Plasma concentrations of morphine,morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain

Morphine, the recommended drug for the management of moderate to severe cancer pain, is metabolized predominantly to the glucuronides morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). The quantitative clinical importance of these metabolites following the administration of oral morphine is unclear. This study investigates the relationship between plasma concentrations of morphine (M), M6G, M3G and clinical effects in patients receiving sustained release oral morphine for cancer-related pain. Peak and trough plasma concentrations of morphine and its metabolites were determined by high-performance liquid chromatography (HPLC). At corresponding time points, pain [Visual Analogue Scales (VAS), Verbal Rating Scales (VRS), Pain Relief Scores (PRS)] and toxicity (VAS and VRS) were assessed. Renal and liver function tests were performed. Forty-six patients were included in the study. There was a significant correlation between dose and both peak and trough plasma M, M6G and M3G (r > 0.60, P < 0.001 for each). Differences between peak and trough M, M6G, M3G, M+M6G, M6G:M, M3G:M and M3G:M6G were all significant (P < 0.001 for each). Pain was generally well controlled in the group, with a median VAS of 15 mm at the peak blood sampling time point. The differences between peak and trough values for VAS pain, VAS nausea and VAS drowsiness were not statistically significant (P = 0.078, 0.45 and 0.099, respectively). There were no differences in peak or trough morphine and metabolite concentrations or ratios between patients with low (< median) or high pain scores. Similarly, there was no significant relationship between high and low plasma concentrations and clinical effect. This study did not identify a simple relationship between plasma concentrations of morphine, morphine metabolites or metabolite ratios and clinical effects in patients with cancer and pain who were receiving chronic oral morphine therapy. Although overall pain control was good, there was marked interpatient variability in the dose of morphine and the plasma concentrations necessary to achieve this degree of analgesia.     

Anti‐smoking advertisements are perceived differently by smokers and individuals with health or advertising knowledge

Objective: Several studies have examined the characteristics of anti‐smoking advertisements that are associated with quitting behaviour. Some studies use researchers or graduate students to code advertisement characteristics, while others recruit smokers or members of the general public. The aim of this study was to assist future campaign development by assessing whether anti‐smoking advertisement characteristics are coded differently by smokers and ‘experts’ (individuals with knowledge of health promotion, public health or advertising). Methods: A total of 49 smokers and 42 experts coded anti‐smoking advertisements according to four key characteristics (emotional/cognitive approach, negative/positive tone, message frame, and main message) and the use of eight executional techniques. Chi‐squared tests were used to measure differences in coding outcomes between smokers and experts. Results: There were significant differences between smokers and experts in the coding of all key characteristics and four of the eight executional techniques. Compared with smokers, experts were more likely to perceive advertisements as negative in tone and as inducing fear. Conclusions: Smokers and experts perceived the characteristics of anti‐smoking advertisements differently. Implications for public health: Differences between smokers and experts may need to be taken into account where studies use either of these groups to code advertisements for campaign development or evaluation purposes.     

Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility

BACKGROUND: Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL). METHODS: To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD. RESULTS: We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P = 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex. CONCLUSION: The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.     

A Molecular Analysis of Fecal and Mucosal Bacterial Communities in Irritable Bowel Syndrome

Purpose  

The objectives of this study were, firstly, to determine the diversity of the host’s gut microbiota in irritable bowel syndrome (IBS) using a culture-independent method (DGGE of the 16S rRNA gene) and, secondly, to examine mucosal biopsies of IBS patients and compare them to their own fecal microbiota.     

Small intestinal bacterial overgrowth

Despite the current increase in interest in the role of the microbiota in health and disease and the recognition, for over 50 years, that an excess of colonic-type flora in the small intestine could lead to a malabsorption syndrome, small intestinal overgrowth remains poorly defined. This lack of clarity owes much to the difficulties that arise in attempting to arrive at consensus with regard to the diagnosis of this condition: there is currently no gold standard and the commonly available methodologies (the culture of jejunal aspirates and a variety of breath tests) suffer from considerable variations in their performance and interpretation, leading to variations in the prevalence of overgrowth in a variety of clinical contexts. Treatment is similarly supported by a scant evidence base and the most commonly used antibiotic regimens owe more to custom than clinical trials.     

Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome

Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a>50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in approximately 25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC.     

Genetic and Epigenetic Analysis of Recurrent Hydatidiform Mole

Familial biparental hydatidiform mole (FBHM) is a maternal‐effect autosomal recessive disorder in which recurrent pregnancy failure with molar degeneration occurs. The phenotype mimics molar pregnancy due to androgenesis, despite the normal genetic makeup of the conceptus. FBHM appears to result from a failure to establish correct maternal epigenetic identity at imprinted loci during oogenesis. Several women affected with FBHM have previously been shown to have biallelic mutations in the NLRP7 gene (NALP7). Here, we present the results of epigenetic and mutational analysis on FBHM patients from 11 families, 10 of them novel. We demonstrate a methylation defect at imprinted loci in tissue from four new FBHM cases. Biallelic NLRP7 mutations, including eight previously undescribed mutations, were found in all but one family. These results indicate for the first time that maternal imprints at some loci may be correctly specified in FBHM conceptions, since differential methylation of SGCE/PEG10 was preserved in all four cases. © 2009 Wiley‐Liss, Inc.     

Carotid plaque, stroke pathogenesis, and CRP: Treatment of ischemic stroke

Opinion statement  Inflammation is receiving increased attention as a cause of atherosclerosis and stroke. Several inflammatory biomarkers, and particularly high-sensitivity C-reactive protein (hsCRP), have been identified as likely predictors of the risk of a future stroke. In clinical settings, it has been consistently observed that higher concentrations of CRP are associated with larger brain infarcts, stroke severity, neurologic disability, and future vascular events. However, there is still controversy over the degree of risk conferred by elevated CRP concentrations. Some studies reported that the predictive value of CRP is moderate compared with classical risk factors and is only weakly related to cardiovascular damage after adjustment for traditional cardiovascular risk factors. CRP like many other hemostatic factors is an acute-phase protein and, therefore, it is not always clear whether its association with cerebrovascular disease reflects its contribution to atherothrombosis, its acute-phase condition, or both. Furthermore, the value of single measurements of CRP in patients with concurrent infection or other inflammatory conditions has not been established and reported data should be interpreted cautiously. Several drugs, especially hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), have been demonstrated to reduce hsCRP levels independently of their effects on plasma cholesterol. Recently, emerging therapies have been aimed at the control of blood pressure and inflammation in stroke patients. Whether a reduction of hsCRP levels could be beneficial to stroke patients remains to be clarified, and it is also unclear whether other drugs may be useful to lower hsCRP levels. More studies are needed before hsCRP becomes a routine part of the evaluation of stroke patients. This should also prompt the search for new agents directly blocking CRP actions.     

Impact of pregnancy and parturition on the anal sphincters and pelvic floor

Incontinence and defecatory difficulties are commonly reported among women and are often ascribed to traumas sustained during childbirth. Specifically, injuries to the anal sphincters (tears) and conformational changes in the various structures that comprise the pelvic floor (prolapse and perineal descent) have been considered as important contributors to the development of anal incontinence, or difficult defaecation (straining, incomplete evacuation), in later life. An understanding of both the effects of pregnancy and parturition on these structures and the natural history of any traumas sustained are, therefore, of key importance. Unfortunately, the literature on these issues, though vast, is far from complete. While it is evident that pregnancy, per se, imposes changes, primarily through hormonal influences, on colonic, ano-rectal and pelvic floor physiology, the long-term impact of such effects is far from clear. Risk factors for the occurrence of significant, though often occult, anal sphincter injuries during birth have been identified and the role of these tears in the etiology of post-partum incontinence has been well delineated. In contrast, the contribution of such intra-partum events to the later onset of incontinence is far from clear and may well have been over-estimated.