Abstract-The question of serum uric acid as an independent risk factor in subjects with essential hypertension remains controversial. For up to 12 years (mean, 4.0) we followed 1720 subjects with essential hypertension. At entry, all subjects were untreated and all were carefully screened for absence of cardiovascular disease, renal disease, cancer, and other important disease. Outcome measures included total cardiovascular events, fatal cardiovascular events, and all-cause mortality. Key Words: uric acid Ⅲ blood pressure Ⅲ cardiovascular disease Ⅲ hypertension, essential Ⅲ blood pressure monitoring Ⅲ hypertrophy, left ventricular S everal cohort studies conducted over the past 5 decades showed a link between serum uric acid (SUA) and subsequent cardiovascular (CV) disease. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] However, in some of these studies such association did not remain significant after adjustment for concomitant risk factors for CV disease 2,4,5,12,15 or it was detected only in women. 6,8,10 Thus, the role of SUA as an independent risk marker remains controversial. 16 An increase in SUA might be simply a marker of obesity, hyperinsulinemia and glucose intolerance, 17,18 hypertension, 5 hyperlipidemia 19 and renal disease. 20,21 The assessment of the independent prognostic value of SUA is clinically relevant in the specific setting of essential hypertension, in which hyperuricemia is frequent 22 and cardiovascular risk stratification is of utmost importance. In a recent cohort study in subjects with hypertension, 14 the association between SUA and future CV events remained significant after adjustment for concomitant diuretic therapy, previous CV events, and other risk factors including office blood pressure (BP). In contrast, pretreatment SUA was not an independent predictor of CV events in the setting of the European Working Party on High Blood Pressure in the Elderly trial. 23 Because of the discrepancy between these findings, we analyzed the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) database to clarify the independent prognostic value of SUA in a large cohort of initially untreated and apparently healthy subjects with essential hypertension. Methods PIUMA StudyThe design of the PIUMA study has been reported previously. 24,25 Office BP had to be Ն140 mm Hg systolic and/or Ն90 mm Hg diastolic on Ն3 visits, and all of the subjects fulfilled the following inclusion criteria: no previous antihypertensive treatment or treat-

Activating mutations of BRAF have been identified in a variety of human cancers, most notably melanomas and papillary thyroid carcinomas (PTCs). The aim of the present study was to disclose the role of BRAF mutations in thyroid carcinoma development.Seventy-two thyroid tumors, including 60 PTCs, six follicular adenomas, five follicular carcinomas, and one anaplastic carcinoma, were studied. BRAF mutation screening focused on exon 15 and exon 11 of the gene by single-stranded conformational polymorphism and sequence analysis. Search of RET/PTC expression was conducted with the RT-PCR technique.The molecular genetic study of the BRAF gene showed the presence of a missense thymine to adenine transversion at nucleotide 1796, resulting in the V599E substitution, in 24 of 60 PTCs (40%), none of six follicular adenomas, and none of five follicular carcinomas or one anaplastic carcinoma. Moreover, nine of 60 PTCs (15%) presented RET/PTC expression. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P ‫؍‬ 0.038). On the contrary, no link could be detected between expression of BRAF V599E and age at diagnosis, gender, dimension, and local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, and multifocality of the disease.These data clearly confirm that BRAF V599E is the more common genetic alteration found to date in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype. (J Clin Endocrinol Metab 89: 2414 -2420, 2004)

Recently, a somatic point mutation of the B-RAF gene (V600E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC), with a prevalence variable among different series. Since discordant data on the clinico-pathologic features of B-RAF mutated PTC are present in the literature, the aim of the present co-operative study was to establish the prevalence of this genetic alteration and to perform a genotype-phenotype correlation in a large cohort of patients with PTC. To this purpose, a series of 260 sporadic PTCs with different histological variants were included in the study. The mutational analysis of the B-RAF gene was performed either by RT-PCR followed by single-stranded conformational polymorphism or by PCR and direct sequencing. Statistical analyses were obtained by means of 2 /Fisher's exact test and t-test. Overall, a heterozygous T > A transversion at nucleotide 1799 (V600E) was found in 99 out of 260 PTCs (38%). According to the histological type of the tumor, the B-RAF V600E mutation was present in 48.3% of cases of classic PTCs (85 out of 176), in 17.6% (nine out of 51) of follicular variants of PTCs, in 21.7% (five out of 23) in other PTC variants and in none of the ten poorly differentiated tumors. B-RAF V600E was significantly associated with the classic variant of PTC (P ¼ 0:0001) and with an older age at diagnosis (P ¼ 0:01). No statistically significant correlation was found among the presence of B-RAF V600E and gender, tumor node metastasis (TNM), multicentricity of the tumor, stage at diagnosis and outcome. In conclusion, the present study reports the prevalence of B-RAF V600E (38%) in the largest series of sporadic PTCs, including 260 cases from three different Italian referring centers. This prevalence is similar to that calculated by pooling together all data previously reported, 39.6% (759 out of 1914 cases), thus indicating that the prevalence of this genetic event lies around 38-40%. Furthermore, B-RAF V600E was confirmed to be associated with the papillary growth pattern, but not with poorer differentiated PTC variants. A significant association of B-RAF mutation was also found with an older age at diagnosis, the mutation being very rare in childhood and adolescent PTCs. Finally, no correlation was found with a poorer prognosis and a worse outcome after a median follow-up of 72 months.

Neuroendocrine tumors may occur in the setting of multiple endocrine neoplasia type 1 (MEN1) syndrome. Among these, a probably underestimated prevalence of well differentiated neuroendocrine thymic carcinoma (carcinoid), a neoplasm characterized by very aggressive behavior, has been described. We report characterization of the seven Italian cases in which this association occurred among a series of 221 MEN1 patients (41 sporadic and 180 familial cases; prevalence, 3.1%). All of the patients were male, and six of seven (85%) were heavy smokers. No associated hormonal hypersecretion was detected. The first diagnosis was between the second and fifth decades. Familial clusters were present in three of seven (42.8%). No genotype-phenotype correlation was found. All seven cases were associated with hyperparathyroidism. In one patient, prophylactic thymectomy revealed a small nodular lesion suggestive of a thymic carcinoid, providing evidence that preventive thymectomy might prevent additional growth of an occult thymic carcinoid. These findings confirm that thymic carcinoids are associated with a very high lethality, with a near-total prevalence in smoker males. Therefore, prophylactic thymectomy should be considered at neck surgery for primary hyperparathyroidism in MEN1 male patients, especially for smokers, and, due to the frequent familial clusters distribution of this pathology, in subjects with affected relatives presenting this feature. Thus, we recommend screening every patient affected with a neuroendocrine thymic neoplasm for MEN1 syndrome.

To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 +/- 0.05 to 0.045 +/- 0.03 episodes/patient-day) and an increase in HbA1c (5.8 +/- 0.3 to 6.9 +/- 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.