Pre-clinical Cushing's syndrome: an unexpected frequent cause of poor glycaemic control in obese diabetic patients

OBJECTIVE Autonomous cortisol secretion without clinical stigmata of Cushing's syndrome (CS) has been recently recognized and termed pre-clinical or sub-clinical CS. The common assumption is that CS is an extremely rare cause of uncontrolled diabetes; however, the prevalence of this entity has not been studied. We assessed the prevalence of pre-clinical CS among obese patients with uncontrolled diabetes. PATIENTS AND DESIGN (1) In a retrospective analysis, the medical records of 63 patients with endogenous CS were reviewed. (2) In a cross-sectional study, 90 obese patients (BMI >25 kg/m²) followed in a University Hospital and the local Health Fund endocrine and diabetes clinics, with poorly controlled diabetes (glycosylated haemoglobin >9%), underwent an overnight 1 mg dexamethasone suppression. In patients with non-suppressible cortisol levels (>140 nmol/l), Liddle's 2 and 8 mg dexamethasone suppression tests and imaging studies were performed. MEASUREMENTS The prevalence of poorly controlled diabetes, the major presenting symptom of CS, was assessed in the retrospective analysis. The prevalence of ‘true’ CS and the false positive rate in the overnight dexamethasone suppression test were calculated. The endocrine evaluation of the patients with pre-clinical CS and the effects of surgical cure on glycaemic control are described. RESULTS In the retrospective analysis, 11 (17.5%) had diabetes and 2 (3.2%) lacked the classic physical characteristics of the syndrome. In the cross-sectional study, 4 patients failed to suppress plasma cortisol (<140 nmol/l). In one patient the diagnosis of CS was not confirmed by a standard Liddle’s test and was therefore considered false positive. In the other 3, the diagnosis of CS was confirmed (prevalence of 3.3%, 95% confidence interval 1–9%). In all other patients the overnight cortisol suppression test was normal (cortisol level 47.3 ± 2.5 nmol/l (mean ± SEM)). After surgical treatment of CS, glycaemic control was markedly improved in all 5 patients (2 from retrospective and 3 from cross-sectional studies). CONCLUSIONS The prevalence of pre-clinical Cushing's syndrome in obese patients with poorly controlled diabetes appears to be considerably higher than previously believed. The overnight dexamethasone suppression test proved to be a simple, sensitive and highly specific screening test for Cushing's syndrome despite the presence of obesity and hyperglycaemia.     

Seasonal recruitment of hippocampal neurons in adult free-ranging black-capped chickadees.

Neurogenesis and neuronal replacement in a population of wild free-ranging animals are described. Our subjects were adult black-capped chickadees (Parus atricapillus). Neuronal birth dates were determined by a single systemic injection of [3H]thymidine, followed by release of the bird and its recapture 6 or more weeks later. Newly formed neurons appeared in the hippocampal complex during all times of year, but with a marked peak in the fall (October). New neurons were also added to the hippocampal complex of captive chickadees, but at levels only half as high as seen in the wild birds. Neurons born at different times of the year lived for a few months and then disappeared. We suggest that the neurons added are part of a process of neuronal replacement and that they are important for the acquisition of new spatial memories, a need that is particularly acute in the fall. Hormonal and experiential factors may determine the rate of neuronal replacement.     

Reconstruction of pectus excavatum with silicone implants.

The pectus excavatum deformity is characterised by a deep depression usually involving the lower one-half to two-thirds of the sternum. The indications for surgery are often aesthetic. Extensive procedures, requiring fracturing and remodelling of the chest wall skeleton are associated with high morbidity and high rate of complications. In this article we describe our renewed experience with reconstruction of mild and moderate pectus excavatum deformities with custom made prefabricated silicone implants. The fabrication of the implant and the surgical technique are described in detail. An excellent aesthetic correction of the deformity was achieved in all of the patients in our series, with high patient satisfaction rate. We conclude that with careful patient selection, artistic implant fabrication and meticulous surgical technique, this approach achieves excellent aesthetic correction with minimal morbidity and a low complication rate and therefore should maintain its place in the armamentarium of surgical techniques for reconstruction of pectus deformities.     

Monte Carlo studies of x-ray scattering in transmission diagnostic radiology

Monte Carlo methods have been used to simulate the scattering of x rays in polystyrene and water phantoms. In particular, the ratio of the scattered to total x-ray fluence (scatter fraction) has been calculated for monoenergetic x-ray beams in the energy region relevant to diagnostic radiology and nuclear medicine (30-660 keV). Simulations have been made for representative values of the pertinent geometrical factors; phantom thickness from 5 to 21 cm, x-ray beam diameters of 10 and 25 cm, and scatterer-to-image-plane separations from 0 to 20 cm. As a function of x-ray energy, the scatter fraction was found to vary slowly between 30 and 100 keV, and to decrease between 100 and 660 keV. The present results were generated with a special transport code which included the effects of special geometries and the response of the x-ray detector. With the inclusion of these effects, the results resolved inconsistencies and showed good agreement with previous measured and calculated data.     

Human sperm chemotaxis: both the oocyte and its surrounding cumulus cells secrete sperm chemoattractants

BACKGROUND: Human sperm chemotaxis to pre-ovulatory follicular fluid is well established in vitro. However, it is not known whether the female's oocyte-cumulus complex secretes sperm chemoattractants subsequent to ovulation (for enabling sperm chemotaxis within the Fallopian tube) and, if so, which of these cell types--the oocyte or the cumulus oophorus--is the physiological origin of the secreted chemoattractant. METHODS: By employing a directionality-based chemotaxis assay, we examined whether media conditioned with either individual, mature (metaphase II) human oocytes or the surrounding cumulus cells attract human sperm by chemotaxis. RESULTS: We observed sperm chemotaxis to each of these media, suggesting that both the oocyte and the cumulus cells secrete sperm chemoattractants. CONCLUSIONS: These observations suggest that sperm chemoattractants are secreted not only prior to ovulation within the follicle, as earlier studies have demonstrated, but also after oocyte maturation outside the follicle, and that there are two chemoattractant origins: the mature oocyte and the surrounding cumulus cells.     

Periovulatory increase in temperature difference within the rabbit oviduct

BACKGROUND: Earlier studies demonstrated a small temperature difference between the sperm storage and fertilization sites within the oviducts of rabbits and pigs. Our aim was to reveal the time dependence of this temperature difference relative to ovulation, and to determine how this difference is generated-by temperature elevation at one of these sites or by temperature decrease at the other site. METHODS: The temperature at the sperm storage site (at the isthmus near the uterotubal junction) and at the fertilization site (the isthmic-ampullary junction) of rabbit oviducts were measured before, during, and after ovulation by two probes, connected to digital thermometers. Rectal temperature was constantly measured and served as a control for body temperature. RESULTS: The temperature difference between the fertilization site and the storage site was 0.8+/-0.2 degrees C before ovulation. This difference increased at ovulation, reaching 1.6+/-0.1 degrees C after ovulation (P<0.03). This increased difference was mainly due to temperature decrease in the sperm storage site. CONCLUSION: The temperature-difference increase within the rabbit oviduct is generated at ovulation by a reduced temperature at the sperm storage site. This temperature gradient may play a role in mammalian reproduction via sperm thermotaxis.     

Recombinant alpha2(IV)NC1 domain inhibits tumor cell-extracellular matrix interactions, induces cellular senescence, and inhibits tumor growth in vivo

Cellular interaction with the extracellular matrix is thought to be a critical event in controlling angiogenesis and tumor growth. In our previous studies, genetically distinct noncollagenous (NC) domains of type-IV collagen were shown to interact with integrin receptors expressed on the surface of endothelial cells. Moreover, these NC1 domains were shown to inhibit angiogenesis in vivo. Here, we provide evidence that a recombinant form of the alpha2(IV)NC1 domain of type-IV collagen could bind integrins alpha1beta1 and alphavbeta3 expressed on melanoma cells and inhibit tumor cell adhesion in a ligand-specific manner. Systemic administration of recombinant alpha2(IV)NC1 domain potently inhibited M21 melanoma tumor growth within full thickness human skin and exhibited a dose-dependent inhibition of tumor growth in nude mice. Interestingly, alpha2(IV)NC1 domain enhanced cellular senescence in tumor cells in vitro and in vivo. Taken together, these results suggest that recombinant alpha2(IV)NC1 domain is not only a potent anti-angiogenic reagent, but it also directly impacts tumor cell behavior. Thus, alpha2(IV)NC1 domain represents a potent inhibitor of tumor growth by impacting both endothelial and tumor cell compartments.     

The yeast VPS genes affect telomere length regulation

Eukaryotic cells invest a large proportion of their genome in maintaining telomere length homeostasis. Among the 173 non-essential yeast genes found to affect telomere length, a large proportion is involved in vacuolar traffic. When mutated, these vacuolar protein-sorting (VPS) genes lead to telomeres shorter than those observed in the wild type. Using genetic analysis, we characterized the pathway by which VPS15, VPS34, VPS22, VPS23 and VPS28 affect the telomeres. Our results indicate that these VPS genes affect telomere length through a single pathway and that this effect requires the activity of telomerase and the Ku heterodimer, but not the activity of Tel1p or Rif2p. We present models to explain the link between vacuolar traffic and telomere length homeostasis.