Doxycycline-doped collagen membranes accelerate in vitro osteoblast proliferation and differentiation.

OBJECTIVE: The aim of the study was to evaluate the effect of doxycycline- and dexamethasone-doped collagen membranes on the proliferation and differentiation of osteoblasts. BACKGROUND: Collagen barrier membranes are frequently used to promote bone regeneration and to boost this biological activity their functionalization with antibacterial and immunomodulatory substances has been suggested. METHODS: The design included commercially available collagen membranes doped with doxycycline (Dox-Col-M) or dexamethasone (Dex-Col-M), as well as undoped membranes (Col-M) as controls, which were placed in contact with cultured MG63 osteoblast-like cells (ATCC). Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay and differentiation by measuring the alkaline phosphatase (ALP) activity using spectrophotometry. Real-time quantitative polymerase chain reaction was used to study the expression of the genes: Runx-2, OSX, ALP, OSC, OPG, RANKL, Col-I, BMP-2, BMP-7, TGF-ß1, VEGF, TGF-ßR1, TGF-ßR2, and TGF-ßR3. Scanning electron microscopy was used to study osteoblast morphology. Data were assessed using one-way analysis of variance or Kruskal-Wallis tests, once their distribution normality was assessed by Kolmogorov-Smirnov tests (p > .05). Bonferroni for multiple comparisons were carried out (p < .05). RESULTS: Osteoblast proliferation was significantly enhanced in the functionalized membranes as follows: (Col-M < Dex-Col-M < Dox-Col-M). ALP activity was significantly higher on cultured osteoblasts on Dox-Col-M. Runx-2, OSX, ALP, OSC, BMP-2, BMP-7, TGF-ß1, VEGF, TGF-ßR1, TGF-ßR2, and TGF-ßR3 were overexpressed, and RANKL was down-regulated in osteoblasts cultured on Dox-Col-M. The osteoblasts cultured in contact with the functionalized membranes demonstrated an elongated spindle-shaped morphology. CONCLUSION: The functionalization of collagen membranes with Dox promoted an increase in the proliferation and differentiation of osteoblasts.

Modulation of Osteogenic Gene Expression by Human Osteoblasts Cultured in the Presence of Bisphenols BPF, BPS, or BPAF.

Bone effects attributed to bisphenols (BPs) include the inhibition of growth and differentiation. This study analyzes the effect of BPA analogs (BPS, BPF, and BPAF) on the gene expression of the osteogenic markers RUNX2, osterix (OSX), bone morphogenetic protein-2 (BMP-2), BMP-7, alkaline phosphatase (ALP), collagen-1 (COL-1), and osteocalcin (OSC). Human osteoblasts were obtained by primary culture from bone chips harvested during routine dental work in healthy volunteers and were treated with BPF, BPS, or BPAF for 24 h at doses of 10-5, 10-6, and 10-7 M. Untreated cells were used as controls. Real-time PCR was used to determine the expression of the osteogenic marker genes RUNX2, OSX, BMP-2, BMP-7, ALP, COL-1, and OSC. The expression of all studied markers was inhibited in the presence of each analog; some markers (COL-1; OSC, BMP2) were inhibited at all three doses and others only at the highest doses (10-5 and 10-6 M). Results obtained for the gene expression of osteogenic markers reveal an adverse effect of BPA analogs (BPF, BPS, and BPAF) on the physiology of human osteoblasts. The impact on ALP, COL-1, and OSC synthesis and therefore on bone matrix formation and mineralization is similar to that observed after exposure to BPA. Further research is warranted to determine the possible contribution of BP exposure to the development of bone diseases such as osteoporosis.

Human adipose tissue-derived mesenchymal stromal cells and their phagocytic capacity.

Mesenchymal stromal cells (MSCs) have evidenced considerable therapeutic potential in numerous clinical fields, especially in tissue regeneration. The immunological characteristics of this cell population include the expression of Toll-like receptors and mannose receptors, among others. The study objective was to determine whether MSCs have phagocytic capacity against different target particles. We isolated and characterized three human adipose tissue MSC (HAT-MSC) lines from three patients and analysed their phagocytic capacity by flow cytometry, using fluorescent latex beads, and by transmission electron microscopy, using Escherichia coli, Staphylococcus aureus and Candida albicans as biological materials and latex beads as non-biological material. The results demonstrate that HAT-MSCs can phagocyte particles of different nature and size. The percentage of phagocytic cells ranged between 33.8% and 56.2% (mean of 44.37% ± 11.253) according to the cell line, and a high phagocytic index was observed. The high phagocytic capacity observed in MSCs, which have known regenerative potential, may offer an advance in the approach to certain local and systemic infections.

Effect of the most common wound antiseptics on human skin fibroblasts.

BACKGROUND: Antiseptics are used for the cleansing of acute or chronic wounds to eliminate micro-organisms from the wound bed. However, they have effects on the skin cells. AIM: To determine the effects of hexetidine, povidone-iodine (PI), undecylenamidopropyl-betaine/polyhexanide (UBP), chlorhexidine, disodium eosin and hydrogen peroxide on human skin fibroblasts. METHODS: CCD-1064Sk cells were treated with hexetidine, PI, UBP, chlorhexidine, disodium eosin or hydrogen peroxide. Spectrophotometry was used to measure cell viability and flow cytometry was used to study apoptosis and necrosis after the treatment. In vitro wound scratch assays were performed to determine the gap closure. RESULTS: All antiseptics significantly reduced the viability of human skin fibroblasts compared with controls. The percentage wound closure was lower with hexetidine, PI and UBP. The scratch assay could not be measured after treatments with chlorhexidine, disodium eosin or hydrogen peroxide, owing to their cytotoxicity. The apoptosis/necrosis experiments evidenced a significant reduction in viable cells compared with controls. An increased percentage of apoptotic cells was observed after treatment with all antiseptics. Compared with controls, the percentage of necrotic cells was significantly increased with all antiseptics except for hexetidine. CONCLUSION: The proliferation, migration and viability of human skin fibroblasts are reduced by treatment with hexetidine, PI, UBP, chlorhexidine, disodium eosin and hydrogen peroxide.

Repercussions of Bisphenol A on the Physiology of Human Osteoblasts.

(1) Background: Bisphenol A (BPA) is an endocrine disruptor that is widely present in the environment and exerts adverse effects on various body tissues. The objective of this study was to determine its repercussions on bone tissue by examining its impact on selected functional parameters of human osteoblasts. (2) Methods: Three human osteoblast lines were treated with BPA at doses of 10-5, 10-6, or 10-7 M. At 24 h post-treatment, a dose-dependent inhibition of cell growth, alkaline phosphatase activity, and mineralization was observed. (4) Results: The expression of CD54 and CD80 antigens was increased at doses of 10-5 and 10-6 M, while the phagocytic capacity and the expression of osteogenic genes (ALP, COL-1, OSC, RUNX2, OSX, BMP-2, and BMP-7) were significantly and dose-dependently reduced in the presence of BPA. (5) Conclusions: According to these findings, BPA exerts adverse effects on osteoblasts by altering their differentiation/maturation and their proliferative and functional capacity, potentially affecting bone health. Given the widespread exposure to this contaminant, further human studies are warranted to determine the long-term risk to bone health posed by BPA.

Role of Salivary MicroRNA and Cytokines in the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is the most prevalent oral malignant tumor worldwide. An early diagnosis can have a major positive impact on its prognosis. Human saliva contains cytokines, DNA and RNA molecules, circulating cells, and derivatives of tissues and extracellular vesicles, among other factors that can serve as biomarkers. Hence, the analysis of saliva may provide useful information for the early diagnosis of OSCC for its prognosis. The objective of this review was to determine the potential usefulness of salivary biomarkers (cytokines and microRNA) to diagnose OSCC and improve its prognosis. A combination of salivary miRNA and proteomic data could allow a definitive and early diagnosis to be obtained. However, there remains a need to optimize and standardize the protocols used to quantify miRNAs.

Antimicrobial properties of olive oil phenolic compounds and their regenerative capacity towards fibroblast cells.

Some micronutrients of vegetable origin are considered potentially useful as wound-healing agents because they can increase fibroblast proliferation and differentiation. THE AIM OF THIS STUDY: was to evaluate the regenerative effects of selected olive oil phenolic compounds on cultured human fibroblasts and explore their antimicrobial properties. MATERIAL AND METHODS: The CCD-1064Sk fibroblast line was treated for 24 h with 10-6M luteolin, apigenin, ferulic, coumaric acid or caffeic acid, evaluating the effects on cell proliferation by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) spectrophotometric assay; the migratory capacity by the scratch assay and determining the expression of Fibroblast Growth Factor (FGF), Vascular Endothelial Growth Factor (VEGF), Transforming Growth Factor- ß1 (TGFß1), Platelet Derived Growth Factor (PDGF), and Collagen Type I (COL-I) genes by real-time polymerase chain reaction. The antimicrobial capacity of the polyphenols was evaluated by the disc diffusion method. RESULTS: All compounds except for ferulic acid significantly stimulated the proliferative capacity of fibroblasts, increasing their migration and their expression of the aforementioned genes. With respect to their antimicrobial properties, treatment with the studied compounds inhibited the growth of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Proteus spp., and Candida Albicans. CONCLUSIONS: The phenolic compounds in olive oil have a biostimulatory effect on the regeneration capacity, differentiation, and migration of fibroblasts and exert major antibacterial activity. According to the present findings, these compounds may have a strong therapeutic effect on wound recovery.

Salivary Biomarkers and Their Application in the Diagnosis and Monitoring of the Most Common Oral Pathologies.

Saliva is a highly versatile biological fluid that is easy to gather in a non-invasive manner-and the results of its analysis complement clinical and histopathological findings in the diagnosis of multiple diseases. The objective of this review was to offer an update on the contribution of salivary biomarkers to the diagnosis and prognosis of diseases of the oral cavity, including oral lichen planus, periodontitis, Sjögren's syndrome, oral leukoplakia, peri-implantitis, and medication-related osteonecrosis of the jaw. Salivary biomarkers such as interleukins, growth factors, enzymes, and other biomolecules have proven useful in the diagnosis and follow-up of these diseases, facilitating the early evaluation of malignization risk and the monitoring of disease progression and response to treatment. However, further studies are required to identify new biomarkers and verify their reported role in the diagnosis and/or prognosis of oral diseases.

Infectious processes and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune chronic inflammatory disease of unknown etiology, although genetic and environmental factors appear to contribute to its pathogenesis. Specifically, infectious processes are associated with SLE onset and exacerbation. However, we are far from a complete understanding of the interactions between infectious agents and the host, explaining the interest in gathering updated scientific information on this topic. According to the literature, the pathogens most frequently associated with SLE are viruses, notably human endogenous retroviruses, Epstein-Barr virus, parvovirus B19, cytomegalovirus and human immunodeficiency virus type 1, alongside certain bacterial components that can also trigger activation of the immune system. The mechanisms underlying autoreactivity remain unclear but various explanations have been proposed, including immunological changes responsible for infectious processes or molecular mimicry between host structures and those of infectious agents.

Effects of Therapeutic Doses of Celecoxib on Several Physiological Parameters of Cultured Human Osteoblasts.

Non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2)-selective NSAIDs, are associated with adverse effects on bone tissue. These drugs are frequently the treatment of choice but are the least studied with respect to their repercussion on bone. The objective of this study was to determine the effects of celecoxib on cultured human osteoblasts. Human osteoblasts obtained by primary culture from bone samples were treated with celecoxib at doses of 0.75, 2, or 5µM for 24 h. The MTT technique was used to determine the effect on proliferation; flow cytometry to establish the effect on cell cycle, cell viability, and antigenic profile; and real-time polymerase chain reaction to measure the effect on gene expressions of the differentiation markers RUNX2, alkaline phosphatase (ALP), osteocalcin (OSC), and osterix (OSX). Therapeutic doses of celecoxib had no effect on osteoblast cell growth or antigen expression but had a negative impact on the gene expression of RUNX2 and OSC, although there was no significant change in the expression of ALP and OSX. Celecoxib at therapeutic doses has no apparent adverse effects on cultured human osteoblasts and only inhibits the expression of some differentiation markers. These characteristics may place this drug in a preferential position among NSAIDs used for analgesic and anti-inflammatory therapy during bone tissue repair.

Impact of bisphosphonates on the proliferation and gene expression of human fibroblasts.

The aim of this study was to elucidate the role of fibroblasts in bisphosphonate-related osteonecrosis of the jaw (BRONJ), evaluating the effect of zoledronate, alendronate, and ibandronate on the proliferation of fibroblasts and on their expression of genes essential for fibroblast physiology. Human CCD-1064Sk epithelial fibroblast cells were incubated in culture medium with 10-5, 10-7, or 10-9 M zoledronate, alendronate, or ibandronate. The proliferative capacity of fibroblasts was determined by spectrophotometry (MTT) at 24 of culture. Real-time polymerase chain reaction (RT-PCR) was used to study the effects of BPs at a dose of 10-9 M on the expression of FGF, CTGF, TGF-ß1, TGFßR1, TGFßR2, TGFßR3, DDR2, α-actin, fibronectin, decorin, and elastin. Fibroblasts proliferation was significantly increased at the lowest dose (10-9M) of each BP but was not affected at the higher doses (10-5 and 10-7M). The proliferation increase may be related to the rise in TGF-ß1 and TGFßR1 expression detected after the treatment of cells with 10-9M of zoledronate, alendronate, or ibandronate. However, the expression of CTGF, DDR2, α-actin, fibronectin, and decorin decreased versus controls. The results of this in vitro study indicate that a very low BP dose (10-9 M) can significantly affect the physiology of fibroblasts, increasing their proliferative capacity and modulating the expression of multiple genes involved in their growth and differentiation.

Influence of pH on osteoclasts treated with zoledronate and alendronate.

OBJECTIVES: The objectives of this study were to analyze the effect of pH on the growth and activity of osteoclasts treated with different doses of two nitrogen-containing BPs, zoledronate and alendronate. MATERIALS AND METHODS: Murine osteoclasts cultured on dentine disks were treated with zoledronate (50 or 500 nM) or alendronate (500 or 5 µM) at two different pH values (7.4 or 7.0). Osteoclasts were counted with transmitted light microscopy, apoptosis/necrosis was studied with flow cytometry and confocal microscopy, and resorption pit number and depth were calculated using reflected light and scanning electron microscopy. RESULTS: The osteoclast count on dentine disks was significantly (p < 0.001) reduced by zoledronate or alendronate treatment at pH 7.0 in comparison to treatment with the same doses at pH 7.4 and untreated disks (controls). The percentage of apoptotic cells was significantly increased by treatment with 500 nM zoledronate or 5 µM alendronate at pH 7.0 in comparison to the same doses at pH 7.4. The number and depth of resorption pits were significantly lower in disks treated at each BP dose studied than in untreated controls at pH 7.0. CONCLUSIONS: Zoledronate and alendronate at therapeutic doses have an adverse effect on the viability and resorptive activity of osteoclasts when the local medium pH is reduced. CLINICAL RELEVANCE: These findings suggest that periodontal or peri-implant oral cavity infection may be a key trigger of the cascade of events that lead to BRONJ.

Effect of olive oil phenolic compounds on osteoblast differentiation.

BACKGROUND: Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes individuals to an increased risk of fracture. Previous in vivo and in vitro studies have reported that phenolic compounds present in extra virgin olive oil have a beneficial effect on osteoblasts in terms of increase cell proliferation. The aim of this study was to determine whether phenolic compounds present in olive oil could modify the expression of cell differentiation markers on osteoblasts. STUDY DESIGN: An in vitro experimental design was performed using MG-63 osteoblasts cell line. METHODS: MG63 cells were exposed to different doses of luteolin, apigenin, or p-coumaric, caffeic or ferulic acid. Alkaline phosphatase (ALP) was evaluated by spectrophotometry and antigen expression (cluster of differentiation [CD] 54, CD80, CD86 and HLA-DR) by flow cytometry. RESULTS: At 24 hour, treated groups showed an increased ALP and modulated antigen profile, with respect to the nontreated group. CONCLUSION: These results demonstrate that the phenolic compounds studied induce cell maturation in vitro, increasing ALP synthesis and reducing the expression of antigens involved in immune functions of the osteoblast which would improve bone density.

Bisphosphonate Modulation of the Gene Expression of Different Markers Involved in Osteoblast Physiology: Possible Implications in Bisphosphonate-Related Osteonecrosis of the Jaw.

The aim of the present study was to elucidate the role of osteoblasts in bisphosphonates-related osteonecrosis of the jaw (BRONJ). The specific objective was to evaluate the effect on osteoblasts of two nitrogen-containing BPs (zoledronate and alendronate) and one non-nitrogen-containing BP (clodronate) by analyzing modulations in their expression of genes essential for osteoblast physiology. Real-time polymerase chain reaction (RT-PCR) was used to study the effects of zoledronate, alendronate, and clodronate at doses of 10-5, 10-7, or 10-9 M on the expression of Runx-2, OSX, ALP, OSC, OPG, RANKL, Col-I, BMP-2, BMP-7, TGF-ß1, VEGF, TGF-ßR1, TGF-ßR2, and TGF-ßR3 by primary human osteoblasts (HOBs) and MG-63 osteosarcoma cells. Expression of these markers was found to be dose-dependent, with no substantive differences between these cell lines. In general, results demonstrated a significant increase in TFG-ß1, TGF-ßR1, TGF-ßR2, TGF-ßR3, and VEGF expressions and a significant reduction in RUNX-2, Col-1, OSX, OSC, BMP-2, BMP-7, ALP, and RANKL expressions, while OPG expression varied according to the dose and cell line. The results of this in vitro study of HOBS and MG-63 cell lines indicate that low BP doses can significantly affect the expression of genes essential for osteoblast growth and differentiation and of genes involved in regulating osteoblast-osteoclast interaction, possibly by increasing TGF-ß1 production. These findings suggest that osteoblasts may play an important role in BRONJ development, without ruling out other factors.

Extreme Surgical Maneuvers in Fungal Endophthalmitis.

PURPOSE: To present the different evolution of 2 cases of endophthalmitis caused by Fusarium solani, an aggressive filamentous fungus, depending on the medical and surgical treatment performed. METHODS: We present 2 cases of endophthalmitis caused by Fusarium solani. Topical, intrastromal, intravitreal, and systemic antifungal treatment (natamycin, voriconazole, amphotericin B) failed in both cases. Corneal perforation took place in one of them, being unsuccessfully treated with cyanoacrylate and several amniotic membrane transplants. It became necessary to perform a hot penetrating keratoplasty (PK) in both patients. The lenses were removed, and the microbiological analysis showed their colonization by Fusarium solani. In one of the cases, a second PK and a more aggressive pars plana vitrectomy (PPV) were performed after corneal recurrence detected by confocal microscopy, as well as the following therapeutic intra- and postoperative maneuvers: anterior chamber washing with povidone-iodine 5% for 1 min; iridectomy of the infiltrated regions; aspiration of the fungal colonies with vitrector; several air/fluid/amphotericin/voriconazole exchanges during PPV; endodiathermy and endophotocoagulation of the chorioretinitis foci; and intrascleral angle injections of voriconazole and amphotericin. RESULTS: These were the only cases of endophthalmitis caused by Fusarium attended to at our hospital during the last 10 years. In the case in which PPV was performed without those maneuvers, endophthalmitis rapidly recurred in a more aggressive way, so finally it became necessary to eviscerate the globe. On the other hand, in the patient who underwent PPV with the specific surgical maneuvers and postoperative procedures described above, we could preserve the eye and even a vision of hand motion without an intraocular lens. CONCLUSIONS: The main objectives of these surgical procedures are to control the fungal infection and to preserve the ocular globe. It is essential to eliminate all ocular structures (iris, lens, vitreous, etc.) affected by this strain of fungus in order to reduce the risk of recurrence. When indicated, early surgery with the appropriate maneuvers detailed above may make an evisceration unnecessary and even recover some visual acuity.

Effect of Clodronate on Antigenic Profile, Growth, and Differentiation of Osteoblast-Like Cells.

PURPOSE: To evaluate the role of osteoblasts in bisphosphonate-related osteonecrosis of the jaw (BRONJ) by studying the effects of different concentrations of clodronate, a non-nitrogen-containing bisphosphonate, on osteoblast growth, differentiation, and antigenic profile. MATERIALS AND METHODS: Osteoblast-like cells (MG63) were incubated in culture medium with different doses of clodronate. Their proliferative capacity was determined with a spectrophotometric technique (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium assay). Flow cytometry was used to study the antigenic profile. Cell differentiation was evaluated by nodule formation and alkaline phosphatase (ALP) activity was measured by spectrophotometric assay. RESULTS: Clodronate had a significant stimulatory effect on osteoblast-like cell (MG63) proliferation (P < .05). A significant decrease in the expression of CD54, CD80, CD86, and HLA-DR membrane antigens versus controls was observed after 24 hours of treatment with the different clodronate doses assayed (P < .05). A significant decrease (P = .004) in ALP activity was found after 24 hours of treatment with the lowest dose (10(-9) mol/L), and a significant decrease in calcium deposition was found after 15 and 21 days of treatment (P < .05). CONCLUSION: Clodronate increases the proliferation of MG63 osteoblast-like cells and decreases their differentiation capacity, generally at low doses, and modulates the expression of costimulatory molecules associated with immune function. Clodronate exerts its effect on osteoblasts by altering their physiology and impairing their repair capacity, which could be related to the development of BRONJ. However, further research is warranted to elucidate fully the mechanisms by which bisphosphonates can produce this disease.

A Bayesian cost-effectiveness analysis of a telemedicine-based strategy for the management of sleep apnoea: a multicentre randomised controlled trial.

BACKGROUND: Compliance with continuous positive airway pressure (CPAP) therapy is essential in patients with obstructive sleep apnoea (OSA), but adequate control is not always possible. This is clinically important because CPAP can reverse the morbidity and mortality associated with OSA. Telemedicine, with support provided via a web platform and video conferences, could represent a cost-effective alternative to standard care management. AIM: To assess the telemedicine impact on treatment compliance, cost-effectiveness and improvement in quality of life (QoL) when compared with traditional face-to-face follow-up. METHODS: A randomised controlled trial was performed to compare a telemedicine-based CPAP follow-up strategy with standard face-to-face management. Consecutive OSA patients requiring CPAP treatment, with sufficient internet skills and who agreed to participate, were enrolled. They were followed-up at 1, 3 and 6 months and answered surveys about sleep, CPAP side effects and lifestyle. We compared CPAP compliance, cost-effectiveness and QoL between the beginning and the end of the study. A Bayesian cost-effectiveness analysis with non-informative priors was performed. RESULTS: We randomised 139 patients. At 6 months, we found similar levels of CPAP compliance, and improved daytime sleepiness, QoL, side effects and degree of satisfaction in both groups. Despite requiring more visits, the telemedicine group was more cost-effective: costs were lower and differences in effectiveness were not relevant. CONCLUSIONS: A telemedicine-based strategy for the follow-up of CPAP treatment in patients with OSA was as effective as standard hospital-based care in terms of CPAP compliance and symptom improvement, with comparable side effects and satisfaction rates. The telemedicine-based strategy had lower total costs due to savings on transport and less lost productivity (indirect costs). TRIAL REGISTER NUMBER: NCT01716676.

Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is a condition producing irreversible damage to the neurological function. Among the leading mechanisms associated to cell death after SCI, excitotoxicity, oxidative stress, inflammatory response and apoptosis are considered potential targets to prevent tissue damage. We recently reported that dapsone an anti-inflammatory drug, decreases the activity of myeloperoxidase, lipid peroxidation, improve neurological function and increase the amount of spared tissue after SCI in rats. In this study, we characterized the anti-apoptotic effect of dapsone administered at 12.5 mg/kg/24 h dose, starting at 3 and 5 h after SCI. We monitored the activity of caspases-8, 9, and 3 and quantitated Annexin V and TUNEL positive cells in the core of the lesion. Results showed increased activities of caspase-8, 9 and 3 at 72 h by SCI to reach increments of 69, 143 and 293 %, respectively, as compared to sham group. Meanwhile, dapsone, administered at 3 and 5 after SCI, reduced caspase-8 activity by 36 and 44 % respectively, whereas the activity of caspase-9 was diminished by 37 %. Likewise, the activity of caspase-3 showed a decrease of 38 %. Finally, both Annexin V and TUNEL-positive cells were significantly reduced by DDS as compared to untreated SCI animals. Results showed that dapsone exerted anti-apoptotic effect after SCI.

Bosutinib shows low cross intolerance, in chronic myeloid leukemia patients treated in fourth line. Results of the Spanish compassionate use program.

The role of bosutinib as rescue treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients after failing three previous tyrosine kinase inhibitors (TKIs) is currently unknown. We report here the largest series (to our knowledge) of patients treated with bosutinib in fourth-line, after retrospectively reviewing 30 patients in chronic phase, and pretreated with imatinib, nilotinib, and dasatinib. With a median follow up of 11.1 months, the probability to either maintain or improve their CCyR response was 56.6% (17/30) and 11 patients (36.7%) achieved or maintained their baseline MMR. In patients not having baseline CCyR, the probabilities of obtaining CCyR, MMR, and MR4.5 were 13, 11, and 14%, respectively. The probabilities of obtaining MMR and deep molecular response MR4.5 in patients with baseline CCyR were 40.0% (6/15) and 20.0% (3/15). At 20 months, progression-free survival was 73%. Grade 3-4 hematological toxicities were more frequent in resistant than intolerant patients (45.4 vs. 0.0%). Nonhematological toxicities were also more frequent in resistant patients, being diarrhea the most conspicuous one. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKI's.

Safety and efficacy of expanded polytetrafluoroethylene-covered transjugular intrahepatic portosystemic shunts in children with acute or recurring upper gastrointestinal bleeding.

BACKGROUND: The transjugular intrahepatic portosystemic shunt (TIPS) is effective for treating complications of portal hypertension in cirrhotic adults but the experience in children is limited. OBJECTIVE: To retrospectively review the safety and efficacy of expanded polytetrafluoroethylene (ePTFE)-covered TIPS in children with acute or recurrent gastrointestinal bleeding. MATERIALS AND METHODS: We reviewed the medical records of children who received implants of 10-mm-diameter PTFE-covered endoprostheses for acute or recurring upper gastrointestinal bleeding caused by medically or endoscopically uncontrollable varices. The recurrence of upper gastrointestinal bleeding, associated complications and permeability were assessed with Doppler sonography sequentially or up to transplantation. RESULTS: In all children (n = 12; mean age 9 years; mean weight 30 kg) a single endoprosthesis was implanted with no associated mortality. The mean initial transhepatic gradient was 15 mmHg (range 3-21 mmHg), dropping to 7 mmHg (range 1-12 mmHg) after TIPS. Immediate complications were mild encephalopathy (n = 1) and acute occlusion of the TIPS (n = 1). Stenosis of the TIPS was observed in two children, at 9 months and 54 months follow-up, and thrombosis was observed in two children, at 7 months and 12 months follow-up. All four stenoses/occlusions were resolved with coaxial endoprostheses. CONCLUSION: The safety profile and efficacy of expanded polytetrafluoroethylene (ePTFE)-covered TIPS were satisfactory in this small series of children with acute or recurrent gastrointestinal bleeding.