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1.  Disk Degeneration and Low Back Pain: Are They Fat-Related Conditions? 
Global Spine Journal  2013;3(3):133-144.
Low back pain (LBP) is the world's most debilitating condition. Disk degeneration has been regarded as a strong determinant associated with LBP. Overweight and obesity are public health concerns that affect every population worldwide and whose prevalence continues to rise. Studies have indicated strong associations between overweight/obesity and disk degeneration as well as with LBP. This broad narrative review article addresses the various mechanisms that may be involved leading to disk degeneration and/or LBP in the setting of overweight/obesity. In particular, our goal is to raise awareness of the role of fat cells and their involvement via altered metabolism or the release of adipokines as well as other pathways that may lead to the development of disk degeneration and LBP. Understanding the role of fat in this process may aid in the development of novel biological therapies and technologies to halt the progression or regenerate the disk. Moreover, with genetic advancements and the appreciation of genetic epidemiology, a more personalized approach to spine care may have to consider the role of fat in any preventative, therapeutic, and/or prognosis modalities toward the disk and LBP.
PMCID: PMC3854598  PMID: 24436864
spine; disk degeneration; low back pain; obesity; fat; adipokines; metabolism
2.  Accumulation of lifestyle and psychosocial problems and persistence of adverse lifestyle over two-year follow-up among Finnish adolescents 
BMC Public Health  2014;14:542.
Adolescent’psychosocial problems associate with unhealthy behaviors, but data on co-occurring patterns is sparse. We investigated 1) whether adolescents could be categorized into meaningful subgroups with respect to psychosocial and lifestyle factors, 2) whether the prevalence of physical inactivity, overweight and smoking vary within the subgroups and 3) whether these unhealthy behaviors persist in a two-year follow-up.
The study was based on a subgroup of the 1986 Northern Finland Birth Cohort, which consisted of adolescents who replied to a postal questionnaire at 16 years (n = 6792) and a subgroup of this sample at 18 years (n = 1552). Latent class analysis (LCA) was performed to establish clusters at 16 years.
Smoking co-existed with emotional and behavioral problems in both genders. Boys with the most inactive lifestyle slept poorly, whereas multiple problems co-occurred among girls. Those with a high body mass index (BMI) separated as groups of their own. Different combinations of adverse lifestyle and emotional and behavioral problems were relatively common in both sexes as only 51% of boys and 67% of girls belonged to the reference cluster with low probability for these findings. Physical inactivity, high BMI and smoking tended to persist over the two-year follow-up.
It seems that lifestyle and psychosocial factors divide adolescents into distinct subgroups in which unhealthy lifestyle patterns remain between the ages of 16 and 18. This may indicate problems in other life areas and expose them to an increased risk of future health problems.
PMCID: PMC4057560  PMID: 24884444
Adolescent; Health behavior; Mental health; Cohort studies; Latent class
3.  Efficacy of zoledronic acid for chronic low back pain associated with Modic changes in magnetic resonance imaging 
Modic changes (MC) are associated with low back pain (LBP), but effective treatments are lacking. The aim of this randomized, placebo-controlled, double-blinded trial was to evaluate the efficacy of zoledronic acid (ZA) for chronic LBP among patients with MC in magnetic resonance imaging (MRI).
Inclusion criteria were LBP lasting ≥3 months, with an intensity of ≥6 on a 10-cm VAS or an Oswestry Disability Index (ODI) of ≥30%, and MC in MRI. Patients were randomized into single intravenous infusion of ZA 5 mg (n = 20), or placebo (n = 20) groups. The primary outcome was LBP intensity, secondary outcomes leg pain intensity, ODI, health-related quality of life (RAND-36), lumbar flexibility, sick leaves and use of pain medication. The treatment differences at one month and one year were analysed using ANCOVA with adjustment for the baseline score.
The mean difference (MD) between the groups in the primary outcome, intensity of LBP, was 1.4 (95% confidence intervals (CI) 0.01 to 2.9) in favour of ZA at one month. We observed no significant between-group difference in the intensity of LBP at one year (MD 0.7; 95% CI −1.0 to 2.4) or in secondary outcomes at any time point except that 20% of patients in the ZA group used non-steroidal anti-inflammatory drugs at one year compared to 60% in the placebo group (P = 0.022). Acute phase reactions (fever, flu-like symptoms, arthralgia) emerged in 95% of the patients in the ZA group, compared to 35% in the placebo group.
ZA was effective in reducing the intensity of LBP in the short term and in reducing the use of NSAIDs within the time span of one year among patients with chronic LBP and MC confirmed in MRI. Although the results seem encouraging, larger studies are required to analyse the effectiveness and safety of ZA for patients with MC.
Trial registration identifier NCT01330238.
PMCID: PMC3996022  PMID: 24588905
Low back pain; Magnetic resonance imaging; Modic changes; Randomized trial; Zoledronic acid
4.  Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant 
The Journal of Clinical Investigation  2013;123(11):4909-4917.
Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.
PMCID: PMC3809787  PMID: 24216480
5.  Associations of metabolic factors and adipokines with pain in incipient upper extremity soft tissue disorders: a cross-sectional study 
BMJ Open  2013;3(8):e003036.
Earlier studies have suggested associations between metabolic factors and musculoskeletal pain or disorders. We studied the associations of obesity, lipids, other features of the metabolic syndrome and adipokines (adiponectin, leptin, resistin, visfatin) with upper extremity pain in a clinical population with incipient upper extremity soft tissue disorders (UESTDs).
A cross-sectional study.
Primary healthcare (occupational health service) with further examinations at a research institute.
Patients (N=163, 86% were women) seeking medical advice in the occupational health service due to incipient upper extremity symptoms with symptom duration of <1 month were referred for consultation to the Finnish Institute of Occupational Health from Spring 2006 to Fall 2008. We included all actively working subjects meeting diagnostic criteria based on physical examination. We excluded subjects meeting predetermined conditions.
Outcome measure
Pain intensity was assessed with visual analogue scale and dichotomised at the highest tertile (cut-point 60).
Obesity (adjusted OR for high waist circumference 2.9, 95% CI 1.1 to 7.3), high-density lipoprotein cholesterol (OR 3.9, 95% CI 1.4 to 10.1 for low level) and triglycerides (OR 2.6, 95% CI 1.0 to 6.8 for high level) were associated with pain intensity. Of four adipokines studied, only visfatin was associated with upper extremity pain (adjusted OR 1.4, 95% CI 1.0 to 2.1 for 1SD increase in level).
Abdominal obesity and lipids may have an impact on pain intensity in UESTDs. They may intensify pain through proinflammatory pain-modifying molecular pathways or by causing soft tissue pathology and dysfunction of their supplying arteries. Of four adipokines studied only one (visfatin) was associated with pain intensity. In the future, further studies are required to better understand the relationship between metabolic factors and UESTDs.
PMCID: PMC3753506  PMID: 23959751
Occupational & Industrial Medicine; Musculoskeletal disorders < ORTHOPAEDIC & TRAUMA SURGERY
6.  Heart rate variability in sciatica patients referred to spine surgery: a case control study 
A chronic pain condition may result in altered autonomic nervous system regulation in various patient populations. We evaluated whether autonomic regulation differs between sciatica patients referred to spine surgery and age-matched healthy controls analyzed with heart rate variability techniques (HRV).
HRV of patients (n = 201) and healthy controls (n = 138) were measured in standing conditions (5 min). High frequency (HF) power as an index of cardiac vagal modulation and the low-to-high-frequency (LF/HF) ratio and short-term fractal scaling exponent α1 as indices of sympathovagal balance were analyzed. Pain intensity was assessed on a Visual Analog Scale (VAS) and perceived disability with Oswestry Disability Index.
The Oswestry and VAS scores were higher in the patients than in the controls (p < 0.0001 for both). HF power was markedly lower for the patients compared to the controls (p < 0.0001). The LF/HF ratio and α1 were higher in the patients than in the controls (p < 0.01 for both). After adjusting for sex, smoking, BMI, and leisure-time physical activity, HF power (p = 0.011) and α1 (p = 0.012) still differed between the groups. Among the patients, HF power was slightly associated with the duration of chronic pain (r = −.232, p = 0.003).
Sciatica patients referred to spine surgery had altered cardiac autonomic regulation expressed as decreased vagal activity and an increased sympathovagal balance toward sympathetic dominance when compared with age-matched healthy controls.
PMCID: PMC3644230  PMID: 23622100
Autonomic nervous system; Back pain; Sciatica; Sympathovagal balance; Vagal activity
7.  Body mass index is associated with lumbar disc degeneration in young Finnish males: subsample of Northern Finland birth cohort study 1986 
The role of environmental factors in lumbar intervertebral disc degeneration (DD) in young adults is largely unknown. Therefore, we investigated whether body mass index (BMI), smoking, and physical activity are associated with lumbar DD among young adults.
The Oulu Back Study (OBS) is a subpopulation of the 1986 Northern Finland Birth Cohort (NFBC 1986) and it originally included 2,969 children. The OBS subjects received a postal questionnaire, and those who responded (N = 1,987) were invited to the physical examination. The participants (N = 874) were invited to lumbar MRI study. A total of 558 young adults (325 females and 233 males) underwent MRI that used a 1.5-T scanner at the mean age of 21. Each lumbar intervertebral disc was graded as normal (0), mildly (1), moderately (2), or severely (3) degenerated. We calculated a sum score of the lumbar DD, and analyzed the associations between environmental risk factors (smoking, physical activity and weight-related factors assessed at 16 and 19 years) and DD using ordinal logistic regression, the results being expressed as cumulative odds ratios (COR). All analyses were stratified by gender.
Of the 558 subjects, 256 (46%) had no DD, 117 (21%) had sum score of one, 93 (17%) sum score of two, and 92 (17%) sum score of three or higher. In the multivariate ordinal logistic regression model, BMI at 16 years (highest vs. lowest quartile) was associated with DD sum score among males (COR 2.35; 95% CI 1.19-4.65) but not among females (COR 1.29; 95% CI 0.72-2.32). Smoking of at least four pack-years was associated with DD among males, but not among females (COR 2.41; 95% CI 0.99-5.86 and 1.59; 95% 0.67-3.76, respectively). Self-reported physical activity was not associated with DD.
High BMI at 16 years was associated with lumbar DD at 21 years among young males but not among females. High pack-years of smoking showed a comparable association in males, while physical activity had no association with DD in either gender. These results suggest that environmental factors are associated with DD among young males.
PMCID: PMC3599904  PMID: 23497297
Disc degeneration; Smoking; Body mass index; Physical activity; Waist circumference; Young adult
8.  Association of Abdominal Obesity with Lumbar Disc Degeneration – A Magnetic Resonance Imaging Study 
PLoS ONE  2013;8(2):e56244.
To evaluate whether midsagittal (abdominal) obesity in magnetic resonance imaging (MRI), waist circumference (WC) and body fat percentage are associated with lumbar disc degeneration in early adulthood.
We obtained the lumbar MRI (1.5-T scanner) of 325 females and 233 males at a mean age of 21 years. Lumbar disc degeneration was evaluated using Pfirrmann classification. We analysed the associations of MRI measures of obesity (abdominal diameter (AD), sagittal diameter (SAD), ventral subcutaneous thickness (VST), and dorsal subcutaneous thickness (DST)), WC and body fat percentage with disc degeneration sum scores using ordinal logistic regression.
A total of 155 (48%) females and 147 (63%) males had disc degeneration. AD and SAD were associated with a disc degeneration sum score of ≥3 compared to disc degeneration sum score of 0–2 (OR 1.67; 95% confidence interval (CI) 1.20–2.33 and OR 1.40; 95% CI 1.12–1.75, respectively) among males, but we found no association among females. WC was also associated with disc degeneration among males (OR 1.03 per one cm; 95% CI 1.00–1.05), but not among females.
Measures of abdominal obesity in MRI and waist circumference were associated with disc degeneration among 21-year-old males.
PMCID: PMC3571955  PMID: 23418543
9.  Genetic Association Studies in Lumbar Disc Degeneration: A Systematic Review 
PLoS ONE  2012;7(11):e49995.
Low back pain is associated with lumbar disc degeneration, which is mainly due to genetic predisposition. The objective of this study was to perform a systematic review to evaluate genetic association studies in lumbar disc degeneration as defined on magnetic resonance imaging (MRI) in humans.
A systematic literature search was conducted in MEDLINE, MEDLINE In-Process, SCOPUS, ISI Web of Science, The Genetic Association Database and The Human Genome Epidemiology Network for information published between 1990–2011 addressing genes and lumbar disc degeneration. Two investigators independently identified studies to determine inclusion, after which they performed data extraction and analysis. The level of cumulative genetic association evidence was analyzed according to The HuGENet Working Group guidelines.
Fifty-two studies were included for review. Forty-eight studies reported at least one positive association between a genetic marker and lumbar disc degeneration. The phenotype definition of lumbar disc degeneration was highly variable between the studies and replications were inconsistent. Most of the associations presented with a weak level of evidence. The level of evidence was moderate for ASPN (D-repeat), COL11A1 (rs1676486), GDF5 (rs143383), SKT (rs16924573), THBS2 (rs9406328) and MMP9 (rs17576).
Based on this first extensive systematic review on the topic, the credibility of reported genetic associations is mostly weak. Clear definition of lumbar disc degeneration phenotypes and large population-based cohorts are needed. An international consortium is needed to standardize genetic association studies in relation to disc degeneration.
PMCID: PMC3503778  PMID: 23185509
10.  Gender difference in genetic association between IL1A variant and early lumbar disc degeneration: a three-year follow-up 
The purpose of the present study was to analyze the associations between specific genetic markers and early disc degeneration (DD) or early disc degeneration progression (DDP) defined by magnetic resonance imaging (MRI).
We selected eleven of the most promising single nucleotide polymorphisms (SNP) and compared the distributions of these genetic markers between groups defined by MRI in a Danish adolescent population (N=166) over a three-year follow-up period.
We observed a ten-fold higher annual incidence of endplate changes than previously reported in adults. The gender difference in IL1A rs1800587 association with DD remained significant and another association with DDP emerged in follow-up assessment. Among girls, the rs1800587 T-allele was associated both with DD (OR 2.82 [95% CI 1.29-6.16]) and with DDP (OR 2.45 [95% CI 1.03-5.82]). Among boys, the IL6 rs1800795 genotype G/C was protective in both DD (OR 0.26 [95% CI 0.09-0.72]) and DDP (OR 0.32 [95% CI 0.12-0.88]) with the IL6 rs1800797 genotype G/A was associated with a decreased likelihood of DD (OR 0.27 [95% CI 0.10-0.77]). Gender-genotype interactions were significant for polymorphisms in both IL1A and IL6. Correction for multiple testing weakened the associations for IL6 polymorphisms.
We conclude that gender specific effects in lumbar disc degeneration and its progression are possible. However, further evaluations in larger populations are needed. Our results provide some support to the hypothesis that early disc degeneration is an especially important phase in the cascade of degenerative disc disease.
PMCID: PMC3459213  PMID: 23050050
Disc degeneration; disc degeneration progression; adolescents; genetics; interleukins
11.  Genetic susceptibility of intervertebral disc degeneration among young Finnish adults 
BMC Medical Genetics  2011;12:153.
Disc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD.
We investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging.
Of the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of IL6 was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, SKT rs16924573 (OR 0.27 95% CI 0.07-0.96) and CILP rs2073711 in women (OR 2.04, 95% CI 1.07-3.89).
Our results indicate that IL6, SKT and CILP are involved in the etiology of DD among young adults.
PMCID: PMC3235967  PMID: 22107760
12.  Multiple chronic pain states are associated with a common amino acid–changing allele in KCNS1 
Brain  2010;133(9):2519-2527.
Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the ‘valine risk allele’, was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18–22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E−08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.
PMCID: PMC2929335  PMID: 20724292
neuropathic pain; phenotype; molecular genetics; axonal injury; gene expression
13.  Is insufficient quantity and quality of sleep a risk factor for neck, shoulder and low back pain? A longitudinal study among adolescents 
European Spine Journal  2009;19(4):641-649.
The quantity and quality of adolescents’ sleep may have changed due to new technologies. At the same time, the prevalence of neck, shoulder and low back pain has increased. However, only a few studies have investigated insufficient quantity and quality of sleep as possible risk factors for musculoskeletal pain among adolescents. The aim of the study was to assess whether insufficient quantity and quality of sleep are risk factors for neck (NP), shoulder (SP) and low back pain (LBP). A 2-year follow-up survey among adolescents aged 15–19 years was (2001–2003) carried out in a subcohort of the Northern Finland Birth Cohort 1986 (n = 1,773). The outcome measures were 6-month period prevalences of NP, SP and LBP. The quantity and quality of sleep were categorized into sufficient, intermediate or insufficient, based on average hours spent sleeping, and whether or not the subject suffered from nightmares, tiredness and sleeping problems. The odds ratios (OR) and 95% confidence intervals (CI) for having musculoskeletal pain were obtained through logistic regression analysis, adjusted for previously suggested risk factors and finally adjusted for specific pain status at 16 years. The 6-month period prevalences of neck, shoulder and low back pain were higher at the age of 18 than at 16 years. Insufficient quantity or quality of sleep at 16 years predicted NP in both girls (OR 4.4; CI 2.2–9.0) and boys (2.2; 1.2–4.1). Similarly, insufficient sleep at 16 years predicted LBP in both girls (2.9; 1.7–5.2) and boys (2.4; 1.3–4.5), but SP only in girls (2.3; 1.2–4.4). After adjustment for pain status, insufficient sleep at 16 years predicted significantly only NP (3.2; 1.5–6.7) and LBP (2.4; 1.3–4.3) in girls. Insufficient sleep quantity or quality was an independent risk factor for NP and LBP among girls. Future studies should test whether interventions aimed at improving sleep characteristics are effective in the prevention and treatment of musculoskeletal pain.
PMCID: PMC2899838  PMID: 19936804
Musculoskeletal pain; Adolescent; Sleep; Risk factors; Prospective study
14.  Modic changes and interleukin 1 gene locus polymorphisms in occupational cohort of middle-aged men 
European Spine Journal  2009;18(12):1963-1970.
According to recent systematic reviews, Modic changes are associated with low-back pain. However, their pathophysiology remains largely unknown. A previous study of Northern Finnish males implicated that IL1A and MMP3 polymorphisms play a role in type II Modic changes. The purpose of the current study was to examine the association of IL1 cluster polymorphisms with Modic changes amongst middle-aged men in Southern Finland. The final study sample consisted of 108 men from three different occupations, who underwent magnetic resonance imaging (MRI) with a 0.1 T-scanner. Six single nucleotide polymorphisms (SNP) in the IL1 gene cluster (IL1A c.1-889C>T; IL1B c.3954C>T; IL1RN c.1812G>A; IL1RN c.1887G>C; IL1RN c.11100T>C; IL1RN c.1506G>A) were genotyped with the SNP-TRAP method or by allele-specific primer extension on modified microarray. In all, 45 subjects had Modic changes at one or more disc levels. The presence of the minor allele of IL1A (c.1-889C>T) was associated with these changes (any Modic change p = 0.031, type II changes p = 0.036). The carriers of the T-allele had a 2.5-fold risk of Modic change and the association was independent of the other IL1 gene cluster loci studied. In addition, a minor haplotype, with a frequency of 7.5% in the study population, including the minor alleles of IL1A c.1-889C>T, IL1RN c.1812G>A, and IL1RN c.1506G>A, was significantly associated with Modic changes. This observation is in accordance with the previous finding from a different geographical area, and thus confirms the importance of the IL1A gene in the pathophysiology of Modic changes.
PMCID: PMC2899448  PMID: 19701653
Modic changes; MRI; Genetic factors; Interleukin
15.  Lifestyle and metabolic factors in relation to shoulder pain and rotator cuff tendinitis: A population-based study 
Shoulder pain is a common health problem. The purpose of this study was to assess the associations of lifestyle factors, metabolic factors and carotid intima-media thickness with shoulder pain and chronic (> 3 months) rotator cuff tendinitis.
In this cross-sectional study, the target population consisted of subjects aged 30 years or older participating in a national Finnish Health Survey during 2000-2001. Of the 7,977 eligible subjects, 6,237 (78.2%) participated in a structured interview and clinical examination. Chronic rotator cuff tendinitis was diagnosed clinically. Weight-related factors, C-reactive protein and carotid intima-media thickness were measured.
The prevalence of shoulder joint pain during the preceding 30 days was 16% and that of chronic rotator cuff tendinitis 2.8%. Smoking, waist circumference and waist-to-hip ratio were related to an increased prevalence of shoulder pain in both genders. Metabolic syndrome, type 2 diabetes mellitus and carotid intima-media thickness were associated with shoulder pain in men, whereas high level of C-reactive protein was associated with shoulder pain in women. Increased waist circumference and type 1 diabetes mellitus were associated with chronic rotator cuff tendinitis in men.
Our findings showed associations of abdominal obesity, some other metabolic factors and carotid intima-media thickness with shoulder pain. Disturbed glucose metabolism and atherosclerosis may be underlying mechanisms, although not fully supported by the findings of this study. Prospective studies are needed to further investigate the role of lifestyle and metabolic factors in shoulder disorders.
PMCID: PMC3161397  PMID: 20646281
16.  Genetic risk factors of disc degeneration among 12-14-year-old Danish children: a population study 
The objective of the present study was to examine the associations between eleven putative predisposing single nucleotide polymorphisms (COL9A3, COL11A2, IL1A, IL1B, IL6 and VDR) and early disc degeneration (DD). The population consisted of 12 to 14-year-old Danish children (N=352). DD was evaluated from magnetic resonance images (MRI). We analysed the association between DD and single nucleotide polymorphisms or haplotypes using logistic regression analyses. Of the 352 children studied, 73 boys and 81 girls had no MRI changes, while 30 boys and 36 girls had lumbar DD. Among girls, IL1A rs1800587 in CT/TT compared to CC resulted in OR 2.85 [1.19-6.83]. In IL6 promoter polymorphism rs1800796, the C-allele was more frequent among the subjects with DD, OR 6.71 [1.71-26.3]. Of the IL6 haplotypes, GCG was associated with DD, OR 6.46 [1.61 – 26.0]. No associations were observed among boys. Our results suggest possible roles for IL1A and IL6 in early DD among girls.
PMCID: PMC3076758  PMID: 21537388
Disc degeneration; children; genetics; interleukins
17.  Vertebral endplate signal changes (Modic change): a systematic literature review of prevalence and association with non-specific low back pain 
European Spine Journal  2008;17(11):1407-1422.
The prevalence of “vertebral endplate signal changes” (VESC) and its association with low back pain (LBP) varies greatly between studies. This wide range in reported prevalence rates and associations with LBP could be explained by differences in the definitions of VESC, LBP, or study sample. The objectives of this systematic critical review were to investigate the current literature in relation to the prevalence of VESC (including Modic changes) and the association with non-specific low back pain (LBP). The MEDLINE, EMBASE, and SveMED databases were searched for the period 1984 to November 2007. Included were the articles that reported the prevalence of VESC in non-LBP, general, working, and clinical populations. Included were also articles that investigated the association between VESC and LBP. Articles on specific LBP conditions were excluded. A checklist including items related to the research questions and overall quality of the articles was used for data collection and quality assessment. The reported prevalence rates were studied in relation to mean age, gender, study sample, year of publication, country of study, and quality score. To estimate the association between VESC and LBP, 2 × 2 tables were created to calculate the exact odds ratio (OR) with 95% confidence intervals. Eighty-two study samples from 77 original articles were identified and included in the analysis. The median of the reported prevalence rates for any type of VESC was 43% in patients with non-specific LBP and/or sciatica and 6% in non-clinical populations. The prevalence was positively associated with age and was negatively associated with the overall quality of the studies. A positive association between VESC and non-specific LBP was found in seven of ten studies from the general, working, and clinical populations with ORs from 2.0 to 19.9. This systematic review shows that VESC is a common MRI-finding in patients with non-specific LBP and is associated with pain. However, it should be noted that VESC may be present in individuals without LBP.
PMCID: PMC2583186  PMID: 18787845
Systematic review; Modic changes; Vertebral endplate; Magnetic resonance imaging; Prevalence; Low back pain
18.  Cardiovascular and lifestyle risk factors in lumbar radicular pain or clinically defined sciatica: a systematic review 
European Spine Journal  2007;16(12):2043-2054.
Lumbar radicular pain is a fairly common health problem, yet its risk factors are far from clear. There are no published systematic reviews on associations between cardiovascular or lifestyle risk factors and lumbar radicular pain or sciatica. The aim of this systematic literature review was to assess associations between these risk factors and lumbar radicular pain or sciatica. We conducted a systematic search of the Medline database for all original articles on lumbar radicular pain or sciatica published until August 2006. Twenty-two papers from 19 studies were included in the review. Overweight or obesity was associated with sciatica in most of the case-control and cohort studies. Some studies showed an increased risk of lumbar radicular pain in smokers with a long smoking history or in those with high levels of physical activity. A few case-control studies showed an association between serum C-reactive protein and sciatica. No consistent associations were found for serum lipids levels or high blood pressure. In summary, the associations of overweight, long smoking history, high physical activity and a high serum C-reactive protein level with lumbar radicular pain or sciatica were substantiated by the present review. However, more prospective studies are needed in order to further clarify these associations and the mechanisms of action.
PMCID: PMC2140143  PMID: 17525856
C-reactive protein; Exercise; Lipids; Overweight; Smoking
19.  Association between promoter -1607 polymorphism of MMP1 and Lumbar Disc Disease in Southern Chinese 
BMC Medical Genetics  2008;9:38.
Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the MMP1 gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD.
Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom® platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test.
Our results showed substantial evidence of association between -1607 promoter polymorphism of MMP1 and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04–1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01–2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033–2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029–2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele.
We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of MMP1 are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.
PMCID: PMC2386444  PMID: 18439317
20.  Are the determinants of vertebral endplate changes and severe disc degeneration in the lumbar spine the same? A magnetic resonance imaging study in middle-aged male workers 
Modic changes are bone marrow lesions visible in magnetic resonance imaging (MRI), and they are assumed to be associated with symptomatic intervertebral disc disease, especially changes located at L5-S1. Only limited information exists about the determinants of Modic changes. The objective of this study was to evaluate the determinants of vertebral endplate (Modic) changes, and whether they are similar for Modic changes and severe disc degeneration focusing on L5-S1 level.
228 middle-aged male workers (159 train engineers and 69 sedentary factory workers) from northern Finland underwent sagittal T1- and T2-weighted MRI. Modic changes and disc degeneration were analyzed from the scans. The participants responded to a questionnaire including items of occupational history and lifestyle factors. Logistic regression analysis was used to evaluate the associations between selected determinants (age, lifetime exercise, weight-related factors, fat percentage, smoking, alcohol use, lifetime whole-body vibration) and Modic type I and II changes, and severe disc degeneration (= grade V on Pfirrmann's classification).
The prevalences of the Modic changes and severe disc degeneration were similar in the occupational groups. Age was significantly associated with all degenerative changes. In the age-adjusted analyses, only weight-related determinants (BMI, waist circumference) were associated with type II changes. Exposure to whole-body vibration, besides age, was the only significant determinant for severe disc degeneration. In the multivariate model, BMI was associated with type II changes at L5-S1 (OR 2.75 per one SD = 3 unit increment in BMI), and vibration exposure with severe disc degeneration at L5-S1 (OR 1.08 per one SD = 11-year increment in vibration exposure).
Besides age, weight-related factors seem important in the pathogenesis of Modic changes, whereas whole-body vibration was the only significant determinant of severe disc degeneration.
PMCID: PMC2373785  PMID: 18416819
21.  Effectiveness of early part-time sick leave in musculoskeletal disorders 
The importance of staying active instead of bed rest has been acknowledged in the management of musculoskeletal disorders (MSDs). This emphasizes the potential benefits of adjusting work to fit the employee's remaining work ability. Despite part-time sick leave being an official option in many countries, its effectiveness has not been studied yet. We have designed a randomized controlled study to assess the health effects of early part-time sick leave compared to conventional full-day sick leave. Our hypothesis is that if work time is temporarily reduced and work load adjusted at the early stages of disability, employees with MSDs will have less disability days and faster return to regular work duties than employees on a conventional sick leave.
The study population will consist of 600 employees, who seek medical advice from an occupational physician due to musculoskeletal pain. The inclusion requires that they have not been on a sick leave for longer than 14 days prior to the visit. Based on the physician's judgement, the severity of the symptoms must indicate a need for conventional sick leave, but the employee is considered to be able to work part-time without any additional risk. Half of the employees are randomly allocated to part-time sick leave group and their work time is reduced by 40–60%, whereas in the control group work load is totally eliminated with conventional sick leave. The main outcomes are the number of days from the initial visit to return to regular work activities, and the total number of sick leave days during 12 and 24 months of follow-up. The costs and benefits as well as the feasibility of early part-time sick leave will also be evaluated.
This is the first randomised trial to our knowledge on the effectiveness of early part-time sick leave compared to conventional full-time sick leave in the management of MSDs. The data collection continues until 2011, but preliminary results on the feasibility of part-time sick leave will be available already in 2008. The increased knowledge will assist in better decision making process regarding the management of disability related to MSDs.
Trial Registration
International Standard Randomised Controlled Trial Number Register, register number ISRCTN30911719
PMCID: PMC2267790  PMID: 18294405
22.  Effect of training and lifting equipment for preventing back pain in lifting and handling: systematic review 
BMJ : British Medical Journal  2008;336(7641):429-431.
Objectives To determine whether advice and training on working techniques and lifting equipment prevent back pain in jobs that involve heavy lifting.
Data sources Medline, Embase, CENTRAL, Cochrane Back Group’s specialised register, CINAHL, Nioshtic, CISdoc, Science Citation Index, and PsychLIT were searched up to September-November 2005.
Review methods The primary search focused on randomised controlled trials and the secondary search on cohort studies with a concurrent control group. Interventions aimed to modify techniques for lifting and handling heavy objects or patients and including measurements for back pain, consequent disability, or sick leave as the main outcome were considered for the review. Two authors independently assessed eligibility of the studies and methodological quality of those included. For data synthesis, we summarised the results of studies comparing similar interventions. We used odds ratios and effect sizes to combine the results in a meta-analysis. Finally, we compared the conclusions of the primary and secondary analyses.
Results Six randomised trials and five cohort studies met the inclusion criteria. Two randomised trials and all cohort studies were labelled as high quality. Eight studies looked at lifting and moving patients, and three studies were conducted among baggage handlers or postal workers. Those in control groups received no intervention or minimal training, physical exercise, or use of back belts. None of the comparisons in randomised trials (17 720 participants) yielded significant differences. In the secondary analysis, none of the cohort studies (772 participants) had significant results, which supports the results of the randomised trials.
Conclusions There is no evidence to support use of advice or training in working techniques with or without lifting equipment for preventing back pain or consequent disability. The findings challenge current widespread practice of advising workers on correct lifting technique.
PMCID: PMC2249682  PMID: 18244957
23.  Determinants of lumbar artery occlusion among patients with sciatica: A three-year follow-up with magnetic resonance angiography 
European Spine Journal  2005;14(7):664-670.
We showed previously that chronic Chlamydia pneumoniae infection increases the risk of lumbar artery occlusion. We did not evaluate, however, the effect of other risk factors for cardiovascular diseases in combination with this chronic infection. The purpose of this study was to investigate the combined effect of chronic C. pneumoniae infection and other known determinants of artery occlusion in a population of sciatica patients. Two-dimensional time-of-flight magnetic resonance angiography (MRA) was used to evaluate lumbar arteries at baseline and three years. The arteries on both sides (L1–L4) were evaluated visually and scored as normal, narrowed or occluded. Logistic regression analysis was performed separately for baseline total arterial stenosis and each L1–L4 segmental artery pair, and for incident new stenosis during the follow-up period. The determinants analyzed included age, body mass index (BMI, kg/m2), education, gender, and smoking, in addition to presence of chronic C. pneumoniae infection. MRA was obtained at baseline for 147 patients and at 3 years for 134 patients. Sixty-four (47.8%) of 134 patients had new arterial stenosis. Total incidence of new arterial stenosis was distributed quite evenly between the individual segmental levels, varying from 12.7 to 18.6%. BMI was the only predictor of new arterial stenosis (odds ratio (OR) 1.13). A reasonable logistic model could be established only for baseline L4 and total arterial scores. At L4, education was a protective factor (OR 0.07), whereas age (OR for the oldest age group 6.7) and BMI (OR 1.17) were associated with increased risk of occlusion. For total arterial score, chronic C. pneumoniae infection was an independent determinant of arterial occlusion, increasing the risk to almost eightfold. Additionally, BMI (OR 1.16), and age (for the oldest age group OR 11.4) were significant determinants for stenosis. Smoking was not statistically significant. As chronic C. pneumoniae infection was an independent determinant of lumbar artery occlusion, treatments of this chronic infection may have an impact on lumbar diseases. The importance of BMI for new arterial stenosis suggests that weight reduction may also have a beneficial effect in lumbar artery disease.
PMCID: PMC3489218  PMID: 15723216
Arterial stenosis; Magnetic resonance imaging; Chlamydia pneumoniae; Risk factors; Sciatica

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