Biomechanical analysis of the upper thoracic spine after decompressive procedures

Background contextDecompressive procedures such as laminectomy, facetectomy, and costotransversectomy are routinely performed for various pathologies in the thoracic spine. The thoracic spine is unique, in part, because of the sternocostovertebral articulations that provide additional strength to the region relative to the cervical and lumbar spines. During decompressive surgeries, stability is compromised at a presently unknown point.PurposeTo evaluate thoracic spinal stability after common surgical decompressive procedures in thoracic spines with intact sternocostovertebral articulations.Study designBiomechanical cadaveric study.MethodsFresh-frozen human cadaveric spine specimens with intact rib cages, C7–L1 (n=9), were used. An industrial robot tested all spines in axial rotation (AR), lateral bending (LB), and flexion-extension (FE) by applying pure moments (±5 Nm). The specimens were first tested in their intact state and then tested after each of the following sequential surgical decompressive procedures at T4–T5 consisting of laminectomy; unilateral facetectomy; unilateral costotransversectomy, and subsequently instrumented fusion from T3–T7.ResultsWe found that in all three planes of motion, the sequential decompressive procedures caused no statistically significant change in motion between T3–T7 or T1–T12 when compared with intact. In comparing between intact and instrumented specimens, our study found that instrumentation reduced global range of motion (ROM) between T1–T12 by 16.3% (p=.001), 12% (p=.002), and 18.4% (p=.0004) for AR, FE, and LB, respectively. Age showed a negative correlation with motion in FE (r=?0.78, p=.01) and AR (r=?0.7, p=.04).ConclusionsThoracic spine stability was not significantly affected by sequential decompressive procedures in thoracic segments at the level of the true ribs in all three planes of motion in intact thoracic specimens. Age appeared to negatively correlate with ROM of the specimen. Our study suggests that thoracic spinal stability is maintained immediately after unilateral decompression at the level of the true ribs. These preliminary observations, however, do not depict the long-term sequelae of such procedures and warrant further investigation.     

Complications,revision fusions,readmissions, and utilization over a 1-year period after bone morphogenetic protein use during primary cervical spine fusions

Background contextNationwide estimates examining bone morphogenetic protein (BMP) use with cervical spine fusions have been limited to perioperative outcomes.PurposeTo determine the 1-year risk of complications, cervical revision fusions, hospital readmissions, and health care services utilization.Study designA retrospective cohort study from 2002 to 2009 using a nationwide claims database.Patient sampleThere were 61,937 primary cervical spine fusions of which 1,677 received BMP.Outcome measuresComplications, revision fusions, 30-day hospital readmission, and health care utilization.MethodsData for these analyses come from the Thomson Reuters MarketScan Commercial Claims and Encounters Database 2010. Patients were aged 18 to 64 years, receiving and not receiving BMP with a primary (C2–C7) cervical spine fusion. All outcomes were defined by International Classification of Diseases, 9th edition Clinical Modification and Current Procedural and Terminology, 4th edition codes. Complications were analyzed as any complication and stratified by nervous system, wound, and dysphagia or hoarseness. Cervical revision fusions were determined in the 1-year follow-up. Hospital readmission discharge records defined 30-day hospital readmission and reason for the readmission. The utilization of at least one health care service of cervical spine imaging, epidural usage or rehabilitation service was examined. Poisson regression models were used to estimate the relative risk and 95% confidence interval (CI). Linear regression was used to determine the time to hospital readmission. Results were stratified by anterior or posterior and circumferential approaches.ResultsPatients receiving BMP were 29% more likely to have a complication (adjusted relative risk [aRR]=1.29 [95% CI, 1.14–1.46]) and a nervous system complication (aRR=1.42 [95% CI, 1.10–1.83]). Cervical revision fusions were more likely among patients receiving BMP (aRR=1.69 [95% CI, 1.35–2.13]). The risk of 30-day readmission was greater with BMP use (aRR=1.37 [95% CI, 1.07–1.73]) and readmission occurred 27.4% sooner on an average. Patients receiving BMP were more likely to receive computed tomography scans (aRR=1.34 [95% CI, 1.06–1.70]) and epidurals with anterior surgical approaches (aRR=1.29 [95% CI, 1.00–1.65]).ConclusionsThese findings question both the safety and effectiveness of off-label BMP use in primary cervical spine fusions.     

Activation of postsynaptic 5-HT1A receptors improve stress adaptation

Rationale

Serotonin-1A (5-HT_1A) receptors modulate the stress response and have been implicated in the etiology and treatment of depression and anxiety disorders. A reduction in postsynaptic 5-HT_1A receptor function in limbic areas has consistently been observed following exposure to chronic stress.

Objectives

To investigate the hypothesis that increased activation of 5-HT_1A receptors in rats having reduced 5-HT function may improve stress adaptation and the behavioral sequelae commonly associated with chronic stress.

Methods

One hundred forty-four Sprague–Dawley rats received injections of para-chlorophenylalanine to partially deplete 5-HT then were given daily systemic pretreatment with the 5-HT_1A receptor agonist, 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), the antagonist, WAY 100635, or vehicle prior to either restraint stress (6 h/day for 10 daily sessions) or control conditions. Anxiety- and depressive-like behaviors were then assessed using the open field and sucrose preference tests. Protein level of hippocampal glucocorticoid receptors (GR) and mineralocorticoid receptors was detected by immunohistochemistry and brain-derived neurotrophic factor (BDNF) was determined by in situ hybridization.

Results

8-OH-DPAT pretreatment prior to stress exposure attenuated later stress-induced anxiety- and depression-like behaviors and increased GR and BDNF mRNA expression in the hippocampus relative to vehicle- and WAY 100635-pretreated, stressed animals.

Conclusion

The stress-related impairments associated with 5-HT deficiency can be improved by 8-OH-DPAT pretreatment prior to stress exposure and are associated with an augmentation of GR-like immunoreactivity and BDNF mRNA expression in the hippocampus. It suggested that selective activation of 5-HT_1A receptors may be a potential treatment strategy for stress-related disorders such as anxiety and depression.     

A High-Fat Diet Differentially Affects the Gut Metabolism and Blood Lipids of Rats Depending on the Type of Dietary Fat and Carbohydrate

The aim of this model study was to investigate how selected gut functions and serum lipid profile in rats on high-fat diets differed according to the type of fat (saturated vs. unsaturated) and carbohydrate (simple vs. complex). The experiment was conducted using 32 male Wistar rats distributed into 4 groups of 8 animals each. For 4 weeks, the animals were fed group-specific diets that were either rich in lard or soybean oil (16% of the diet) as the source of saturated or unsaturated fatty acids, respectively; further, each lard- and soybean oil-rich diet contained either fructose or corn starch (45.3% of the diet) as the source of simple or complex carbohydrates, respectively. Both dietary factors contributed to changes in the caecal short-chain fatty acid concentrations, especially to the butyrate concentration, which was higher in rats fed lard- and corn starch-rich diets compared to soybean oil- and fructose-rich diets, respectively. The lowest butyrate concentration was observed in rats fed the soybean oil- and fructose-rich diet. On the other hand, the lard- and fructose-rich diet vs. the other dietary combinations significantly increased serum total cholesterol concentration, to more than two times serum triglyceride concentration and to more than five times the atherogenic index. In conclusion, a high-fat diet rich in fructose can unfavorably affect gut metabolism when unsaturated fats are predominant in the diet or the blood lipids when a diet is rich in saturated fats.     

Vitamin D Status Is Associated With Grip Strength in Centenarians

Low serum concentrations of 25-hydroxyvitamin D (25(OH)D) have been associated with poor physical function in older adults, but few, if any, studies have examined this relationship in the very old. Therefore, the purpose of this study is to examine this relationship in the very old. Serum 25(OH)D concentrations were obtained from 194 centenarians and near centenarians (98 years and older). The associations between 25(OH)D concentrations and measures of physical function were evaluated with unadjusted and adjusted regression models. We found that 35% of centenarians had 25(OH)D concentrations less than 50 nmol/L. Adjusted mean grip strength was lower for centenarians with 25(OH)D concentrations less than 75 nmol/L than for centenarians with higher concentrations (P<0.05). However, there were no differences in the Georgia Centenarian Study (GCS) Composite Scale, a global measure of physical function, between those with higher and lower 25(OH)D concentrations. We conclude that low 25(OH)D concentrations are associated with poor grip strength, but not GCS Composite Scale, in the very old. Considering the high burden of poor physical function in older adults, understanding the relationship between vitamin D and different measures of physical function, including strength, becomes increasingly important.     

A novel fluorometric assay for aldo-keto reductase 1C3 predicts metabolic activation of the nitrogen mustard prodrug PR-104A in human leukaemia cells

Aldo-keto reductase 1C3 (AKR1C3, EC 1.1.1.188) metabolises steroid hormones, prostaglandins and xenobiotics, and activates the dinitrobenzamide mustard prodrug PR-104A by reducing it to hydroxylamine PR-104H. Here, we describe a functional assay for AKR1C3 in cells using the fluorogenic probe coumberone (a substrate for all AKR1C isoforms) in conjunction with a specific inhibitor of AKR1C3, the morpholylurea SN34037. We use this assay to evaluate AKR1C3 activity and PR-104A sensitivity in human leukaemia cells. SN34037-sensitive reduction of coumberone to fluorescent coumberol correlated with AKR1C3 protein expression by immunoblotting in a panel of seven diverse human leukaemia cell lines, and with SN34037-sensitive reduction of PR-104A to PR-104H. SN34037 inhibited aerobic cytotoxicity of PR-104A in high-AKR1C3 TF1 erythroleukaemia cells, but not in low-AKR1C3 Nalm6 pre-B cell acute lymphocytic leukaemia (B-ALL) cells, although variation in PR-104H sensitivity confounded the relationship between AKR1C3 activity and PR-104A sensitivity across the cell line panel. AKR1C3 mRNA expression showed wide variation between leukaemia patients, with consistently higher levels in T-ALL than B-ALL. In short term cultures from patient-derived paediatric ALL xenografts, PR-104A was more potent in T-ALL than B-ALL lines, and PR-104A cytotoxicity was significantly inhibited by SN34037 in T-ALL but not B-ALL. Overall, the results demonstrate that SN34037-sensitive coumberone reduction provides a rapid and specific assay for AKR1C3 activity in cells, with potential utility for identifying PR-104A-responsive leukaemias. However, variations in PR-104H sensitivity indicate the need for additional biomarkers for patient stratification.     

Effectiveness of newspaper advertising for patient recruitment into a clinical trial

Aims

To measure the impact of newspaper advertising across Scotland on patient interest, and subsequent recruitment into the Standard Care vs. Celecoxib Outcome Trial (SCOT), a clinical trial investigating the cardiovascular safety of non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis.

Methods

Newspaper advertisements about the SCOT trial were placed sequentially in regional and national Scottish newspapers. The number of phone calls as a result of exposure to the advertisements and ongoing study recruitment rates were recorded before, during and after the advertising campaign. To enroll in SCOT individuals had to be registered with a participating GP practice.

Results

The total cost for the advertising campaign was £46 250 and 320 phone calls were received as a result of individuals responding to the newspaper advertisements. One hundred and seventy-two individuals were identified as possibly suitable to be included in the study. However only 36 were registered at participating GP practices, 17 completed a screening visit and 15 finally were randomized into the study. The average cost per respondent individual was £144 and the average cost per randomized patient was £3083. Analysis of recruitment rate trends showed that there was no impact of the newspaper advertising campaign on increasing recruitment into SCOT.

Conclusions

Advertisements placed in local and national newspapers were not an effective recruitment strategy for the SCOT trial. The advertisements attracted relatively small numbers of respondents, many of whom did not meet study inclusion criteria or were not registered at a participating GP practice.