Functions and effects of creatine in the central nervous system

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.

The role of purinergic signaling in the liver and in transplantation: effects of extracellular nucleotides on hepatic graft vascular injury, rejection and metabolism

Extracellular nucleotides (e.g. ATP, UTP, ADP) are released by activated endothelium, leukocytes and platelets within the injured vasculature and bind specific cell-surface type-2 purinergic (P2) receptors. This process drives vascular inflammation and thrombosis within grafted organs. Importantly, there are also vascular ectonucleotidases i.e. ectoenzymes that hydrolyze extracellular nucleotides in the blood to generate nucleosides (viz. adenosine). Endothelial cell NTPDase1/CD39 has been shown to critically modulate levels of circulating nucleotides. This process tends to limit the activation of platelet and leukocyte expressed P2 receptors and also generates adenosine to reverse inflammatory events. This vascular protective CD39 activity is rapidly inhibited by oxidative reactions, such as is observed with liver ischemia reperfusion injury. In this review, we chiefly address the impact of these signaling cascades following liver transplantation. Interestingly, the hepatic vasculature, hepatocytes and all non-parenchymal cell types express several components co-ordinating the purinergic signaling response. With hepatic and vascular dysfunction, we note heightened P2- expression and alterations in ectonucleotidase expression and function that may predispose to progression of disease. In addition to documented impacts upon the vasculature during engraftment, extracellular nucleotides also have direct influences upon liver function and bile flow (both under physiological and pathological states). We have recently shown that alterations in purinergic signaling mediated by altered CD39 expression have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses. Future clinical applications in transplantation might involve new therapeutic modalities using soluble recombinant forms of CD39, altering expression of this ectonucleotidase by drugs and/or using small molecules to inhibit deleterious P2-mediated signaling while augmenting beneficial adenosine-mediated effects within the transplanted liver.

Entropy and bispectral index for assessment of sedation, analgesia and the effects of unpleasant stimuli in critically ill patients: an observational study

INTRODUCTION: Sedative and analgesic drugs are frequently used in critically ill patients. Their overuse may prolong mechanical ventilation and length of stay in the intensive care unit. Guidelines recommend use of sedation protocols that include sedation scores and trials of sedation cessation to minimize drug use. We evaluated processed electroencephalography (response and state entropy and bispectral index) as an adjunct to monitoring effects of commonly used sedative and analgesic drugs and intratracheal suctioning. METHODS: Electrodes for monitoring bispectral index and entropy were placed on the foreheads of 44 critically ill patients requiring mechanical ventilation and who previously had no brain dysfunction. Sedation was targeted individually using the Ramsay Sedation Scale, recorded every 2 hours or more frequently. Use of and indications for sedative and analgesic drugs and intratracheal suctioning were recorded manually and using a camera. At the end of the study, processed electroencephalographical and haemodynamic variables collected before and after each drug application and tracheal suctioning were analyzed. Ramsay score was used for comparison with processed electroencephalography when assessed within 15 minutes of an intervention. RESULTS: The indications for boli of sedative drugs exhibited statistically significant, albeit clinically irrelevant, differences in terms of their association with processed electroencephalographical parameters. Electroencephalographical variables decreased significantly after bolus, but a specific pattern in electroencephalographical variables before drug administration was not identified. The same was true for opiate administration. At both 30 minutes and 2 minutes before intratracheal suctioning, there was no difference in electroencephalographical or clinical signs in patients who had or had not received drugs 10 minutes before suctioning. Among patients who received drugs, electroencephalographical parameters returned to baseline more rapidly. In those cases in which Ramsay score was assessed before the event, processed electroencephalography exhibited high variation. CONCLUSIONS: Unpleasant or painful stimuli and sedative and analgesic drugs are associated with significant changes in processed electroencephalographical parameters. However, clinical indications for drug administration were not reflected by these electroencephalographical parameters, and barely by sedation level before drug administration or tracheal suction. This precludes incorporation of entropy and bispectral index as target variables for sedation and analgesia protocols in critically ill patients.

Does aortic crossclamping during the cooling phase affect the early clinical outcome of acute type A aortic dissection?

OBJECTIVES: The purpose of this study is to evaluate the effects of crossclamping the ascending aorta in acute type A aortic dissection during the cooling phase for deep hypothermic arrest on early clinical outcome. METHODS: The records of 275 consecutive patients who underwent surgery for acute type A aortic dissection were reviewed. Ten patients have been excluded. Overall, 265 patients who underwent surgery under deep hypothermia and circulatory arrest in the "open technique" were divided retrospectively into two groups: those who underwent surgery with crossclamping of the ascending aorta during the cooling phase at the begin of the procedure (group 1, n = 191; 72.1 %) and those in whom the aorta was not clamped (group 2, n = 74; 27.9 %). RESULTS: Preoperative characteristics were similar in both groups. In group 1, femoral artery cannulation, composite graft repair, and aortic arch replacement were significantly more frequent. In-hospital mortality was 15.2 % in group 1 and 17.6 % in group 2 (P = not significant). Neurologic deficits were observed in 9.4% in group 1 and in 10.8% in group 2 (= not significant). There were no significant differences in clinical outcome between the two groups of patients. CONCLUSIONS: This study demonstrates that both options, aortic crossclamping or noclamping, may be used during the induction of deep hypothermia to repair acute type A aortic dissections with similar early clinical outcome. For the selection of the most appropriate technique, we recommend case by case evaluation, weighing the potential risks and benefits of aortic crossclamping.

Effects of the glucocorticoid antagonist, mifepristone, on the consequences of withdrawal from long term alcohol consumption

BACKGROUND: Studies were carried out to test the hypothesis that administration of a glucocorticoid Type II receptor antagonist, mifepristone (RU38486), just prior to withdrawal from chronic alcohol treatment, would prevent the consequences of the alcohol consumption and withdrawal in mice. MATERIALS AND METHODS: The effects of administration of a single intraperitoneal dose of mifepristone were examined on alcohol withdrawal hyperexcitability. Memory deficits during the abstinence phase were measured using repeat exposure to the elevated plus maze, the object recognition test, and the odor habituation/discrimination test. Neurotoxicity in the hippocampus and prefrontal cortex was examined using NeuN staining. RESULTS: Mifepristone reduced, though did not prevent, the behavioral hyperexcitability seen in TO strain mice during the acute phase of alcohol withdrawal (4 hours to 8 hours after cessation of alcohol consumption) following chronic alcohol treatment via liquid diet. There were no alterations in anxiety-related behavior in these mice at 1 week into withdrawal, as measured using the elevated plus maze. However, changes in behavior during a second exposure to the elevated plus maze 1 week later were significantly reduced by the administration of mifepristone prior to withdrawal, indicating a reduction in the memory deficits caused by the chronic alcohol treatment and withdrawal. The object recognition test and the odor habituation and discrimination test were then used to measure memory deficits in more detail, at between 1 and 2 weeks after alcohol withdrawal in C57/BL10 strain mice given alcohol chronically via the drinking fluid. A single dose of mifepristone given at the time of alcohol withdrawal significantly reduced the memory deficits in both tests. NeuN staining showed no evidence of neuronal loss in either prefrontal cortex or hippocampus after withdrawal from chronic alcohol treatment. CONCLUSIONS: The results suggest mifepristone may be of value in the treatment of alcoholics to reduce their cognitive deficits.

Effects of cognitive behavioral stress management on HIV-1 RNA, CD4 cell counts and psychosocial parameters of HIV-infected persons

OBJECTIVE: To determine the effects of cognitive-behavioral stress management (CBSM) training on clinical and psychosocial markers in HIV-infected persons. METHODS: A randomized controlled trial in four HIV outpatient clinics of 104 HIV-infected persons taking combination antiretroviral therapy (cART), measuring HIV-1 surrogate markers, adherence to therapy and well-being 12 months after 12 group sessions of 2 h CBSM training. RESULTS: Intent-to-treat analyses showed no effects on HIV-1 surrogate markers in the CBSM group compared with the control group: HIV-1 RNA < 50 copies/ml in 81.1% [95% confidence interval (CI), 68.0-90.6] and 74.5% (95% CI, 60.4-85.7), respectively (P = 0.34), and mean CD4 cell change from baseline of 53.0 cells/microl (95% CI, 4.1-101.8) and 15.5 cells/microl (95% CI, -34.3 to 65.4), respectively (P = 0.29). Self-reported adherence to therapy did not differ between groups at baseline (P = 0.53) or at 12 month's post-intervention (P = 0.47). Significant benefits of CBSM over no intervention were observed in mean change of quality of life scores: physical health 2.9 (95% CI, 0.7-5.1) and -0.2 (95% CI, -2.1 to 1.8), respectively (P = 0.05); mental health 4.8 (95% CI, 1.8-7.3) and -0.5 (95% CI, -3.3 to 2.2) (P = 0.02); anxiety -2.1 (95% CI, -3.6 to -1.0) and 0.3 (95% CI, -0.7 to 1.4), respectively (P = 0.002); and depression -2.1 (95% CI, -3.2 to -0.9) and 0.02 (95% CI, -1.0 to 1.1), respectively (P = 0.001). Alleviation of depression and anxiety symptoms were most pronounced among participants with high psychological distress at baseline. CONCLUSION: CBSM training of HIV-infected persons taking on cART does not improve clinical outcome but has lasting effects on quality of life and psychological well-being.

Effects of gender and dementia severity on Alzheimer's disease caregivers' sleep and biomarkers of coagulation and inflammation

BACKGROUND: Being a caregiver for a spouse with Alzheimer's disease is associated with increased risk for cardiovascular illness, particularly for males. This study examined the effects of caregiver gender and severity of the spouse's dementia on sleep, coagulation, and inflammation in the caregiver. METHODS: Eighty-one male and female spousal caregivers and 41 non-caregivers participated (mean age of all participants 70.2 years). Full-night polysomnography (PSG) was recorded in each participants home. Severity of the Alzheimer's disease patient's dementia was determined by the Clinical Dementia Rating (CDR) scale. The Role Overload scale was completed as an assessment of caregiving stress. Blood was drawn to assess circulating levels of D-dimer and Interleukin-6 (IL-6). RESULTS: Male caregivers who were caring for a spouse with moderate to severe dementia spent significantly more time awake after sleep onset than female caregivers caring for spouses with moderate to severe dementia (p=.011), who spent a similar amount of time awake after sleep onset to caregivers of low dementia spouses and to non-caregivers. Similarly, male caregivers caring for spouses with worse dementia had significantly higher circulating levels of D-dimer (p=.034) than females caring for spouses with worse dementia. In multiple regression analysis (adjusted R(2)=.270, p<.001), elevated D-dimer levels were predicted by a combination of the CDR rating of the patient (p=.047) as well as greater time awake after sleep onset (p=.046). DISCUSSION: The findings suggest that males caring for spouses with more severe dementia experience more disturbed sleep and have greater coagulation, the latter being associated with the disturbed sleep. These findings may provide insight into why male caregivers of spouses with Alzheimer's disease are at increased risk for illness, particularly cardiovascular disease.

Effects of decontamination and implant surface characteristics on re-osseointegration following treatment of peri-implantitis

BACKGROUND: Although considerable bone fill may occur following treatment of peri-implantitis, re-osseointegration appears to be limited and unpredictable. Objectives: To evaluate the effects of various decontamination techniques and implant surface configurations on re-osseointegration of contaminated dental implants. MATERIAL AND METHODS: Three months after tooth extraction, implants consisting of a basal part and an exchangeable intraosseous implant cylinder (EIIC) were placed in the mandibles of dogs. The EIIC was machined (M), sandblasted and acid-etched (SLA), or titanium plasma sprayed (TPS). Ligature-induced peri-implantitis was initiated 8 weeks post-implantation and lasted until bone loss reached the junction of the two implant parts. Three treatment modalities were applied: (T1) the EIIC was exchanged for a pristine EIIC; (T2) the EIIC was sprayed in situ with saline; and (T3) the EIIC was removed, cleansed outside the mouth by spraying with saline, steam-sterilized, and remounted. A collagen barrier was placed over each fixture, and 3 months later, samples were processed for histology and histomorphometry. RESULTS: T2 revealed the highest bone-to-implant contact (BIC) level (significantly better than T1 and T3). T2 also yielded the highest bone crest level (significantly better than T1), followed by T3 (significantly better than T1). SLA showed the highest BIC level (significantly better than M), followed by TPS. There were no statistically significant differences in bone crest height between implant types. CONCLUSIONS: Both SLA implants and in situ cleansing resulted in the best re-osseointegration and bone fill of previously contaminated implants.

A systematic review of the clinical performance of CAD/CAM single-tooth restorations

PURPOSE: This systematic review sought to determine the long-term clinical survival rates of single-tooth restorations fabricated with computer-aided design/computer-assisted manufacture (CAD/CAM) technology, as well as the frequency of failures depending on the CAD/CAM system, the type of restoration, the selected material, and the luting agent. MATERIALS AND METHODS: An electronic search from 1985 to 2007 was performed using two databases: Medline/PubMed and Embase. Selected keywords and well-defined inclusion and exclusion criteria guided the search. All articles were first reviewed by title, then by abstract, and subsequently by a full text reading. Data were assessed and extracted by two independent examiners. The pooled results were statistically analyzed and the overall failure rate was calculated by assuming a Poisson-distributed number of events. In addition, reported failures were analyzed by CAD/CAM system, type of restoration, restorative material, and luting agent. RESULTS: From a total of 1,957 single-tooth restorations with a mean exposure time of 7.9 years and 170 failures, the failure rate was 1.75% per year, estimated per 100 restoration years (95% CI: 1.22% to 2.52%). The estimated total survival rate after 5 years of 91.6% (95% CI: 88.2% to 94.1%) was based on random-effects Poisson regression analysis. CONCLUSIONS: Long-term survival rates for CAD/CAM single-tooth Cerec 1, Cerec 2, and Celay restorations appear to be similar to conventional ones. No clinical studies or randomized clinical trials reporting on other CAD/CAM systems currently used in clinical practice and with follow-up reports of 3 or more years were found at the time of the search.

Mechanical non-surgical treatment of peri-implantitis: a double-blind randomized longitudinal clinical study. I: clinical results

BACKGROUND: Peri-implantitis is a frequent finding in patients with dental implants. The present study compared two non-surgical mechanical debridement methods of peri-implantitis. MATERIAL AND METHODS: Thirty-seven subjects (mean age 61.5; S.D+/-12.4), with one implant each, demonstrating peri-implantitis were randomized, and those treated either with titanium hand-instruments or with an ultrasonic device were enrolled. Data were obtained before treatment, and at 1, 3, and 6 months. Parametric and non-parametric statistics were used. RESULTS: Thirty-one subjects completed the study. The mean bone loss at implants in both groups was 1.5 mm (SD +/-1.2 mm). No group differences for plaque or gingival indices were found at any time point. Baseline and 6-month mean probing pocket depths (PPD) at implants were 5.1 and 4.9 mm (p=0.30) in both groups. Plaque scores at treated implants decreased from 73% to 53% (p<0.01). Bleeding scores also decreased (p<0.01), with no group differences. No differences in the total bacterial counts were found over time. Higher total bacterial counts were found immediately after treatment (p<0.01) and at 1 week for ultrasonic-treated implants (p<0.05). CONCLUSIONS: No group differences were found in the treatment outcomes. While plaque and bleeding scores improved, no effects on PPD were identified.

One-year outcomes of repeated adjunctive photodynamic therapy during periodontal maintenance: a proof-of-principle randomized-controlled clinical trial

BACKGROUND: Single photodynamic therapy (PDT) has been effective in initial periodontal therapy, but only improved bleeding on probing (BoP) in maintenance patients after a single use. Repeated PDT has not been addressed. OBJECTIVES: To study the possible added benefits of repeated adjunctive PDT to conventional treatment of residual pockets in patients enrolled in periodontal maintenance. MATERIAL AND METHODS: Ten maintenance patients with 70 residual pockets [probing pocket depth (PPD)>or=5 mm] were randomly assigned for treatment five times in 2 weeks (Days 0, 1, 2, 7, 14) with PDT (test) or non-activated laser (control) following debridement. The primary outcome variable was PPD, and the secondary variables were clinical attachment level (CAL) and BoP. These were assessed at 3, 6 and 12 months following the interventions. RESULTS: Greater PPD reductions were observed in the test (-0.67 +/- 0.34; p=0.01) compared with the control patients (-0.04 +/- 0.33; NS) after 6 months. Significant CAL gain (+0.52 +/- 0.31; p=0.01) was noted for the test, but not in the control (-0.27 +/- 0.52; NS) patients after 6 months. BoP percentages decreased significantly in test (97-64%, 67%, 77%), but not control patients after 3, 6 and 12 months. CONCLUSIONS: Repeated (five times) PDT adjunctive to debridement yielded improved clinical outcomes in residual pockets in maintenance patients. The effects were best documented after 6 months.

Comparison of the immediate effects of gaseous ozone and chlorhexidine gel on bacteria in cavitated carious lesions in children in vivo

Clinical application of ozone gas has been shown to arrest the progression of dentinal caries in children. In this study, we compare the immediate effects of gaseous ozone and chlorhexidine gel on bacteria in cavitated carious lesions in children. Forty children, each with at least two open occlusal carious lesions, were enrolled in the study. Two teeth were chosen randomly. In one lesion, overlying soft biological material was removed, whilst the other lesion was not excavated. Cavities were rinsed with sterile water and dried with air. A standardised sample was taken from the mesial part of each lesion. Then, gaseous ozone (HealOzone) or 1% chlorhexidine gel (Corsodyl) was applied for 30 s on both lesions of 20 children each, and a second sample was taken from the distal part of each lesion. The anaerobic microbiota was cultivated; the number of colony forming units was calculated per milligram sample. The two-sided paired t test showed no significant (P > 0.05) differences in the reduction of total bacterial counts per milligram comparing samples before and after ozone or chlorhexidine application. The tests also showed no statistically significant difference whether the superficial decayed dentine had been removed before ozone or with chlorhexidine treatment or not. It can be concluded that gaseous ozone or chlorhexidine gel application for 30 s to deep occlusal carious cavities had no significant immediate antimicrobial effects whether the superficial decayed layers dentine were removed or not.

Oral hygiene indirect instruction and periodic reinforcements: effects on index plaque in schoolchildren

The aim of this study was to evaluate the effectiveness of the indirect instruction and the influence of the periodic reinforcement on the plaque index in schoolchildren. Forty schoolchildren aged from 7 to 9 years old were selected from a public school. After determining the initial O'Leary Plaque Index all schoolchildren were submitted to a program for oral hygiene through indirect instruction -"The Smiling Robot". The schoolchildren were divided into 2 groups: with and without motivation reinforcement. The index plaque exam was performed in both groups after 30, 60 and 90 days of the educational program. Comparing the groups, the plaque index decreasing could be observed in the group with reinforcement with statistically significant difference. For the group with reinforcement, statistically significant difference among the evaluations was found. For the group without reinforcement, significant decrease in the plaque index was found after 30 days when compared to the first, third and fourth evaluations. The indirect instruction with "The Smiling Robot "promoted a positive initial impact on the decrease of plaque index in the schoolchildren. The periodic reinforcements showed more suitable results and significant reduction of the plaque index in the course of the evaluations.

Management of infusion reactions in clinical trials and beyond: the US and EU perspectives

Monoclonal antibodies have expanded our cancer-fighting armamentarium in both the United States and Europe. While in general, monoclonal antibodies are well tolerated and do not have significant overlapping side effects with traditional cytotoxic agents, severe infusion reactions (IRs)--sometimes severe enough to be life threatening--have been reported. The pathophysiology of severe infusion reactions associated with monoclonal antibodies is poorly understood, but mechanisms are beginning to be elucidated. Geographic differences in the incidence of IRs have become apparent. Understanding the risk, recognizing the signs and symptoms, and being ready to promptly manage severe IRs are key for the clinician to avoid unnecessarily discontinuing these effective anticancer agents and prevent potentially tragic consequences for their patients. To date, clinical trials have incorporated monoclonal antibodies into combinations with standard cytotoxic regimens; it is expected that in time clinical trials will be testing promising new combinations utilizing multiple targeted agents, resulting in improved toxicity profiles and efficacy for cancer patients.