Effect of subcutaneous insulin on intestinal adaptation in a rat model of short bowel syndrome

Insulin has been shown to influence intestinal structure and absorptive function. The purpose of the present study was to evaluate the effects of parenteral insulin on structural intestinal adaptation, cell proliferation, and apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection and reanastomosis, SBS rats underwent a 75% small bowel resection, and SBS-INS rats underwent a 75% small bowel resection and were treated with insulin given subcutaneously at a dose of 1 U/kg, twice daily, from day 3 through day 14. Parameters of intestinal adaptation, enterocyte proliferation, and enterocyte apoptosis were determined on day 15 following operation. SBS rats demonstrated a significant increase in jejunal and ileal bowel and mucosal weight, villus height and crypt depth, and cell proliferation index compared with the sham group. SBS-INS animals demonstrated higher jejunal and ileal bowel and mucosal weights, jejunal and ileal mucosal DNA and protein, and jejunal and ileal crypt depth compared with SBS animals. SBS-INS rats also had a greater cell proliferation index in both jejunum and ileum and a trend toward a decrease in enterocyte apoptotic index in jejunum and ileum compared with the SBS untreated group. In conclusion, parenteral insulin stimulates structural intestinal adaptation in a rat model of SBS. Increased cell proliferation is the main mechanism responsible for increased cell mass.     

Acupuncture treatment for chronic knee pain: a systematic review

Objectives. To evaluate the effects of acupuncture on pain andfunction in patients with chronic knee pain. Methods. Systematic review and meta-analysis of randomized controlledtrials of adequate acupuncture. Computerized databases and referencelists of articles were searched in June 2006. Studies were selectedin which adults with chronic knee pain or osteoarthritis ofthe knee were randomized to receive either acupuncture treatmentor a control consisting of sham (placebo) acupuncture, othersham treatments, no additional intervention (usual care), oran active intervention. The main outcome measures were short-termpain and function, and study validity was assessed using a modificationof a previously published instrument. Results. Thirteen RCTs were included, of which eight used adequateacupuncture and provided WOMAC outcomes, so were combined inmeta-analyses. Six of these had validity scores of more than50%. Combining five studies in 1334 patients, acupuncture wassuperior to sham acupuncture for both pain (weighted mean differencein WOMAC pain subscale score = 2.0, 95% CI 0.57–3.40)and for WOMAC function subscale (4.32, 0.60–8.05). Thedifferences were still significant at long-term follow-up. Acupuncturewas also significantly superior to no additional intervention.There were insufficient studies to compare acupuncture withother sham or active interventions. Conclusions. Acupuncture that meets criteria for adequate treatmentis significantly superior to sham acupuncture and to no additionalintervention in improving pain and function in patients withchronic knee pain. Due to the heterogeneity in the results,however, further research is required to confirm these findingsand provide more information on long-term effects. KEY WORDS: Acupuncture, Systematic review, Meta-analysis, Chronic knee pain, Osteoarthritis, WOMAC, Function Submitted 4 July 2006; revised version accepted 7 November 2006.     

OxNASH Score Correlates with Histologic Features and Severity of Nonalcoholic Fatty Liver Disease

Background and Aim

Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). By employing a highly sensitive liquid chromatography–tandem mass spectrometry (LC/MS/MS) approach we recently were able to define the circulating profile of bioactive lipid peroxidation products characteristic of patients with nonalcoholic steatohepatitis (NASH) and developed the OxNASH score for NASH diagnosis. The aims of this study were to assess the utility of OxNASH as a predictor of NASH and study the association between OxNASH and specific histologic features of NAFLD.

Methods

Our cohort consisted of 122 patients undergoing liver biopsy for clinical suspicion of NAFLD. The NAFLD activity score (NAS) was calculated for each patient. Levels of fatty acid oxidation products were quantified using stable isotope dilution LC/MS/MS, and OxNASH was calculated.

Results

The mean age of our patients was 49.3 (±11.6) years, and the mean body mass index was 31.5 (±4.8) kg/m². The majority of patients were Caucasian (82 %) and 48 % were female. OxNASH correlated with NAS and with the individual histologic features of NAFLD, namely, steatosis, inflammation, and ballooning (P < 0.05), with the strongest association being with inflammation [rho (ρ) 0.40, 95 % confidence interval 0.23, 0.57, P < 0.001]. There was also a correlation between the stage of fibrosis and OxNASH (P = 0.001). These associations remained statistically significant after adjustment for multiple confounders.

Conclusions

Based on our results, in adult patients with NAFLD, OxNASH correlates with histologic features of NASH and appears to be a promising noninvasive marker.     

A comparison of the efficacy and safety of nonsteroidal antiinflammatory agents versus acetaminophen in the treatment of osteoarthritis: A meta‐analysis

Objective

To perform a meta‐analysis comparing the efficacy and safety of recommended dosages of nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase 2 inhibitors, versus acetaminophen in the treatment of symptomatic hip and knee osteoarthritis.

Methods

Medline and EMBASE searches were performed for original clinical trials directly comparing NSAIDs with acetaminophen. A standardized form was used to abstract all data, including outcome measures of pain at rest, walking pain, and dropouts due to adverse effects. Inverse‐variance‐weighted mean differences (WMDs) and 95% confidence intervals (95% CI) for pain measures were determined for treatment groups. Odds ratios (ORs) and 95% CIs were calculated for withdrawals due to adverse events. Results were compared using a random effects model.

Results

Seven articles met inclusion criteria with sufficient data for analysis. Participants had a mean age of 61.1 years and 71.1% were women. Test of heterogeneity was not significant for either rest (P = 0.73) or walking (P = 0.76) pain. The scores for overall pain at rest (WMD ?6.33 mm on a 100‐mm visual analog scale [VAS], 95% CI ?9.24, ?3.41) and walking pain (WMD –5.76 mm on a 100‐mm VAS, 95% CI –8.99, –2.52) favored the NSAID‐treated group. Although NSAIDs elevated the risk of withdrawals due to adverse events, the difference was not statistically significant (OR 1.45, 95% CI 0.93, 2.27).

Conclusion

NSAIDs are statistically superior in reducing rest and walking pain compared with acetaminophen for symptomatic osteoarthritis. Safety, measured by discontinuation due to adverse events, was not statistically different between NSAID‐ and acetaminophen‐treated groups.

     

Effects of simultaneous dual-site TENS stimulation on experimental pain

Transcutaneous electrical nerve stimulation (TENS) is commonly used for pain relief. However, little robust research exists regarding the combination of parameters required to provide effective doses. This study investigated the hypoalgesic effects of different parameter combinations, applied simultaneously at two sites (segmental and extrasegmental), on pressure pain threshold (PPT) in pain-free humans. Two-hundred and eight volunteers (median age 22 years, range 20–26) were randomized to eight groups: six active TENS groups, placebo and control. Parameter combinations were such that frequency always differed at each site (110 Hz or 4 Hz), but intensity could be either the same or different levels: high (to tolerance without pain) or low (strong but comfortable). TENS was administered to the forearm over the radial nerve and the ipsilateral leg below the fibular head for 30 min with monitoring for 30 further minutes. PPT measurements were taken bilaterally from the mid-point of first dorsal interosseous muscle, by an independent blinded rater, at baseline and at six subsequent 10-min intervals. Log-transformed data were analysed using repeated-measures analysis of covariance (baseline values and gender as covariates). Those groups using high-intensity stimulation at the segmental stimulation sites showed significantly greater hypoalgesia than placebo (p < 0.025 in each case). The largest hypoalgesic effect was for simultaneous high-intensity stimulation at segmental and extrasegmental sites, using different frequencies. These results reaffirm that high-intensity stimulation (regardless of frequency) is of fundamental importance in effective dosage.     

Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.     

CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications

CONTEXT: Receptor activator of nuclear factor-kappaB ligand (RANKL), receptor activator of nuclear factor-kappaB (RANK), and osteoprotegerin (OPG) play a central role in bone remodeling and disorders of mineral metabolism. EVIDENCE ACQUISITION: A PubMed search was conducted from January 1992 until 2007 for basic, observational, and clinical studies in subjects with disorders related to imbalances in the RANK/RANKL/OPG system. EVIDENCE SYNTHESIS: RANK, RANKL, and OPG are members of the TNF receptor superfamily. The pathways involving them in conjunction with various cytokines and calciotropic hormones play a pivotal role in bone remodeling. Several studies involving mutations in the genes encoding RANK and OPG concluded in the discovery of a number of inherited skeletal disorders. In addition, basic and clinical studies established a consistent relationship between the RANK/RANKL/OPG pathway and skeletal lesions related to disorders of mineral metabolism. These studies were a stepping stone in further defining the role of the RANK/RANKL/OPG pathway in osteoporosis, rheumatoid arthritis, bone loss associated with malignancy-related skeletal diseases, and its relationship to vascular calcifications. Subsequently, the further understanding of this pathway led to the development of new therapeutic modalities including the human monoclonal antibody to RANKL and recombinant OPG as a target for treatment of postmenopausal osteoporosis and multiple myeloma. CONCLUSIONS: The RANK/RANKL/OPG system mediates the effects of calciotropic hormones and, consequently, alterations in their ratio are key in the development of several clinical conditions. New agents with the potential to block effects of RANKL have emerged for treatment of postmenopausal osteoporosis and malignancy-related skeletal disease.