Mechanisms for the bone anabolic effect of parathyroid hormone treatment in humans

Intermittent low-dose treatment with parathyroid hormone (PTH) analogues has become widely used in the treatment of severe osteoporosis. During normal physiological conditions, PTH stimulates both bone formation and resorption, and in patients with primary hyperparathyroidism, bone loss is frequent. However, development of the biochemical measurement of PTH in the 1980s led us to understand the regulation of PTH secretion and calcium metabolism which subsequently paved the way for the use of PTH as an anabolic treatment of osteoporosis as, when given intermittently, it has strong anabolic effects in bone. This could not have taken place without the basic understanding achieved by the biochemical measurements of PTH. The stimulatory effects of PTH on bone formation have been explained by the so-called 'anabolic window', which means that during PTH treatment, bone formation is in excess over bone resorption during the first 6-18 months. This is due to the following: (1) PTH up-regulates c-fos expression in bone cells, (2) IGF is essential for PTH's anabolic effect, (3) bone lining cells are driven to differentiate into osteoblasts, (4) mesenchymal stem cells adhesion to bone surface is enhanced, (5) PTH has a direct antiapoptotic effect on osteoblasts and (6) when PTH interferes with remodelling, the osteoblasts over-compensate, and (7) PTH also decreases sclerostin levels, thereby removing inhibition of Wnt signalling which is required for PTH's anabolic actions. Thus, the net formative effect of PTH given in intermittent treatment emerges through a complex network of pathways. In summary, the effects of PTH on bone turnover are dependent on the mode and dose of administration and studies investigating the mechanisms underlying this effect are reviewed in this article.     

Vancomycin–Triacetyl Cyclodextrin Interaction Products for Prolonged Drug Delivery

The aim of the present work was to investigate the capability of vancomycin (VCM) to interact with three hydrophobic cyclodextrins (TACD) (triacetyl alfa-, beta-, or gamma cyclodextrin) and the role played by the preparation technique in the formation of interaction products aimed at prolonging drug delivery for site-specific treatment of bone infections. Physical mixtures of VCM with triacetyl α-, β-, or γ-cyclodextrin in a 1:1 molar ratio were subjected to kneading, coevaporation, and spray drying from aqueous suspensions or hydroacetonic solution. Thermal behavior (TG, DSC), percent drug content (HPLC), and drug release (Franz cell) of VCM from the physical mixtures, and the relevant binary systems obtained by the various complexation methods were evaluated. All binary systems were characterized by having a particle size compatible with parenteral site-specific administration and with drug-loading efficiencies close to 100%, thus indicating the stability of vancomycin toward each and every complexation process. In vitro drug release measurements showed that the preparation technique plays a different role depending on the type of cyclodextrin used. In the kneading process, the binary system containing TAαCD is the most efficient in slowing down the VCM release. With the coevaporation technique, the system based on TAβCD was most effective in prolonging drug release. None of the triacetyl-cyclodextrins is suitable in prolonging VCM release upon spray drying from aqueous suspensions, because this preparation technique does not determine drug-cyclodextrin interaction. On the other hand, spray drying from hydroacetonic solutions always results in a reduction in drug release, linked to the formation of VCM-TACD interaction products and is particularly pronounced for the VCM-TAγCD interaction product. The unique properties of prolonging drug release and maintaining the antimicrobial activity of the native drug render such an interaction product the most promising candidate in the development of delivery systems intended for parenteral site-specific administration of VCM.     

Telomere loss in Philadelphia-negative hematopoiesis after successful treatment of chronic myeloid leukemia: evidence for premature aging of the myeloid compartment

Telomere shortening, a well-known marker of aging and cellular stress, occurs under several conditions in the hematopoietic compartment, including aplastic anemia and following iatrogenic noxae. We decided to verify whether pathological telomere erosion also arises in restored Philadelphia-negative (Ph-negative) hematopoiesis following successful treatment of chronic myeloid leukemia (CML). Eighty-one CML patients in complete cytogenetic remission were compared to 76 age-matched healthy subjects. Myeloid cells of CML patients had shorter telomeres than controls (6521 bp vs 7233 bp, p < 0.001). This difference was specific for the myeloid compartment, since it was not observed in lymphoid cells (6774 bp vs 6909 bp, p = 0.620). Acquired Ph-negative cytogenetic abnormalities (p = 0.010), lack of complete molecular remission (p = 0.016) and age (p = 0.013) were independent predictors of telomere shortening. Telomere dynamics were assessed over a median follow-up period of 22 months. We documented accelerated non-physiological ongoing telomere shortening in 17/59 CML patients (28%). Patients experiencing grade 2-4 hematological toxicity, during CML remission possessed significantly shorter telomeres compared to those lacking toxicity (p = 0.005 for any toxicity, p = 0.007 for anemia). CML patients suffer from significant and often ongoing telomere stress resulting in premature and selective aging of the myeloid compartment which might have long-term consequences on function and integrity of Ph-negative hematopoiesis.     

Low prevalence of depressive disorder in ambulatory advanced cancer patients using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN 2.1)

Depressive disorder is assumed to be highly prevalent in advanced cancer patients, but the diagnosis of depressive disorder in patients with advanced cancer is difficult. The more robust the assessment instrument to diagnose depressive disorder is, the lower the reported prevalence of depressive disorder in advanced cancer patients. This study confirms a low prevalence of depressive disorder (3%) in 64 advanced cancer outpatients using a robust structured clinical assessment (SCAN 2.1). Furthermore, in this article we discuss possible implications of using predefined psychiatric labeling in the assessment of mood symptoms in advanced cancer patients.     

Recalling pain experienced during a colonoscopy: Pain expectation and variability

Objectives. This study investigated the relationship between participants' expected levels of pain intensity before a colonoscopy, pain intensity experienced while they were undergoing this medical procedure (real‐time pain), and their retrospective evaluation of this experience. Design. Correlational design. Regression analyses were performed and mediational models were tested. Methods. Ninety patients who were about to undergo a colonoscopy were asked to report the pain intensity on a scale ranging from 0 (no pain) to 10 (extreme pain). They reported the expected intensity of pain before the examination, their real‐time intensity of pain every 60 s during the colonoscopy, and their global retrospective evaluation of the pain experienced when the procedure was over. Results. Results confirmed that, regardless of participants' gender, the variability of the real‐time pain distribution was a significant predictor of the accuracy of recall (i.e. the discrepancy between recalled pain and mean real‐time pain). Moreover, participants' pain expectations preceding the examination were a significant predictor of the accuracy of recall. It was further demonstrated that the effect of patients' expectations on the discrepancy was mediated by the real‐time pain variability. Conclusions. The results of the present study provide useful indications about what the target of interventions aimed at reducing the bias in pain recall should be.     

Intense physical exercise increases systemic 11β-hydroxysteroid dehydrogenase type 1 activity in healthy adult subjects

Intense physical exercise activates the hypothalamic–pituitary–adrenocortical axis but little is known about changes in glucocorticoid sensitivity at the target cell level. No data are available on the acute effects of exercise on 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 activity, which generates biologically active cortisol from inactive cortisone and is expressed also in skeletal muscle. Fifteen healthy, trained males (age mean ± SE 28 ± 1) were assessed on three non-consecutive days: at rest, during an endurance and strength sessions. During each session, between 1000 and 1600 hours, 6-h urine and four salivary samples were collected. Urinary total tetrahydrocortisol (THF) + alloTHF, tetrahydrocortisone (THE), cortisol (F) and cortisone (E) were measured with HPLC-tandem mass spectrometry; urinary-unconjugated F and E were measured by HPLC-UV. Salivary cortisol and interleukin (IL)-6 were measured by RIA and ELISA, respectively. Both endurance and strength exercises caused an increase in (THF + alloTHF)/THE ratio (mean ± SE 1.90 ± 0.07 and 1.82 ± 0.05 vs. 1.63 ± 0.06, P < 0.01 and P = 0.03, respectively), consistent with increased systemic 11β-HSD type 1 activity. No relationship was found with age, BMI, $ V{{{\text{O}}_{2\max } }} , $ maximal power load or perceived exertion. No significant change was apparent in F/E ratio, an index of 11β-HSD type 2 activity. No effect of exercise on salivary cortisol and IL-6 was observed, whereas a significant effect of sampling time was found. Intense physical exercise acutely increases systemic 11β-HSD type 1 activity in humans. Such an increase may lead to higher cortisol concentration in target tissues, notably in skeletal muscle where it could contribute to limit exercise-induced muscle inflammatory response.     

Ascending aorta dilatation in aortic valve disease: morphological analysis of medial changes

We investigated whether and how the severity of medial degeneration lesions varies along the circumference of the dilated intrapericardial aorta. Two groups of aortic wall specimens, respectively harvested in the convexity and concavity of ascending aorta in 72 patients undergoing surgery for dilatation of the intrapericardial aorta associated with aortic valve disease, were separately sent for pathology, morphometry, and ultrastructural examination. Cystic medial necrosis, fibrosis, and elastic fiber fragmentation were classified into three degrees of severity; their mean degree and morphometric findings in the convexity and in the concavity specimens were compared by paired t-test. Correlation between echocardiographic degree of aortic dilatation and severity of medial degeneration was assessed separately for each of the two groups of specimens. Morphologically, medial degeneration was found in all cases; a higher mean degree was found in the convexity group (2.39 ± 0.58 vs 1.44 ± 0.65 in the concavity group; P < 0.001). At morphometry normal smooth muscle cells in the convexity specimens were significantly reduced (P = 0.007); the length (P = 0.012) and number (P = 0.009) of elastic fibers reduced and increased, respectively. Moreover, in the convexity specimens a significantly smaller amount of smooth muscle cells and an increase of immunohistochemical labeling of apoptosis-associated proteins in the subintimal layer of the media was noticed. Correlation between aortic ratio and medial degeneration degree was significant in the convexity group (P < 0.001), but not in the concavity group (P = 0.249). Scanning electron microscopy analysis confirmed morphological results and allowed us to better distinguish the early pathological cavities from the microvessels, which were in the outer media in normal aorta and ubiquitous in aortitis or atherosclerosis. Electron transmission microscopy analysis showed changes in the extracellular matrix and smooth muscle cells, and these changes increased from the intima to the adventitial layer of the media. In dilated intrapericardial aorta, medial degeneration changes and expression of apoptosis-associated proteins are more marked in the ascending aorta convexity, likely due to hemodynamic stress asymmetry. Ultrastructural findings allow us to distinguish the early medial changes not yet evident on light microscopy.