Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation In Vitro

Bisphosphonates are widely used for the treatment of bone diseases associated with increased osteoclastic bone resorption. Bisphosphonates are known to inhibit biochemical markers of bone formation in vivo, but it is unclear to what extent this is a consequence of osteoclast inhibition or a direct inhibitory effect on cells of the osteoblast lineage. In order to investigate this issue, we studied the effects of various bisphosphonates on osteoblast growth and differentiation in vitro. The aminobisphosphonates pamidronate and alendronate inhibited osteoblast growth, caused osteoblast apoptosis, and inhibited protein prenylation in osteoblasts in a dose-dependent manner over the concentration range 20-100 microM. Further studies showed that alendronate in a dose of 0.1 mg/kg inhibited protein prenylation in calvarial osteoblasts in vivo, indicating that alendronate can be taken up by osteoblasts in sufficient amounts to inhibit protein prenylation at clinically relevant doses. Pamidronate and alendronate inhibited bone nodule formation at concentrations 10-fold lower than those required to inhibit osteoblast growth. These effects were not observed with non-nitrogen-containing bisphosphonates or with other inhibitors of protein prenylation and were only partially reversed by cotreatment with a fourfold molar excess of ss-glycerol phosphate. We conclude that aminobisphosphonates cause osteoblast apoptosis in vitro at micromolar concentrations and inhibit osteoblast differentiation at nanomolar concentrations by mechanisms that are independent of effects on protein prenylation and may be due in part to inhibition of mineralization. While these results need to be interpreted with caution because of uncertainty about the concentrations of bisphosphonates that osteoblasts are exposed to in vivo, our studies clearly demonstrate that bisphosphonates exert strong inhibitory effects on cells of the osteoblast lineage at similar concentrations to those that cause osteoclast inhibition. This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage.     

Sagittal alignment and kinematics at instrumented and adjacent levels after total disc replacement in the cervical spine

Background

The purpose of the study was to report radiological outcomes after total disc replacement (TDR) in the cervical spine through a 24 months follow-up (FU) prospective study with a special focus on sagittal alignment and kinematics at instrumented and adjacent levels.

Materials and methods

Thirty-two patients, who sustained one-level TDR with a ball-and-socket arthroplasty (Discocerv^™ implant, Scient’x/Alphatec Spine, USA) were consecutively included in the study. Clinical (visual analogical scale and neck disability index) and radiological parameters were measured preoperatively and postoperatively at 3/6 months, 1-year and 2-year FU. Sagittal alignment, ranges of motion (ROM) and center of rotations (CORs) were analyzed using specific motion analysis software (Spineview^™, Paris, France). Patients CORs were compared with those of a control group of 39 normal and asymptomatic subjects.

Results

Both local and C3–C7 lordosis significantly increased postoperatively (+8° and +13° at 2 years, respectively). At instrumented level ROM in flexion–extension (FE) was measured to 10.2° preoperatively versus 7.5° at 1 year and 6.1° at 2 years. There were no differences in ROM at adjacent levels between pre and postoperative assessments. When compared with control group and preoperative measurements, we noted postoperative cranial shift of the COR at instrumented level for patients group. In contrast, there was no difference in CORs location at adjacent levels.

Conclusion

Through this prospective study, we observed that cervical lordosis consistently increased after TDR. In addition, although ball-and-socket arthroplasty did not fully restore native segmental kinematics with significant reduction of motion in FE and consistent cranial shift of the COR, no significant changes in terms of ROM and CORs were observed at adjacent levels.     

Progress and prospects in the management of bacterial infections and developments in Phytotherapeutic modalities

The advent of antibiotics revolutionized medical care resulting in significantly reduced mortality and morbidity caused by infectious diseases. However, excessive use of antibiotics has led to the development of antibiotic resistance and indeed, the incidence of multidrug-resistant pathogens is considered as a major disadvantage in medication strategy, which has led the scholar's attention towards innovative antibiotic sources in recent years. Medicinal plants contain a variety of secondary metabolites with a wide range of therapeutic potential against the resistant microbes. Therefore, the aim of this review is to explore the antibacterial potential of traditional herbal medicine against bacterial infections. More than 200 published research articles reporting the therapeutic potential of medicinal plants against drug-resistant microbial infections were searched using different databases such as Google Scholar, Science Direct, PubMed and the Directory of Open Access Journals (DOAJ), etc., with various keywords like medicinal plants having antibacterial activities, antimicrobial potentials, phytotherapy of bacterial infection, etc. Articles were selected related to the efficacious herbs easily available to local populations addressing common pathogens. Various plants such as Artocarpus communis, Rheum emodi, Gentiana lutea L., Cassia fistula L., Rosemarinus officinalis, Argemone maxicana L, Hydrastis canadensis, Citrus aurantifolia, Cymbopogon citrates, Carica papaya, Euphorbia hirta, etc, were found to have significant antibacterial activities. Although herbal preparations have promising potential in the treatment of multidrug-resistant bacterial infection, still more research is required to isolate phytoconstituents, their mechanism of action as well as to find their impacts on the human body.     

Genetic Background Modifies the Effects of Type 2 Cannabinoid Receptor Deficiency on Bone Mass and Bone Turnover

Cannabinoid receptors and their ligands play significant roles in regulating bone metabolism. Previous studies of type 1 cannabinoid receptor-deficient mice have shown that genetic background influences the skeletal phenotype. Here, we investigated the effects of genetic background on the skeletal phenotype of mice with type 2 cannabinoid receptor deficiency (Cnr2 ^?/?). We studied Cnr2 ^?/? mice on a CD1 background and compared the findings with those previously reported in Cnr2 ^?/? C57BL/6 mice. Young female Cnr2 ^?/? CD1 mice had low bone turnover and high trabecular bone mass compared with wild-type (WT), contrasting with the situation in Cnr2 ^?/? C57BL/6 mice where trabecular bone mass has been reported to be similar to WT. The Cnr2 ^?/? CD1 mice lost more trabecular bone at the tibia with age than WT due to reduced bone formation, and at 12 months there was no difference in trabecular bone volume between genotypes. This differs from the phenotype previously reported in C57BL/6 Cnr2 ^?/? mice, where bone turnover is increased and bone mass reduced with age. There were no substantial differences in skeletal phenotype between Cnr2 ^?/? and WT in male mice. Cortical bone phenotype was similar in Cnr2 ^?/? and WT mice of both genders. Deficiency of Cnr2 has site- and gender-specific effects on the skeleton, mainly affecting trabecular bone, which are influenced by genetic differences between mouse strains. Further evaluation of the pathways responsible might yield new insights into the mechanisms by which cannabinoid receptors regulate bone metabolism.     

A new automatic image analysis method for assessing estrogen receptors’ status in breast tissue specimens

Manual assessment of estrogen receptors′ (ER) status from breast tissue microscopy images is a subjective, time consuming and error prone process. Automatic image analysis methods offer the possibility to obtain consistent, objective and rapid diagnoses of histopathology specimens. In breast cancer biopsies immunohistochemically (IHC) stained for ER, cancer cell nuclei present a large variety in their characteristics that bring various difficulties for traditional image analysis methods. In this paper, we propose a new automatic method to perform both segmentation and classification of breast cell nuclei in order to give quantitative assessment and uniform indicators of IHC staining that will help pathologists in their diagnostic. Firstly, a color geometric active contour model incorporating a spatial fuzzy clustering algorithm is proposed to detect the contours of all cell nuclei in the image. Secondly, overlapping and touching nuclei are separated using an improved watershed algorithm based on a concave vertex graph. Finally, to identify positive and negative stained nuclei, all the segmented nuclei are classified into five categories according to their staining intensity and morphological features using a trained multilayer neural network combined with Fisher's linear discriminant preprocessing. The proposed method is tested on a large dataset containing several breast tissue images with different levels of malignancy. The experimental results show high agreement between the results of the method and ground-truth from the pathologist panel. Furthermore, a comparative study versus existing techniques is presented in order to demonstrate the efficiency and the superiority of the proposed method.     

Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.     

Laser utility in the treatment of hemorrhoidal pathology: a review of literature

Lasers in Medical Science - Hemorrhoidal disease is a common reason for consultation in proctology. It can be treated in several ways (medical, endoscopic, and surgical). Laser treatment has been...