Genomic instability, DNA methylation, and natural selection in colorectal carcinogenesis.

Neoplastic transformation is increasingly understood in terms of evolutionary mechanisms, and it is now widely accepted that tumor progression involves natural selection of genetic variants occurring in the somatic environment. Here we give a review of data that substantiate this Darwinian view to tumorigenesis, with particular emphasis on recent advances related to colorectal cancer. We specifically focus on the controversies related to genomic instability and DNA methylation, and present a model, which interrelates these phenomena to the basic evolutionary concept of biology.     

Intra-articular morphine for pain relief after knee arthroscopy

BACKGROUND: Peripheral opioid analgesia is well documented. But the clinical usefulness of intra-articular morphine after surgery is uncertain. The aim of the present study was to evaluate the analgesic effects of intra-articular morphine after knee arthroscopy. METHODS: In this parallel-group, double-blind study, 90 patients were randomised to receive either morphine 1 mg, morphine 2 mg or placebo in 5 ml saline intra-articularly at the end of arthroscopic knee surgery. Anaesthetic technique was local infiltration and intra-articular injection of lidocaine. Analgesic efficacy was evaluated by a global pain score, pain intensity (visual analogue scale), and analgesic requirements (paracetamol) during the first 48 h postoperatively. RESULTS: No significant differences between the groups were found for any of the efficacy variables. A majority of the patients had mild pain throughout the study, thus possibly compromising study sensitivity. In a subgroup with more intense pain early after arthroscopy, intra-articular morphine 2 mg reduced pain intensity (P < 0.05) and analgesic requirements (P < 0.05) compared with placebo. CONCLUSION: Postoperative analgesic effect of intra-articular morphine was found only in a subgroup of patients with higher pain intensity in the immediate postanaesthetic period. Possible reasons for our overall negative findings include low study sensitivity due to weak pain stimulus, lack of inflammation that may be a prerequisite for peripheral opioid analgesia, and the local anaesthetic, which impedes local inflammatory reaction and expression of peripheral opioid receptors. These factors may also explain the conflicting results in other studies.     

Methylprednisolone and ketorolac rapidly reduce hyperalgesia around a skin burn injury and increase pressure pain thresholds

BACKGROUND: Glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) decrease acute postoperative pain and hyperalgesia. The objectives of this study were to investigate the effects of methylprednisolone and ketorolac on hyperalgesia around a skin burn injury and on pressure pain thresholds. METHODS: In a double-blind, placebo-controlled, randomized trial with cross-over design, methylprednisolone 125 mg, ketorolac 60 mg or placebo was administered intravenously in 12 male volunteers on three separate days at least 4 days apart. Primary and secondary hyperalgesia were produced by a first-degree burn injury on abdominal skin 45 min before injection of the test medicines. The area of secondary mechanical hyperalgesia outside the site of injury was measured. Pressure pain stimuli were applied on the base of a fingernail, increasing until the pressure pain detection threshold (PPDT) and pressure pain tolerance threshold (PPTT) were reached. RESULTS: Compared with placebo, the active drugs reduced the area of secondary hyperalgesia (methylprednisolone, P < 0.001; ketorolac, P < 0.01). Ketorolac but not methylprednisolone increased PPDT compared with placebo (P < 0.05). Both active drugs increased PPTT compared with placebo (methylprednisolone, P < 0.01; ketorolac, P < 0.001). Ketorolac increased PPTT more than methylprednisolone (P < 0.05). CONCLUSIONS: Methylprednisolone and ketorolac increased PPTT attenuated secondary hyperalgesia around a skin burn injury. PPTT increased after both methylprednisolone and ketorolac. The present study demonstrates analgesic and anti-hyperalgesic properties of a glucocorticoid and a non-selective NSAID that have not been demonstrated previously in human subjects.     

Moderate-to-severe pain after knee arthroscopy is relieved by intraarticular saline: a randomized controlled trial

We have previously studied intraarticular (IA) analgesics compared with saline 10 mL in 2 randomized clinical trials. The patients who were given IA saline experienced rapid pain relief. Hypothetically, saline may produce a local analgesic effect by cooling or by diluting IA algogenic substances. This randomized double-blind study compared the analgesic effect of IA saline 10 mL with saline 1 mL, which should be a pure placebo. A soft catheter was left IA in 79 patients. We included 60 patients who developed moderate-to-severe pain within 1 h after knee arthroscopy under general anesthesia. A randomized, double-blind controlled comparison of IA saline 10 mL with saline 1 mL followed. Outcome measures were pain intensity, pain relief, and analgesic consumption. Within 1 h pain intensity decreased in both groups from approximately 50 to approximately 27 on a 0-100 mm visual analog scale. Pain intensity remained low and other pain outcome measures were similar during the 36-h observation period. The patients experienced equally good pain relief after IA injection of saline 10 mL and 1 mL. Our finding of a major placebo effect may have implications for the interpretation of previously published placebo-controlled IA analgesia studies. IMPLICATIONS: In a randomized controlled trial we showed that pain after knee arthroscopy is modest and short-lived and can successfully be treated with intraarticular saline as placebo.     

Stability of an epidural analgesic solution containing adrenaline, bupivacaine and fentanyl

BACKGROUND: A low dose solution of adrenaline 2 microg x ml(-1), fentanyl 2 microg x ml(-1) and bupivacaine 1 mg x ml(-1) has been reported to give superior pain control when used for epidural analgesia after major surgery. The present paper describes the compounding and chemical stability of this triple-component solution during storage and use. METHODS: Sterile triple-component concentrates (11X) were diluted by the use of gas isolator technology to give ready-to-use infusion solutions. Eight solutions were analysed by reverse phase high-performance liquid chromatography (HPLC) methods, and assays were performed on 1, 45, 90 and 180 days after storage at 2-8 degrees C. After 180 days the solutions were subsequently stored at 22 degrees C for four days before they were reanalysed. HPLC quantification of adrenaline was also performed on samples from solutions given to 28 different patients. RESULTS: The concentration of adrenaline and fentanyl decreased approximately 3.5% from 1 to 180 days at 4 degrees C and four days at 22 degrees C. The corresponding figure for bupivacaine was an apparent increase by 2.4% in concentration. No absorption to the polypropylene plastic bags of fentanyl and bupivacaine was detected. None of the 28 samples derived from used infusion bags contained less than 95% of the declared content of adrenaline. CONCLUSIONS: The triple-component epidural analgesic solution remained stable during six months of cold storage, followed by four days of storage at room temperature. No significant degradation of adrenaline was observed in infusion solutions returned from the wards.     

The relationship of some negative events and psychological factors to periodontal disease in an adult Swedish population 50 to 80 years of age

Background: Clinical observations and epidemiological studies suggest that experiences of negative life events, especially those manifested as depression, may contribute to an increased susceptibility to periodontal disease. Objective: In the present study, the prevalence of some negative life events and psychological factors and their relation to periodontal disease were investigated. The sample consisted of individuals 50–80 years of age from an extensive cross‐sectional epidemiological study performed in 1993 in the city of Jönköping, Sweden. Method: 298 dentate individuals from the Jönköping study were randomly selected. Clinical and radiographic examinations included registration of the number of existing teeth, plaque index, gingival index, pocket depth, and alveolar bone loss. In addition, a questionnaire about socioeconomic status, life events, and psychological and stress‐related factors was used. Results: The results revealed that, in addition to the well‐documented periodontal disease risk factors such as increased age, oral hygiene status, and smoking, the loss of a spouse (being a widow or widower) and the personality trait of exercising extreme external control were also associated with severe periodontal disease. Conclusion: The findings support recent studies suggesting that traumatic life events such as the loss of a spouse may increase the risk for periodontal disease. Above all, the present results indicate that an individual's ability to cope with stressful stimuli (coping behavior), as measured by the beliefs of locus of control of reinforcements may play a role in the progression of periodontal disease.     

Effects of hippocampal lesioning on experimental periodontitis in Wistar rats

The hippocampus, which is a brain structure involved in learning and memory processes, plays a key role in the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic sympathetic nervous system, and the subsequent secretion of immuno-modulatory hormones in response to pathogenic microorganisms. Dysregulation of these brain-neuroendocrine-immune regulatory networks, which act in concert to maintain homeostasis, is found to be of critical importance to the host defence against pathogens, as well as susceptibility to diseases, including periodontal disease. The present study was designed to determine the effects of hippocampal lesioning on the progression of periodontitis. Experimental ligature-induced periodontitis was induced in 16 Wistar rats, which were bilaterally lesioned in their hippocampal region with an aspiration technique that is well documented to impair learning and memory, as well as in 15 sham-operated control rats. The disease progression was evaluated radiographically and histometrically. The results revealed that the hippocampal lesioned rats developed significantly more destruction of the periodontium than did the sham-operated controls. This finding supports recent studies that indicate that inappropriate brain-neuroendocrine regulation of inflammatory responses to infectious agents may play an important role in disease susceptibility and progression.