Fkbp10 Deletion in Osteoblasts Leads to Qualitative Defects in Bone

Osteogenesis imperfecta (OI), also known as brittle bone disease, displays a spectrum of clinical severity from mild (OI type I) to severe early lethality (OI type II), with clinical features including low bone mass, fractures, and deformities. Mutations in the FK506 Binding Protein 10 (FKBP10), gene encoding the 65‐kDa protein FKBP65, cause a recessive form of OI and Bruck syndrome, the latter being characterized by joint contractures in addition to low bone mass. We previously showed that Fkbp10 expression is limited to bone, tendon, and ligaments in postnatal tissues. Furthermore, in both patients and Fkbp10 knockout mice, collagen telopeptide hydroxylysine crosslinking is dramatically reduced. To further characterize the bone specific contributions of Fkbp10, we conditionally ablated FKBP65 in Fkbp10^fl/fl mice (Mus musculus; C57BL/6) using the osteoblast‐specific Col1a1 2.3‐kb Cre recombinase. Using μCT, histomorphometry and quantitative backscattered electron imaging, we found minimal alterations in the quantity of bone and no differences in the degree of bone matrix mineralization in this model. However, mass spectroscopy (MS) of bone collagen demonstrated a decrease in mature, hydroxylysine‐aldehyde crosslinking. Furthermore, bone of mutant mice exhibits a reduction in mineral‐to‐matrix ratio and in crystal size as shown by Raman spectroscopy and small‐angle X‐ray scattering, respectively. Importantly, abnormalities in bone quality were associated with impaired bone biomechanical strength in mutant femurs compared with those of wild‐type littermates. Taken together, these data suggest that the altered collagen crosslinking through Fkbp10 ablation in osteoblasts primarily leads to a qualitative defect in the skeleton. © 2017 American Society for Bone and Mineral Research.     

Antagonistic effects of naloxone and naloxonazine on sufentanil-induced antinociception and respiratory depression in rats.

Several binding studies in rodent brain homogenates have revealed two distinct micro-opiate binding sites based on differences in binding affinity of several opiate peptides and opiate alkaloids. Naloxonazine (NLZ), which preferentially binds to the high affinity micro(1) sites, is often used to discriminate between pharmacological effects mediated by micro(1) and micro(2) binding sites. The present series of experiments were undertaken to compare the opioid antagonistic properties of naloxonazine and naloxone (NLX) (a non-selective micro(1)-antagonist) on intravenous (i.v.) and intrathecal (i.t.) sufentanil (SUF)-induced antinociception and respiratory depression. The opioid antagonists were given either intravenously at 5 min after SUF, or subcutaneously (s.c.) 24 h prior to the opioid. Intravenous NLX and NLZ reduced the i.v. and i. t. SUF-induced antinociception, hypercapnia and hypoxia when given directly after the opioid. There were no major differences in activity between both antagonists. Pretreatment with 30 mg/kg NLX did not reverse the i.v. or i.t. SUF-induced antinociception and respiratory depression. Subcutaneous pretreatment with doses up to 30 mg/kg NLX only partially antagonized the i.v. SUF-induced antinociception, while a complete reversal was present of the opioid-induced hypercapnia and hypoxia. With regard to i.t. SUF, doses up to 30 mg/kg NLZ were unable to reduce the antinociception. The respiratory depression was partially affected; with 30 mg/kg NLZ, the i.t. SUF-induced hypercapnia returned to baseline levels, whereas the SUF-induced hypoxia was only minimally affected. These results challenge the classical view of the selectivity of NLZ for the high affinity micro(1) binding sites. They further fail to conform an exclusive role for micro(2) receptor sites in the respiratory depression and spinal analgesia induced by a strong lipophilic opioid such as SUF in rats.     

Palliative noninvasive ventilation in patients with acute respiratory failure

Over the last two decades, the increasing use of noninvasive ventilation (NIV) has diminished the need for endotracheal ventilation, thus decreasing the rate of ventilation-induced complications. Thus, NIV has decreased both intubation rates and mortality rates in specific subsets of patients with acute respiratory failure (e.g., patients with hypercapnia, cardiogenic pulmonary edema, immune deficiencies, or post-transplantation acute respiratory failure). NIV is also increasingly used as a palliative strategy when endotracheal ventilation is deemed inappropriate. In this context, palliative NIV can either be administered to offer a chance for survival, or to alleviate the symptoms of respiratory distress in dying patients. The literature provides information from 10 studies published between 1992 and 2006, in which 458 patients received palliative NIV. The technique was feasible, usually well tolerated, and half of the patients survived. The objectives of this review article are to define palliative NIV, to delineate the place for palliative NIV among overall indications of NIV, and to define the contribution of NIV to the palliative strategies available for patients with acute respiratory failure. Potential benefits and harm from NIV in patients who are not eligible for endotracheal ventilation are discussed. The appropriateness of palliative NIV should be reported in a study that relies on both quantitative criteria (rate of palliative NIV use and mortality) and qualitative criteria (patient comfort, end-of-life process, family burden, and health-care provider satisfaction).     

Ritanserin,a new therapeutic approach for drug abuse. Part 2: Effects on cocaine

After a period of forced exposure to cocaine, rats developed a preference for cocaine when given the choice to drink either a cocaine solution or water. The development of cocaine preference was dependent on the cocaine concentration given during choice but appeared to be independent of the presence of an cocaine withdrawal phase. The serotonin antagonist ritanserin reduced cocaine (0.1 mg/ml solution) preference and cocaine intake in a dose-related manner. The activity of ritanserin started at doses ≥ 0.04 mg/kg when given subcutaneously once daily. Changes in test procedure did not affect the effectivity of ritanserin, although shifts in the lowest active dose were present. In the active dose range (i.e., between 0.04 and 10.00 mg/kg) ritanserin reduced cocaine intake by 29 to 53% and cocaine preference decreased by 19 to 32%. At any time during treatment, the decrease in cocaine consumption was compensated by an increase in water consumption. As a consequence, total fluid intake remained at a constant level. Body weight gain in ritanserin-treated rats was not different from vehicle-treated animals. In additional experiments it was shown that ritanserin neither directly interacted with the discriminative stimulus properties of cocaine nor induced a cocaine aversion. The activity of ritanserin against chronic exposure to cocaine is discussed in terms of a serotonin 5-HT₂ antagonism.