Impaired flow-mediated dilatation response in uncomplicated Type 1 diabetes mellitus: influence of shear stress and microvascular reactivity.

Impaired FMD (flow-mediated dilatation) has traditionally been recognized as an indirect marker of NO bioactivity, occurring in disease states such as DM (diabetes mellitus). Endothelium-dependent FMD is a homoeostatic response to short-term increases in local shear stress. Microvascular dysfunction in DM influences blood flow velocity patterns. We explored the determinants of the FMD response in relation to evoked DSS (diastolic shear stress) and forearm microcirculation haemodynamics by quantifying changes in Doppler flow velocity waveforms between groups. Forty patients with uncomplicated Type 1 DM and 32 controls underwent B-mode and Doppler ultrasound scanning to interrogate the brachial artery. Postischaemic Doppler velocity spectral envelopes were recorded and a wavelet-based time-frequency spectral analysis method was employed to track change in distal microcirculatory haemodynamics. No difference in baseline brachial artery diameter was evident between the groups (4.15 compared with 3.94 mm, P=0.23). FMD was significantly impaired in patients with Type 1 DM (3.95 compared with 7.75%, P<0.001). Endothelium-independent dilatation in response to GTN (glyceryl trinitrate) was also significantly impaired (12.07 compared with 18.77%, P<0.001). DSS (dyn/cm2) was significantly reduced in the patient group (mean 20.19 compared with 29.5, P=0.001). Wavelet interrogation of postischaemic flow velocity waveforms identified significant differences between groups. In conclusion, DSS, microcirculatory function and endothelium-independent vasodilatation in response to GTN are important determinants that impact on the magnitude of FMD response and are impaired in patients with Type 1 DM. Impaired FMD response is multifactorial in origin and cannot be attributed solely to a diminished NO bioavailability.

The RET mutation E768D confers a late-onset familial medullary thyroid carcinoma -- only phenotype with incomplete penetrance: implications for screening and management of carrier status.

OBJECTIVE: We describe a 4-generation family with familial medullary thyroid carcinoma (FMTC) -- a variant of multiple endocrine neoplasia type 2 (MEN 2) without extra-thyroid features. RET mutation analysis confirmed an E768D mutation in exon 13 in 8 family members, 3 affected with medullary thyroid cancer alone while the other 5 were detected to be mutation carriers. This mutation has been described in very few families worldwide and the spectrum of disease and natural history is unclear. RESULTS: Three affected members had medullary thyroid cancer (MTC) confirmed histologically at ages 25, 50 and 56 years, respectively. The E768D mutation appears to have a less aggressive clinical course compared to other high risk RET mutations with no evidence of clinical recurrence up to 11 years after initial therapy. Of five gene carriers identified, two are asymptomatic at the age of 70 and 61, and three had raised calcitonin levels at 46, 39, and 45 years. Following total thyroidectomy, one gene carrier had a histologically normal thyroid at age 46, following a mildly elevated calcitonin, one had C-cell hyperplasia at the age of 39, and one had a frank focus of carcinoma in the left thyroid lobe at the age of 45. No members had evidence of phaeochromocytoma or parathyroid disease on screening. CONCLUSION: The RET E768D mutation is associated with MTC with a later age at presentation, incomplete penetrance and less aggressive course compared with other high risk RET mutations. To date in this family the E768D mutation has not been associated with either phaeochromocytoma or hyperparathyroidism. The appropriate screening strategy for and management of E768D carriers is difficult reflecting the phenotypic heterogeneity.