Understanding how the 24-hour blood-pressure rhythm is programmed has been one of the most challenging questions in cardiovascular research. The 24-hour blood-pressure rhythm is primarily driven by the circadian clock system, in which the master circadian pacemaker within the suprachiasmatic nuclei of the hypothalamus is first entrained to the light/dark cycle and then transmits synchronizing signals to the peripheral clocks common to most tissues, including the heart and blood vessels. However, the circadian system is more complex than this basic hierarchical structure, as indicated by the discovery that peripheral clocks are either influenced to some degree or fully driven by temporal changes in energy homeostasis, independent of the light entrainment pathway. Through various comparative genomic approaches and through studies exploiting mouse genetics and transgenics, we now appreciate that cardiovascular tissues possess a large number of metabolic genes whose expression cycle and reciprocally affect the transcriptional control of major circadian clock genes. These findings indicate that metabolic cycles can directly or indirectly affect the diurnal rhythm of cardiovascular function. Here, we discuss a framework for understanding how the 24-hour blood-pressure rhythm is driven by the circadian system that integrates cardiovascular and metabolic function.
In papillary thyroid carcinoma (PTC), extrathyroid extension (Ex) and clinical lymph node metastasis (N) significantly affect the prognosis. We investigated the prognosis of patients with PTC 1 cm or less (1,220 patients), 1.1-2 cm (2,101 patients), 2.1-3 cm (1,249 patients), 3.1-4 cm (645 patients), and larger than 4 cm (563 patients). We classified N factor into three categories: N0, no clinical node metastasis: N1, clinical node metastasis smaller than 3 cm and without extranodal tumor extension requiring at least partial excision of adjacent organs for node dissection: and N2, clinical node metastasis 3 cm or larger or showing extranodal tumor extension. N2 markedly affected lymph node and distant recurrence-free survivals and cause-specific survival, regardless of the tumor size. N1 also adversely affected lymph node and distant recurrence-free survival but not cause-specific survival. Ex did not affect patients’ prognosis with PTC 1 cm or less. It became a prognostic factor with PTC larger than 1 cm, and worsened lymph node and distant recurrence-free survival not only for N0 but also for N1 PTC larger than 3 cm and larger than 2 cm, respectively. However, its influence is limited for N2 PTC patients. Furthermore, Ex worsened the CSS with PTC larger than 2 cm in combination with N2. We have to note that the prognostic significance for lymph node and distant recurrence-free and cause-specific survival of Ex and N varies according to the tumor size in order to accurately predict the clinical outcomes and establish therapeutic strategies for PTC patients.
We examined the correlation between plasma glucose (PG) and hemoglobin A1c (HbA1c) to evaluate the usefulness and limitations of applying the new diagnostic criteria for diabetes to Japanese pediatric patients. Data were collected from 298 school children who took an oral glucose tolerance test (OGTT) at a school-based urinary glucose screening program in the Tokyo Metropolitan Area between 1988 and 2009. Mean (SD) age of the children was 11.9 (2.5) years. Male-to-female ratio was 1:1.1. Children were diagnosed with renal glucosuria (n=146), diabetes mellitus (n=133), or the Japan Diabetes Society (JDS) “borderline type” (n=19). Median (range) values of fasting plasma glucose (FPG), 2-h plasma glucose in an OGTT (OGTT-2h), and HbA1c were 101 (76-378) mg/dL, 146.5 (57-563) mg/dL, and 6.05 (4.7-14.1) %. The correlation between PG and HbA1c was analyzed using least squares regression, and HbA1c was found to highly correlate with PG. From estimated regression equations, mean values of FPG and OGTT-2h corresponding to an HbA1c of 6.5% were calculated to be 111.4 mg/dL and 170.4 mg/dL. The mean values of HbA1c corresponding to an FPG of 126 mg/dL and OGTT-2h of 200 mg/dL were calculated to be 7.5% and 7.8%. The mean values of PG corresponding to HbA1c of 6.5% were lower than found in adults as analyzed by JDS. The mean values of HbA1c corresponding to diabetic type PG were higher than found in adults.
Triptolide, a major active component of Tripterygium wilfordii Hook F (TWHF), is known to have multiple pharmacological activities. However, studies have also shown that triptolide is highly toxic to the reproductive system by disrupting normal androgen and estrogen signaling. In the present study, we investigated the effect of triptolide (5, 10, or 20 nM for 24 h) on estradiol production by rat granulosa cells. Triptolide inhibited basal and human chorionic gonadotropin (HCG)- or 8-bromo-cAMP-stimulated estradiol production as revealed by RIA assay. Furthermore, the HCG-evoked increase in cellular cAMP content was also inhibited by triptolide, indicating that disruption of the cAMP/PKA signaling pathway may mediate the deleterious effects of triptolide on steroid hormone regulation. In addition, 3H2O tests showed that aromatase activity was significantly inhibited by triptolide in granulosa cells. Western blot and quantitative real-time PCR (qRT-PCR) assays further revealed that triptolide decreased protein and mRNA expression of aromatase in granulosa cells. Moreover, mRNA expression of luteinizing hormone receptor (LHR) was induced by triptolide also using qRT-PCR method. In contrast, cell viability tests using Cell Counting Kit-8 (CCK-8) and 3-(4,5-dimethyl-thiazol-2-yl)-2,5- diphenyl-tetrazolium bromide (MTT) method indicated that triptolide did not cause measurable cell death at doses that suppressed steroidogenesis. The reproductive toxicity of triptolide may be mainly caused by disruption of cAMP/PKA-mediated expression of estrogen synthesis enzymes, leading to reduced estradiol synthesis and reproductive dysfunction.
The purpose of this study was to clarify the cytopathological features of well-differentiated tumors of uncertain malignant potential (WDT-UMP), a possible borderline lesion of thyroid follicular cell tumor. We analysed the cytopathological findings of fine needle aspiration (FNA) smears from 6 cases histologically diagnosed as WDT-UMP. WDT-UMP, benign and malignant lesions were compared retrospectively and morphologically. No (0%) nuclear pseudoinclusions were found in adenomatous goiter (AG), follicular adenoma (FTA) and WDT-UMP. Nuclear pseudoinclusions were increased in number in papillary thyroid carcinoma (PTC) with indeterminate cytology (0.8%) and PTC with malignant cytology (1.2%). The incidence of nuclear grooves increased gradually from AG/FTA (0%), WDT-UMP (4.5%), PTC with indeterminate cytology (6.2%) and PTC with malignant cytology (6.5%). The nuclear area of WDT-UMP, an average of 40.0 μm2, was between that for benign AG/FTA and PTC with malignant cytology. The maximum/minimum axis of WDT-UMP (0.934) lied between that of AG/FTA and PTC. The degree of the nuclear circularity of WDT-UMP was less than that for PTC. WDT-UMP belong to indeterminate category between PTC and follicular adenoma morphologically, and this is one of the major reasons why some of PTC can be found in the indeterminate category. Questionable PTC-N including questionable nucler inclusions (artifact vacuole) may be seen in WDT-UMP, but absolute or definite nuclear inclusions with sharp border are not found in our 6 cases. Therefore this group of thyroid tumors (EnFVPTC and WDT-UMP) may be found in indeterminate category more often, because of intermediate nuclear morphology and incomplete nuclear vacuoles.
Thyroid carcinoma (TC) has an increasing incidence in the last decade and continues to represent the most frequent form of endocrine tumor. The aim of the study was to analyze the pediatric files of TC from the registry of “Prof. Dr. Ion Chiricuta” Institute of Oncology Cluj-Napoca, Romania (IOCN) and to provide the data related to the impact of nuclear fallout of Chernobyl on this pathology. We studied 72 children with TC treated between 1991 and 2010. The mean age was 15.3 years; the ratio female/male was 6.2:1. Twenty-nine children (40.2%) revealed metastasis in regional lymph nodes or lungs at the initial diagnostic. There were 63 differentiated thyroid carcinoma (DTC), 6 cases with medullary cancer (MC), 1 case with anaplastic carcinoma (AC), and 2 mixed cases. All patients underwent total thyroidectomy and the radioiodine was administered in 64 cases (activities between 1.1 - 28.1 GBq I-131). Fifty-two children (80.5%) are free of disease, 8 are in partial remission and 4 children are in evolution of the disease at minimum 12 months of follow-up. The incidence of TC was significantly increased 10 years after the accident. In the years after, the increasing trendline was stopped and at 25 years, the number of cases is stationary. The diagnosis of pediatric TC is made frequently in metastatic disease and the therapies must be conducted for many years till complete remission. A more clear strategy adapted to children is needed in the future.
Familial hyperaldosteronism (FH) encompasses 3 types of autosomal dominant hyperaldosteronisms leading to inheritable hypertension. FH type II (FH-II), undistinguishable from sporadic hyperaldosteronism, represents the most frequent cause of inheritable hypertension and is believed to only manifest in adults. FH-III is a severe variety of PA resistant to pharmacotherapy and recently demonstrated to be caused by mutations in the gene encoding the potassium channel KCNJ5. In this report, we describe a FH pediatric patient, remarkable both for age at onset and unusual presentation: a two-years old girl with polyuric-polydipsic syndrome and severe hypertension, successfully treated with canrenone and amiloride. The girl had severe hypertension, hypokalemia, hypercalciuria, suppressed renin activity, high aldosterone, and unremarkable adrenal imaging. FH type I was ruled out by glucocorticoid suppression test, PCR test for CYP11B1/CYP11B2 gene, and urinary 18-oxo-cortisol and 18-hydroxy-cortisol excretion, which was in FH-II range. In spite of a clear-cut FH-II phenotype, the girl and her mother were found to harbor a FH-III genotype with KCNJ5 mutation (c.452G>A). Treatment with canrenone was started, resulting in prompt normalization of electrolytes and remission of polyuric-polydypsic syndrome. The addition of amiloride led to a complete normalization of blood pressure. This report expands the phenotypic spectrum of FH-III to a milder end, mimiking FH-II phenotype demonstrating that pharmacotherapy may be effective. This also implies that FH-II/III should be considered in the differential diagnosis of hypertensive children and, perhaps, that the offspring of patients with hyperaldosteronism should be screened for hypertension.
In thyroid nodule management, ultrasound (US) features, such as hypoechogenicity of the lesion, irregular margins, microcalcifications, and intralesional vascular signal, alone or combined, have to be considered as suggestive for malignancy. Because of the low prevalence of medullary thyroid cancer (MTC), a few papers analyzed US characteristics associated with this cancer in small series, with controversial results. Aim of this study was to evaluate in MTC the US risk factors of thyroid nodule. In this order, a series of nodules histologically proven as MTC and a group of nodules with histology of papillary cancer (PTC) were retrospectively compared with a control group of benign nodule. Fifty percent MTC were solid hypoechoic and 16% showed microcalcifications with significant difference with respect to the benign group (p<0.05 for both parameters), while no significant difference was recorded regarding margins nor nodular vascularization. The presence of at least one US risk feature was almost equal in MTC (58.3%) and controls (55.5%). On the contrary, at least one US risk factor was significantly (p<0.001) more frequent in PTC than in benign group or MTC series. This study showed low frequency of ultrasound features associated to PTC when analyzed in medullary cancer. Because of the poor literature focusing on this topic, and the herein used design, these data contribute to the knowledge about presentation of MTC at US. We advice for further prospective studies on larger series to define the US presentation of this cancer type.
The amount of epicardial adipose tissue (EAT), a component of body visceral adiposity, has been linked to the presence and severity of cardiovascular disease through multiple mechanisms. Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and subclinical inflammation, which participate in the mechanism of atherosclerosis. We searched if the patients with PCOS have increased EAT thickness (EATT), along with its relation to the measures of adiposity and insulin sensitivity. A total of 41 subjects with PCOS and 46 age and body mass index (BMI) matched healthy controls were enrolled. EAT was measured by echocardiography above the free wall of the right ventricle. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) formula, and plasma adiponectin level was measured by ELISA. Compared to healthy controls EATT and HOMA-IR score were significantly higher (p=0.0001 for both) while plasma adiponectin concentration was significantly lower (p=0.048) in women with PCOS. EATT correlated positively with total cholesterol, triglyceride, luteinizing hormone (LH) and negatively with sex hormon binding globuline (p<0.05 for all), whereas it displayed no correlation to plasma adiponectin level (p=0.924). Triglyceride level was the significant determinant of EATT in logistic regression analysis (p=0.035). Thickness of the EAT is increased in patients with PCOS in conjunction with hyperandrogenity. Prospective studies are required to identify the relation of EAT and cardiovascular risk in patients with PCOS.
Thyroglossal duct cyst (TDC) carcinoma is a comparable rare entity and treatment strategies have not been standardized. Here, we report a favorable outcome of TDC carcinoma patients based on our therapeutic strategy. Twelve patients with TDC carcinoma treated in our department from 1986 to 2012 were enrolled. Ten patients underwent Sistrunk’s procedure in other institutions and referred to our institution for re-operation after the diagnosis of TDC carcinoma and the remaining two underwent initial surgery in our institution. Eleven patients were diagnosed as papillary and one as follicular carcinoma originating from TDC. We performed total thyroidectomy for 11, and limited thyroidectomy for one patient. Three patients (25%) had carcinoma lesions in the thyroid. We routinely dissected level I bilaterally and 6 of 11 patients (55%) with papillary carcinoma-type TDC carcinoma had metastasis. Level II/III nodes were biopsied and if positive, we performed level II-IV dissection. Of the 5 patients positive for level II/III, 2 were also positive for level IV. For the 3 patients with synchronous carcinoma in the thyroid, we performed level VI dissection and two had metastasis in this level. To date, 1 patient showed a recurrence to the lung, but none of the patients in our series died of carcinoma. For surgery of TDC carcinoma, Sistrunk’s procedure, total thyroidectomy with level I dissection is mandatory. Whether level II-IV dissection is performed depends on pathology of biopsied level II/III nodes. Level VI dissection is also recommended especially when carcinoma lesions are pre/intra operatively detected in the thyroid.
Heterozygous germline mutation of the tumor suppressor gene MEN1 is responsible for multiple endocrine neoplasia type 1 (MEN1), a familial cancer syndrome characterized by pituitary, parathyroid and enteropancreatic tumors. Various mutations have been identified throughout the entire gene region in patients with MEN1 and its incomplete forms often manifested as familial isolated hyperparathyroidism and apparently sporadic parathyroid tumor. Mutation analysis of the MEN1 gene is a powerful tool for the early diagnosis of MEN1; however, the clinical significance of the identified mutations is not always obvious. In this study, a previously unreported missense MEN1 mutation, c.824G>T was identified in a patient with primary hyperparathyroidism and evaluated for its pathogenicity. This mutation was predicted to generate a putative missense menin protein, R275M. A stability test of the menin protein demonstrated that the stability of R275M mutant was reduced only slightly as compared with wild type menin, and therefore could not preclude the possibility that it was a rare benign polymorphism. However, further analysis of leukocyte mRNA and minigene experiments indicated that the mutant c.824G>T allele gives rise to abnormally spliced menin mRNA, and thereby confirmed that c.824G>T mutation is causative for MEN1. Thus, leukocyte mRNA analysis has been demonstrated useful to identify a splicing mutation of the MEN1 gene.