Selective serotonin reuptake inhibitors and the risk of osseointegrated implant failure: a cohort study.

Selective serotonin reuptake inhibitors (SSRIs), the most widely used drugs for the treatment of depression, have been reported to reduce bone formation and increase the risk of bone fracture. Since osseointegration is influenced by bone metabolism, this study aimed to investigate the association between SSRIs and the risk of failures in osseointegrated implants. This retrospective cohort study was conducted on patients treated with dental implants from January 2007 to January 2013. A total of 916 dental implants in 490 patients (94 implants on 51 patients using SSRIs) were used to estimate the risk of failure associated with the use of SSRIs. Data analysis involved Cox proportional hazards, generalized estimating equation models, multilevel mixed effects parametric survival analysis, and Kaplan-Meier analysis. After 3 to 67 mo of follow-up, 38 dental implants failed and 784 succeeded in the nonusers group, while 10 failed and 84 succeeded in the SSRI-users group. The main limitation of this retrospective study was that drug compliance dose and treatment period could not be acquired from the files of the patients. The primary outcome was that compared with nonusers of SSRIs, SSRI usage was associated with an increased risk of dental implants failure (hazard ratio, 6.28; 95% confidence interval, 1.25-31.61; p = .03). The failure rates were 4.6% for SSRI nonusers and 10.6% for SSRI users. The secondary outcomes were that small implant diameters (≤4 mm; p = .02) and smoking habits (p = .01) also seemed to be associated with higher risk of implant failure. Our findings indicate that treatment with SSRIs is associated with an increased failure risk of osseointegrated implants, which might suggest a careful surgical treatment planning for SSRI users.

Local gene transfer to calcified tissue cells using prolonged infusion of a lentiviral vector.

Gene transfer using viral vectors offers the potential for the sustained expression of proteins in specific target tissues. However, in the case of calcified tissues, in vivo delivery remains problematic because of limited accessibility. The aim of this study was to test the efficiency of lentiviral vectors (LVs) on osteogenic cells in vitro, and determine the feasibility of directly transducing resident bone cells in vivo. LVs encoding for green fluorescent protein (GFP) and ameloblastin (AMBN), a protein associated with mineralization not reported in bone, were generated. The transduction efficiency of the LVs was evaluated using the MC3T3 cell line and primary calvaria-derived osteogenic cells. For in vivo delivery, the LVs were infused using osmotic minipumps through holes created in the bone of the rat hemimandible and tibia. The production of GFP and AMBN in vitro and in vivo was monitored using fluorescence microscopy. Both transgenes were expressed in MC3T3 and primary osteogenic cells. In vivo, GFP was detected at the infusion site and fibroblast-like cells, osteoblasts, osteocytes and osteoclasts expressed AMBN. Our data demonstrate, for the first time, that primary osteogenic cells are efficiently transduced with LVs and that their infusion is advantageous for locally delivering DNA to bone cells.

Symptom distress as rated by advanced cancer patients, caregivers and physicians in the last week of life.

OBJECTIVES: To study the symptom distress as rated by patients with advanced cancer during their last week of life, and to compare patients' ratings with those perceived by caregivers and physicians. METHOD: This was a prospective study on all patients admitted to the Hospice Unit of the Caritas Medical Centre with an estimated life expectancy of two weeks or less from May 2002 to September 2002. A questionnaire with a list of 13 symptoms, including pain, dyspnoea, nausea, vomiting, dry mouth, cough, fatigue, cachexia, anorexia, constipation, diarrhoea, insomnia and haemoptysis, was administered to assess the distress. Distress was rated by a verbal rating scale consisting of five grades (grade 0 to grade 4). Patients, caregivers and physicians completed the questionnaire weekly until the patient died. Only the questionnaires completed in the last week of life were included for analysis. RESULTS: Of 82 patients who were recruited in the study, 30 patients were able to complete the questionnaire within the last week of life. Their median age was 69 years and the gender ratio was 1:1. Lung cancer was the most common primary tumour. Fatigue, cachexia and anorexia caused distress of all grades in nearly all 30 patients and caused significant distress of grade 3 and above in two-thirds of patients. Neither the caregivers nor the physicians gave congruent distress scores for these three symptoms (kappa<0.4). Caregivers' ratings agreed well with those of patients for five symptoms (kappa>0.4, P<0.005), including dyspnoea, cough, dry mouth, constipation and insomnia. For physicians, good agreement was found for three symptoms only, including pain, dyspnoea and cough. Moreover, physicians tended to underrate the distress. CONCLUSION: Fatigue, cachexia and anorexia were the three most distressful symptoms in the last week of life in this group of patients, but caregivers and physicians failed to rate them in agreement with patients.

In vivo model for the experimental manipulation of calcified tissues: a surgical approach for accessing the odontogenic organ and associated tissues of the rat incisor.

The tooth organ is extensively used in developmental biology to investigate organogenesis and cell differentiation. It also represents an advantageous system for the study of the various cellular and extracellular matrix events that regulate the formation of both collagenous and noncollagenous calcified tissues. This article describes an in vivo surgical approach to access and experimentally manipulate the tooth organ and supporting tissues of the rat incisor. By use of a dental drill, a "window" was created through the alveolar bone on the buccal aspect of the hemimandible at the apical end of the incisor. It is at this site that epithelial and mesenchymal precursors are situated and undergo cellular differentiation to give rise to cells of the odontogenic organ. Active bone remodeling is also observed in this area to accommodate posterior growth of the tooth. An osmotic minipump connected to the bony window through an outlet catheter was used for controlled and continuous administration of experimental agents over a predetermined period of time. To validate the model, vinblastine sulfate, fetuingold, and dinitrophenylated albumin were thus infused. The animals were then sacrificed and the hemimandibles were processed for histological and immunocytochemical analyses. The effects of the drug and the presence of tracers were restricted to the treated hemimandible and were found in the enamel organ and pulp, as well as in the tooth supporting tissues. Cellular changes typically associated with the administration of vinblastine were obtained, and tracers were localized both in the extracellular milieu and within the endosomal/lysosomal elements of cells. These results suggest that this new surgical approach could serve as an advantageous in vivo model in which various chemical agents, therapeutic drugs, molecular probes are locally administered to study the molecular events that regulate calcified tissue formation.

Structural and functional analysis of the membrane-spanning domain of the human immunodeficiency virus type 1 Vpu protein.

The human immunodeficiency virus type 1 (HIV-1) vpu gene product is a class I integral membrane phosphoprotein that is capable of oligomerization. Two distinct biological activities have been attributed to Vpu: induction of CD4 degradation in the endoplasmic reticulum and enhancement of viral particle release from the plasma membrane of infected cells. These two biological activities were shown to involve two separable structural domains: the N-terminal transmembrane (TM) domain and the C-terminal cytoplasmic domain. The TM domain mediates enhancement of viral particle release, whereas phosphorylation of the cytoplasmic domain is essential for Vpu-induced CD4 degradation. In this study, we performed a mutational analysis of the TM domain of Vpu to delineate amino acids that are important in the process of viral particle release or in Vpu-induced CD4 degradation. Substitution of conserved amino acids from the N-terminal, middle, or C-terminal parts of the native VpuTM domain generated proteins that integrated normally into canine pancreatic microsomal membranes, exhibited subcellular localization similar to those of wild-type Vpu, but partially lost their ability to enhance viral particle release, strongly suggesting that the VpuTM domain contains determinants responsible for Vpu-mediated enhancement of viral particle release. Interestingly, the C-terminal TM mutant VpuIVW, in contrast to the other mutants, also lost its ability to bind and consequently degrade the CD4 molecule, indicating that the alteration of the C-terminal part of the TM did interfere with this function of Vpu. Taken together, our study supports the notion that both structural elements of Vpu (TM and cytoplasmic) contribute to the biological activities of Vpu.

Effects of Vpu expression on Xenopus oocyte membrane conductance.

The HIV-1-specific vpu gene encodes an integral membrane phosphoprotein which affects three aspects of the HIV-1 infectious cycle: it enhances virion release from infected cells; it causes degradation of the CD4 protein in the endoplasmic reticulum; and it delays syncytia formation in HIV-1-infected CD4+ T-cells. Although little is known about how Vpu mediates these effects, it has been proposed to function as a nonspecific cation channel. In this report, voltage clamp measurements of Xenopus oocytes show that Vpu expression is not associated with increased transmembrane currents. Instead, Vpu expression diminishes membrane conductance. Injection of 4.6 ng of Vpu mRNA into these cells reduces endogenous potassium conductance by 50%. Only Vpu mutants which retain the ability to degrade CD4 can diminish K+ conductance. Inhibition by Vpu is not unique to K+ channels as it is also observed on several coexpressed membrane proteins but not on a coexpressed cytoplasmic protein. These results indicate that the CD4 degradative capability of Vpu and the Vpu-mediated modulation of membrane protein expression are mechanistically coupled and that Vpu may contribute to HIV pathogenesis by altering plasma membrane protein expression at the cell surface.