Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

Medication-related osteonecrosis of the jaw after tooth extraction in cancer patients: a multicenter retrospective study.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents. INTRODUCTION: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab. METHODS: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed. RESULTS: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ. CONCLUSIONS: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Effect of membrane solubilization on the inhibition of rat and hamster liver microsomal type I 11ß-hydroxysteroid dehydrogenase by bile acids.

The aim of this study was to investigate the differences between rats and hamsters, Two of the most widely used experimental animals, with respect to the effects of microsomal membrane solubilization on the inhibition of liver 11ß-hydroxysteroid dehydrogenase (11ß-HSDI) enzyme by bile acids. Liver microsome fractions were prepared, and the 11ß-HSDI enzymatic activity was measured using cortisone as a substrate. The substrate and various concentrations of bile acids were added to the assay mixtures. After incubation, the products were extracted and analyzed using high-performance liquid chromatography. To investigate the effect of detergent on the inhibitory effects of bile acids, we conducted inhibition tests using Triton X-100-solubilized animal liver microsomes. When solubilized microsomes were used, all bile acids inhibited 11ß-HSDI from rats and hamsters to various degrees. 7α-Hydroxycholanoic acids (cholic acid and chenodeoxycholic acid) in particular had strong inhibitory activities. In hamsters, 7ß-hydroxycholanoic acid (ursodeoxycholic acid) was the strongest inhibitor among the bile acids tested, although its effect was not very strong. When nonsolubilized microsomes were used, deoxycholic acid did not inhibit but rather enhanced the enzymatic activity in both animals. Microsomal content of cholesterol and phospholipids are significantly different between rats and hamsters. Species differences in bile acid inhibition of nonsolubilized microsomes might be reflected not only by structural difference of bile acids, which affect membrane solubilization and enzyme activity directly, but also species difference in microsomal membrane lipid content.

Non-destructive elemental analysis of large meteorite samples by prompt gamma-ray neutron activation analysis with the internal mono-standard method.

Prompt gamma-ray neutron activation analysis (PGNAA) using the internal mono-standard method was tested for its applicability to analyzing large solid samples including irregularly shaped meteorite samples. For evaluating the accuracy and precision of the method, large quantities of the Geological Survey of Japan standardized rock powders (JB-1a, JG-1a, and JP-1) were analyzed and 12 elements (B, Na, Mg, Al, Cl, K, Ca, Ti, Mn, Fe, Sm, and Gd) were determined by using Si as an internal standard element. Analytical results were mostly in agreement with literature values within 10 %. The precision of the method was also shown to be within 10 % (1σ) for most of these elements. The analytical procedure was then applied to four stony meteorites (Allende, Kimble County, Leedey, Lake Labyrinth) and four iron meteorites (Canyon Diablo, Toluca (Mexico), Toluca (Xiquipilco), Squaw Creek) consisting of large chunks or single slabs. For stony meteorites, major elements (Mg, Al, Si, S, Ca, and Ni), minor elements (Na and Mn) and trace element (B, Cl, K, Ti, Co, and Sm) were determined with adequate accuracy. For iron meteorites, results for the Co and Ni mass fractions determined are all consistent with corresponding literature values. After the analysis, it was confirmed that the residual radioactivity remaining in the sample after PGNAA was very low and decreased down to the background level. This study shows that PGNAA with the internal mono-standard method is highly practical for determining the elemental composition of large, irregularly shaped solid samples including meteorites.

Electric and mass transport of a carbon nanotube encapsulating a copper nano-rod studied by in-situ transmission electron microscopy.

Electric properties and current-induced structural changes of carbon nanotubes (CNTs) encapsulating copper nano-rods were studied by in-situ transmission electron microscopy (TEM). The diameter and the length of a copper filled CNT were 18 nm and 256 nm, respectively. The thickness of the graphite layer was about 1 nm. The bias voltage was applied between the two ends of the CNT inside the TEM, and the current as well as TEM images were recorded simultaneously. At a bias voltage of 1.4 V, the current increased to 10 microA, corresponding to a current density of 4.0 x 10(6) A/cm2, and at the same time the nano-rods inside the CNT started to move to an end of the CNT. After the movement of the nano-rods, an empty CNT was left. Resistivities of the CNT and the copper nano-rod were measured to be 3.0 x 10(-5) ohm m and 1.2 x 10(-4) ohm m, respectively.

Laboratory and febrile features after joint surgery in patients with rheumatoid arthritis treated with tocilizumab.

OBJECTIVES: To understand the acute phase responses to surgical intervention in patients with rheumatoid arthritis (RA) treated with the anti-interleukin (IL)6 receptor antibody, tocilizumab. METHODS: In a retrospective 1:1 pair-matched case-control study, 22 tocilizumab-treated RA cases and 22 cases treated with conventional disease-modifying antirheumatic drugs (DMARDs) and matched for type of surgery, age and sex were evaluated for body temperature every day, and blood C-reactive protein (CRP) levels and white blood cell (WBC), neutrophil and lymphocyte counts on days -1, 1, 3 and weeks 1 and 2 after joint surgery. Safety issues were also monitored. RESULTS: No complications of infection or delay of wound healing occurred in either patient group. Tocilizumab partially, but significantly, suppressed the increase in body temperature on postoperative days 1 and 2, compared with DMARDs (average (SD) maximum increase in temperature was 0.45 (0.1) degrees C in the tocilizumab group and 0.78 (0.1) degrees C in the DMARD group; p<0.01). Tocilizumab completely suppressed the increase in CRP after surgery, whereas all cases treated with DMARDs showed a significant increase of CRP at postoperative day 1 (5.5 (0.6) mg/dl; p<0.001). WBC, neutrophil and lymphocyte counts showed no remarkable change after surgery, and there was no significant difference in any cell counts between the patient groups. CONCLUSIONS: Within this small number of cases, safe operations on patients were performed during tocilizumab treatment. Tocilizumab suppressed fever and increase of CRP after surgery, whereas there was no influence on the transition in number of leukocytes. This characteristic postoperative response should be considered during tocilizumab treatment.

[Large saphenous vein graft aneurysm after coronary artery bypass grafting].

A 64-year-old man underwent coronary artery bypass grafting (CABG) in 1994. Eleven years later, coronary angiography (CAG) showed a saphenous vein graft (SVG) aneurysm. In April 2008, the CAG demonstrated enlargement of the aneurysm. Enhanced computed tomography showed a large aneurysm measuring 53 x 44 mm in diameter of the SVG-right coronary artery (RCA) [#3] anastomosis. Off-pump coronary surgery to RCA and aneurysmectomy was planned through a median epigastric incision. However re-grafting was difficult because of severe adhesion and calcification of the coronary artery. We confirmed sufficient back flow from the distal coronary artery without hemodynamic and electrocardiographic changes under SVG clamp. Aneurysmectomy was then performed without coronary bypass. The patient was discharged 9 days after surgery and has been well for 8 months in outpatient clinic.

[Proximal anastomotic pseudoaneurysm due to gelatin-resorcin-formalin (GRF) glue after replacement of ascending aorta for acute aortic dissection; report of a case].

A 78-year-old man had previously undergone replacement of ascending aorta using gelatin-resorcin-formalin (GRF) glue for acute aortic dissection. Five years later, a follow-up computed tomography (CT) showed an aortic root pseudoaneurysm. Ultrasound cardiography revealed moderate aortic regurgitation and pseudoaneurysm of aortic root. Aortic root replacement was planned based on a clinical diagnosis of an anastomotic pseudoaneurysm of the aortic root. The patient was discharged without complication 26 days after surgery. In the histopathological examination, the necrotic change of smooth muscle cells in the aortic media was revealed. Previous reports suggests that the use of GRF glue for reconstructing the dissected aorta results in higher rates of postoperative redissection or pseudoaneurysm. Therefore, careful postoperative follow-up is necessary in such cases and further improvements in the quality of glue or alternative methods will be necessary to prevent problems in the first place.

A baseline impedance analysis in neurologically impaired children: A potent parameter for estimating the condition of the esophageal mucosa.

BACKGROUND: The aim of the present study was to investigate whether the baseline impedance (BI) value is a useful parameter to evaluate the condition of the esophageal mucosa in neurologically impaired (NI) children undergoing multichannel intraluminal impedance pH measurements (pH/MII). METHODS: The retrospective study included 55 NI patients ≤15 years. The patients were divided into acid gastroesophageal reflux disease (GERD), non-acid GERD and GERD (-) groups. Furthermore, the patients in the acid GERD group were subdivided into erosive reflux disease (ERD) and non-erosive reflux disease (NERD) groups. pH/MII parameters and BI values (Z1-6) were compared among three groups or between two groups, respectively. A Spearman's correlation analysis was used for the correlation analysis of pH/MII parameters and BI values. A receiver operator characteristic curve analysis was used to evaluate the optimum cut-off values of BI to discriminate ERD patients. KEY RESULTS: The BI values of the proximal and the distal channels in ERD group were significantly lower than those in NERD group. The BI values of the distal channels demonstrated significant negative correlations with acid exposure related pH/MII parameters. The optimal cut off value of BI in the most distal channel was determined to be 1500 Ω. CONCLUSIONS & INFERENCES: The present study suggested that NI children with reflux esophagitis were likely to suffer mucosal damage up to the proximal esophagus and cut-off BI values may help estimate the presence of reflux esophagitis. Baseline impedance is a potent parameter, reflecting the esophageal mucosal damage in NI children who have difficulty in undergoing endoscopic examinations.

Isolation of gene sets affected specifically by polyglutamine expression: implication of the TOR signaling pathway in neurodegeneration.

Transcriptional dysregulation as a result of sequestration of essential transcription factors into protein aggregates formed by polyglutamine (polyQ) expansions can lead to late-onset progressive neurodegeneration. DNA microarray analysis of Drosophila expressing polyQ in the compound eye over time revealed large numbers of transcriptional changes at the earliest stages of the disease including repression of the transient receptor potential calcium channels in a polyQ-induced cell death specific manner. While significant differences in expression profiles were found between the Drosophila compound eye and polyQ-sensitive neural cells, a number of possible key overlapping regulators were extracted. Among these, PDK1 was shown to act as a mediator for polyQ-toxicity, suggesting the involvement of the TOR pathway in polyQ-induced neurodegeneration.

Parallel neural networks for learning sequential procedures.

Recent studies have shown that multiple brain areas contribute to different stages and aspects of procedural learning. On the basis of a series of studies using a sequence-learning task with trial-and-error, we propose a hypothetical scheme in which a sequential procedure is acquired independently by two cortical systems, one using spatial coordinates and the other using motor coordinates. They are active preferentially in the early and late stages of learning, respectively. Both of the two systems are supported by loop circuits formed with the basal ganglia and the cerebellum, the former for reward-based evaluation and the latter for processing of timing. The proposed neural architecture would operate in a flexible manner to acquire and execute multiple sequential procedures.

Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension.

BACKGROUND: Protein C inhibitor (PCI) plays a role in multiple biological processes including fertilization, coagulation, fibrinolysis and kinin systems. OBJECTIVES: We hypothesized that PCI participates in the pathogenesis of pulmonary hypertension. To demonstrate this, we compared the development of pulmonary hypertension in mice overexpressing PCI in the lung with wild-type (WT) mice. Pulmonary hypertension was induced by s.c. injection of 600 mg kg-1 of monocrotaline weekly for 8 weeks. RESULTS: Right ventricular arterial pressure was significantly increased in monocrotaline-treated WT mice compared with that in monocrotaline-treated transgenic mice. Bronchoalveolar lavage fluid (BALF) levels of thrombin-antithrombin complex, monocyte chemoattractant protein-1 and platelet-derived growth factor, and the plasma level of tumor necrosis factor-alpha were significantly increased in monocrotaline-treated WT mice as compared with monocrotaline-treated PCI transgenic mice. Increased level of PCI-thrombin complex was detected in BALF from monocrotaline-treated PCI transgenic mice as compared with saline-treated PCI transgenic mice. CONCLUSIONS: This study showed that increased expression of PCI in the lung is protective against monocrotaline-induced pulmonary hypertension, suggesting a potential beneficial effect of PCI for the therapy of this disease.

Time course of blood pressure changes immediately after maximal exercise.

AIM: The aim of this study was to investigate the effect of exhaustive exercise on the time course of arterial blood pressure (BP) and heart rate (HR) during upright resting (inactive) and loadless pedaling (active) recovery from a bicycle exercise to exhaustion. METHODS: The subjects were 11 healthy normotensive males. Systolic, diastolic and mean BP, and HR were recorded every 20 s for the initial 6 min of the recovery period. RESULTS: The time course of all BP measures during inactive and active recovery was characterized by a marked and sudden drop during the initial 20-s period, followed by a quick rise. This was followed by a gradual decline till the end of the recovery period. The time course of HR recovery, on the other hand, exhibited a smooth decline without the initial drop. With active recovery, the initial drop of diastolic and mean BP was less than the inactive recovery. After the 20 s period, the diastolic BP and HR were kept slightly higher with the active recovery than the inactive recovery. CONCLUSIONS: A sudden drop of the BP occurred at the initial recovery period of postcycle exercise to exhaustion though HR did not show such a change. The initial BP drop could be attenuated by the actively pedaling the cycle without load.

Aspects of carbonic anhydrase and carbonate content during mineralization of the rat enamel.

We examined carbonic anhydrase and carbonate content in developing dental enamel to clarify some problems in connection with the initial mineralization. Two-dimensional electrophoretic analysis showed that the type of carbonic anhydrase isoenzyme in developing enamel tissue was a low-activity form. A relatively high activity of carbonic anhydrase was detected in the developing enamel of rat lower incisors. We also determined that the content rate of carbonic anhydrase accounts for about 4% of the total matrix proteins of early developing enamel. A remarkable reduction of carbonic anhydrase activity occurred at the maturation stage, and then disappeared in the fully matured enamel. The carbonate content also decreased gradually, showing a parallel profile to that of carbonic anhydrase activity, from 3.5% to 1.9% in mineral phase. From the present study, we proposed that carbonic anhydrase in the initial site of mineralization may act as a trigger for the crystal nucleation by supplying the carbonate ions into the precursor mineral at the early stage of crystal development.

Demonstration of the central dark line in crystals of dental calculus.

Using an electron microscope and Fourier transform infrared (FTIR) microspectroscopy, we studied the lattice images of crystallites of dental calculus to demonstrate the presence of the central dark line (CDL) in its crystallite and to compare this CDL with that of bone and synthetic hydroxyapatite crystals. Ultrastructural observations revealed clearly a number of crystallites, which displayed a proper lattice image and CDL similar to that of bone, in the dental calculus. FTIR microspectroscopy revealed that the dental calculus displayed a set of major spectra analogous to that of bone. These results suggest that the formation process of hydroxyapatite crystals with CDL in dental calculus, which is considered to be an unusual type of calcified structure in association with microorganisms, is basically similar to that of the ordinary calcifying hard tissues (bone, enamel, etc.).

In vivo biological behavior of a water-miscible fullerene: 14C labeling, absorption, distribution, excretion and acute toxicity.

BACKGROUND: Water-soluble fullerenes have recently been shown to exhibit considerable in vitro biological activity including cytotoxicity, site-selective DNA cleavage and inhibition of HIV protease. To assess the potential of these compounds as drugs, studies on the in vivo behavior of fullerenes are needed. We therefore set out to synthesize a radiolabeled, water-soluble fullerene, in order to obtain data on the oral absorption, distribution and excretion of this class of compounds. RESULTS: We synthesized a 14C-labeled water-soluble [60]fullerene using dipolar trimethylenemethane, which undergoes cycloaddition to [60]fullerene. When administered orally to rats, this compound was not efficiently absorbed and was excreted primarily in the feces. When injected intravenously, however, it was distributed rapidly to various tissues, and most of the material was retained in the body after one week. The compound was also able to penetrate the blood-brain barrier. Acute toxicity of the water-miscible fullerene was found to be quite low. CONCLUSIONS: Although the water-soluble fullerenes (and possibly their simple metabolites) are not acutely toxic, they are retained in the body for long periods, raising concerns about chronic toxic effects. The fact that fullerenes distribute rapidly to many tissues suggests that they may eventually be useful to deliver highly polar drugs through membranes to a target tissue, however, and they may even have applications in the delivery of drugs to the brain. Recent advances in fullerene synthetic chemistry may also make it possible to control fullerene absorption/excretion profiles in the future.

Bone morphogenetic protein 2 stimulates osteogenesis but does not affect chondrogenesis in osteochondrogenic differentiation of periosteum-derived cells.

The effects of recombinant human bone morphogenetic protein 2 (rhBMP-2) on osteochondrogenesis were examined in high-density cultures of periosteum-derived cells, which have the potential to differentiate into bone and hypertrophic cartilage in vitro. Proliferation of these cells was inhibited by treatment with rhBMP-2. The time course for alkaline phosphatase (ALP) expression was shortened and the mineralization of the culture was increased by supplementation with rhBMP-2. These stimulatory effects of rhBMP-2 were observed at doses of 10-100 ng/m. Bone Gla protein (BGP) was immunocytochemically detectable earlier in the culture treated with rhBMP-2, and the BGP-positive layer of the rhBMP-2-treated cultures was thicker than that of the control cultures. On the other hand, there was no difference in uronic acid content or the time course of alpha 1(II) collagen mRNA expression between the rhBMP-2-treated and the control cultures. These results indicate that rhBMP-2 shortens the time course of osteogenesis and increases the amount of bone formation, whereas chondrogenesis remains unaffected.

Transforming growth factor-beta 1 stimulates chondrogenesis and inhibits osteogenesis in high density culture of periosteum-derived cells.

Chick periosteum-derived mesenchymal cells have been reported to exhibit both osteogenic and chondrogenic potentials in high cell density culture conditions. Using this culture system, the effects of transforming growth factor-beta (TGF beta) on proliferation and differentiation of periosteal mesenchymal cells were studied. Supplementation with TGF beta 1 at doses of 0.3-1.0 ng/ml shortened the time course of chondrogenesis and increased the amount of cartilage formed in the lower part of the culture. On the other hand, the amount of bone formed in the upper part of the culture decreased with TGF beta treatment, whereas the time course of osteogenesis remained unaffected.