A self-matched leaky-wave antenna for ultrahigh-field magnetic resonance imaging with low specific absorption rate.

The technology of magnetic resonance imaging is developing towards higher magnetic fields to improve resolution and contrast. However, whole-body imaging at 7 T or even higher flux densities remains challenging due to wave interference, tissue inhomogeneities, and high RF power deposition. Nowadays, proper RF excitation of a human body in prostate and cardiac MRI is only possible to achieve by using phased arrays of antennas attached to the body (so-called surface coils). Due to safety concerns, the design of such coils aims at minimization of the local specific absorption rate (SAR), keeping the highest possible RF signal in the region of interest. Most previously demonstrated approaches were based on resonant structures such as e.g. dipoles, capacitively-loaded loops, TEM-line sections. In this study, we show that there is a better compromise between the transmit signal [Formula: see text] and the local SAR using non-resonant surface coils generating a low electric field in the proximity of their conductors. With this aim, we propose and experimentally demonstrate a leaky-wave antenna implemented as a periodically-slotted microstrip transmission line. Due to its non-resonant radiation, it induces only slightly over half the peak local SAR compared to a state-of-the-art dipole antenna but has the same transmit efficiency in prostate imaging at 7 T. Unlike other antennas for MRI, the leaky-wave antenna does not require to be tuned and matched when placed on a body, which makes it easy-to-use in prostate imaging at 7 T MRI.

Variable workup calls for guideline development for type 2A hereditary haemochromatosis.

BACKGROUND: Type 2A hereditary haemochromatosis (type 2A HH) is a rare iron-loading disorder caused by mutations in the HFE2 gene, which encodes the HJV protein. We present characteristics, treatment and follow-up of subjects diagnosed with type 2A HH in the Netherlands to increase awareness of the disease and its treatment, and to define knowledge gaps. METHODS: We collected clinical, biochemical and genetic data from seven patients (two female; five probands) from six families genetically diagnosed with type 2A HH at the Expertise Center for Iron Disorders, Radboud University Medical Centre between 2006 and 2016. RESULTS: The five probands presented with heterogeneous complaints between the ages of 19 and 39. One of two patients with delayed clinical diagnosis developed hypogonadism and Y. enterocolitica sepsis. Diagnostic workup and follow-up varied. When assessed, elevated transferrin saturation (79-98%), ferritin (1400-6200 µg/l) and severely elevated liver iron levels were found, and in all subjects, phlebotomies were initiated. One subject was switched to erythrocytapheresis. Target ferritin levels varied. Despite long-term iron depletion, two subjects developed clinical complications. Sanger sequencing revealed two pathogenic HFE2 variants (homozygous or compound heterozygous) for the five families of Dutch descent and one new pathogenic variant in the family of non-Dutch descent. CONCLUSION: Three genetic variants caused type 2A HH in six families. Clinical diagnosis was delayed in two subjects. We observed variance in presentation, workup, follow-up and treatment. We found new complications in long-term iron-depleted patients. We recommend research and guidelines for optimal workup, follow-up and treatment of type 2A HH.

TFR2-related haemochromatosis in the Netherlands: a cause of arthralgia in young adulthood.

BACKGROUND: Type 3 hereditary haemochromatosis (HH) is a rare iron overload disorder caused by variants in the transferrin 2 receptor (TFR2) gene. We aim to present characteristics of patients diagnosed with TFR2-HH in the Netherlands, in order to increase knowledge and awareness of this disease. METHODS: We collected clinical, biochemical and genetic data from four patients from three families diagnosed with HH type 3 in the Netherlands between 2009 and 2016. RESULTS: Three women and one man diagnosed with HH type 3 presented with arthralgia and elevated ferritin levels and transferrin saturation (TSAT) at ages 25-41 years. The hepcidin/ferritin ratio as measured in three patients was low. Liver iron content in two patients as assessed by MRI or liver biopsy was highly increased (250 and 362.7 µmol iron/g dry weight, respectively, reference < 35 µmol/g). DNA analysis revealed four different TFR2 pathogenic variants: one nonsense, one splicing and two missense variants, of which three are novel. Phlebotomy decreased the serum iron parameters but did not relieve the arthralgia. CONCLUSION: In patients with a combination of elevated TSAT and ferritin in the absence of anaemia, and after exclusion of HFE-related HH, rare forms of HH should be considered. In these cases, presentation with arthralgia in young adulthood, low hepcidin/ferritin ratio and/or liver iron content > 100 µmol/g form an indication for analysis of the TFR2 gene. Although type 3 HH is extremely rare, awareness of the disease among physicians is important in order to achieve an early diagnosis and prevent complications, such as liver damage.

Preserved response to diuretics in rosiglitazone-treated subjects with insulin resistance: a randomized double-blind placebo-controlled crossover study.

Thiazolidinediones (TZDs) are associated with fluid retention that has been suggested to be resistant to treatment with loop diuretics. This resistance is thought to be caused by upregulation of renal epithelial sodium channels (ENaCs). In this study, we tested whether these mechanisms are of clinical significance. We conducted a well-controlled study in 12 insulin-resistant nondiabetic participants, who received treatment for 9 weeks with either rosiglitazone at a dosage of 4 mg b.i.d. or placebo. The aim of the study was to investigate whether upregulation of ENaCs by rosiglitazone reduces furosemide's natriuretic response and enhances the response to the ENaC inhibitor amiloride. The natriuretic response to furosemide and amiloride and the amount of α-ENaC in urinary exosomes were quantified. Rosiglitazone neither reduced furosemide-induced natriuresis nor changed furosemide's concentration-effect curve. Furthermore, rosiglitazone did not change either amiloride-induced natriuresis nor the amount of urinary α-ENaC. This study challenges previous findings regarding TZD-related ENaC upregulation and suggests that TZD-induced fluid retention should respond normally to loop diuretics.

Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage.

AIMS/HYPOTHESIS: The mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy. METHODS: We conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (<2.5 or >or=2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume. RESULTS: Thirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (DeltaTERalb: rosiglitazone +2.43 +/- 0.45%/h, placebo -0.11 +/- 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation. CONCLUSIONS/INTERPRETATION: Rosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00422955. FUNDING: GlaxoSmithKline.

Exposure setups for laboratory animals and volunteer studies using body-mounted antennas.

For two different in vivo exposure setups body-mounted antenna systems have been designed. The first setup is designed for investigation of volunteers during simulated mobile phone usage. The setup consists of a dual-band antenna for GSM/WCDMA with enhanced carrying properties, which enables exposure for at least 8 h a day. The 10 g averaged localised SAR--normalised to an antenna input power of 1 W--measured in the flat phantom area of the SAM phantom amounts to 7.82 mW g(-1) (900 MHz) and 10.98 mW g(-1) (1966 MHz). The second exposure setup is used for a laboratory behavioural study on rats. The design goal was a localised, well-defined SAR distribution inside the animals' heads at 900 MHz. To fulfil the biological requirements, a loop antenna was developed. For tissues around the ears, a localised SAR value of 50.12 W kg(-1) averaged over a mass of 2.2 g for an antenna input power of 1 W is obtained.

Diazoxide-mediated insulin suppression in obese men: a dose-response study.

BACKGROUND: It has been suggested that diazoxide (DZX)-mediated insulin suppression may be useful to promote weight loss in obese subjects. AIM: To assess the DZX-dose range that is safe to use in obese hyperinsulinaemic men. METHODS: Assessment of DZX efficacy and safety was based on plasma glucose and insulin responses to a standardized 500-kcal breakfast, taken on the sixth day of treatment. Basic information regarding the potential efficacy of DZX treatment was first evaluated in an open-label study in five non-obese men. Subsequently, a double-blind, randomized, placebo-controlled study was performed in 12 obese but otherwise healthy men, comparing placebo treatment with DZX in doses of 50, 75 and 100 mg three times daily for 6 days. RESULTS: In non-obese subjects, DZX 50 mg decreased peak insulin levels by +/-28% and raised peak glucose concentration from 7.1 +/- 0.6 to 7.8 +/- 0.6 mmol/l (p < 0.05). DZX 100 mg reduced peak insulin levels by 45% and caused a rise in peak glucose levels from 7.1 +/- 0.6 to 9.0 +/- 0.9 mmol/l (p < 0.05). In obese men, the 50 and 75 mg doses had no significant effects on glucose or insulin levels. DZX 100 mg reduced the peak insulin levels and insulin area under the curve by +/-20% (p < 0.05) but did not affect fasting or postprandial glucose levels. The relatively limited insulin-suppressive effects in obese subjects were attributed to the low plasma DZX levels that were achieved in this group. For comparable doses, plasma DZX levels were about 30% lower in obese than in non-obese men. Plasma DZX levels were highly dependent on dose (p < 0.001) and body weight (p < 0.001). Ninety-two percent of the total variability in DZX levels was explained by these two parameters. CONCLUSION: DZX-mediated insulin suppression is dose dependent in normal and in obese men. However, the efficacy of DZX is much less in obese than in non-obese subjects. This is attributed to weight-dependent differences in distribution volume that lead to markedly lower plasma DZX levels in obese subjects. Weight-adjusted doses will be needed to achieve biologically effective plasma DZX levels. Extrapolation of the data suggests that effective insulin suppression in obese men will at least require a daily dose of 3.2-4.2 mg/kg.

A novel 13C NMR method to assess intracellular glucose concentration in muscle, in vivo.

Intracellular glucose concentration in skeletal muscle of awake rats was determined under conditions of hyperglycemic (10.2 +/- 0.6 mM) hyperinsulinemia (approximately 1,200 pM) and hyperglycemic (20.8 +/- 1.5 mM) hypoinsulinemia (< 12 pM) by use of 13C nuclear magnetic resonance (NMR) spectroscopy during a prime-constant infusion of [1-13C]glucose and [1-13C]mannitol with either insulin (10 mU.kg-1.min-1) or somatostatin (1.0 microgram.kg-1.min-1). Intracellular glucose was calculated as the difference between the concentrations of total tissue glucose (calculated from the in vivo 13C NMR spectrum with mannitol as an internal concentration standard) and extracellular glucose, corrected by the ratio of intra- and extracellular water space. Extracellular concentration was corrected for an interstitial fluid-to-plasma glucose concentration gradient of 0.83 +/- 0.07, determined by open-flow microperfusion. The mean ratio of intra- to extracellular glucose space, determined from the relative NMR signal intensities and concentrations of mannitol and total creatine, was 9.2 +/- 1.1 (hyperglycemic hyperinsulinemia, n = 10), and 9.0 +/- 1.7 (hyperglycemic hypoinsulinemia, n = 7). Mean muscle intracellular glucose concentration was < 0.07 mM under hyperglycemic-hyperinsulinemic conditions (n = 10) and 0.32 +/- 0.06 mM under hyperglycemic-hypoinsulinemic conditions (n = 7). This method is noninvasive and should prove useful for resolving the question of whether glucose transport or phosphorylation is responsible for the reduced rate of muscle glycogen synthesis observed in diabetic subjects.

In vivo NMR investigation of intramuscular glucose metabolism in conscious rats.

In vivo 13C nuclear magnetic resonance (NMR) spectroscopy was used to determine quantitatively the flux of muscle glycolysis, glycogen synthesis, pyruvate dehydrogenase, and pyruvate carboxylation in the hindlimb of conscious rats. 13C NMR spectroscopy was used to observe [1-13C]glucose label precursor incorporation into intramuscular [1-13C]glycogen, [3-13C]lactate, and [3-13C]alanine during a hyperglycemic (approximately 11 mM)-hyperinsulinemic (10 mU.kg-1.min-1) clamp. The glycogen synthesis rate was calculated to be 224 +/- 23 nmol.g-1.min-1. The kinetic data obtained from the label turnover in the intramuscular C-3 lactate and C-3 alanine metabolite pools, as well as in plasma C-3 lactate and C-3 alanine, were combined with a steady-state rate analysis to determine the glycolytic flux (67.4 +/- 10.1 nmol.g-1.min-1). Steady-state isotopomer analysis of glutamate and pyruvate in skeletal muscle tissue extracts was used to determine the anaplerotic contribution of substrate via pyruvate carboxylation (Vpc). The pyruvate dehydrogenase flux (Vpdh) was calculated after a steady-state flux correction for Vpc. Calculated values of Vpc and Vpdh were 24.8 +/- 4.3 and 110.0 +/- 18.7 nmol.g-1.min-1, respectively. In addition, [2-13C]acetate was used in a separate study to determine that pyruvate carboxylation was the major pathway for anaplerosis in skeletal muscle under conditions of hyperglycemia-hyperinsulinemia.

13C and 31P NMR studies on the effects of increased plasma free fatty acids on intramuscular glucose metabolism in the awake rat.

The effects of increased plasma free fatty acids (FFA) on insulin-dependent whole body glucose disposal, skeletal muscle glycolysis, glycogen synthesis, pyruvate versus FFA/ketone oxidation, and glucose 6-phosphate (Glu-6-P) were investigated in the awake rat. A control group (glycerol-infused) and high plasma FFA group (Liposyn-infused) were clamped at euglycemia (approximately 6 mM)-hyperinsulinemia (10 milliunits/kg/min) throughout the experiment (180-240 min). In the initial experiment, 13C NMR was used to observe [1-13C]glucose incorporation into [1-13C]glycogen in the rat hindlimb for glycogen synthesis calculations and into [3-13C]lactate and [3-13C]alanine for glycolytic flux calculations. These experiments were followed by 31P NMR measurements of Glu-6-P changes under identical conditions of the initial experiment. Plasma FFA concentrations were 2.25 +/- 0.36 and 0.20 +/- 0.03 mM in the high plasma FFA and control groups respectively (p < 0.0005). Glucose infusion rates (Ginf) decreased significantly in the Liposyn-infused rats (29.5 +/- 0.7 and 27.2 +/- 1.2 mg/kg/min for control and high plasma FFA group, respectively, at 15 min to 30.7 +/- 2.3 and 17.7 +/- 1.3 mg/kg/min, respectively, at the end of the experiment, p < 0.002). Glycogen synthesis rates were 163 +/- 32 and 104 +/- 17 nmol/g/min, and glycolytic rates were 57.9 +/- 8.0 and 19. 5 +/- 3.6 nmol/g/min (p < 0.002) in the control and high plasma FFA groups, respectively. The relative flux of pyruvate versus free fatty acids and ketones entering the tricarboxylic acid cycle was greater in the control (57 +/- 9%) versus high plasma FFA group (25 +/- 4%) (p < 0.005) as assessed by [4-13C]glutamate/[3-13C]lactate steady state isotopic enrichment measurements. Finally, Glu-6-P concentrations increased by 29.8 +/- 7.0 and 52.8 +/- 12.3% (p < 0. 05) in the control and high plasma FFA groups, respectively, above their basal concentrations by 180 min. In conclusion, we have demonstrated the ability to use in vivo NMR to elucidate the metabolic fate of glucose within skeletal muscle of an awake rat during a euglycemic-hyperinsulinemic clamp and increased levels of plasma FFA. These data suggest that increased concentrations of plasma FFA inhibit insulin-stimulated muscle glucose metabolism in the rat through inhibition of glycolysis.