined as modified ATA-RR (ATAm-RR). For each patient, post-surgical basal and stimulated thyroglobulin (Tg) levels, neck ultrasound (US) and post-ablative 131-I whole body scan (WBS) reports were considered. The predictive performance (PP) of disease recurrence was calculated both for each single parameter, as well as for all of them. RESULTS: According to ATAm-RR classification, 19/100 patients (19%) were downstaged. ATA-RR proved a significant PP for disease recurrence (DR) (sensitivity 75.0%, specificity 63.0%, p = 0.023). However, ATAm-RR performed slightly better due to an increased specificity (sensitivity 75.0%, specificity 83.7%, p < 0.001). For both classifications, the PP was optimal when all the above-mentioned predictive parameters were considered. CONCLUSION: Our results suggest that the new assessment of T considering mETE resulted in a downgrading of ATA-RR class in a significant number of patients. This provides a better PP for disease recurrence, and the best PP was obtained when considering the whole predictive variables together.

The effect of sodium restriction on iodine prophylaxis: a review.

PURPOSE: Sodium is essential to life. However, its dietary excess is detrimental to the cardiovascular system, and sodium restriction is a crucial step in cardiovascular prevention. Iodine deficiency has been fought worldwide for decades, and substantial success has been achieved introducing the use of iodine-enriched salt. Nevertheless, areas of iodine deficiency persist around the world, both in developing and industrialized countries, and a major concern affecting dietary sodium reduction programs is represented by a possible iodine intake deficiency. There are substantial differences in the source of alimentary iodine among countries, such as iodized salt added, household tap water, seafood, or salt employed in packaged food. It is clear that a sodium-restricted diet can induce differences in terms of iodine intake, depending on the country considered. Moreover, iodine status has undergone relevant changes in many countries in the last years. METHODS: Systematic review of literature evidence about the possible effects of sodium restriction on population iodine status. RESULTS: To date, the available results are conflicting, depending on country, salt iodization policy, as well as time frame of data collection. However, to ensure an optimal iodine supply by salt fortification, without exceeding the current recommendation by World Health Organization for salt intake, seems to be an achievable goal. CONCLUSION: A balanced approach may be obtained by an adequate iodine concentration in fortified salt and by promoting the availability of iodized salt for household consumption and food industry use. In this scenario, updated prospective studies are strongly needed.

Possible protective role of metformin therapy on colonic polyps in acromegaly: an exploratory cross-sectional study.

CONTEXT: Colonic polyps occur in 30-40% of acromegalic patients, increasing the risk of colon carcinoma. Although debated, there is emerging evidence that metformin may play a protective role in diabetic and non-diabetic patients with colonic polyps and its use in chemoprevention is currently explored. OBJECTIVE: Evaluate the prevalence of colonic polyps in acromegalic patients treated or not with metformin and explore its possible protective role. DESIGN: Exploratory cross-sectional study in two tertiary Italian referral centres. MET: hods: Out of 153 acromegalic patients, we selected 58 patients (36-82 years; f: 33) who had at least one colonoscopy performed within the first 2 years of diagnosis. Presence of colonic polyps/cancer and related risk factors, current metformin and acetylsalicylic acid intake, disease duration, therapies for acromegaly, hormonal and metabolic parameters were assessed. RESULTS: An overall prevalence of 36% polyps was found. Based on the presence of polyps, we identified two groups, comparable for age, BMI, disease duration, glucose, insulin, HOMA-IR, HbA1c, GH and IGF-I levels. Of the patients with polyps (including three adenocarcinomas) only 24% were treated with metformin vs 57% of patients without polyps. Multivariate analysis confirmed a significant negative association between colonic polyps and metformin intake (OR: 0.22, 95% CI: 0.06-0.77, P = 0.01), whereas no significant association was found between polyps and age (P = 0.10), overweight/obesity (P = 0.54), smoking (P = 0.15), acetylsalicylic acid intake (P = 0.99), disease duration (P = 0.96), somatostatin analogues treatment (P = 0.70). CONCLUSIONS: These findings, though deriving from an exploratory study, could suggest a protective role of metformin on the development of colonic polyps in acromegaly, and need to be confirmed in an extended study population.

Growth factors and metabolic markers in cord blood: relationship to birth weight and length.

Low birth weight and length for gestational age are associated with a high risk of short stature and metabolic syndrome in adulthood. The mechanisms that link prenatal growth to adult stature and metabolic syndrome have not yet been entirely clarified. The aim of our study was to evaluate the relationship between standardized anthropometric measures at birth and insulin-like growth factor (IGF)-I, IGF-II, insulin, adiponectin, and non-esterified fatty acid (NEFA) cord blood levels in the general population. One hundred fifty-eight random newborn subjects (77F, 81M) from Genoa, Italy, were analyzed. Anthropometric parameters were measured and standardized according to standard Italian tables. Insulin values were treated as categorical, since in several cases the results fell below detection cut-off. Mean birth weight was 3,214.23∓488.99 gr and mean length was 49.82∓2.17 cm. Females had higher mean IGF-I (p=0.04), and were more likely to have insulin values either <2 μU/ml or >4.5μU/ml (p= 0.04) compared to males. Weight and length SD scores (SDS) were higher in subjects with elevated insulin levels (p=0.002). A moderate correlation was found between weight and IGF-II (r=0.354). Multivariable analysis demonstrated that standardized birth weight was associated with IGFII and insulin values. Our data highlight the importance of IGF-II in fetal growth and suggest that gender differences should be taken into consideration when evaluating prenatal growth.

Replacement therapy and cardiovascular diseases.

It is known that hypopituitarism reduces life expectancy and increases the risk of death for cardio- and cerebrovascular disease. Many studies report this phenomenon due to vascular diseases, and GH deficiency (GHD) seems to significantly contribute to the higher mortality. Aim of this article is to review the relationship between GH and cardiovascular risk factors to evaluate the beneficial effects of therapy in the adult GHD. GH replacement therapy (GHRT) improves insulin sensitivity, and reduces LDL cholesterol and triglyceride levels. Several studies also documented a decrease in the intima-media thickness at major arteries and improvement in microvascular and endothelial function. Other studies showed a decrease of inflammatory markers and the normalization of coagulation parameters. Finally, some authors have reported improvements in cardiac performance as well. These data evidence the positive effects of GHRT in the prevention of premature atherosclerosis in adults with GHD, and encourage the early administration of replacement therapy.

Normal age-dependent values of serum insulin growth factor-I: results from a healthy Italian population.

Serum IGF-I levels were measured in 547 non-hypopituitaric, non-acromegalic healthy subjects of both sexes in Italy to develop reference values in relation to age and sex. Participant subjects were stratified in three age classes (25- 39, 40-59 and >or=60 yr) and IGF-I assay was carried out by double-antibody radio immunoassay. Pearson's correlation coefficient between age and IGF-I values was calculated by sex and predefined age ranges. IGF-I levels significantly decreased with age (p<0.001, Kruskal-Wallis test) while sex was not a significant factor. The median IGF-I levels were 206 ng/ml in the 25-39 yr range, 147 ng/ml in the 40-59 yr range and 103 ng/ml in the >or=60 yr range. Pearson's correlation coefficient confirmed the negative correlation between age and IGF-I levels in the total sample of subjects (r=-0.529). The r coefficient between age and IGF-I levels did not differ between sexes (r=-0.570 in males and r=-0.529 in females), thus reflecting no sex-effect on IGF-I levels decline over years. No correlations were found in the 25-39 yr range (r=-0.036) or in the 40-59 yr range (r=-0.080) either, while in subjects aged >60 yr, IGF-I levels tended to further decrease with increased age (r=0.389). Ranges of normal values set at the 2.5th-97.5th percentile in the three age ranges were 95.6-366.7 ng/ml between 25 and 39 yr, 60.8-297.7 ng/ml between 40 and 59 yr and 34.5-219.8 ng/ml in subjects aged >or=60 yr. This study may contribute to the development of age-specific reference ranges for IGF-I determination in serum of normal subjects of both sexes in Italy.

Efficacy of a slow-release formulation of lanreotide (Autogel) 120 mg) in patients with acromegaly previously treated with octreotide long acting release (LAR): an open, multicentre longitudinal study.

OBJECTIVE: Lanreotide Autogel 120 mg (ATG120; Ipsen S.p.A, Milan, Italy) is a high-dose, sustained-release aqueous gel formulation, supplied in a prefilled syringe and given by deep subcutaneous injection. The aim of this study was to compare efficacy and tolerability of ATG120 given every 4-8 weeks with those of octreotide LAR (o-LAR) given every 4 weeks. DESIGN PATIENTS AND INTERVENTION: A phase III multicentre Italian open clinical study of 23 acromegalic patients (15 female, 8 male). All patients had received o-LAR for 6-18 months and, after 3 months wash out, ATG120 was given every 6 weeks for a total of four injections (Period 1). Then the interval between ATG120 injections was adjusted according to three different schemes: every 4, 6 or 8 weeks depending on GH levels (GH > 2.5 microg/l; 1 < GH

The IGF system in a case of Costello syndrome.

Costello syndrome is characterized by facial dysmorphia, hyperpigmented skin, palmar and plantar hyperkeratosis, curly hair, perioral and nasal papillomata (more rarely localized anally and on vocal cords), short stature, mental retardation and sociable personality. Although growth retardation is typical of Costello syndrome, its cause is not defined. We report on a 10-yr-old Caucasian girl affected by Costello syndrome with fasting hypoglycemia and short stature, associated low circulating levels of acid-labile subunit (ALS), relatively low levels of IGF-I and IGFBP-3, and normal IGF-II, mostly circulating in a binary complex with IGFBP-2 and -6 instead of in a 150 kDa ternary complex. The reduced ALS concentration and the consequent impaired formation of the circulating 150 kDa ternary complex can induce an accelerated clearance rate of IGF peptides and of IGFBP-3, contributing to the decreased IGF-I growth promoting activity in our patient. Moreover, the presence of IGF-II in the binary complex, which has been postulated to increase the insulin-like effects of these peptides, can explain, at least in part, the patient's asymptomatic fasting hypoglycemia.

Pituitary tumor disappearance in a patient with newly diagnosed acromegaly primarily treated with octreotide LAR.

We describe the case of an acromegalic patient primarily treated with octreotide LAR in whom the pituitary tumor disappeared after 18 months of treatment. A 68-yr-old woman, with clinical suspicion of acromegaly, was admitted to our Unit with the ultrasonographical evidence of cardiac hypertrophy, arrhythmias, right branch block and interatrial septum aneurism. She referred hands and feet enlargement since the age of 30 and facial disfigurements since the age of 50. At the age of 45 she underwent surgery for carpal tunnel syndrome and at the age of 61 an euthyroid nodular goiter was diagnosed. Hormonal evaluation showed elevated circulating GH levels (25+/-3.2 ng/ml), not suppressible after oral glucose load, and elevated IGF-I levels (646 ng/ml), whereas the remaining pituitary function was normal. Visual perimetry was normal, whereas magnetic resonance imaging (MRI) showed an intrasellar pituitary adenoma with maximal diameter of 9 mm. In order to improve cardiovascular function before surgery, the patient started octreotide LAR 20 mg every 4 weeks for 3 months. Then based on IGF-I values, the dose was adjusted to 30 mg. After 6 months a second MRI showed significant tumor reduction (>50% of baseline maximal diameter), GH and IGF-I were within the normal range and the patient continued the treatment. After one-year therapy, an improvement of cardiac alterations was recorded and the patient was referred to the neurosurgeon. However, she refused the operation. At 18-month follow-up, MRI showed the complete disappearance of direct and indirect signs of pituitary adenoma. To our knowledge, this is the first case of complete radiological remission of pituitary tumor during octreotide LAR treatment in acromegaly.

Potential indications for somatostatin analogues: immune system and limphoproliferative disorders.

Among hormones and neuropeptides influencing the immune system, somatostatin seems to play a key role not only in inhibiting specific immune cell activities, but also in promoting selected functions of particular immune cell subsets. Indeed, controversial effects have been observed in experimental conditions where somatostatin seems to stimulate certain cell functions, such as secretion of specific products (immunoglobulin, cytokines), cell migration and adhesion to extracellular matrix components. However, interestingly, cortistatin (CST), a neuropeptide that strongly resembles somatostatin, from both the structural and functional points of view, seems to have potential roles in regulating immune responses, as well as other lymphoid cell functions. The unexpected wide distribution of CST in a number of human organs, but particularly in immune cells, points to a broader physiological role of CST than previously presumed. The actions of somatostatin and its synthetic analogs (SSA) are mediated by five membrane G protein-coupled receptors subtypes (SSTR1-5), displaying a tissue specific distribution. The majority of somatostatin-target tissues, including lymphoid tissues, may co-express multiple somatostatin receptor (SSTR). The number of SSTRs in lymphoid cells is significantly lower compared to neuroendocrine tissues. However, the presence of receptors allowed the localization by in vivo SSTR scintigraphy of lymphoproliferative disorders, as well as granulomatous and autoimmune diseases. In specific cases, this technique may contribute to establishing the diagnosis and staging the disease. Recent studies evaluating the specific and quantitative SSTR distribution in lymphoid organs and cells, in both normal conditions and immune disorders, have largely contributed to better understand the phenomenology of in vivo receptor imaging and also the involvement of the different SSTR in determining the uptake of radiolabeled SSAs. Moreover, since lymphomas are highly radiosensitive malignancies, a promising approach in refractory patients with malignant lymphomas may be represented by radionuclide-targeted therapy with radioactive-coupled SSAs combined with gene therapy. This latter technique seems effective in inducing the expression or increasing the number of given SSTR in order to ameliorate the impact of radionuclide-targeted therapy. Medical treatment of lymphoproliferative diseases with currently available synthetic analogs have produced unsatisfactory and conflicting results. This might be due to the affinity of the current available SSAs for specific SSTR. However, the synthesis of new compounds with distinct properties has reopened a challenge in this field. The application of receptor-based localization and anti-tumor strategies should also be taking into account the new knowledge recently emerged on the physiopathology of neuropeptide receptors: firstly, neuropeptide receptor homo- and heterodimerization, which may involve different subtypes of SSTRs, as well as other neuropetide receptors, and secondly, the role of endogenous SSTR ligands, such as CST.

HIV-1 Rev transactivator: a beta-subunit directed substrate and effector of protein kinase CK2.

The phosphorylation of HIV-1 Rev by protein kinase CK2 is strictly dependent on the regulatory beta subunit of the kinase and is deeply affected by conformational changes of the substrate outside the phosphorylation site. Here we show that Rev modulates a variety of CK2 properties, including autophosphorylation, catalytic activity toward calmodulin, and susceptibility to polycationic effectors, whose common denominator is the involvement of the beta subunit. Rev's two major CK2 sites are located at its N-terminus, immediately adjacent to a helix-loop-helix motif. By comparing the behaviour of full-size Rev with that of synthetic peptides reproducing, with suitable modifications, its N-terminal 26 amino acids including the phosphoacceptor site (Ser 5, Ser 8) and amphipathic helix-1, it appears that the functional interaction of the N-terminal portion of Rev with the N-terminal domain of the beta subunit must rely on both electrostatic and hydrophobic interactions. The former mainly involve Rev's arginine-rich domain (residues 35-50) in helix-2, while the latter are mostly mediated by residues 12-24 of helix-1. These data disclose the possibility that, besides displaying protective, regulatory and targeting properties with respect to the catalytic subunit, the CK2 beta subunit also plays a role as a docking site for a subset of CK2 substrates.

Cooperative modulation of protein kinase CK2 by separate domains of its regulatory beta-subunit.

Protein kinase CK2 ("casein kinase 2") holoenzyme is composed of two catalytic (alpha and/or alpha') and two regulatory beta-subunits. A truncated form of the beta-subunit lacking its C-terminal region (betaDelta171-215) has lost the ability to stably associate with the catalytic subunits and to display a number of properties which are mediated by structural elements still present in its sequence, notably down-regulation of catalytic activity, autophosphorylation, and responsiveness to polycationic effectors. All these functions are restored by simultaneous addition of a synthetic peptide reproducing the deleted fragment, beta170-215, which is able to associate with the catalytic subunits and to stimulate catalytic activity. This peptide includes a segment displaying significant sequence similarity with a region of cyclin A which interacts with the PSTAIRE motif of CDK2 eliciting its catalytic activity. A peptide reproducing this sequence (beta181-203), but not its derivative in which three nonpolar side chains have been replaced by polar ones, interacts with the alpha-subunit and stimulates its catalytic activity; it also partially restores the ability of truncated betaDelta171-215 to autophosphorylate. These data disclose the essential role of a structural module located between residues 181 and 203 in conferring regulatory properties to the beta-subunit of CK2.

Unique features of HIV-1 Rev protein phosphorylation by protein kinase CK2 ('casein kinase-2').

The HIV-1 Rev transactivator is phosphorylated in vitro by protein kinase CK2 at two residues, Ser-5 and Ser-8; these sites are also phosphorylated in vivo. Here we show that the mechanism by which CK2 phosphorylates Rev is unique in several respects, notably: (i) it is fully dependent on the regulatory, beta-subunit of CK2; (ii) it relies on the integrity of an acidic stretch of CK2 beta which down-regulates the phosphorylation of other substrates; (iii) it is inhibited in a dose-dependent manner by polyamines and other polycationic effectors that normally stimulate CK2 activity. In contrast, a peptide corresponding to the amino-terminal 26 amino acids of Rev, including the phosphoacceptor site, is readily phosphorylated by the catalytic subunit of CK2 even in the absence of the beta-subunit. These data, in conjunction with the observation that two functionally inactive derivatives of Rev with mutations in its helix-loop-helix motif are refractory to phosphorylation, indicate the phosphorylation of Rev by CK2 relies on conformational features of distinct regions that are also required for the transactivator's biological activity.

[Medical nephropathies: what has changed in 20 years]. / Nefropatie mediche: cosa è cambiato in 20 anni.

The authors analyse the series of patients with medical nephropathy undergoing renal biopsy between 1973 and 1993 in order to make a diagnostic and prognostic comparison between the first (ID) and second (IID) decade. Clinical indications for biopsy, which became more precise during the second decade, led to the diagnosis of fewer patients with normal histology; the introduction of ME and IF allowed non-significant histological conditions to be reduced during IID; echo-guided biopsy has led to a reduced number of post-biopsy complications in IID compared to ID. Epidemiological analysis reveals the reduction of focal glomerulosclerosis in IID in favour of glomerulonephritis with IgA deposits in correlation with the use of IF; the increase in mebranous glomerulonephritis secondary to increased antigenic stimuli; reduced acute post-infective glomerulonephritis and membrane-proliferative glomerulonephritis owing to an improved prophylaxis of sources of infection. Among the patients undergoing renal biopsy and commencing dialysis an increase was observed in IID in the number of cases of membranous glomerulonephritis or caused by IgA deposits. There was an increased interval between biopsy and the start of dialysis in IID compared to ID, in spite of fewer patients receiving immunosuppressive therapy. This was probably due to the increased number of pathologies with a slower evolution, thus justifying the postponement of the start of dialysis.

Uric acid homeostasis in lean and obese girls during pubertal development.

Serum uric acid concentration and fractional excretion were evaluated in lean (n = 67) and obese (n = 56) girls before and during pubertal development. In both lean and obese girls, uricemia gradually increased as puberty advanced. Obese girls were hyperuricemic compared with lean controls (prepubertal: 184 +/- 83 v 130 +/- 29 mumol/L, P = .007; Tanner stage II-III: 190 +/- 53 v 178 +/- 47 mumol/L, NS; Tanner stage IV-V: 232 +/- 53 v 191 +/- 53 mumol/L, P = .02). Fractional excretion of urate decreased with puberty in lean girls (6.46% +/- 2.29%, 4.61% +/- 2.48%, and 3.54% +/- 1.84%), but not in obese subjects (3.74% +/- 2.27%, 4.01% +/- 1.90%, and 4.26% +/- 2.26%). Urate homeostasis was similar in prepubertal obese girls and in adolescent lean controls. We conclude that an increased serum urate concentration occurring at puberty may be due to decreased renal clearance of urate in lean girls, and at least in part to urate overproduction in obese subjects. Obesity may prematurely evoke changes in urate metabolism usually observed at puberty.