Relation of psychological distress to the INR in Patients with venous thromboembolism with and without oral anticoagulant therapy

Psychological distress might affect the international normalized ratio (INR), but effects might vary depending on oral anticoagulant (OAC) therapy.

Major bleeding of the upper aerodigestive tract due to oral anticoagulant/antibiotic interactions

INTRODUCTION Although a well-known complication in certain medical specialties, major bleeding due to the interaction between oral anticoagulants and antibiotics has been rarely reported concerning the upper aerodigestive tract. We report three cases of life-threatening bleeding of the upper aerodigestive tract in a context of antibiotic therapy in patients treated with oral anticoagulants. CASE SERIES Three male patients under coumadin anticoagulation therapy presented major bleeding in three different contexts (epistaxis, peritonsillar abscess and postoperative course after total laryngectomy). Surgical intervention for hemostasis was required in all cases, with coagulation correction in two. Complications were severe anemia (2/3) and chronic heart failure (1/3). DISCUSSION/CONCLUSIONS Interactions between two drugs commonly used in otolaryngology can result in major bleeding. The goal of this article is to raise practitioners' awareness of a potentially fatal, although rare, complication. We also review the main preventive strategies.

Scores to predict major bleeding risk during oral anticoagulation therapy: a prospective validation study

Clinical scores may help physicians to better assess the individual risk/benefit of oral anticoagulant therapy. We aimed to externally validate and compare the prognostic performance of 7 clinical prediction scores for major bleeding events during oral anticoagulation therapy.

Effect of oral melatonin on the procoagulant response to acute psychosocial stress in healthy men: a randomized placebo-controlled study

Acute mental stress is a potent trigger of acute coronary syndromes. Catecholamine-induced hypercoagulability with acute stress contributes to thrombus growth after coronary plaque rupture. Melatonin may diminish catecholamine activity. We hypothesized that melatonin mitigates the acute procoagulant stress response and that this effect is accompanied by a decrease in the stress-induced catecholamine surge. Forty-five healthy young men received a single oral dose of either 3 mg melatonin (n = 24) or placebo medication (n = 21). One hour thereafter, they underwent a standardized short-term psychosocial stressor. Plasma levels of clotting factor VII activity (FVII:C), FVIII:C, fibrinogen, D-dimer, and catecholamines were measured at rest, immediately after stress, and 20 min and 60 min post-stress. The integrated change in D-dimer levels from rest to 60 min post-stress differed between medication groups controlling for demographic and metabolic factors (P = 0.047, eta(p)(2) = 0.195). Compared with the melatonin group, the placebo group showed a greater increase in absolute D-dimer levels from rest to immediately post-stress (P = 0.13; eta(p)(2) = 0.060) and significant recovery of D-dimer levels from immediately post-stress to 60 min thereafter (P = 0.007; eta(p)(2) = 0.174). Stress-induced changes in FVII:C, FVIII:C, fibrinogen, and catecholamines did not significantly differ between groups. Oral melatonin attenuated the stress-induced elevation in the sensitive coagulation activation marker D-dimer without affecting catecholamine activity. The finding provides preliminary support for a protective effect of melatonin in reducing the atherothrombotic risk with acute mental stress.

Salivary Pellicle vs Whole Saliva: The Response of Oral Fibroblasts Based on a Genome-Wide Microarray.

PURPOSE Whole saliva comprises components of the salivary pellicle that spontaneously forms on surfaces of implants and teeth. However, there are no studies that functionally link the salivary pellicle with a possible change in gene expression. MATERIALS AND METHODS This study examined the genetic response of oral fibroblasts exposed to the salivary pellicle and whole saliva. Oral fibroblasts were seeded onto a salivary pellicle and the respective untreated surface. Oral fibroblasts were also exposed to freshly harvested sterile-filtered whole saliva. A genome-wide microarray of oral fibroblasts was performed, followed by gene ontology screening with DAVID functional annotation clustering, KEGG pathway analysis, and the STRING functional protein association network. RESULTS Exposure of oral fibroblasts to saliva caused 61 genes to be differentially expressed (P < .05). Gene ontology screening assigned the respective genes into 262 biologic processes, 3 cellular components, 13 molecular functions, and 7 pathways. Most remarkable was the enrichment in the inflammatory response. None of the genes regulated by whole saliva was significantly changed when cells were placed onto a salivary pellicle. CONCLUSION The salivary pellicle per se does not provoke a significant inflammatory response of oral fibroblasts in vitro, whereas sterile-filtered whole saliva does produce a strong inflammatory response.

Delayed osteoblast differentiation and altered inflammatory response around implants placed in incisor sockets of type 2 diabetic rats

Objective: Central to the process of osseointegration is the recruitment of mesenchymal progenitor cells to the healing site, their proliferation and differentiation to bone synthesising osteoblasts. The process is under the control of pro-inflammatory cytokines and growth factors. The aim of this study was to monitor these key stages of osseointegration and the signalling milieu during bone healing around implants placed in healthy and diabetic bone. Methods: Implants were placed into the sockets of incisors extracted from the mandibles of normal Wistar and diabetic Goto-Kakizaki rats. Mandibles 1-12 weeks post-insertion of the implant were examined by histochemistry and immunocytochemistry to localise the presence of Stro-1- positive mesenchymal progenitor cells, proliferating cellular nuclear antigen proliferative cells, osteopontin and osteocalcin, macrophages, pro-inflammatory cytokines interleukin (IL)-1 , IL-6, tumour necrosis factor (TNF)- and tumour growth factor (TGF)- 1. Image analysis provided a semi-quantification of positively expressing cells. Results: Histological staining identified a delay in the formation of mineralised bone around implants placed in diabetic animals. Within the diabetic bone, the migration of Stro-1 mesenchymal cells in the healing tissue appeared to be unaffected. However, in the diabetic healing bone, the onset of cell proliferation and osteoblast differentiation were delayed and subsequently prolonged compared with normal bone. Similar patterns of change were observed in diabetic bone for the presence of IL-1 , TNF- , macrophages and TGF- 1. Conclusion: The observed alterations in the extracellular presence of pro-inflammatory cytokines, macrophages and growth factors within diabetic tissues that correlate to changes in the signalling milieu, may affect the proliferation and differentiation of mesenchymal progenitor cells in the osseointegration process. To cite this article: Colombo JS, Balani D, Sloan AJ, St Crean J, Okazaki J, Waddington RJ. Delayed osteoblast differentiation and altered inflammatory response around implants placed in incisor sockets of type 2 diabetic rats Clin. Oral Impl. Res22, 2011; 578-586 doi: 10.1111/j.1600-0501.2010.01992.x.

Tissue response and wound healing after placement of two types of bioengineered grafts containing vital cells in submucosal maxillary pouches: an experimental pilot study in rabbits

PURPOSE: This pilot study evaluated the wound healing and tissue response after placement of two different skin substitutes in subgingival mucosal pouches in rabbits. MATERIALS AND METHODS: Four rabbits were selected to receive a commercially available skin substitute consisting of a collagen matrix with fibroblasts and an epithelial layer (test membrane 1) and a prototype device consisting of a collagen matrix with fibroblasts only (test membrane 2). In each rabbit, two horizontal incisions were made in the buccal alveolar mucosa of the maxilla bilaterally to create submucosal pouches. Three pouches in each animal were filled with either the test 1 or test 2 membranes, and one pouch was left without a membrane (sham-operated control). All rabbits were sacrificed after a healing period of 4 weeks, and histologic samples were prepared and examined. RESULTS: After a healing period of 1 month, both tested membranes were still visible in the sections. Test membrane 1 was still bilayered, contained inflammatory cells in its center, and was encapsulated by a thick fibrous tissue. Numerous ectopic calcifications were evident in the collagenous part of the membrane and in association with some basal epithelial cells. Test membrane 2 was also encapsulated in fibrous tissue, with inflammatory cells present only between the fibrous encapsulation and the remnants of the membrane. For test membrane 2, no calcifications were visible. CONCLUSIONS: Test membrane 1 seemed to be more resistant to degradation, but there was also a more pronounced inflammatory reaction in comparison to test membrane 2, especially in the vicinity of the keratinocytes. The significance of the ectopic calcifications, along with that of the resorption or degradation processes of both tested membranes, must be evaluated in future experimental studies, with different time points after implantation examine

Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: a report from the Children's Oncology Group

To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma.

Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets

Background PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a circulating protein that promotes hypercholesterolemia by decreasing hepatic LDL receptor protein. Under non interventional conditions, its expression is driven by sterol response element binding protein 2 (SREBP2) and follows a diurnal rhythm synchronous with cholesterol synthesis. Plasma PCSK9 is associated to LDL-C and to a lesser extent plasma triglycerides and insulin resistance. We aimed to verify the effect on plasma PCSK9 concentrations of dietary interventions that affect these parameters. Methods We performed nutritional interventions in young healthy male volunteers and offspring of type 2 diabetic (OffT2D) patients that are more prone to develop insulin resistance, including: i) acute post-prandial hyperlipidemic challenge (n=10), ii) 4 days of high-fat (HF) or high-fat/high-protein (HFHP) (n=10), iii) 7 (HFruc1, n=16) or 6 (HFruc2, n=9) days of hypercaloric high-fructose diets. An acute oral fat load was also performed in two patients bearing the R104C-V114A loss-of-function (LOF) PCSK9 mutation. Plasma PCSK9 concentrations were measured by ELISA. For the HFruc1 study, intrahepatocellular (IHCL) and intramyocellular lipids were measured by 1H magnetic resonance spectroscopy. Hepatic and whole-body insulin sensitivity was assessed with a two-step hyperinsulinemic-euglycemic clamp (0.3 and 1.0 mU.kg-1.min-1). Findings HF and HFHP short-term diets, as well as an acute hyperlipidemic oral load, did not significantly change PCSK9 concentrations. In addition, post-prandial plasma triglyceride excursion was not altered in two carriers of PCSK9 LOF mutation compared with non carriers. In contrast, hypercaloric 7-day HFruc1 diet increased plasma PCSK9 concentrations by 28% (p=0.05) in healthy volunteers and by 34% (p=0.001) in OffT2D patients. In another independent study, 6-day HFruc2 diet increased plasma PCSK9 levels by 93% (p<0.0001) in young healthy male volunteers. Spearman’s correlations revealed that plasma PCSK9 concentrations upon 7-day HFruc1 diet were positively associated with plasma triglycerides (r=0.54, p=0.01) and IHCL (r=0.56, p=0.001), and inversely correlated with hepatic (r=0.54, p=0.014) and whole-body (r=−0.59, p=0.0065) insulin sensitivity. Conclusions Plasma PCSK9 concentrations vary minimally in response to a short term high-fat diet and they are not accompanied with changes in cholesterolemia upon high-fructose diet. Short-term high-fructose intake increased plasma PCSK9 levels, independent on cholesterol synthesis, suggesting a regulation independent of SREBP-2. Upon this diet, PCSK9 is associated with insulin resistance, hepatic steatosis and plasma triglycerides.

PTH and 1.25 vitamin D response to a low-calcium diet is associated with bone mineral density in renal stone formers

BACKGROUND: Renal calcium stones and hypercalciuria are associated with a reduced bone mineral density (BMD). Therefore, the effect of changes in calcium homeostasis is of interest for both stones and bones. We hypothesized that the response of calciuria, parathyroid hormone (PTH) and 1.25 vitamin D to changes in dietary calcium might be related to BMD. METHODS: A single-centre prospective interventional study of 94 hyper- and non-hypercalciuric calcium stone formers consecutively retrieved from our stone clinic. The patients were investigated on a free-choice diet, a low-calcium diet, while fasting and after an oral calcium load. Patient groups were defined according to lumbar BMD (z-score) obtained by dual X-ray absorptiometry (group 1: z-score <-0.5, n = 30; group 2: z-score -0.5-0.5, n = 36; group 3: z-score >0.5, n = 28). The effect of the dietary interventions on calciuria, 1.25 vitamin D and PTH in relation to BMD was measured. RESULTS: An inverse relationship between BMD and calciuria was observed on all four calcium intakes (P = 0.009). On a free-choice diet, 1.25 vitamin D and PTH levels were identical in the three patient groups. However, the relative responses of 1.25 vitamin D and PTH to the low-calcium diet were opposite in the three groups with the highest increase of 1.25 vitamin D in group 1 and the lowest in group 3, whereas PTH increase was most pronounced in group 3 and least in group 1. CONCLUSION: Calcium stone formers with a low lumbar BMD exhibit a blunted response of PTH release and an apparently overshooting production of 1.25 vitamin D following a low-calcium diet.

The effects of aspirin and nonselective beta blockade on the acute prothrombotic response to psychosocial stress in apparently healthy subjects

We hypothesized that the 2 cardiovascular drugs aspirin and propranolol attenuate the prothrombotic response to acute psychosocial stress relative to placebo medication. We randomized 56 healthy subjects, double-blind, to 5-day treatment with an oral dose of either 100 mg of aspirin plus 80 mg of propranolol combined, single aspirin, single propranolol, or placebo medication. Thereafter, subjects underwent a 13-minute psychosocial stressor. Plasma levels of von Willebrand factor antigen (VWF:Ag), fibrinogen, coagulation factor VII (FVII:C) and XII (FXII:C) activity, and D-dimer were determined in blood samples collected immediately pre- and post-stress and 45 minutes post-stress. The stress-induced changes in prothrombotic measures were adjusted for gender, age, body mass index, mean arterial blood pressure, smoking status, and sleep quality. There was an increase in VWF:Ag levels from immediately pre-stress to 45 minutes post-stress in the placebo group relative to the 3 subject groups with verum medication (P's response to stress was not significantly different between the three groups with verum medication. The stress responses in fibrinogen, FVII:C, FXII:C, and D-dimer were similar in all 4 medication groups. The combination of aspirin with propranolol, single aspirin, and single propranolol all attenuated the acute response in plasma VWF:Ag levels to psychosocial stress. This suggests that these cardiovascular drugs might exert limited protection from the development of stress-triggered coronary thrombosis.

Effects of aspirin and propranolol on the acute psychological stress response in factor VIII coagulant activity: a randomized, double-blind, placebo-controlled experimental study

Activity of clotting factor VIII has been shown to acutely increase with sympathetic nervous system stimulation. We investigated whether aspirin and propranolol affect the responsiveness of plasma clotting factor VIII activity levels to acute psychosocial stress. We randomized 54 healthy subjects double-blind to 5-day treatment with a single daily oral dosage of either 100 mg aspirin plus 80 mg propranolol combined, 100 mg of aspirin, 80 mg of propranolol, or placebo medication. Thereafter, subjects underwent a 13-min standardized psychosocial stressor. Plasma levels of clotting factor VIII activity were determined immediately before, immediately after, 45 min and 105 min after stress. Controlling for demographic, metabolic, and life style factors repeated measures analysis of covariance showed that the change in clotting factor VIII activity from prestress to 105 min poststress differed between medication groups (P = 0.023; partial eta = 0.132). The clotting factor VIII activity level decreased from prestress to immediately poststress in the aspirin/propranolol group relative to the placebo group (P = 0.048) and the aspirin group (P < 0.06). Between 45 min and 105 min poststress, clotting factor VIII levels increased in the aspirin/propranolol group relative to the placebo group (P = 0.007) and the aspirin group (P = 0.039). The stress response in clotting factor VIII activity levels was not significantly different between the aspirin/propranolol group and the propranolol group. Propranolol in combination with aspirin diminished the acute response in clotting factor VIII activity to psychosocial stress compared with placebo medication and aspirin alone. The effect of single aspirin on the acute clotting factor VIII stress response was indistinguishable from a placebo effect.

Oral melatonin reduces blood coagulation activity: a placebo-controlled study in healthy young men

Melatonin has previously been suggested to affect hemostatic function but studies on the issue are scant. We hypothesized that, in humans, oral administration of melatonin is associated with decreased plasma levels of procoagulant hemostatic measures compared with placebo medication and that plasma melatonin concentration shows an inverse association with procoagulant measures. Forty-six healthy men (mean age 25 +/- 4 yr) were randomized, single-blinded, to either 3 mg of oral melatonin (n = 25) or placebo medication (n = 21). One hour thereafter, levels of melatonin, fibrinogen, and D-dimer as well as activities of coagulation factor VII (FVII:C) and VIII (FVIII:C) were measured in plasma. Multivariate analysis of covariance and regression analysis controlled for age, body mass index, mean arterial blood pressure, heart rate, and norepinephrine plasma level. Subjects on melatonin had significantly lower mean levels of FVIII:C (81%, 95% CI 71-92 versus 103%, 95% CI 90-119; P = 0.018) and of fibrinogen (1.92 g/L, 95% CI 1.76-2.08 versus 2.26 g/L, 95% CI 2.09-2.43; P = 0.007) than those on placebo explaining 14 and 17% of the respective variance. In all subjects, increased plasma melatonin concentration independently predicted lower levels of FVIII:C (P = 0.037) and fibrinogen (P = 0.022) explaining 9 and 11% of the respective variance. Melatonin medication and plasma concentration were not significantly associated with FVII:C and D-dimer levels. A single dose of oral melatonin was associated with lower plasma levels of procoagulant factors 60 min later. There might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity.

Bone response to loaded implants with non-matching implant-abutment diameters in the canine mandible

BACKGROUND: One way to evaluate various implant restorations is to measure the amount of bone change that occurs at the crestal bone. The objective of this study was to histologically evaluate the alveolar bone change around a bone-level, non-matching implant-abutment diameter configuration that incorporated a horizontal offset and a Morse taper internal connection. METHODS: The study design included extraction of all mandibular premolars and first molars in five canines. After 3 months, 12 dental implants were placed at three levels in each dog: even with the alveolar crest, 1 mm above the alveolar crest, and 1 mm below the alveolar crest. The implants were submerged on one side of the mandible. On the other side, healing abutments were exposed to the oral cavity (non-submerged). Gold crowns were attached 2 months after implant placement. The dogs were sacrificed 6 months postloading, and specimens were processed for histologic and histometric analyses. RESULTS: Evaluation of the specimens indicated that the marginal bone remained near the top of the implants under submerged and non-submerged conditions. The amount of bone change for submerged implants placed even with, 1 mm below, and 1 mm above the alveolar crest was -0.34, -1.29, and 0.04 mm, respectively (negative values indicate bone loss). For non-submerged implants, the respective values were -0.38, -1.13, and 0.19 mm. For submerged and non-submerged implants, there were significant differences in the amount of bone change among the three groups (P <0.05). The percentage of bone-to-implant contact for submerged implants was 73.3%, 71.8%, and 71.5%. For non-submerged implants, the respective numbers were 73.2%, 74.5%, and 76%. No significant differences occurred with regard to the percentage of bone contact. CONCLUSIONS: Minimal histologic bone loss occurred when dental implants with non-matching implant-abutment diameters were placed at the bone crest and were loaded for 6 months in the canine. The bone loss was significantly less (five- to six-fold) than that reported for bone-level implants with matching implant-abutment diameters (butt-joint connections).