Frequency of temporomandibular joint osteoarthritis and related symptoms in a hand osteoarthritis cohort.

OBJECTIVE: The prevalence of osteoarthritis (OA) in the temporomandibular joints (TMJs) in hand OA patients is largely unknown. Our aims were to explore (1) The frequency of TMJ-related symptoms and clinical findings; (2) The TMJ OA frequency defined by cone beam computed tomography (CBCT); and (3) The relationship between TMJ-related symptoms/clinical findings and CBCT-defined TMJ OA, in a hand OA cohort. METHODS: We calculated the frequencies of TMJ-related symptoms, clinical findings and diagnosis of TMJ OA by CBCT and clinical examination in 54 patients from the Oslo hand OA cohort (88% women, mean (range) age 71 (61-83) years). Participants with and without CBCT-defined TMJ OA were compared for differences in proportions (95% confidence interval (CI)) of symptoms and clinical findings. Sensitivity and specificity of the clinical TMJ OA diagnosis were calculated using CBCT as reference. RESULTS: Self-reported symptoms and clinical findings were found in 24 (44%) and 50 (93%) individuals (93%), respectively, whereas 7 (13%) had sought healthcare. Individuals with CBCT-defined TMJ OA (n = 36, 67%) reported statistically significantly more pain at mouth opening (22%, 95% CI 4-40%), clicking (33%, 95% CI 14-52%) and crepitus (25%, 95% CI 4-46%). By clinical examination, only crepitus was more common in TMJ OA (33%, 95% CI 29-77%). Clinical diagnosis demonstrated low sensitivity (0.42) and high specificity (0.93). CONCLUSIONS: CBCT-defined TMJ OA was common in hand OA patients, suggesting that TMJ OA may be part of generalized OA. Few had sought healthcare, despite high burden of TMJ-related symptoms/findings. Clinical examination underestimated TMJ OA frequency.

Perioperative COX-2 inhibitors may increase the risk of post-operative acute kidney injury.

BACKGROUND: In enhanced recovery protocols (ERP), a restrictive fluid regimen is proposed. Patients who undergo major surgery have an increased risk of post-operative acute kidney injury (AKI). This combination may pose difficulties when ERP is used for patients undergoing major surgery. The aim of this study was to evaluate whether patients undergoing pancreatic surgery and treated with a restrictive fluid regimen are at greater risk of post-operative AKI. Furthermore, if there was an increased risk of AKI, we aimed to identify its cause. METHODS: We reviewed the medical records of patients who underwent pancreatic surgery during 2014 (preERP, n = 58) and 2015 (ERP, n = 65). Fluid balance, the administration of cyclooxygenase-2 inhibitors, creatinine levels and mean arterial pressure were recorded. The Kidney Disease: Improving Global Outcomes criteria were used to define AKI. RESULTS: The incidence of AKI was higher in the ERP group than in the PreERP group (12.5% vs. 1.8%, respectively, P = 0.035). The increased incidence of AKI could not be explained by differences in comorbidities, age, pre-operative creatinine or perioperative hypotension. Administration of coxibs was higher in the ERP group and was associated with increased incidence of post-operative AKI (P = 0.018). The combination of coxibs and restrictive fluid regimen seems particularly harmful. CONCLUSION: Pancreatic surgery with a restrictive fluid regimen carries an increased risk of post-operative AKI if patients are also treated with cyclooxygenase-2 inhibitors. It is therefore suggested that in protocols including a restrictive fluid regimen for open pancreatic surgery, the use of cyclooxygenase-2 inhibitors should be avoided.

Temporomandibular joint diagnostics using CBCT.

The present review will give an update on temporomandibular joint (TMJ) imaging using CBCT. It will focus on diagnostic accuracy and the value of CBCT compared with other imaging modalities for the evaluation of TMJs in different categories of patients; osteoarthritis (OA), juvenile OA, rheumatoid arthritis and related joint diseases, juvenile idiopathic arthritis and other intra-articular conditions. Finally, sections on other aspects of CBCT research related to the TMJ, clinical decision-making and concluding remarks are added. CBCT has emerged as a cost- and dose-effective imaging modality for the diagnostic assessment of a variety of TMJ conditions. The imaging modality has been found to be superior to conventional radiographical examinations as well as MRI in assessment of the TMJ. However, it should be emphasized that the diagnostic information obtained is limited to the morphology of the osseous joint components, cortical bone integrity and subcortical bone destruction/production. For evaluation of soft-tissue abnormalities, MRI is mandatory. There is an obvious need for research on the impact of CBCT examinations on patient outcome.

The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects.

UNLABELLED: Suboptimal gastrointestinal absorption is a problem for many direct thrombin inhibitors. The studies presented herein describe the new oral direct thrombin inhibitor H 376/95, a prodrug with two protecting residues added to the direct thrombin inhibitor melagatran. Absorption properties in vitro: H 376/95 is uncharged at intestinal pH while melagatran is charged. H 376/95 is 170 times more lipophilic (octanol water partition coefficient) than melagatran. As a result, the permeability coefficient across cultured epithelial Caco-2 cells is 80 times higher for H 376/95 than for melagtran. Pharmacokinetic studies in healthy volunteers: H 376/95 is converted to melagatran in man. Oral bioavailability, measured as melagatran in plasma, is about 20% after oral administration of H 376/95, which is 2.7-5.5 times higher than after oral administration of melagatran. The variability in the area under the drug plasma concentration vs. time curve (AUC) is much smaller with oral H 376/95 (coefficient of variation 20%) than with oral melagatran (coefficient of variation 38%). Pharmacodynamic properties: H 376/95 is inactive towards human alpha-thrombin compared with melagatran [inhibition constant (K(i)) ratio, 185 times], a potential advantage for patients with silent gastrointestinal bleeding. In an experimental thrombosis model in the rat, oral H 376/95 was more effective than the subcutaneous low molecular weight heparin dalteparin in preventing thrombosis. CONCLUSION: By the use of the prodrug principle, H 376/95 endows the direct thrombin inhibitor melagatran with pharmacokinetic properties required for oral administration without compromising the promising pharmacodynamic properties of melagatran.

Bile acids and lipoprotein metabolism: effects of cholestyramine and chenodeoxycholic acid on human hepatic mRNA expression.

Modulation of bile acid synthesis in human by cholestyramine or by chenodeoxycholic acid (CDCA) treatment affects lipoprotein metabolism leading to altered plasma lipid levels. The molecular changes caused by these treatments, which in turn influence lipoprotein metabolism, are still not entirely known in humans. In this study, mRNA levels were analyzed using real time RT-PCR in liver tissue from patients undergoing cholecystectomy due to gallstone disease. The patients were treated with either CDCA (n=6) or cholestyramine (n=5) for three weeks prior to surgery, six patients received no treatment and served as controls. Cholestyramine increased the expression of the LDL receptor (LDLR) by about 65% and that of proprotein convertase subtilisin kexin 9 (PCSK9) by 70%. After CDCA the levels of both LDLR and hydroxy-methyl-glutaryl coenzyme A reductase mRNA decreased approximately by 50%. The expression of PCSK9 was not changed. The mRNA levels of PCSK9, LDLR, and HMGCoAR were significantly correlated to those of sterol regulatory element binding protein 2 (SREBP2), indicating that SREBP2 is of importance in the regulation of the expression of these genes also in human liver.

Polymorphism in the coding part of the sterol 12alpha-hydroxylase gene does not explain the marked differences in the ratio of cholic acid and chenodeoxycholic acid in human bile.

OBJECTIVE: In humans, two primary bile acids are synthesized: cholic acid (CA) and chenodeoxycholic acid (CDCA), the first and rate-limiting enzyme being cholesterol 7alpha-hydroxylase (CYP7A1). CA has one more hydroxyl group at position 12alpha. This hydroxylation is carried out by the sterol 12alpha-hydroxylase (CYP8B1). Earlier, we and others have noticed a marked variation in the ratio between CA and CDCA in human bile. The aim of this study was to investigate whether this marked difference could be due to a genetic polymorphism in the gene of the CYP8B1. MATERIAL AND METHODS: Screening for genetic polymorphisms was carried out in a 2.4-kb-long area including the exon and part of the promoter region in subjects who had undergone cholecystectomy earlier, and where bile acid analysis had been performed. Among these subjects those with very high or low CA/CDCA ratios (ranging from 0.9 to 6.8) were investigated. The subjects were all female, normolipidaemic, having normal weight and a normal thyroid function. RESULTS: No polymorphisms were found in the investigated sequence. However, a statistically significant correlation was found between the activity of the CYP7A1 and the ratio between CA and CDCA. The difference in ratio could, at least in part, be explained by the difference in rate of bile acid synthesis. CONCLUSION: The difference in ratio between CA and CDCA cannot be explained by a polymorphism in the coding area of the CYP8B1.

Bile acid synthesis in primary cultures of rat and human hepatocytes.

The regulation of hepatic bile acid formation is incompletely understood. Primary cultures of mammalian hepatocytes offer an opportunity to examine putative regulatory factors in relative isolation. Using rat and human hepatocytes in primary culture, we examined bile acid composition and the expression of the rate-limiting enzyme of formation, cholesterol 7alpha-hydroxylase. Control rat hepatocytes showed a declining bile acid production over 4 days, from 156 +/- 24 ng/mL (67% cholic acid) on day 1 to 55 +/- 11 ng/mL (55% cholic acid) on day 4. In addition to cholic acid, chenodeoxycholic acid, alpha-muricholic acid, and beta-muricholic acid were formed. Treatment with triidothyronine (T3) or dexamethasone alone had no significant effect on bile acid production. A combination of T3 and dexamethasone significantly increased the total bile acid production on day 4 (224 +/- 54 ng/mL) and resulted in a marked change in composition to 23% cholic acid and 77% non-12alpha-hydroxylated bile acids. Control rat hepatocytes had a cholesterol 7alpha-hydroxylase activity of 3.3 +/- 0.6 pmol/mg protein/min after 4 days in culture. Cells treated with the combination of dexamethasone and T3 had an activity of 16.4 +/- 3.6 pmol/mg protein/min. The cholesterol 7alpha-hydroxylase messenger RNA (mRNA) levels, determined by solution hybridization after 4 days of culture, showed results similar to those for the activity data; control cells had 5.3 +/- 0.9 cpm/microg total nucleic acids (tNAs). T3 or dexamethasone-treated cells did not differ from control cells, whereas the combination of T3 and dexamethasone increased the mRNA levels to 20.6 +/- 2.8 cpm/microg tNAs. In human hepatocytes, isolated from donor liver, bile acid formation increased from 206 +/- 79 ng/mL on day 2 to 1490 +/- 594 ng/mL on day 6 and then declined slightly. Cholic acid and chenodeoxycholic acid were formed, constituting about 80% and 20%, respectively. The combined addition of T3 and dexamethasone had a tendency to decrease rather than increase bile acid formation. Also, mRNA levels of the cholesterol 7alpha-hydroxylase increased severalfold in the human hepatocytes from day 2 to day 4 and then declined. The addition of T3 or dexamethasone did not effect the mRNA levels in any consistent way. It is noteworthy that the capacity of the cultured human hepatocytes to produce bile acids was higher than that of cultured rat hepatocytes, in spite of the fact that the production of bile acids in rat liver is 3- to 5-fold higher than that in human liver in vivo. It is also evident that while hormonal factors appear to regulate bile acid synthesis in the rat, no evidence for this was found in human hepatocytes. As the composition of bile acids secreted by human hepatocytes in primary culture closely resembles that found in vivo, this represents a useful model for further studies of the synthesis and regulation of bile acids.

Bile acid synthesis in cultured human hepatocytes: support for an alternative biosynthetic pathway to cholic acid.

The biosynthesis of bile acids by primary cultures of normal human hepatocytes has been investigated. A general and sensitive method for the isolation and analysis of sterols and bile acids was used, based on anion exchange chromatography and gas chromatography-mass spectrometry (GC/MS). Following incubation for 5 days, 8 oxysterols and 8 C(27)- or C(24)-bile acids were identified in media and cells. Cholic and chenodeoxycholic acids conjugated with glycine or taurine were by far the major steroids found, accounting for 70% and 24% of the total, respectively, being consistent with bile acid synthesis in human liver. Small amounts of sulfated 3beta-hydroxy-5-cholenoic acid and 3beta,7alpha-dihydroxy-5beta-cholanoic acid were also detected. Nine steroids were potential bile acid precursors (2% of total), the major precursors being 7alpha, 12alpha-dihydroxy-3-oxo-4-cholenoic acid and its 5beta-reduced form. These 2 and 5 other intermediates formed a complete metabolic sequence from cholesterol to cholic acid (CA). This starts with 7alpha-hydroxylation of cholesterol, followed by oxidation to 7alpha-hydroxy-4-cholesten-3-one and 12alpha-hydroxylation. Notably, 27-hydroxylation of the product 7alpha, 12alpha-dihydroxy-4-cholesten-3-one and further oxidation and cleavage of the side chain precede A-ring reduction. A-Ring reduction may also occur before side-chain cleavage, but after 27-hydroxylation, yielding 3alpha,7alpha, 12alpha-trihydroxy-5beta-cholestanoic acid as an intermediate. The amounts of the intermediates increased in parallel to those of CA during 4 days of incubation. Suppressing 27-hydroxylation with cyclosporin A (CsA) resulted in a 10-fold accumulation of 7alpha, 12alpha-dihydroxy-4-cholesten-3-one and a decrease of the production of CA and its acidic precursors. These results suggest that the observed intermediates reflect an alternative biosynthetic pathway to CA, which may be quantitatively significant in the cells.