Monitoring of gliomas in vivo by diffusion MRI and 1H MRS during gene therapy‐induced apoptosis: interrelationships between water diffusion and mobile lipids

The measurement of water diffusion by diffusion‐weighted MRI (DWI) in vivo offers a non‐invasive method for assessing tissue responses to anti‐cancer therapies. The pathway of cell death after anti‐cancer treatment is often apoptosis, which leads to accumulation of mobile lipids detectable by ¹H MRS in vivo. However, it is not known how these discrete MR markers of cell death relate to each other. In a rodent tumour model [i.e. ganciclovir‐treated herpes simplex thymidine kinase (HSV‐tk) gene‐transfected BT4C gliomas], we studied the interrelationships between water diffusion (Trace{D}) and mobile lipids during apoptosis. Water diffusion and water‐referenced concentrations of mobile lipids showed clearly increasing and interconnected trends during treatment. Of the accumulating ¹H MRS‐visible lipids, the fatty acid ? CH ?CH ? groups and cholesterol compounds showed the strongest associations with water diffusion (r² = 0.30; P < 0.05 and r² = 0.48; P < 0.01, respectively). These results indicate that the tumour histopathology and apoptotic processes during tumour shrinkage can be interrelated in vivo by DWI of tissue water and ¹H MRS of mobile lipids, respectively. However, there is considerable individual variation in the associations, particularly at the end of the treatment period, and in the relative compositions of the accumulating NMR‐visible lipids. The findings suggest that the assessment of individual treatment response in vivo may benefit from combining DWI and ¹H MRS. Absolute and relative changes in mobile lipids may indicate initiation of tumour shrinkage even when changes in tissue water diffusion are still small. Conversely, greatly increased water diffusion probably indicates that substantial cell decomposition has taken place in the tumour tissue when the ¹H MRS resonances of mobile lipids alone can no longer give a reliable estimate of tissue conditions. Copyright © 2008 John Wiley & Sons, Ltd.     

Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the Thrombolysis in Myocardial Infarction trials

OBJECTIVES: We hypothesized that early recurrent myocardial infarction (MI) following fibrinolytic administration would be assessed with higher mortality at both 30 days and 2 years. BACKGROUND: Although early recurrent MI after fibrinolytic therapy has been associated with increased early mortality in the acute MI setting, its relation to long-term mortality has not been fully explored. METHODS: Mortality data were ascertained in 20,101 patients enrolled in the Thrombolysis In Myocardial Infarction (TIMI) 4, 9, and 10B and Intravenous NPA for the Treatment of Infarcting Myocardium Early (InTIME-II) acute MI trials. RESULTS: The frequency of symptomatic recurrent MI during the index hospitalization was 4.2% (836/20,101). Recurrent MI during the index hospital period was associated with increased 30-day mortality (16.4% [137/836] vs. 6.2% [1,188/19,260], p < 0.001). Likewise, recurrent MI was associated with a sustained increase in mortality up to two years, even after adjustments were made for covariates known to be associated with mortality and recurrent MI (hazard ratio 2.11, p < 0.001). However, this higher mortality at 2 years was due to an early divergence in mortality by 30 days and was not due to a significant increase in late mortality between 30 days and 2 years (4.38% [31/707] vs. 3.76% [685/18,206], p = NS). Percutaneous coronary intervention during the index hospitalization was associated with a lower rate of in-hospital recurrent MI (1.6% vs. 4.5%, p < 0.001) and lower two-year mortality (5.6% vs. 11.6%, p < 0.001). Performance of coronary artery bypass graft surgery was also associated with a lower recurrent rate of MI (0.7% vs. 4.3%, p < 0.001) and lower two-year mortality rate (7.95% vs. 10.6%, p = 0.0008). CONCLUSIONS: Early recurrent MI is associated with increased mortality up to two years. However, most deaths occur early, and the risk of additional deaths between the index hospital period and two years was not significantly increased among patients with recurrent MI. Percutaneous coronary intervention during the index hospitalization was associated with a lower risk of recurrent MI and a lower risk of two-year mortality.     

Comparison of Swanson and Sutter metacarpophalangeal arthroplasties in patients with rheumatoid arthritis: a prospective and randomized trial

PURPOSE: To perform a prospective and randomized comparison of the clinical outcome of patients with rheumatoid arthritis who had Swanson or Sutter implant replacement arthroplasty of the metacarpophalangeal joints. METHODS: There were 45 patients (3 men, 42 women) and 49 hands; a total of 75 Swanson and 99 Sutter implants were inserted. The mean time between surgery and the final follow-up control visit was 58 months (range, 37-80 mo). Preoperative and postoperative measurements were performed including active extension and flexion, correction of ulnar deviation, and strength. RESULTS: There was no statistically significant difference between groups with regard to active extension deficit correction. Mean active flexion decreased less in the Sutter group than in the Swanson group but difference between the groups was statistically significant in only the index finger. At the final follow-up examination no significant differences existed between the groups in the correction of ulnar deviation or arc of motion. Grip strengths, chuck pinch, and thump-to-fingertip grip strengths did not improve in either of the groups. CONCLUSIONS: In this study clinical results showed no significant difference between the groups with the single exception of the amount of index finger metacarpophalangeal joint flexion.     

Molecular imaging of apoptosis in cancer

Apoptosis plays an important role in cancer. Mechanisms hindering its action are implicated in a number of malignancies. Also, the induction of apoptosis plays a pivotal role in non-surgical cancer treatment regimes such as irradiation, chemotherapy, or hormones. Recent advanced in imaging science have made it now possible for us to detect and visualize previously inaccessible and even unrecognized biological phenomena in cells and tissue undergoing apoptosis in vivo. Not only are these imaging techniques painting an intriguing picture of the spatiotemporal characteristics and metabolic and biophysical of apoptosis in situ, but they are expected to have an ever increasing impact in preclinical testing and design of new anticancer agents as well. Rapid and accurate visualization of apoptotic response in the clinical settings can also be of significant diagnostic and prognostic worth. With the advent of molecular medicine and patient-tailored treatment options and therapeutic agents, such monitoring techniques are becoming paramount.     

Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling

Summary: Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X‐linked agammaglobulinemia (XLA) in humans and X‐linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B‐lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full‐length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only selected amino acids are sensitive to replacement (P < 0.001). Although genotype–phenotype correlations have not been established in XLA, based on these findings, we hypothesize that this relationship indeed exists. Using short interfering‐RNA technology, we have previously generated active constructs downregulating Btk expression. However, application of recently established guidelines to enhance or decrease the activity was not successful, demonstrating the importance of the primary sequence. We also review the outcome of expression profiling, comparing B lymphocytes from XLA‐, Xid‐, and Btk‐knockout (KO) donors to healthy controls. Finally, in spite of a few genes differing in expression between Xid‐ and Btk‐KO mice, in vivo competition between cells expressing either mutation shows that there is no selective survival advantage of cells carrying one genetic defect over the other. We conclusively demonstrate that for the R28C‐missense mutant (Xid), there is no biologically relevant residual activity or any dominant negative effect versus other proteins.     

Diazepam binding inhibitor overexpression in mice causes hydrocephalus, decreases plasticity in excitatory synapses and impairs hippocampus-dependent learning

Diazepam binding inhibitor (DBI) and its processing products are endogenous modulators of GABAA and linked to various brain disorders ranging from anxiety and drug dependence to epilepsy. To investigate the physiological role of endogenously expressed DBI in the brain we created a transgenic mouse line overexpressing DBI gene. Transgenic mice had a 37x increased protein expression and immunohistochemistry showed excessive glial expression in the infragranular region of the dentate gyrus. Transgenic animals had significantly larger lateral ventricles and decreased plasticity of excitatory synapses without affecting either inhibitory or excitatory synaptic transmission. In behavioral tests transgenic animals had no differences in motor and exploratory activity, yet impaired hippocampus-dependent learning and memory. Overexpression did not cause anxiety or proconflict behavior, nor influenced kainic acid or pentylenetetrazole induced seizure activity. Our transgenic mouse line demonstrates that endogenously overexpressed DBI impairs hippocampus-dependent learning without anxiety or proconflict behavior.     

Achilles tendon elongation after rupture repair: a randomized comparison of 2 postoperative regimens

BACKGROUND: A few prospective controlled trials comparing early functional rehabilitation after Achilles tendon repair and non-operative immobilization have been reported. HYPOTHESES: There is no difference in Achilles tendon elongation between early motion and immobilization after Achilles tendon repair. Tendon elongation does not correlate with the clinical outcome. STUDY DESIGN: Randomized clinical trial; Level of evidence, 2. METHODS: Fifty patients with acute Achilles tendon rupture were randomized postoperatively to receive either early movement of the ankle between neutral and plantar flexion in a brace for 6 weeks or immobilization in tension using a below-knee cast with the ankle in a neutral position for 6 weeks. Full weightbearing was allowed after 3 weeks in both groups. Standardized radiographs to measure previously placed radiographic markers were taken on the first day postoperatively and at 1, 3, 6, 12, 24 weeks postoperatively, with the final radiograph a mean of 60 (SD, 6.4) weeks postoperatively. The outcome was assessed at the 3-month and final checkups by the clinical scoring method described by Leppilahti et al and included subjective factors and objective factors. RESULTS: Tendon elongation occurred in both groups but was somewhat less in the early motion group (median 2 mm in the early motion group vs median 5 mm in the cast group a mean of 60 weeks postoperatively, P = .054). The elongation curves first rose and then slowly fell in both groups. The patients who had less elongation achieved a better clinical outcome (rho = -.42, P = .017). Tendon elongation did not correlate significantly with age, body mass index, or isokinetic peak torques. CONCLUSION: Achilles tendon elongation was somewhat less in the early motion group and correlated with the clinical outcome scores. We recommend early functional postoperative treatment after Achilles rupture repair.     

Tibiotalocalcaneal arthrodesis with a compressive retrograde intramedullary nail: a report of 34 consecutive patients

BACKGROUND: Tibiotalocalcaneal arthrodesis is a treatment modality for severe arthrosis and malalignment of the hindfoot. Complications, such as delayed union and nonunion, are well-known risks of the procedure. Arthrodesis can be done with a plate, screws, an external fixator, or an intramedullary nail. Compression with an intramedullary nail was the focus of this report. METHODS: Thirty-four consecutive patients (23 men and 11 women) with an average age range of 57 (range 25-77) years had tibiotalocalcaneal arthrodesis using retrograde intramedullary compression nail fixation. Mean followup was 24 (range 6 to 43) months. One patient died of an unrelated cause, but 30 (91%) of the remaining 33 patients answered the questionnaire. RESULTS: Bony consolidation was achieved in 26 (76%) patients, the mean time to fusion being 16 weeks. Five patients (15%) had complications and seven (20%) had repeat surgery. Of the 30 patients who responded to the questionnaire, three patients (10%) evaluated the overall result subjectively as being of no benefit and 27 (90%) as improved. The visual analog scale (VAS) score for preoperative pain was 66 at rest and 83 when walking, and the mean postoperative scores were 19 and 32, respectively (p<0.001). CONCLUSIONS: Tibiotalocalcaneal arthrodesis with a compressive retrograde intramedullary nail is an effective and safe procedure for patients with severe malalignment or arthrosis of the hindfoot. It is essentially a salvage procedure, and most patients benefit from it, but excellent results are rare.