Neuropeptide Y Attenuates Stress‐Induced Bone Loss Through Suppression of Noradrenaline Circuits

Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress‐induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress‐induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6‐week restraint, or cold‐stress protocol, Npy‐null mice exhibit three‐fold greater bone loss compared to wild‐type mice, owing to suppression of osteoblast activity. This stress‐protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin‐releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy‐null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy‐null mice blocks the increase in circulating noradrenaline and the stress‐induced bone loss. Thus, NPY protects against excessive stress‐induced bone loss, through Y2 receptor‐mediated modulation of central and peripheral noradrenergic neurons. © 2014 American Society for Bone and Mineral Research.     

Altered Interhemispheric and Temporal Lobe White Matter Microstructural Organization in Severe Chronic Schizophrenia

Diffusion MRI investigations in schizophrenia provide evidence of abnormal white matter (WM) microstructural organization as indicated by reduced fractional anisotropy (FA) primarily in interhemispheric, left frontal and temporal WM. Using tract-based spatial statistics (TBSS), we examined diffusion parameters in a sample of patients with severe chronic schizophrenia. Diffusion MRI data were acquired on 19 patients with chronic severe schizophrenia and 19 age- and gender-matched healthy controls using a 64 gradient direction sequence, (b=1300 s/mm²) collected on a Siemens 1.5T MRI scanner. Diagnosis of schizophrenia was determined by Diagnostic and Statistical Manual for Mental Disorders 4th Edition (DSM-IV) Structured Clinical Interview for DSM disorder (SCID). Patients were treatment resistance, having failed to respond to at least two antipsychotic medications, and had prolonged periods of moderate to severe positive or negative symptoms. Analysis of diffusion parameters was carried out using TBSS. Individuals with chronic severe schizophrenia had significantly reduced FA with corresponding increased radial diffusivity in the genu, body, and splenium of the corpus callosum, the right posterior limb of the internal capsule, right external capsule, and the right temporal inferior longitudinal fasciculus. There were no voxels of significantly increased FA in patients compared with controls. A decrease in splenium FA was shown to be related to a longer illness duration. We detected widespread abnormal diffusivity properties in the callosal and temporal lobe WM regions in individuals with severe chronic schizophrenia who have not previously been exposed to clozapine. These deficits can be driven by a number of factors that are indistinguishable using in vivo diffusion-weighted imaging, but may be related to reduced axonal number or packing density, abnormal glial cell arrangement or function, and reduced myelin.     

Dopamine agonists and pituitary tumor shrinkage.

The primary aim of this review has been to clarify the tumor shrinking effects of dopamine agonists on pituitary macroadenomas of different cell types. Shrinkage is most dramatic for macroprolactinomas and is due to cell size reduction. Seventy-nine percent of 271 definite macroprolactinomas were reduced in size by at least 25%, and 89% shrank to some degree. Most shrinkage occurs during the first 3 months of treatment, although in a minority shrinkage is delayed. Dopamine agonist resistance during long-term therapy is exceptional. Drug withdrawal nearly always leads to a return of hyperprolactinemia, even after several years treatment, although early tumor reexpansion is unusual. About 10% of true macroprolactinomas do not shrink with dopamine agonists; the molecular mechanisms of such resistance have yet to be determined. Alternative formulations of BC and new dopamine agonists (CV 205-502 and cabergoline) are useful for the minority of patients unable to tolerate oral BC, but do not seem to further improve overall shrinkage rates. The risks of pregnancy have probably been overstated, and BC is suitable primary treatment for women with prolactinomas of all sizes; the drug can be used safely during pregnancy in the event of clinically relevant tumor expansion. The interpretation of different degrees of hyperprolactinemia is discussed and management strategies suggested. Most patients with macroprolactinomas now avoid surgery, but drug-induced, time-dependent tumor fibrosis should be remembered if surgery is contemplated. Nonfunctioning pituitary tumors are mostly of gonadotroph cell origin and may be associated with significant disconnection hyperprolactinaemia. Seventy-six of 84 well-characterized tumors showed no tumor shrinkage during dopamine agonist therapy. Possible explanations include abnormalities of dopamine receptor number and function. Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery. In contrast to macroprolactinomas, other functioning pituitary tumors (GH-, TSH-, and ACTH-secreting) rarely shrink during dopamine agonist therapy, although the number of tumors studied is small.     

Hemodynamic effects of contrast media during coronary angiography: a comparison of three nonionic agents to Hypaque-76

Coronary angiography with standard ionic contrast media is associated with marked alterations in cardiac hemodynamics because of the depressant effects of the contrast media on cardiac contractility. Nonionic contrast media have been reported to produce less hemodynamic alteration than standard ionic contrast media. However, there is no information on how one nonionic media compares to another. Thus we compared the hemodynamic effects of three nonionic contrast media, Iopamidol (IOP), Iohexol (IOH), and Ioversol (IOV) to each other as well as to the standard ionic contrast media Hypaque-76 (H76). In 20 closed-chest anesthetized dogs, we recorded the maximal change in left ventricular systolic pressure (LVSP), mean aortic pressure, left ventricular diastolic pressure (LVDP), and left ventricular dp/dt during 10-cc left main coronary artery injections of H76, IOP, IOH, and IOV. The mean aortic pressure and LVSP decreased 36 +/- 17 mm Hg and 46 +/- 21 mm Hg with H76 but only 5 +/- 5 mm Hg and 6 +/- 5 mm Hg with IOP, 5 +/- 4 mm Hg and 6 +/- 6 mm Hg with IOH, and 5 +/- 4 mm Hg and 7 +/- 6 mm Hg with IOV (P less than 0.001). The LVDP increased 6 +/- 5.0 mm Hg with H76 but only 0.2 +/- 0.5 mm Hg with IOP, 0.2 +/- 0.3 mm Hg with IOH, and 0.5 +/- 1.0 mm Hg with IOV (P less than 0.001). The LV dp/dt decreased 545 +/- 261 mm Hg/sec with H76 but increased 886 +/- 477 mm Hg/sec with IOP, 910 +/- 96 mm Hg/sec with IOH, and 473 +/- 335 mm Hg/sec with IOV (P less than 0.001). Whereas each nonionic agent produced significantly less hemodynamic abnormalities than H76, there was no significant difference between any of the nonionic agents on any hemodynamic parameter. Thus, as compared to H76, these nonionic contrast media produced only trivial alterations in hemodynamics and LV dp/dt. These agents may be preferable in patients with LV dysfunction.     

The mechanism and significance of ventricularization of intracoronary pressure during coronary angiography

Ventricularization of pressure during coronary angiography has been said to identify the presence of left main coronary artery disease, but the hemodynamic features and the mechanism of this process have not been studied. Twenty consecutive patients with ventricularization were identified prospectively in our laboratory. Four patients had a discrete ostial left main stenosis and 16 patients had stenosis of the entire length of the left main coronary artery. The degree of pressure drop upon cannulation of the diseased left main coronary artery was highly variable; the systolic pressure decreased by 9 to 94 mm Hg, and the diastolic pressure decreased by 6 to 60 mm Hg. The morphology of the ventricularized pressure was distinct. It had a presystolic deflection resembling an a wave. The upstroke of this waveform was slower and the downstroke was steeper than that of the aortic pressure. An identical waveform was observed in dogs after partial occlusion of the left main coronary artery with a balloon-tipped catheter. The waveform of the so-called ventricularized pressure is derived from the aortic pressure, which is altered by its transmission across the left main coronary stenosis. The appearance of ventricularization is an important clue to the presence of left main coronary artery disease.