Endocrine dysfunction in patients with Fabry disease

BACKGROUND: Fabry disease (FD) is a genetic disorder caused by lysosomal alpha-galactosidase-A deficiency and is characterized by the systemic accumulation of globotriaosylceramide. All endocrine glands are susceptible to globotriaosylceramide accumulation because of their high vascularization and low cellular proliferation rate. Nevertheless, this endocrine system has never been investigated in detail. OBJECTIVE: We aimed to investigate the function and morphology of the endocrine glands in FD. PATIENTS: The thyroid, gonadal, adrenal, and GH/IGF-I axes were evaluated in 18 FD patients (nine females and nine males, aged 21-64 yr) and 18 sex- and age-matched healthy subjects. STUDY DESIGN: We conducted an observational, analytical, open, prospective study. INTERVENTIONS: Ten of the 18 patients received enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase-A (agalsidase beta) at a dose of 1 mg/kg body weight every 2 wk. RESULTS: FD patients had higher baseline TSH levels than controls (P < 0.01). Three subjects were diagnosed with an early stage of subclinical primary hypothyroidism associated with negative antithyroid antibodies. A history of menses abnormalities, miscarriage, or assisted delivery was found in 89% of FD women. Asthenozoospermia, oligozoospermia, or both were found in all FD men through seminal fluid analysis. FD patients had significantly higher circulating ACTH and lower cortisol levels than controls (P < 0.05). In patients under ERT, a suboptimal cortisol response to the 250-microg ACTH test was found in 10%, and the ACTH-stimulated cortisol peak was significantly correlated to the health status profile (P < 0.05). CONCLUSION: A variety of latent endocrine dysfunctions, including life-threatening conditions, occur in patients with FD. Endocrine dysfunctions are also present in patients already receiving ERT and are in part related to their persistent poor quality of life. An endocrine work-up should be recommended in all FD patients. Adequate monitoring and hormonal therapy, when required, have to be performed in cases of subclinical endocrine dysfunction to avoid life-threatening events

Peripheral artery disease assessed by ankle-brachial index in patients with established cardiovascular disease or at least one risk factor for atherothrombosis - CAREFUL Study: A national, multi-center, cross-sectional observational study

<p>Abstract</p> <p>Background</p> <p>To investigate the presence of peripheral artery disease (PAD) via the ankle brachial index (ABI) in patients with known cardiovascular and/or cerebrovascular diseases or with at least one risk factor for atherothrombosis.</p> <p>Methods</p> <p>Patients with a history of atherothrombotic events, or aged 50-69 years with at least one cardiovascular risk factor, or > = 70 years of age were included in this multicenter, cross-sectional, non-interventional study (DIREGL04074). Demographics, medical history, physical examination findings, and physician awareness of PAD were analyzed. The number of patients with low ABI (< = 0.90) was analyzed.</p> <p>Results</p> <p>A total of 530 patients (mean age, 63.4 ± 8.7 years; 50.2% female) were enrolled. Hypertension and dyslipidemia were present in 88.7% and 65.5% of patients, respectively. PAD-related symptoms were evident in about one-third of the patients, and at least one of the pedal pulses was negative in 6.5% of patients. The frequency of low ABI was 20.0% in the whole study population and 30% for patients older than 70 years. Older age, greater number of total risk factors, and presence of PAD-related physical findings were associated with increased likelihood of low ABI (<it>p </it>< 0.001). There was no gender difference in the prevalence of low ABI, PAD symptoms, or total number of risk factors. Exercise (33.6%) was the most common non-pharmacological option recommended by physicians, and acetylsalicylic acid (ASA) (45.4%) was the most frequently prescribed medication for PAD.</p> <p>Conclusion</p> <p>Our results indicate that advanced age, greater number of total risk factors and presence of PAD-related physical findings were associated with increased likelihood of low ABI. These findings are similar to those reported in similar studies of different populations, and document a fairly high prevalence of PAD in a Mediterranean country.</p

Lineage-Specific Restraint of Pituitary Gonadotroph Cell Adenoma Growth

Although pituitary adenomas are usually benign, unique trophic mechanisms restraining cell proliferation are unclear. As GH-secreting adenomas are associated with p53/p21-dependent senescence, we tested mechanisms constraining non-functioning pituitary adenoma growth. Thirty six gonadotroph-derived non-functioning pituitary adenomas all exhibited DNA damage, but undetectable p21 expression. However, these adenomas all expressed p16, and >90% abundantly expressed cytoplasmic clusterin associated with induction of the Cdk inhibitor p15 in 70% of gonadotroph and in 26% of somatotroph lineage adenomas (p = 0.006). Murine LβT2 and αT3 gonadotroph pituitary cells, and αGSU.PTTG transgenic mice with targeted gonadotroph cell adenomas also abundantly expressed clusterin and exhibited features of oncogene-induced senescence as evidenced by C/EBPβ and C/EBPδ induction. In turn, C/EBPs activated the clusterin promoter ∼5 fold, and elevated clusterin subsequently elicited p15 and p16 expression, acting to arrest murine gonadotroph cell proliferation. In contrast, specific clusterin suppression by RNAis enhanced gonadotroph proliferation. FOXL2, a tissue-specific gonadotroph lineage factor, also induced the clusterin promoter ∼3 fold in αT3 pituitary cells. As nine of 12 pituitary carcinomas were devoid of clusterin expression, this protein may limit proliferation of benign adenomatous pituitary cells. These results point to lineage-specific pathways restricting uncontrolled murine and human pituitary gonadotroph adenoma cell growth

A MODEL FOR VEHICLE DYNAMIC SIMULATION WITH PID AND FUZZY LOGIC DRIVE CONTROLLERS

Abstract A computer code oriented to S.I. engine control and powertrain simulation is presented. The model predicts engine and driveline states, taking into account the dynamics of air and fuel flows into the intake manifold and the transient response of crankshaft, clutch, transmission gearing and vehicle. The whole model is integrated in the code O.D.E.C.S., now in use at Magneti Marelli, and is based on a hierarchical structure composed of different classes of models, ranging from black-box Neural Network to grey-box mean value models. By adopting the proposed approach, a satisfactory accuracy is achieved with limited computational demand, which makes the model suitable for the optimization of engine control strategies. Furthermore, in order to simulate the driver behavior during the assigned vehicle mission profile, two drive controllers have been implemented for throttle and brakes actuation, based on classical PID and fuzzy-logic theory. In the paper a detailed description of the whole driveline system is presented and the results achieved making use of both driver-behavior models are compared with respect to a set of arbitrary transient maneuvers and vehicle speed profiles

Oral and maxillofacial manifestations of Gardner's syndrome associated with growth hormone deficiency: case report and literature review

Gardner's syndrome (GS) is a hereditary disorder inherited as autosomal dominant with complete penetrance and variable expression. GS is a variant of familial adenomatous polyposis characterized by extracolonic manifestations including osteomas, dental anomalies, and epidermoid cysts. The association between GS and endocrine abnormalities has been well documented but a direct pituitary involvement has never been reported. We present a case of oral and maxillofacial manifestations in an adult patient affected by GS associated with growth hormone deficiency, a hitherto unreported association. The possible pathogenic mechanisms are discussed