Hannu Manninen

Determinants of Lumbar Disc Degeneration: A Study Relating Lifetime Exposures and Magnetic Resonance Imaging Findings in Identical Twins

Study Design Retrospective cohort. Objectives To investigate the effects of lifetime exposure to commonly suspected risk factors on disc degeneration using magnetic resonance imaging, and to estimate the effects of these suspected risk factors relative to age and familial aggregation, reflecting genetic and shared environmental influences. Summary of Background Data Structural and biochemical changes associated with disc degeneration are suspected as the underlying conditions of many back-related symptoms. Little is known about the determinants of disc degeneration. Methods Based on lifetime discordance in suspected environmental risk factors for disc degeneration, 115 male identical twin pairs were selected. An indepth interview was conducted of occupational and leisure time physical loading, driving, and smoking. Disc degeneration was evaluated using observational and digital magnetic resonance imaging assessment methods. Results Heavier lifetime occupational and leisure physical loading was associated with greater disc degeneration in the upper lumbar levels (P = 0.055− 0.001), whereas sedentary work was associated with lesser degeneration (P = 0.006). These univariate associations did not reasch statistical significance in the lower lumbar region. In multivariate analyses of the upper lumbar levels, the mean job code explained 7% of the variability in observational disc degeneration scores; the addition of age explained 16%, and familial aggregation improved the model such that 77% of the variability was explained. In the lower lumbar levels, leisure time physical loading entered the multivariate model, explaining 2% of the variability. Adding age explained 9%, and familial aggregation raised the variability in disc degeneration scores explained to 43%. Conclusion The present study findings suggest that disc degeneration may be explained primarily by genetic influences and by unidentified factors, which may include complex, unpredictable interactions. The particular environmental factors studied, which have been among those most widely suspected of accelerating disc degeneration, had very modest effects.

Prospective trial of infrapopliteal artery balloon angioplasty for critical limb ischemia: angiographic and clinical results.

PURPOSE To evaluate the safety and efficacy of infrapopliteal percutaneous transluminal angioplasty (PTA) as a primary treatment of chronic critical limb ischemia in a prospective trial. MATERIALS AND METHODS Infrapopliteal PTA was performed on 72 limbs of 60 patients (mean age, 72 y; range, 38-92 y) and patients were followed for 12-24 months. RESULTS The primary angiographic success rate for the stenoses was 84% (102 of 121) and that for the occlusions was 61% (41 of 67) with corresponding restenosis rates of 32% and 52% at follow-up angiography performed a mean of 10 months after primary PTA. The rate of major complications was 2.8% (access site pseudoaneurysms in two patients). The primary clinical success was 63% (45 of 72). A 48% cumulative primary patency rate, a 56% secondary patency rate, and a 80% cumulative limb salvage rate were registered at 18 months, as determined with use of Kaplan-Meier analysis. Lack of angiographic improvement at the site of the most severe ischemia and renal insufficiency (serum creatinine level > 130 micromol/L) were independent predictors of poorer long-term clinical results, as determined with use of Cox multiple regression analysis. CONCLUSIONS Infrapopliteal PTA is a feasible primary treatment of chronic critical limb ischemia with moderate primary angiographic and clinical success, a low complication rate, and a cumulative limb salvage rate comparable with surgical techniques.

Catheter-Mediated Vascular Endothelial Growth Factor Gene Transfer to Human Coronary Arteries after Angioplasty

Blood vessels are among the easiest targets for gene therapy. However, no data are available about the safety and feasibility of intracoronary gene transfer in humans. We studied the safety and efficacy of catheter-mediated vascular endothelial growth factor (VEGF) plasmid/liposome (P/L) gene transfer in human coronary arteries after percutaneous translumenal coronary angioplasty (PTCA) in a randomized, double-blinded, placebo-controlled study. The optimized angioplasty/gene delivery method was previously shown to lead to detectable VEGF gene expression in human peripheral arteries as analyzed from amputated leg samples. Gene transfer to coronary arteries was done with a perfusion-infusion catheter, using 1000 microg of VEGF or beta-galactosidase plasmid complexed with 1000 microl of DOTMA:DOPE liposomes. Ten patients received VEGF P/L, three patients received beta-galactosidase P/L, and two patients received Ringer lactate. Gene transfer to coronary arteries was feasible and well tolerated. Except for a slight increase in serum C-reative protein in all study groups, no adverse effects or abnormalities in laboratory parameters were detected. No VEGF plasmid or recombinant VEGF protein was present in the systemic circulation after the gene transfer. In control angiography 6 months later, no differences were detected in the degree of coronary stenosis between treatment and control groups. We conclude that catheter-mediated intracoronary gene transfer performed after angioplasty is safe and well tolerated and potentially applicable for the prevention of restenosis and myocardial ischemia.

Associations between back pain history and lumbar MRI findings.

Study Design. Retrospective monozygotic twin cohort study. Objectives. Our goal was to investigate the associations between different spinal MRI findings and current, past year, and lifetime low back pain after adjusting for occupational physical loading, smoking, genetics, and early family influences. Summary of Background Data. The role of spinal pathology in back symptoms continues to be controversial. Methods. The study participants consisted of 115 monozygotic male twin pairs 35 to 69 years of age. The qualitatively assessed MRI parameters were as follows: disc height, bulging, herniations, anular tears, osteophytes, spinal stenosis, and endplate changes. Signal intensity was measured quantitatively. Results. After controlling for age, disc height was associated with all back pain variables studied and anular tears with LBP frequency and intensity during the 12 months before imaging. Both were associated with lifetime frequency of low back pain interfering with daily activities, disability, and intensity of the worst lifetime pain episode. Other MRI findings did not explain the various symptom histories. Adjusting for physical loading in the past 12 months increased the associations of anular tears and “low back pain today” and 12-month low back pain parameters. After controlling for genotype and other familial influences, the within-pair differences in disc height and anular tears accounted for 6% to 12% of the total variance in the within-pair differences of low back pain variables. Conclusion. These findings raise new questions about the underlying mechanisms of LBP. The sensitivities of the only significant MRI parameters, disc height narrowing and anular tears, are poor, and these findings alone are of limited clinical importance.

Wide-necked intracranial aneurysms: treatment with stent-assisted coil embolization during acute (<72 hours) subarachnoid hemorrhage--experience in 61 consecutive patients.

PURPOSE To evaluate the safety and efficacy of stent-assisted embolization of ruptured wide-necked intracranial aneurysms during acute subarachnoid hemorrhage (SAH). MATERIALS AND METHODS Institutional review board approval for this retrospective study was obtained; the need to obtain informed consent was waived. Results in 61 consecutive patients (20 men, 41 women; mean age, 55.1 years; range, 26-83 years) with acutely ruptured wide-necked intracranial aneurysms who were treated with stent-assisted coil embolization were evaluated. The mean length of angiographic follow-up was 12.1 months (range, 0-52 months). Statistical analysis was performed to determine whether the features of the patient and the ruptured aneurysm affected the primary angiographic result or the patients clinical outcome. Categoric and dichotomous variables were examined with the chi(2) test or the Fisher exact test; the Mann-Whitney U test and Kruskal-Wallis one-way analysis were used to compare continuous-scale data for non-normally distributed variables. RESULTS The technical success rate was 72% (44 of 61). The technique-related complication rate was 21% (13 of 61), and the 30-day mortality rate was 20% (12 of 61). There was only one case of rebleeding, and clinical outcome was good for the majority of the patients (69% [42 of 61] had Glasgow Outcome Scale scores of 4 or 5 at the end of the study period). CONCLUSION Stent-assisted coil embolization is a feasible method for the endovascular treatment of wide-necked intracranial aneurysms that are difficult to treat surgically or with balloon-assisted embolization during acute SAH. The risk of subsequent rerupture of the aneurysm seems to be reduced for aneurysms treated early compared with that for nonsecured aneurysms.

Magnetic resonance imaging findings and their relationships in the thoracic and lumbar spine. Insights into the etiopathogenesis of spinal degeneration.

Study Design Descriptive epidemiologic study about magnetic resonance imaging findings in the spine. Objectives To describe the prevalence of magnetic resonance imaging findings in a general population at spinal levels T6-S1, and to examine the relationships of these findings within each spinal level and between levels. Summary of Background Data The prevalence of specific findings and the associations between findings and spinal levels can provide general insights into the etiopathogenesis of spinal degeneration. Methods Subjects consisted of 232 men from a population sample (mean age 49.3 years). Signal intensity, disc bulging, disc herniation, and endplate irregularities were among 11 findings assessed from magnetic resonance images. Results The disc signal intensities were assessed to be lowest in the lumbar and middle thoracic regions. Disc bulging and disc height narrowing were most common in the lower levels of both the thoracic and lumbar regions. All magnetic resonance imaging findings except herniations and endplate irregularities were clearly associated with age. Osteophytes were most highly associated with disc bulging in levels T6-L3, and with endplate irregularities in the lower lumbar levels. Disc herniations were not consistently associated with any other findings. The disc levels that most highly correlated are grouped as follows: T6-T10, T10-L4, and L4-S1. Conclusions With the exception of endplate irregularities and herniations, the magnetic resonance imaging findings appeared to be associated with the same pathogenic process. The interaction of mechanical factors and spinal structures varies between spinal levels, and the degeneration common in the lower parts of the thoracic and lumbar spine could be an outcome of vulnerability for torsional forces. Some gross guidelines for grouping findings can be drawn from disc level correlations.

Determinants of the progression in lumbar degeneration: a 5-year follow-up study of adult male monozygotic twins.

Study Design. A 5-year follow-up study of exposure of discordant monozygotic twin pairs with repeated interviews and spine imaging. Objective. The primary goals were to record changes in the degenerative signs over a 5-year interval and to estimate the effects of familial influences and suspected environmental risk factors on the speed of lumbar degeneration. Summary of Background Data. Traditionally, disc degeneration has been attributed to aging and environmental exposures; recently, a dominant effect of genetics has been revealed. Yet the etiopathogenesis of disc degeneration remains poorly understood and controversial despite being a primary target of diagnostic and therapeutic interventions. Methods. Among 116 monozygotic twin pairs, which had been examined 5 years earlier, 75 pairs (150 men) were reexamined. They were imaged using the same MRI scanner and examination protocol as at baseline. The data were analyzed using statistical methods for longitudinal studies. Results. Progression in disc height narrowing, disc bulging, osteophytosis, and fatty degeneration in the lumbar spine was seen in about 7% to 13% of the discs in 7% to 46% of subjects during 5-year follow-up. Few degenerative findings appear to reverse; few disc height measures increased, some anular tears were no longer visible, and bulging/herniation diminished. New anular tears (in axial view) were detected in 1.5%, disappeared in 2%, and were unchanged in 5.3% of discs; in the sagittal view, new high intensity zones findings were identified in 0.5%, were no longer apparent in 1.6%, and were unchanged in 7.1% of discs. There were no clear changes in upper endplates: in 2.1% of discs, the irregularity score increased and in 1.8% it decreased. Familial aggregation, reflecting genetic, and shared environmental influences, explained 47% to 66% of the variance in progression of degenerative signs on lumbar MRI, and resistance training and occupational physical loading together explained 2% to 10% of the progression in the degenerative signs in lumbar MRIs. Conclusions. Progression of disc height narrowing, bulging, osteophytes, and fatty degeneration was detected in about 10% or less of the T12–S1 discs. Development and disappearance of anular lesions were rarer. No clear changes were seen in endplate irregularities. The results also confirm that hereditary effects have a dominant role in the progression of disc degeneration and suggest that occupational lifting and leisure time resistance training have modest additional effects.

Evaluation of angiogenesis and side effects in ischemic rabbit hindlimbs after intramuscular injection of adenoviral vectors encoding VEGF and LacZ

Recent studies have suggested the therapeutic potential of vascular endothelial growth factor (VEGF) gene therapy in ischemic skeletal muscle. However, only limited information is available about the effects of VEGF gene therapy in different regions of ischemic limbs, effects of control adenoviruses, and biodistribution of the transgenes after intramuscular (i.m.) administration. Here we studied angiogenesis and side effects of adenovirus‐mediated VEGF and β‐galactosidase (LacZ) gene transfers in ischemic rabbit hindlimbs.

Occupational driving and lumbar disc degeneration: a case- control study

BACKGROUND Back problems are reported more by occupational drivers than by any other occupational group. One explanation is that whole-body vibration caused by the vehicle leads to accelerated disc degeneration, herniation, and associated symptoms. We aimed to investigate the effects of lifetime driving exposure on lumbar disc degeneration in monozygotic twins with very different histories of occupational driving during their life. METHODS We assessed 45 male monozygotic twin pairs from the population-based Finnish Twin Cohort who had greatly different patterns of occupational driving during their life. Data were obtained for driving exposures and potential confounding factors through an extensive, structured interview. We assessed disc degeneration with lumbar MRI. FINDINGS Disc degeneration did not differ between occupational drivers and their twin brothers. We also did not identify any overall tendency for greater degeneration or pathology in occupational drivers than their twin brothers. INTERPRETATIONS Although driving may exacerbate symptoms of back problems, it does not damage the disc. Our inability to identify structural damage should be encouraging to those employed in occupations involving motorised vehicles and operation of heavy equipment.

Complications of lower-limb percutaneous transluminal angioplasty: A prospective analysis of 410 procedures on 295 consecutive patients

Purpose: To evaluate complications and their predictors in percutaneous transluminal angioplasty (PTA) of lower-limb arteries.Methods: Complications in 410 angioplasty procedures in 295 consecutive patients (192 claudicants and 103 suffering from chronic critical ischemia) were prospectively analyzed.Results: The total complication rate was 10.5% (43/410). There were 21 major complications (5%), eight of which required surgical treatment, including four hematomas, two arteriovenous fistulae, and two pseudoaneurysms at the puncture site, two retroperitoneal hematomas, and 11 thrombotic/thromboembolic complications. There were significantly more complications with treatment of occlusions compared with stenoses (18% vs 7%, p=0.002). Women had significantly more bleeding complications than men (15% vs 6%, p=0.032). The 30-day mortality rate in patients with critical ischemia was 10%.Conclusion: In lower-limb PTA a few target lesion- and patient-related determinants of complications could be identified. In patients with critical ischemia, the 30-day mortality was rather high and mainly due to associated coronary and cerebrovascular diseases.