Immunohistochemical localization of RANK, RANKL and OPG in healthy and arthritic canine elbow joints

OBJECTIVE: To determine if the receptor activator of nuclear factor-kappaB-receptor activator of nuclear factor-kappaB ligand-osteoprotegerin (RANK-RANKL-OPG) system is active in bone remodeling in dogs and, if so, whether differences in expression of these mediators occur in healthy and arthritic joints. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Fragmented processus coronoidei (n=20) were surgically removed from dogs with elbow arthritis and 5 corresponding healthy samples from dogs euthanatized for reasons other than elbow joint disease. METHODS: Bright-field immunohistochemistry and high-resolution fluorescence microscopy were used to investigate the distribution of RANK, RANKL, and OPG in healthy and arthritic joints. RESULTS: All 3 molecules were identified by immunostaining of canine bone tissue. In elbow dysplasia, the number of RANK-positive osteoclasts was increased. In their vicinity, cells expressing RANKL, a mediator of osteoclast activation, were abundant whereas the number of osteoblasts having the potential to limit osteoclastogenesis and bone resorption via OPG was few. CONCLUSIONS: The RANK-RANKL-OPG system is active in bone remodeling in dogs. In elbow dysplasia, a surplus of molecules promoting osteoclastogenesis was evident and is indicative of an imbalance between the mediators regulating bone resorption and bone formation. Both OPG and neutralizing antibodies against RANKL have the potential to counterbalance bone resorption. CLINICAL RELEVANCE: Therapeutic use of neutralizing antibodies against RANKL to inhibit osteoclast activation warrants further investigation.

A 10-year retrospective analysis of marginal bone-level changes around implants in periodontally healthy and periodontally compromised tobacco smokers

to compare the 10-year marginal bone loss rates around implants supporting single-unit crowns in tobacco smokers with and without a history of treated periodontitis.

Antagonistic effects of ondansetron and tramadol? A randomized placebo and active drug controlled study

Opposing effects of ondansetron and tramadol on the serotonin pathway have been suggested which possibly increase tramadol consumption and emesis when co-administered. In a randomized, double-blinded study, 179 patients received intravenous ondansetron, metoclopramide, or placebo for emesis prophylaxis. Analgesic regimen consisted of tramadol intraoperative loading and subsequent patient-controlled analgesia. Tramadol consumption and response to antiemetic treatment were compared. Additionally, plasma concentrations of ondansetron and (+)O-demethyltramadol and CYP2D6 genetic variants were analyzed as possible confounders influencing analgesic and antiemetic efficacy. Tramadol consumption did not differ between the groups. Response rate to antiemetic prophylaxis was superior in patients receiving ondansetron (85.0%) compared with placebo (66.7%, P = .046), with no difference to metoclopramide (69.5%). Less vomiting was reported in the immediate postoperative hours in the verum groups (ondansetron 5.0%, metoclopramide 5.1%) compared with placebo (18.6%; P = .01). Whereas plasma concentrations of (+)O-demethyltramadol were significantly correlated to CYP2D6 genotype, no influence was detected for ondansetron. Co-administration of ondansetron neither increased tramadol consumption nor frequency of PONV in this postoperative setting. PERSPECTIVE: Controversial findings were reported for efficacy of tramadol and ondansetron when co-administered due to their opposing serotonergic effects. Co-medication of these drugs neither increased postoperative analgesic consumption nor frequency of emesis in this study enrolling patients recovering from major surgery.

Distribution of lactate dehydrogenase in healthy and degenerative canine stifle joint cartilage

In dogs, degenerative joint diseases (DJD) have been shown to be associated with increased lactate dehydrogenase (LDH) activity in the synovial fluid. The goal of this study was to examine healthy and degenerative stifle joints in order to clarify the origin of LDH in synovial fluid. In order to assess the distribution of LDH, cartilage samples from healthy and degenerative knee joints were investigated by means of light and transmission electron microscopy in conjunction with immunolabeling and enzyme cytochemistry. Morphological analysis confirmed DJD. All techniques used corroborated the presence of LDH in chondrocytes and in the interterritorial matrix of healthy and degenerative stifle joints. Although enzymatic activity of LDH was clearly demonstrated in the territorial matrix by means of the tetrazolium-formazan reaction, immunolabeling for LDH was missing in this region. With respect to the distribution of LDH in the interterritorial matrix, a striking decrease from superficial to deeper layers was present in healthy dogs but was missing in affected joints. These results support the contention that LDH in synovial fluid of degenerative joints originates from cartilage. Therefore, we suggest that (1) LDH is transferred from chondrocytes to ECM in both healthy dogs and dogs with degenerative joint disease and that (2) in degenerative joints, LDH is released from chondrocytes and the ECM into synovial fluid through abrasion of cartilage as well as through enhanced diffusion as a result of increased water content and degradation of collagen.

Effects of an aging vascular model on healthy and diseased hearts

The vitamin D(3) and nicotine (VDN) model is a model of isolated systolic hypertension (ISH) due to arterial calcification raising arterial stiffness and vascular impedance similar to an aged and stiffened arterial tree. We therefore analyzed the impact of this aging model on normal and diseased hearts with myocardial infarction (MI). Wistar rats were treated with VDN (n = 9), subjected to MI by coronary ligation (n = 10), or subjected to a combination of both MI and VDN treatment (VDN/MI, n = 14). A sham-treated group served as control (Ctrl, n = 10). Transthoracic echocardiography was performed every 2 wk, whereas invasive indexes were obtained at week 8 before death. Calcium, collagen, and protein contents were measured in the heart and the aorta. Systolic blood pressure, pulse pressure, thoracic aortic calcium, and end-systolic elastance as an index of myocardial contractility were highest in the aging model group compared with MI and Ctrl groups (P(VDN) < 0.05, 2-way ANOVA). Left ventricular wall stress and brain natriuretic peptide (P(VDNxMI) = not significant) were highest, while ejection fraction, stroke volume, and cardiac output were lowest in the combined group versus all other groups (P(VDNxMI) < 0.05). The combination of ISH due to this aging model and MI demonstrates significant alterations in cardiac function. This model mimics several clinical phenomena of cardiovascular aging and may thus serve to further study novel therapies.

Supplemental oxygen, but not supplemental crystalloid fluid, increases tissue oxygen tension in healthy and anastomotic colon in pigs

BACKGROUND: Low tissue oxygen tension is an important factor leading to the development of wound dehiscence and anastomotic leakage after colon surgery. We tested whether supplemental fluid and supplemental oxygen can increase tissue oxygen tension in healthy and injured, perianastomotic, and anastomotic colon in an acutely instrumented pig model of anastomosis surgery. METHODS: Sixteen Swiss Landrace pigs were anesthetized (isoflurane 0.8%-1%) and their lungs ventilated. The animals were randomly assigned to low fluid treatment ("low" group, 3 mL x kg(-1) x h(-1) lactated Ringer's solution) or high fluid treatment ("high" group, 10 mL/kg bolus, 18 mL x kg(-1) x h(-1) lactated Ringer's solution) during colon anastomosis surgery and a subsequent measurement period (4 h). Two-and-half hours after surgery, tissue oxygen tension was recorded for 30 min during ventilation with 30% oxygen. Three hours after surgery, the animals' lungs were ventilated with 100% oxygen for 60 min. Tissue oxygen tension was recorded in the last 30 min. Tissue oxygen tension was measured with polarographic Clark-type electrodes, positioned in healthy colonic wall, close (2 cm) to the anastomosis, and in the anastomosis. RESULTS: In every group, tissue oxygen tension during ventilation with 100% oxygen was approximately twice as high as during ventilation with 30% oxygen, a statistically significant result. High or low volume crystalloid fluid treatment had no effect on colon tissue oxygen tension. CONCLUSIONS: Supplemental oxygen, but not supplemental crystalloid fluid, increased tissue oxygen tension in healthy, perianastomotic, and anastomotic colon tissue.

Goal-directed colloid administration improves the microcirculation of healthy and perianastomotic colon

BACKGROUND: The aim of this study was to compare the effects of goal-directed colloid fluid therapy with goal-directed crystalloid and restricted crystalloid fluid therapy on healthy and perianastomotic colon tissue in a pig model of colon anastomosis surgery. METHODS: Pigs (n = 27, 9 per group) were anesthetized and mechanically ventilated. A hand-sewn colon anastomosis was performed. The animals were subsequently randomized to one of the following treatments: R-RL group, 3 ml x kg(-1) x h(-1) Ringer lactate (RL); GD-RL group, 3 ml x kg(-1) x h(-1) RL + bolus 250 ml of RL; GD-C group, 3 ml x kg(-1) x h(-1) RL + bolus 250 ml of hydroxyethyl starch (HES 6%, 130/0.4). A fluid bolus was administered when mixed venous oxygen saturation dropped below 60%. Intestinal tissue oxygen tension and microcirculatory blood flow were measured continuously. RESULTS: After 4 h of treatment, tissue oxygen tension in healthy colon increased to 150 +/- 31% in group GD-C versus 123 +/- 40% in group GD-RL versus 94 +/- 23% in group R-RL (percent of postoperative baseline values, mean +/- SD; P < 0.01). Similarly perianastomotic tissue oxygen tension increased to 245 +/- 93% in the GD-C group versus 147 +/- 58% in the GD-RL group and 116 +/- 22% in the R-RL group (P < 0.01). Microcirculatory flow was higher in group GD-C in healthy colon. CONCLUSIONS: Goal-directed colloid fluid therapy significantly increased microcirculatory blood flow and tissue oxygen tension in healthy and injured colon compared to goal-directed or restricted crystalloid fluid therapy.

Can a novel web-based computer test predict poor simulated driving performance? A pilot study with healthy and cognitive-impaired participants

BACKGROUND Driving a car is a complex instrumental activity of daily living and driving performance is very sensitive to cognitive impairment. The assessment of driving-relevant cognition in older drivers is challenging and requires reliable and valid tests with good sensitivity and specificity to predict safe driving. Driving simulators can be used to test fitness to drive. Several studies have found strong correlation between driving simulator performance and on-the-road driving. However, access to driving simulators is restricted to specialists and simulators are too expensive, large, and complex to allow easy access to older drivers or physicians advising them. An easily accessible, Web-based, cognitive screening test could offer a solution to this problem. The World Wide Web allows easy dissemination of the test software and implementation of the scoring algorithm on a central server, allowing generation of a dynamically growing database with normative values and ensures that all users have access to the same up-to-date normative values. OBJECTIVE In this pilot study, we present the novel Web-based Bern Cognitive Screening Test (wBCST) and investigate whether it can predict poor simulated driving performance in healthy and cognitive-impaired participants. METHODS The wBCST performance and simulated driving performance have been analyzed in 26 healthy younger and 44 healthy older participants as well as in 10 older participants with cognitive impairment. Correlations between the two tests were calculated. Also, simulated driving performance was used to group the participants into good performers (n=70) and poor performers (n=10). A receiver-operating characteristic analysis was calculated to determine sensitivity and specificity of the wBCST in predicting simulated driving performance. RESULTS The mean wBCST score of the participants with poor simulated driving performance was reduced by 52%, compared to participants with good simulated driving performance (P<.001). The area under the receiver-operating characteristic curve was 0.80 with a 95% confidence interval 0.68-0.92. CONCLUSIONS When selecting a 75% test score as the cutoff, the novel test has 83% sensitivity, 70% specificity, and 81% efficiency, which are good values for a screening test. Overall, in this pilot study, the novel Web-based computer test appears to be a promising tool for supporting clinicians in fitness-to-drive assessments of older drivers. The Web-based distribution and scoring on a central computer will facilitate further evaluation of the novel test setup. We expect that in the near future, Web-based computer tests will become a valid and reliable tool for clinicians, for example, when assessing fitness to drive in older drivers.

Lake-level rise in the late Pleistocene and active subaquatic volcanism since the Holocene in Lake Kivu; East African Rift

The history of Lake Kivu is strongly linked to the activity of the Virunga volcanoes. Subaerial and subaquatic volcanoes, in addition to lake-level changes, shape the subaquatic morphologic and structural features in Lake Kivu's Main Basin. Previous studies revealed that volcanic eruptions blocked the former outlet of the lake to the north in the late Pleistocene, leading to a substantial rise in the lake level and subsequently the present- day thermohaline stratification. Additional studies have speculated that volcanic and seismic activities threaten to trigger a catastrophic release of the large amount of gases dissolved in the lake. The current study presents a bathymetric mapping and seismic profiling survey that covers the volcanically active area of the Main Basin at a resolution that is unprecedented for Lake Kivu. New geomorphologic features identified on the lake floor can accurately describe related lake-floor processes for the first time. The late Pleistocene lowstand is observed at 425 m depth, and volcanic cones, tuff rings, and lava flows observed above this level indicate both subaerial and subaquatic volcanic activities during the Holocene. The geomorphologic analysis yields new implications on the geologic processes that have shaped Lake Kivu's basin, and the presence of young volcanic features can be linked to the possibility of a lake overturn.

Effects of ex vivo γ-tocopherol on airway macrophage function in healthy and mild allergic asthmatics

Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate γ-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from nonsmoking healthy (n = 6) and mild house dust mite-sensitive allergic asthmatics (n = 6) were treated ex vivo with GT (300 µM) or saline (control). Phagocytosis of opsonized zymosan A bioparticles (Saccharomyces cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (p < 0.05) internalization of attached zymosan bioparticles and decreased (p < 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused downregulation of both innate and adaptive immune response elements, and atopic status appears to be an important factor.

Event-relating to potential dementia. Semantic processing in the course of healthy and pathological aging

While most healthy elderly are able to manage their everyday activities, studies showed that there are both stable and declining abilities during healthy aging. For example, there is evidence that semantic memory processes which involve controlled retrieval mechanism decrease, whereas the automatic functioning of the semantic network remains intact. In contrast, patients with Alzheimer’s disease (AD) suffer from episodic and semantic memory impairments aggravating their daily functioning. In AD, severe episodic as well as semantic memory deficits are observable. While the hallmark symptom of episodic memory decline in AD is well investigated, the underlying mechanisms of semantic memory deterioration remain unclear. By disentangling the semantic memory impairments in AD, the present thesis aimed to improve early diagnosis and to find a biomarker for dementia. To this end, a study on healthy aging and a study with dementia patients were conducted investigating automatic and controlled semantic word retrieval. Besides the inclusion of AD patients, a group of participants diagnosed with semantic dementia (SD) – showing isolated semantic memory loss – was assessed. Automatic and controlled semantic word retrieval was measured with standard neuropsychological tests and by means of event-related potentials (ERP) recorded during the performance of a semantic priming (SP) paradigm. Special focus was directed to the N400 or N400-LPC (late positive component) complex, an ERP that is sensitive to the semantic word retrieval. In both studies, data driven topographical analyses were applied. Furthermore, in the patient study, the combination of the individual baseline cerebral blood flow (CBF) with the N400 topography of each participant was employed in order to relate altered functional electrophysiology to the pathophysiology of dementia. Results of the aging study revealed that the automatic semantic word retrieval remains stable during healthy aging, the N400-LPC complex showed a comparable topography in contrast to the young participants. Both patient groups showed automatic SP to some extent, but strikingly the ERP topographies were altered compared to healthy controls. Most importantly, the N400 was identified as a putative marker for dementia. In particular, the degree of the topographical N400 similarity was demonstrated to separate healthy elderly from demented patients. Furthermore, the marker was significantly related to baseline CBF reduction in brain areas relevant for semantic word retrieval. Summing up, the first major finding of the present thesis was that all groups showed semantic priming, but that the N400 topography differed significantly between healthy and demented elderly. The second major contribution was the identification of the N400 similarity as a putative marker for dementia. To conclude, the present thesis added evidence of preserved automatic processing during healthy aging. Moreover, a possible marker which might contribute to an improved diagnosis and lead consequently to a more effective treatment of dementia was presented and has to be further developed.