Metabolic effects of aromatase inhibition

Aromatase, a member of the cytochrome P450 superfamily, catalyses the conversion of androgens to estrogens; specifically, testosterone to estradiol and androstenedione to estrone. Aromatase is widely expressed across a range of tissues and deleterious metabolic effects are observed in both murine aromatase knock-out models and in rare human cases of aromatase deficiency. The effects of pharmacological inhibition of aromatase, as employed in the treatment of breast cancer, are not well characterised. This thesis addresses the hypothesis that aromatase inhibition, and consequent changes in sex steroid hormone action (higher androgen:estrogen ratio), results in disadvantageous changes in body composition and reduced insulin sensitivity. In a cohort study of 197 community-dwelling men, lower testosterone and SHBG concentrations were observed in those fulfilling criteria for metabolic syndrome, although no relationship with estrogens was observed. The strongest determinant of circulating estrogens was substrate androgen concentration. A case-control study of aromatase inhibitor treated breast cancer patients and age-matched controls (n=40) demonstrated decreased insulin sensitivity and increased body fat in those treated with aromatase inhibitors; serum leptin concentration and leptin mRNA transcript levels (in subcutaneous adipose tissue) were elevated in this group. In healthy male volunteers (n=17), 6 weeks of aromatase inhibition (1 mg anastrozole daily) resulted in reduced glucose disposal during a hyperinsulinaemic euglycaemic clamp study, with d2-glucose and d5-glycerol tracers. No effects upon hepatic insulin sensitivity, lipolysis or body composition were noted, although serum leptin concentration was reduced following aromatase inhibitor administration. In conclusion, aromatase inhibition is associated with increased insulin resistance and, in women, increased body fat. This may be relevant for patients receiving aromatase inhibitor therapy, where more careful monitoring of glucose tolerance may be warranted

Infrared spectroscopy of solid CO-CO2 mixtures and layers

The spectra of pure, mixed and layered CO and CO2 ices have been studied systematically under laboratory conditions using infrared spectroscopy. This work provides improved resolution spectra (0.5 cm-1) of the CO2 bending and asymmetric stretching mode, as well as the CO stretching mode, extending the existing Leiden database of laboratory spectra to match the spectral resolution reached by modern telescopes and to support the interpretation of the most recent data from Spitzer. It is shown that mixed and layered CO and CO2 ices exhibit very different spectral characteristics, which depend critically on thermal annealing and can be used to distinguish between mixed, layered and thermally annealed CO-CO2 ices. CO only affects the CO2 bending mode spectra in mixed ices below 50K under the current experimental conditions, where it exhibits a single asymmetric band profile in intimate mixtures. In all other ice morphologies the CO2 bending mode shows a double peaked profile, similar to that observed for pure solid CO2. Conversely, CO2 induces a blue-shift in the peak-position of the CO stretching vibration, to a maximum of 2142 cm-1 in mixed ices, and 2140-2146 cm-1 in layered ices. As such, the CO2 bending mode puts clear constraints on the ice morphology below 50K, whereas beyond this temperature the CO2 stretching vibration can distinguish between initially mixed and layered ices. This is illustrated for the low-mass YSO HH46, where the laboratory spectra are used to analyse the observed CO and CO2 band profiles and try to constrain the formation scenarios of CO2.Comment: Accepted in A&

Hypoglycaemia in type 2 diabetes treated with pre-mixed insulin

The burden of hypoglycaemia in type 2 diabetes is increasingly recognised, regardless of treatment regimen.1-3 However, time in hypoglycaemia for individuals with type 2 diabetes who use pre-mixed (biphasic) insulin remains unclear. The aim of our prospective, open-label, single arm, pilot, observational study was to determine the amount of time individuals in this cohort spent in hypoglycaemia (ISRCTN 10603608). The primary endpoint was sensor derived time in hypoglycaemia (TBR

Effects of CO2 on H2O band profiles and band strengths in mixed H2O:CO2 ices

H2O is the most abundant component of astrophysical ices. In most lines of sight it is not possible to fit both the H2O 3 um stretching, the 6 um bending and the 13 um libration band intensities with a single pure H2O spectrum. Recent Spitzer observations have revealed CO2 ice in high abundances and it has been suggested that CO2 mixed into H2O ice can affect relative strengths of the 3 um and 6 um bands. We used laboratory infrared transmission spectroscopy of H2O:CO2 ice mixtures to investigate the effects of CO2 on H2O ice spectral features at 15-135 K. We find that the H2O peak profiles and band strengths are significantly different in H2O:CO2 ice mixtures compared to pure H2O ice. In all H2O:CO2 mixtures, a strong free-OH stretching band appears around 2.73 um, which can be used to put an upper limit on the CO2 concentration in the H2O ice. The H2O bending mode profile also changes drastically with CO2 concentration; the broad pure H2O band gives way to two narrow bands as the CO2 concentration is increased. This makes it crucial to constrain the environment of H2O ice to enable correct assignments of other species contributing to the interstellar 6 um absorption band. The amount of CO2 present in the H2O ice of B5:IRS1 is estimated by simultaneously comparing the H2O stretching and bending regions and the CO2 bending mode to laboratory spectra of H2O, CO2, H2O:CO2 and HCOOH.Comment: 12 pages, 11 figures, accepted by A&

Presentation, diagnostic assessment and surgical outcomes in primary hyperparathyroidism:a single centre's experience

Objective: Primary hyperparathyroidism (PHPT) is a common reason for referral to endocrinology but the evidence base guiding assessment is limited. We evaluated the clinical presentation, assessment and subsequent management in PHPT. Design: Retrospective cohort study. Patients: PHPT assessed between 2006 and 2014 (n = 611) in a university hospital. Measurements: Symptoms, clinical features, biochemistry, neck radiology and surgical outcomes. Results: Fatigue (23.8%), polyuria (15.6%) and polydipsia (14.9%) were associated with PHPT biochemistry. Bone fracture was present in 16.4% but was not associated with biochemistry. A history of nephrolithiasis (10.0%) was associated only with younger age (P = 0.006) and male gender (P = 0.037). Thiazide diuretic discontinuation was not associated with any subsequent change in calcium (P = 0.514). Urine calcium creatinine clearance ratio (CCCR) was <0.01 in 18.2% of patients with confirmed PHPT. Older age (P < 0.001) and lower PTH (P = 0.043) were associated with failure to locate an adenoma on ultrasound (44.0% of scans). When an adenoma was identified on ultrasound the lateralisation was correct in 94.5%. Non-curative surgery occurred in 8.2% and was greater in those requiring more than one neck imaging modality (OR 2.42, P = 0.035). Conclusions: Clinical features associated with PHPT are not strongly related to biochemistry. Thiazide cessation does not appear to attenuate hypercalcaemia. PHPT remains the likeliest diagnosis in the presence of low CCCR. Ultrasound is highly discriminant when an adenoma is identified but surgical failure is more likely when more than one imaging modality is required

HbA1c response and hospital admissions following commencement of flash glucose monitoring in adults with type 1 diabetes

Introduction Our aim was to assess the effect of introducing flash monitoring in adults with type 1 diabetes with respect to change in hemoglobin A1c (HbA1c) and frequency of hospital admissions.Research design and methods Prospective observational study of adults with type 1 diabetes in our center, in whom a prescription for a flash monitoring sensor was collected. Primary outcome was change in HbA1c between 2016 and after flash monitoring. Rates of hospital admission were compared between the first year after flash monitoring and the corresponding 12-month period 2 years earlier.Results Approximately half of all adults with type 1 diabetes, attending our center, collected prescriptions for flash monitoring sensors (n=2216). Median fall in HbA1c was −1 (−0.1) mmol/mol (%) (p&lt;0.001) and was greatest in those with baseline HbA1c &gt;75 (9.0) mmol/mol (%): −10 (−0.9) mmol/mol (%), p&lt;0.001. 43% of those with a baseline HbA1c &gt;53 mmol/mol (7%) experienced a ≥5 mmol/mol (0.5%) fall in HbA1c. In addition to higher HbA1c, early commencement within 1 month of NHS-funded flash monitoring (p&lt;0.001), and male gender (p=0.013) were associated with a fall in HbA1c of ≥5 (0.5) mmol/mol (%). Socioeconomic deprivation (p=0.009) and collecting fewer than 2 sensors per month (p=0.002) were associated with lack of response. Overall, hospital admissions did not change but an increase in admissions for hypoglycemia was observed (1.1% vs 0.3%, p=0.026).Conclusions Flash monitoring is associated with reduction in HbA1c in individuals with HbA1c &gt;58 mmol/mol. Numerous clinical features are independently associated with HbA1c response. An increase in hypoglycemia admissions occurred following flash monitoring