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1.  High sensitive C-reactive protein-Effective tool in determining postoperative recovery in lumbar disc disease 
Indian Journal of Orthopaedics  2014;48(4):354-359.
It is common in medical practice to see patients having persistent pain and radiculopathy even after undergoing discectomy surgery. Inflammatory cytokines, such as interleukins are produced at the site of disc herniation and are now considered responsible for the pain perceived by the patient. This study has used high sensitive C-reactive protein (HSCRP) assay for predicting inflammation around the nerve roots on very same principle, which has used HSCRP for predicting coronary artery diseases in current clinical practice. Thus, purpose of this study is to test whether HSCRP can stand as an objective tool to predict postoperative recovery in patients undergoing lumbar discectomy. That is, to study association between preoperative HSCRP blood level and postoperative recovery with the help of modified Oswestry Back Disability Score.
Materials and Methods:
A study group consisting of 50 cases of established lumbar disc disease and control group of 50 normal subjects, matched with the study group. Both the study and control groups were subjected to detailed evaluation with the help of modified Oswestry Low Back Pain Scale both pre and postoperatively at 3 months, 6 months and 1-year. The preoperative blood samples were analyzed to assess the HSCRP concentration. All the cases underwent surgery over a period of 1-year by the same surgeon.
The level of HSCRP in the study group was between 0.050– and 0.710 mg/dL and in the control group, 0.005-0.020 mg/dL. There was highly significant positive correlation between preoperative HSCRP level and postoperative score at P < 0.005. Cases with HSCRP level in the range of 0.1820 ± 0.079 mg/dL, showed better recovery (score improved > 10 points), while those with HSCRP level in the range of 0.470 ± 0.163 mg/dL, showed poor recovery (score improved < 10 points).
HSCRP will serve as a good supplementary prognostic marker for operative decision making in borderline and troublesome cases of lumbar disc disease.
PMCID: PMC4137511  PMID: 25143637
Lumbar disc disease; sciatica; discectomy; high sensitive C-reactive protein; Lumbar; disc; herniated; sciatica; blood proteins
2.  Isolated septic facet joint arthritis as a rare cause of acute and chronic low back pain – a case report and literature review 
Polish Journal of Radiology  2012;77(4):72-76.
The most common cause of low back pain is degenerative disease of the intervertebral disc and other structures of the lumbar spine. However, in some cases other less frequent causes of such pain can be seen, for example septic facet joint arthritis. Until now, only 40 cases of such inflammatory changes within the spine have been reported in the literature. The disease is probably underestimated due to improper diagnostic pathway.
Case Report:
The authors describe a case of a 53-year-old woman who was repeatedly hospitalized during a five-month period because of an acute, severe low back pain, with sphincter dysfunction, partially resembling sciatic symptoms. Physical examinations revealed also focal tenderness in the area of the lumbar spine. Inflammatory markers (ESR – erythrocyte sedimentation rate, CRP – C-reactive protein) were elevated. Conservative analgetic treatment brought only partial and temporary relief of the pain and symptoms. The final accurate diagnosis of isolated septic facet joint arthritis at the level of L5/S1 was established after several months from the onset of the first symptoms, after performing various imaging examinations, including bone scintigraphy as well as CT and MRI of the lumbosacral spine. The patient fully recovered after antibiotic therapy and surgery, which was proven in several follow-up examinations showing no relevant pathology of the lumbar spine. The authors broadly describe the etiology and clinical symptoms of the septic facet joint arthritis as well as the significant role of imaging methods, especially MRI, in diagnostic process. The authors also discuss currently available treatment options, both conservative and surgical.
The diagnostic procedure of septic facet joint arthritis requires several steps to be taken. Establishing a correct diagnosis may be difficult, that is why it is important to remember about rare causes of low back pain and to perform detailed physical examination, laboratory tests and choose appropriate imaging techniques.
PMCID: PMC3529718  PMID: 23269942
low back pain; diagnostics; facet joint arthritis
3.  Pain and high sensitivity C reactive protein in patients with chronic low back pain and acute sciatic pain 
Annals of the Rheumatic Diseases  2005;64(6):921-925.
Background: The severity of pain from musculoskeletal disorders might be associated with high sensitivity C reactive protein (hsCRP), a sensitive marker of low grade systemic inflammation.
Objective: To study the association between pain as assessed by a visual analogue scale (VAS) and hsCRP in patients with chronic low back pain and acute sciatic pain.
Methods: Information on pain severity, determinants of hsCRP, and hsCRP values were obtained prospectively at up to 10 time points during six months in 72 consecutive patients (mean age 43.3 years; 59.7% female): 41 with chronic low back pain and 31 with acute sciatic pain. The association between severity of pain and raised (highest quartile) hsCRP values at any time point was estimated by multivariable logistic regression using generalised estimating equations to adjust odds ratios (OR) and their confidence intervals (CI) for intraindividual dependence of measurements.
Results: Mean intensity of pain (VAS 0–10) at baseline was 4.9 and 5.5 in patients with chronic low back and acute sciatic pain, respectively. Highest v lowest tertile of average intensity of pain during the last 24 hours was associated with increased hsCRP levels among patients with acute sciatic pain (adjusted OR = 3.4 (95% CI, 1.1 to 10), but not in patients with chronic low back pain (adjusted OR = 0.87 (0.25 to 3.0)).
Conclusions: Mean intensity of pain during the previous 24 hours as assessed by VAS was independently associated with high levels of hsCRP in patients with acute sciatic pain but not in those with chronic low back pain.
PMCID: PMC1755532  PMID: 15897311
4.  Analysis of Efficacy Differences between Caudal and Lumbar Interlaminar Epidural Injections in Chronic Lumbar Axial Discogenic Pain: Local Anesthetic Alone vs. Local Combined with Steroids 
Study Design: Comparative assessment of randomized controlled trials of caudal and lumbar interlaminar epidural injections in chronic lumbar discogenic pain.
Objective: To assess the comparative efficacy of caudal and lumbar interlaminar approaches of epidural injections in managing axial or discogenic low back pain.
Summary of Background Data: Epidural injections are commonly performed utilizing either a caudal or lumbar interlaminar approach to treat chronic lumbar axial or discogenic pain, which is pain exclusive of that associated with a herniated intervertebral disc, or that is due to degeneration of the zygapophyseal joints, or due to dysfunction of the sacroiliac joints, respectively. The literature on the efficacy of epidural injections in managing chronic axial lumbar pain of presumed discogenic origin is limited.
Methods: The present analysis is based on 2 randomized controlled trials of chronic axial low back pain not caused by disc herniation, radiculitis, or facet joint pain, utilizing either a caudal or lumbar interlaminar approach, with a total of 240 patients studied, and a 24-month follow-up. Patients were assigned to receive either local anesthetic only or local anesthetic with a steroid in each 60 patient group.
Results: The primary outcome measure was significant improvement, defined as pain relief and functional status improvement of at least 50% from baseline, which was reported at 24-month follow-ups in 72% who received local anesthetic only with a lumbar interlaminar approach and 54% who received local anesthetic only with a caudal approach. In patients receiving local anesthetic with a steroid, the response rate was 67% for those who had a lumbar interlaminar approach and 68% for those who had a caudal approach at 12 months. The response was significantly better in the lumbar interlaminar group who received local anesthetic only, 77% versus 56% at 12 months and 72% versus 54% at 24 months.
Conclusion: This assessment shows that in patients with axial or discogenic pain in the lumbar spine after excluding facet joint and SI Joint pain, epidural injections of local anesthetic by the caudal or lumbar interlaminar approach may be effective in managing chronic low back pain with a potential superiority for a lumbar interlaminar approach over a caudal approach.
PMCID: PMC4323359
Chronic low back pain; axial low back pain; lumbar discogenic pain; caudal epidural injections; lumbar interlaminar epidural injections.
5.  A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis: Implications for Clinical Interpretation 
PLoS Medicine  2010;7(9):e1000341.
A genetic association study by Timothy Vyse and colleagues suggests that there is a significant association between CRP variants and acute-phase serum CRP concentrations in patients with rheumatoid arthritis, including those with chronic inflammation.
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. Little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation.
Methods and Findings
We studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients). A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modelling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients. Common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h the expected geometric mean CRP (95% confidence interval) concentration was 43.1 mg/l (32.1–50.0) for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
Our findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events: our findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Please see later in the article for the Editors' Summary
Editors' Summary
C-reactive protein (CRP) is a serum marker for inflammation or infection and acts by binding to a chemical (phosphocholine) found on the surface of dead or dying cells (and some types of bacteria) in order to activate the immune system (via the complement system). Fat cells release factors that stimulate the liver to produce CRP, and serum levels greater than 10 mg/l are generally considered indicative of an infectious or inflammatory process. After an inflammatory stimulus, serum CRP levels may exceed 500 times baseline, so CRP is used in all medical specialities to help diagnose inflammation and infection. Although patients with chronic inflammatory diseases, such as rheumatoid arthritis, have raised levels of CRP, levels of CRP are still highly variable. Some studies have suggested that there may be genetic variations of CRP (CRP variants) that determine the magnitude of the acute-phase CRP response, a finding that has important clinical implications: CRP thresholds are used as a diagnostic component of formal clinical algorithms and play an important role in a clinician's decision-making process when diagnosing inflammatory disease and choosing treatment options. Therefore, it is possible that false reassurance could be given to a patient with disease, or optimal treatment withheld, because some patients are genetically predisposed to have only a modest increase in acute-phase CRP.
Why Was This Study Done?
Although some studies have looked at the CRP gene variant response, few, if any, studies have examined the CRP gene variant response in the context of chronic inflammation, such as in rheumatoid arthritis. Therefore, this study aimed to determine whether CRP gene variants could also influence CRP serum levels in rheumatoid arthritis.
What Did the Researchers Do and Find?
The authors studied two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients): one patient set used a cohort of 281 patients in the UK, and the other patient set (used for replication) consisted of 414 patients from New Zealand and Australia. A genetic technique (a tagSNP approach) was used to capture common variations at the CRP locus (haplotype association analysis) at both the population and the individual level. The relationship between genotype and serum CRP was explored by linear modeling. The researchers found that common genetic variants at the CRP locus were associated with acute-phase serum CRP in both patient sets translating into an approximate 3.5-fold change in expected serum CRP between carriers of two common CRP variants. For example, when ESR = 50 mm/h the expected CRP serum level for one common CRP variant was 43.1 mg/l and for another CRP variant was 14.2 mg/l.
What Do These Findings Mean?
The findings of this study raise questions about the interpretation of acute-phase serum CRP, as they suggest that there is a significant association between CRP variants and acute-phase serum CRP concentrations in a group of patients with rheumatoid arthritis, including those with chronic active inflammation. The size of the genetic effect may be large enough to have a clinically relevant impact on the assessment of inflammatory disease activity, which in turn may influence therapeutic decision making. Failure to take into account the potential for genetic effects may result in the inappropriate reassurance or undertreatment of patients simply because they carry low-CRP–associated genetic variants. CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events, so these findings impact on the use of such algorithms. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
Additional Information
Please access these Web sites via the online version of this summary at
Lab Test Online provides information on CRP
The Wellcome Trust provides a glossary of genetic terms
Learn.Genetics provides access to the Genetic Science Learning Center, which is part of the human genome project
PMCID: PMC2943443  PMID: 20877716
6.  Lumbar Periradicular Abscess Mimicking a Fragmented Lumbar Disc Herniation : An Unusual Case 
We herein describe the case of a focal spontaneous spinal epidural abscess who was initially diagnosed to have a free fragment of a lumbar disc. A 71-year-old woman presented with history of low back and right leg pain. Magnetic resonance imaging suggested a peripherally enhancing free fragment extending down from S1 nerve root axilla. Preoperative laboratory investigation showed elevation of c-reactive protein (CRP), erythrocyte sedimentation rate (ESR) levels. She was taken for surgery and a fluctuating mass at the axilla of S1 nerve was found. When the mass was probed with a dissector, a dark yellow, thick pus drained out. Pus cultures were negative. Patients who present with extreme low back plus leg pain and increased leucocyte count, ESR and CRP levels should raise the suspicion of an infection of a vertebral body or spinal epidural space.
PMCID: PMC2615143  PMID: 19137084
Abscess; Disc; Periradicular; Spinal
7.  High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment: an SEAS substudy 
Open Heart  2015;2(1):e000152.
To assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in Aortic Stenosis (SEAS).
Methods and results
In 1620 SEAS patients, we measured lipids and hsCRP at baseline and after 1 year of treatment and registered during 4 years of follow-up major cardiovascular events (MCE) composed of ischaemic cardiovascular events (ICE) and aortic valve-related events (AVE). Simvastatin/ezetimibe reduced low-density lipoprotein cholesterol (3.49 (2.94 to 4.15) to 1.32 (1.02 to 1.69) vs 3.46 (2.92 to 4.08) to 3.34 (2.81 to 3.92) mmol/L) and hsCRP (2.1 (0.9 to 4.1) to 1.2 (0.6 to 2.4) vs 2.2 (0.9 to 4.9) to 1.8 (0.85 to 4.35) mg/L, all p<0.05) during the first year of treatment. In multivariable Cox regression analysis adjusting for traditional risk factors and baseline hsCRP, ICE was associated with a 1-year increase of hsCRP (HR=1.19 (95% CI 1.12 to 1.25), p<0.001) but not with active treatment (HRTreatment=0.86 (0.67 to 1.13), p=0.28). Patients in the top quartile of baseline hsCRP versus the rest were associated with a higher risk of MCE (HR=1.34(1.09 to 1.64), p=0.02). The prognostic benefit of reduction in hsCRP after 1 year was significantly larger (p<0.01 for interaction) in patients with high versus low baseline hsCRP; hence, a reduction in hsCRP abolished the difference in incidence of MCE between high versus low baseline hsCRP in patients with reduced hsCRP (31.1 vs 31.9%, NS) in contrast to patients with increased hsCRP.
The treatment-associated reduction in ICE was in part related to a reduction in hsCRP but not in lipids. hsCRP reduction was associated with less MCE, especially in patients with high baseline hsCRP.
Trial registration
PMCID: PMC4322313
8.  Salt Intake Is Associated with Inflammation in Chronic Heart Failure 
Chronic Heart Failure (CHF) is highly prevalent and is associated with high morbidity and mortality rates. It has been well established that excessive intake of sodium chloride (salt) induced hypertension in some populations. Although salt seems to induce cardiovascular diseases through elevation of blood pressure, it has also been indicated that salt can induce cardiovascular diseases independently from blood pressure elevation.
The present study aimed to evaluate the association between salt consumption and inflammation in CHF patients.
Patients and Methods:
This study was conducted on 86 patients between 18 and 65 years old who were diagnosed with New York Heart Association (NYHA) functional class I and II heart failure. Salt intake was calculated by using 24 hour urine sodium excretion. Besides, the association between inflammation and daily salt intake was evaluated regarding C - reactive protein (CPR), High sensitive CRP (HsCPR), Erythrocyte Sedimentation Rate (ESR), and ferritin and fibrinogen levels using Pearson correlation analysis.
Our results showed a statistically significant difference between the low (n = 41) and high (n = 45) salt intake groups in terms of serum HsCRP levels (5.21 ± 2.62 vs. 6.36 ± 2.64) (P < 0.048). Additionally, a significant correlation was observed between the amount of salt consumption and HsCRP levels. In this study, daily salt consumption of the enrolled patients was 8.53 gram/day. The medications and even the blood pressures were similar in the two groups, but daily pill count, prevalence of hypertension, and coronary heart disease were higher in the high salt intake group; however, the differences were not statistically significant (P = 0.065). Also, no significant difference was observed between the groups concerning the inflammation markers, such as CRP, ESR, ferritin, and fibrinogen.
Neurohumoral and inflammatory factors are thought to contribute to high mortality and morbidity rates in CHF. Yet, inflammatory markers may early diagnose CHF and predict the prognosis. Excessive salt intake also worsens the inflammation as well as volume control.
PMCID: PMC4109042  PMID: 25177670
Heart Failure; Inflammation; Sodium Dietary
9.  Hormonal and Nutritional Effects on Cardiovascular Risk Markers in Young Women 
Cardiovascular (CV) risk markers, including high-sensitivity C-reactive protein (hsCRP), are increasingly important in predicting cardiac events. A favorable CV risk profile might be expected in anorexia nervosa (AN) due to low body weight and dietary fat intake. However, women with AN have decreased IGF-I levels reflecting decreased GH action, and IGF-I deficiency is associated with elevated hsCRP. Moreover, oral estrogens, known to increase hsCRP in other populations, are commonly prescribed in AN. To date, hsCRP levels and their physiological determinants have not been reported in women with AN.
We examined the relationship between CV risk markers, undernutrition, IGF-I, and oral estrogens, specifically hypothesizing that in the setting of undernutrition, AN would be associated with low hsCRP despite low IGF-I levels and that those women taking oral contraceptive pills (OCPs) would have higher hsCRP and lower IGF-I levels.
Design and Setting
We conducted a cross-sectional study at a clinical research center.
Study Participants
Subjects included 181 women: 140 women with AN [85 not receiving OCPs (AN-E) and 55 receiving OCPs (AN+E)] and 41 healthy controls [28 not receiving OCPs (HC-E) and 13 receiving OCPs (HC+E)].
Main Outcome Measures
We assessed hsCRP, IL-6, IGF-I, low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
Despite low weight, more than 20% of AN+E had high-risk hsCRP levels. AN+E had higher hsCRP than AN-E. AN-E had lower mean hsCRP levels than healthy controls (HC+E and HC-E). IL-6 levels were higher in AN+E with elevated hsCRP (>3 mg/liter) than in AN+E with normal hsCRP levels. IGF-I was inversely associated with hsCRP in healthy women, suggesting a protective effect of GH on CV risk. However, this was not seen in AN. Few patients in any group had high-risk LDL or HDL levels.
Although hsCRP levels are lower in AN than healthy controls, OCP use puts such women at a greater than 20% chance of having hsCRP in the high-CV-risk (>3 mg/liter) category. The elevated mean IL-6 in women with AN and high-risk hsCRP levels suggests that increased systemic inflammation may underlie the hsCRP elevation in these patients. Although OCP use in AN was associated with slightly lower mean LDL and higher mean HDL, means were within the normal range, and few patients in any group had high-risk LDL or HDL levels. IGF-I levels appear to be important determinants of hsCRP in healthy young women. In contrast, IGF-I does not appear to mediate hsCRP levels in AN.
PMCID: PMC3211045  PMID: 17519306
10.  Retrolisthesis and Lumbar Disc Herniation: A Pre-operative Assessment of Patient Function 
Retrolisthesis is relatively rare but when present has been associated with increased back pain and impaired back function. Neither the prevalence of this condition in individuals with lumbar disc herniations nor its possible relation to pre-operative back pain and dysfunction has been well studied.
The purposes of this study were as follows: 1) to determine the prevalence of retrolisthesis (alone or in combination with other degenerative conditions) in individuals with confirmed L5 – S1 disc herniation who later underwent lumbar discectomy; 2) to determine if there is any association between retrolisthesis and degenerative changes within the same vertebral motion segment; and 3) to determine the relation between retrolisthesis (alone or in combination with other degenerative conditions) and pre-operative low back pain, physical function, and quality of life.
Cross-sectional study.
A total of 125 individuals were identified for incorporation into this study. All patients had confirmed L5-S1 disc herniation on MRI and later underwent L5-S1 discectomy. All patients were enrolled in the SPORT (Spine Patient Outcomes Research Trial) study; data was obtained from the multi-institutional database comprised of SPORT patients from across the United States.
Retrolisthesis, Degenerative change on MRI, Modic Changes.
MRI scans of the lumbar spine were assessed at spinal level L5–S1 for all 125 patients. Retrolisthesis was defined as posterior subluxation of 8% or more. Disc degeneration was defined as any loss of disc signal on T2 imaging. Modic changes were graded 1 – 3 and collectively classified as vertebral endplate degenerative changes. The presence of facet arthropathy and ligamentum flavum hypertrophy were classified jointly as posterior degenerative changes.
The overall incidence of retrolisthesis at L5-S1 in our study was 23.2%. Retrolisthesis combined with posterior degenerative changes, degenerative disc disease, or vertebral endplate changes had incidences of 4.8%, 16%, and 4.8% respectively. The prevalence of retrolisthesis did not vary by sex, age, race, smoking status, or education level when compared to individuals with normal sagittal alignment. However, individuals with retrolisthesis were more likely to be receiving worker compensation than those without retrolisthesis. Increased age was found to be associated with individuals having vertebral endplate degenerative changes (both alone and in conjunction with retrolisthesis) and degenerative disc disease. Individuals who had retrolisthesis with concomitant vertebral endplate degenerative changes were more often smokers and had no insurance. The presence of retrolisthesis was not associated with an increased incidence of having degenerative disc disease, posterior degenerative changes, or vertebral endplate changes. No statistical significance was found between the presence of retrolisthesis on the degree of patient pre-operative low back pain and physical function. Patients with degenerative disc disease were found to have increased leg pain compared to those patients without degenerative disc changes.
We found no significant relationship between retrolisthesis in patients with L5-S1 disc herniation and worse baseline pain or function. It is possible that the contribution of pain or dysfunction related to retrolisthesis was far overshadowed by the presence of symptoms due to the concomitant disc herniation. It remains to be seen whether retrolisthesis will affect outcome following discectomy in these patients.
PMCID: PMC2278018  PMID: 17630138
Retrolisthesis; Pre-operative; Lumbar Discectomy; Lumbar Disc Herniation; Back pain; Physical function; Degenerative Lumbar Disease
11.  Influence of preoperative nucleus pulposus status and radiculopathy on outcomes in mono-segmental lumbar total disc replacement: results from a nationwide registry 
Currently, herniated nucleus pulposus (HNP) with radiculopathy and other preconditions are regarded as relative or absolute contraindications for lumbar total disc replacement (TDR). In Switzerland it is left to the surgeon's discretion when to operate. The present study is based on the dataset of SWISSspine, a governmentally mandated health technology assessment registry. We hypothesized that preoperative nucleus pulposus status and presence or absence of radiculopathy has an influence on clinical outcomes in patients treated with mono-segmental lumbar TDR.
Between March 2005 and April 2009, 416 patients underwent mono-segmental lumbar TDR, which was documented in a prospective observational multicenter mode. The data collection consisted of perioperative and follow-up data (physician based) and clinical outcomes (NASS, EQ-5D).
Patients were divided into four groups according to their preoperative status: 1) group degenerative disc disease ("DDD"): 160 patients without HNP and no radiculopathy, classic precondition for TDR; 2) group "HNP-No radiculopathy": 68 patients with HNP but without radiculopathy; 3) group "Stenosis": 73 patients without HNP but with radiculopathy, and 4) group "HNP-Radiculopathy": 132 patients with HNP and radiculopathy. The groups were compared regarding preoperative patient characteristics and pre- and postoperative VAS and EQ-5D scores using general linear modeling.
Demographics in all four groups were comparable. Regarding the improvement of quality of life (EQ-5D) there were no differences across the four groups. For the two main groups DDD and HNP-Radiculopathy no differences were found in the adjusted postoperative back- and leg pain alleviation levels, in the stenosis group back- and leg pain relief were lower.
Despite higher preoperative leg pain levels, outcomes in lumbar TDR patients with HNP and radiculopathy were similar to outcomes in patients with the classic indication; this because patients with higher preoperative leg pain levels benefit from a relatively greater leg pain alleviation. The group with absence of HNP but presence of radiculopathy showed considerably less benefits from the operation, which is probably related to ongoing degenerative processes of the posterior segmental structures. This observational multicenter study suggests that the diagnoses HNP and radiculopathy, combined or alone, may not have to be considered as absolute or relative contraindications for mono-segmental lumbar TDR anymore, whereas patients without HNP but with radiculopathy seem to be suboptimal candidates for the procedure.
PMCID: PMC3250959  PMID: 22136141
12.  A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation 
PLoS Genetics  2012;8(1):e1002480.
Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals—5 of which were identified only with the custom arrays—and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10−29); for ESR, at the HBB (rs4910472, p = 2.31×10−11) and UCN119B/SPPL3 (rs11829037, p = 8.91×10−10) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10−13) and in CADM3 (rs3026968, p = 7.63×10−13); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10−21), near DARC (rs3845624, p = 1.43×10−10), UNC119B/SPPL3 (rs11829037, p = 1.50×10−14), and ICOSLG/AIRE (rs113459440, p = 1.54×10−08) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
Author Summary
Inflammation is a protective response of our organism to harmful stimuli—such as germs, damaged cells, or irritants—and to initiate the healing process. It has also been implicated, with both protective and predisposing effects, in a number of different diseases; but many important details of this complex phenomenon are still unknown. Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the factors and mechanisms underlying inflammation and their consequence on health. Genome-wide association scans (GWAS) have proved successful in revealing robust associations in both common diseases and quantitative traits. Here, we thus performed a multistage GWAS in a large cohort of individuals from Sardinia to examine the role of common genetic variants on the key inflammatory biomarkers Interleukin-6, erythrocyte sedimentation rate, monocyte chemotactic protein-1, and high-sensitivity C-reactive protein. Our work identified new genetic determinants associated with the quantitative levels of these inflammatory biomarkers and confirmed known ones. Overall, the data highlight an intricate regulation of this complex biological phenomenon and reveal proteins and mechanisms that can now be followed up with adequate functional studies.
PMCID: PMC3266885  PMID: 22291609
13.  Artificial Discs for Lumbar and Cervical Degenerative Disc Disease –Update 
Executive Summary
To assess the safety and efficacy of artificial disc replacement (ADR) technology for degenerative disc disease (DDD).
Clinical Need
Degenerative disc disease is the term used to describe the deterioration of 1 or more intervertebral discs of the spine. The prevalence of DDD is roughly described in proportion to age such that 40% of people aged 40 years have DDD, increasing to 80% among those aged 80 years or older. Low back pain is a common symptom of lumbar DDD; neck and arm pain are common symptoms of cervical DDD. Nonsurgical treatments can be used to relieve pain and minimize disability associated with DDD. However, it is estimated that about 10% to 20% of people with lumbar DDD and up to 30% with cervical DDD will be unresponsive to nonsurgical treatments. In these cases, surgical treatment is considered. Spinal fusion (arthrodesis) is the process of fusing or joining 2 bones and is considered the surgical gold standard for DDD.
Artificial disc replacement is the replacement of the degenerated intervertebral disc with an artificial disc in people with DDD of the lumbar or cervical spine that has been unresponsive to nonsurgical treatments for at least 6 months. Unlike spinal fusion, ADR preserves movement of the spine, which is thought to reduce or prevent the development of adjacent segment degeneration. Additionally, a bone graft is not required for ADR, and this alleviates complications, including bone graft donor site pain and pseudoarthrosis. It is estimated that about 5% of patients who require surgery for DDD will be candidates for ADR.
Review Strategy
The Medical Advisory Secretariat conducted a computerized search of the literature published between 2003 and September 2005 to answer the following questions:
What is the effectiveness of ADR in people with DDD of the lumbar or cervical regions of the spine compared with spinal fusion surgery?
Does an artificial disc reduce the incidence of adjacent segment degeneration (ASD) compared with spinal fusion?
What is the rate of major complications (device failure, reoperation) with artificial discs compared with surgical spinal fusion?
One reviewer evaluated the internal validity of the primary studies using the criteria outlined in the Cochrane Musculoskeletal Injuries Group Quality Assessment Tool. The quality of concealment allocation was rated as: A, clearly yes; B, unclear; or C, clearly no. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the overall quality of the body of evidence (defined as 1 or more studies) supporting the research questions explored in this systematic review. A random effects model meta-analysis was conducted when data were available from 2 or more randomized controlled trials (RCTs) and when there was no statistical and or clinical heterogeneity among studies. Bayesian analyses were undertaken to do the following:
Examine the influence of missing data on clinical success rates;
Compute the probability that artificial discs were superior to spinal fusion (on the basis of clinical success rates);
Examine whether the results were sensitive to the choice of noninferiority margin.
Summary of Findings
The literature search yielded 140 citations. Of these, 1 Cochrane systematic review, 1 RCT, and 10 case series were included in this review. Unpublished data from an RCT reported in the grey literature were obtained from the manufacturer of the device. The search also yielded 8 health technology assessments evaluating ADR that are also included in this review.
Six of the 8 health technology assessments concluded that there is insufficient evidence to support the use of either lumbar or cervical ADR. The results of the remaining 2 assessments (one each for lumbar and cervical ADR) led to a National Institute for Clinical Excellence guidance document supporting the safety and effectiveness of lumbar and cervical ADR with the proviso that an ongoing audit of all clinical outcomes be undertaken owing to a lack of long-term outcome data from clinical trials.
Regarding lumbar ADR, data were available from 2 noninferiority RCTs to complete a meta-analysis. The following clinical, health systems, and adverse event outcome measures were synthesized: primary outcome of clinical success, Oswestry Disability Index (ODI) scores, pain VAS scores, patient satisfaction, duration of surgery, amount of blood loss, length of hospital stay, rate of device failure, and rate of reoperation.
The meta-analysis of overall clinical success supported the noninferiority of lumbar ADR compared with spinal fusion at 24-month follow-up. Of the remaining clinical outcome measures (ODI, pain VAS scores, SF-36 scores [mental and physical components], patient satisfaction, and return to work status), only patient satisfaction and scores on the physical component scale of the SF-36 questionnaire were significantly improved in favour of lumbar ADR compared with spinal fusion at 24 months follow-up. Blood loss and surgical time showed statistical heterogeneity; therefore, meta-analysis results are not interpretable. Length of hospital stay was significantly shorter in patients receiving the ADR compared with controls. Neither the number of device failures nor the number of neurological complications at 24 months was statistically significantly different between the ADR and fusion treatment groups. However, there was a trend towards fewer neurological complications at 24 months in the ADR treatment group compared with the spinal fusion treatment group.
Results of the Bayesian analyses indicated that the influence of missing data on the outcome measure of clinical success was minimal. The Bayesian model indicated that the probability for ADR being better than spinal fusion was 79%. The probability of ADR being noninferior to spinal fusion using a -10% noninferiority bound was 92%, and using a -15% noninferiority bound was 94%. The probability of artificial discs being superior to spinal fusion in a future trial was 73%.
Six case series were reviewed, mainly to characterize the rate of major complications for lumbar ADR. The Medical Advisory Secretariat defined a major complication as any reoperation; device failure necessitating a revision, removal or reoperation; or life-threatening event. The rates of major complications ranged from 0% to 13% per device implanted. Only 1 study reported the rate of ASD, which was detected in 2 (2%) of the 100 people 11 years after surgery.
There were no RCT data available for cervical ADR; therefore, data from 4 case series were reviewed for evidence of effectiveness and safety. Because data were sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time.
The rate of major complications was assessed up to 2 years after surgery. It was found to range from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature.
The total cost of a lumbar ADR procedure is $15,371 (Cdn; including costs related to the device, physician, and procedure). The total cost of a lumbar fusion surgery procedure is $11,311 (Cdn; including physicians’ and procedural costs).
Lumbar Artificial Disc Replacement
Since the 2004 Medical Advisory Secretariat health technology policy assessment, data from 2 RCTs and 6 case series assessing the effectiveness and adverse events profile of lumbar ADR to treat DDD has become available. The GRADE quality of this evidence is moderate for effectiveness and for short-term (2-year follow-up) complications; it is very low for ASD.
The effectiveness of lumbar ADR is not inferior to that of spinal fusion for the treatment of lumbar DDD. The rates for device failure and neurological complications 2 years after surgery did not differ between ADR and fusion patients. Based on a Bayesian meta-analysis, lumbar ADR is 79% superior to lumbar spinal fusion.
The rate of major complications after lumbar ADR is between 0% and 13% per device implanted. The rate of ASD in 1 case series was 2% over an 11-year follow-up period.
Outcome data for lumbar ADR beyond a 2-year follow-up are not yet available.
Cervical Artificial Disc Replacement
Since the 2004 Medical Advisory Secretariat health technology policy assessment, 4 case series have been added to the body of evidence assessing the effectiveness and adverse events profile of cervical ADR to treat DDD. The GRADE quality of this evidence is very low for effectiveness as well as for the adverse events profile. Sparse outcome data are available.
Because data are sparse, the effectiveness of cervical ADR compared with spinal fusion cannot be determined at this time.
The rate of major complications was assessed up to 2 years after surgery; it ranged from 0% to 8.1% per device implanted. The rate of ASD is not reported in the clinical trial literature.
PMCID: PMC3379529  PMID: 23074480
14.  Endoscopic Foraminal Decompression for Failed Back Surgery Syndrome under local Anesthesia 
The most common causes of failed back surgery are residual or recurrent herniation, foraminal fibrosis and foraminal stenosis that is ignored, untreated, or undertreated. Residual back ache may also be from facetal causes or denervation and scarring of the paraspinal muscles.1–6 The original surgeon may advise his patient that nothing more can be done on the basis of his opinion that the nerve was visually decompressed by the original surgery, supported by improved post-op imaging and follow-up studies such as EMG and conduction velocity studies. Post-op imaging or electrophysiological assessment may be inadequate to explain all the reasons for residual or recurrent symptoms. Treatment of Failed back surgery by repeat traditional open revision surgery usually incorporates more extensive decompression causing increased instability and back pain, therefore necessitating fusion. The authors, having limited their practice to endoscopic MIS surgery over the last 15-20 years, report on their experience gained during that period to relieve pain by endoscopically visualizing and treating unrecognized causative patho-anatomy in FBSS.7
Thirty consecutive patients with FBSS presenting with back and leg pain that had supporting imaging diagnosis of lateral stenosis and /or residual / recurrent disc herniation, or whose pain complaint was supported by relief from diagnostic and therapeutic injections (Figure 1), were offered percutaneous transforaminal endoscopic discectomy and foraminoplasty over a repeat open procedure. Each patient sought consultation following a transient successful, partially successful or unsuccessful open translaminar surgical treatment for disc herniation or spinal stenosis. Endoscopic foraminoplasty was also performed to either decompress the bony foramen for foraminal stenosis, or foraminoplasty to allow for endoscopic visual examination of the affected traversing and exiting nerve roots in the axilla, also known as the “hidden zone” of Macnab (Figure 2).8, 9 The average follow up time was, average 40 months, minimum 12 months. Outcome data at each visit included Macnab, VAS and ODI.
A diagnostic and therapeutic epidural gram may help identify unrecognized lateral recess stenosis underestimated by MRI. An excellent result from a therapeutic block lends excellent prognosis for a more lasting and “permanent” result from transforaminal endoscopic lateral recess decompression.
Kambin's Triangle provides access to the “hidden zone” of Macnab by foraminoplasty. The foramen and lateral recess is decompressed by removing the ventral aspect and tip of the superior articular process to gain access to the axilla between the traversing and exiting nerve. FBSS contains patho-anatomy in the axilla between the traversing and exiting nerve that hides the pain generators of FBSS.
The average pre-operative VAS improved from 7.2 to 4.0, and ODI 48% to 31%. While temporary dysesthesia occurred in 4 patients in the early post-operative period, all were happy, as all received additional relief of their pre-op symptoms. They were also relieved to be able to avoid “open” decompression or fusion surgery.
Conclusions / Level of Evidence 3
The transforaminal endoscopic approach is effective for FBSS due to residual/recurrent HNP and lateral stenosis. Failed initial index surgery may involve failure to recognize patho-anatomy in the axilla of the foramen housing the traversing and the exiting nerve, including the DRG, which is located cephalad and near the tip of SAP.10 The transforaminal endoscopic approach effectively decompresses the foramen and does not further destabilize the spine needing stabilization.11 It also avoids going through the previous surgical site.
Clinical Relevance
Disc narrowing as a consequence of translaminar discectomy and progressive degenerative narrowing and spondylolisthesis (Figure 3) as a natural history of degenerative disc disease can lead to central and lateral stenosis. The MRI may underestimate the degree of stenosis from a bulging or a foraminal disc protrusion and residual lateral recess stenosis. Pain can be diagnosed and confirmed by evocative discography and by clinical response to transforaminal diagnostic and therapeutic steroid injections.12 Foraminal endoscopic decompression of the lateral recess is a MIS technique that does not “burn bridges” for a more conventional approach and it adds to the surgical armamentarium of FBSS.
Cadaver Illustration of Foraminal Stenosis (courtesy of Wolfgang Rauschning). As the disc narrows, the superior articular process impinges on the exiting nerve and DRG, creating lateral recess stenosis, lumbar spondylosis, and facet arthrosis.
PMCID: PMC4325507
Failed Back Surgery Syndrome(FBSS); Hidden zone; Foraminal decompression; Recurrent herniation; Lateral stenosis; Foraminal osteophyte
15.  Fluoroscopic lumbar interlaminar epidural injections in managing chronic lumbar axial or discogenic pain 
Journal of Pain Research  2012;5:301-311.
Among the multiple causes of chronic low back pain, axial and discogenic pain are common. Various modalities of treatments are utilized in managing discogenic and axial low back pain including epidural injections. However, there is a paucity of evidence regarding the effectiveness, indications, and medical necessity of any treatment modality utilized for managing axial or discogenic pain, including epidural injections. In an interventional pain management practice in the US, a randomized, double-blind, active control trial was conducted. The objective was to assess the effectiveness of lumbar interlaminar epidural injections of local anesthetic with or without steroids for managing chronic low back pain of discogenic origin. However, disc herniation, radiculitis, facet joint pain, or sacroiliac joint pain were excluded. Two groups of patients were studied, with 60 patients in each group receiving either local anesthetic only or local anesthetic mixed with non-particulate betamethasone. Primary outcome measures included the pain relief-assessed by numeric rating scale of pain and functional status assessed by the, Oswestry Disability Index, Secondary outcome measurements included employment status, and opioid intake. Significant improvement or success was defined as at least a 50% decrease in pain and disability. Significant improvement was seen in 77% of the patients in Group I and 67% of the patients in Group II. In the successful groups (those with at least 3 weeks of relief with the first two procedures), the improvement was 84% in Group I and 71% in Group II. For those with chronic function-limiting low back pain refractory to conservative management, it is concluded that lumbar interlaminar epidural injections of local anesthetic with or without steroids may be an effective modality for managing chronic axial or discogenic pain. This treatment appears to be effective for those who have had facet joints as well as sacroiliac joints eliminated as the pain source.
PMCID: PMC3442746  PMID: 23055773
lumbar disc herniation; axial or discogenic pain; lumbar interlaminar epidural injections; local anesthetic; steroids; controlled comparative local anesthetic blocks; NCT00681447
16.  C-reactive Protein and Risk of Colorectal Adenoma According to Celecoxib Treatment 
Inflammation, as measured by the circulating inflammatory marker high sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data regarding CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial demonstrated that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined if serum hsCRP modified these results.
We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive three years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at Year 1 and 3.
Among 1,680 patients, the estimated three-year cumulative incidence of adenoma was 42% for patients with hsCRP <1mg/L, compared with 43% (RR=1.02; 95% confidence interval (CI)=0.85–1.22) for hsCRP 1–3mg/L, and 41% (RR=1.1; CI=0.90–1.34) for hsCRP >3mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3mg/L) compared with low (≦3mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95%CI=0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (CI=1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (CI=0.53–1.83) and 1.11 (CI=0.61–2.02).
HsCRP may predict risk of celecoxib-associated cardiovascular toxicity, but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention.
PMCID: PMC3151679  PMID: 21816845
Adenoma; celecoxib; c-reactive protein; inflammation; chemoprevention
17.  Magnetic resonance imaging findings in low back pain and lower extremity radicular chronic pain 
Journal of Injury and Violence Research  2012;4(3 Suppl 1): Paper No. 37.
Low back pain (LBP) is one of the most prevalent complaints among the people worldwide. According to the medical statistics, about 80 percent of people have at least one episode of LBP during their lifetime cause them to visit a physician for treatment. LBP is the most prevalent cause of work disability and its related leaves among people under 45 years old. Numerous studies have been conducted on the connection between clinical signs, patients’ complaints, the level of lumbar disc herniation, and abnormal findings of magnetic resonance imaging (MRI). In many cases, contradictory views have been reported and even in some cases canal stenosis and herniated disc have been reported in patient without clinical sings. The aim of this study was to analyze MRI findings in patients with LBP and radicular chronic pain (RCP) attending Imam Reza Hospital (Kermanshah, Iran).
This cross-sectional study was conducted on 200 patients (100 with LBP and 100 with RCP). Following unsuccessful results of medical treatment for 1 to 48 months, the examination results, demographic information (age, sex, job, etc.) and their complaints along with MRI findings were documented and statistically analyzed. Patients with history of lumbar surgery, infective inflammatory diseases, fractures, tumors, etc were excluded from the study. To determine the significant correlation between qualitative and quantitative variables, the Chi-Square test and the independent t-test were respectively performed using the statistical package of SPSS (Version 12) The P-value of less than 0.05 was considered significant.
In the LBP group, patients complained only of posterior and inferior spinal column pain and did not have any pain distribution toward lower limbs or any other signs. However, in the RCP group, in addition to pain distribution towards the lower limbs, they were complaining about muscular myotonia and sensational disorder and 88% also had low back pain. 94 of them were men and 106 were women.106 subjects (80.5%) were urban residents and 39 (19.5%) rural residents. There were 42.5% housewife, 21.5% employee, 15% workers, 9.5% self-employed, and 8.5% were unemployed. In terms of education, 27% were uneducated, 40.5% with incomplete high school diploma, and 32.5% with high school diploma and higher levels of education. 33.5% of patients had the treatment period of one month, while for the rest this period was more than one month to 4 years. Twenty percent did not rest, 52.5% rested up to 3 weeks and 24% rested up to 3 months. In the RCP group, 41% complained of pain in the right leg, 36% in the left leg, and 23% in both legs. However, in the RCP group, 26% had limb paresis, 5% atrophy, 25% some levels of sensational disorders, and 2% had sphincter disorders.
MRI findings:
Herniated disc in the form of protrusion and extrusion at L4-L5 and L5-S1 spaces were mainly observed in patients with RCP rather than those with LBP. Twenty-six patients (13%) had spondylolisthesis of which 12 (46.2%) were in LBP group and the other 14 patients (53.8) in RCP group. Forty-eight patients (24%) had canal stenosis of which 11 patients were from LBP group and 37 from RCP group. Of these 48 patients, 11 had partial stenosis and 37 had absolute stenosis that were in the RCP group.
The most prevalent herniated disc spaces were at the levels of L4-L5 (87%) and S1-S2 (65%). This is because that most of the movements occur in the mobile parts of disc surface and the stresses that are exerted on the mentioned part. Generally, a meaningful correlation between existence of canal stenosis at L4-L5 and L5-S1 levels and the existence of pressure effect on nerve in THECAL SAC and lat recess in patients with RCP was seen; and also a meaningful correlation among muscular myotonia, radicular distribution of limbs’ pain along with compressive effects on the nerve in the lat recess and the thecal sac and spinal canal stenosis were observed. A significant correlation between complaints of RCP in lower limbs and muscular myotonia with these findings was seen but in analyzing the distributing pain patterns or muscular myotonia on the base of RCP such a correlation was not seen.
Low back pain, Radicular back pain, Magnetic resonance imaging
PMCID: PMC3571563
18.  Hypersensitivity to Rabbit Antithymocyte Globulin in an Islet Transplant Recipient: A Case Report 
Transplantation proceedings  2011;43(9):3302-3306.
The aim was to describe a case of hypersensitivity to rabbit antithymocyte globulin (rATG) occurring in the context of islet transplantation.
A 36-year-old woman with type 1 diabetes was admitted for islet transplantation. rATG was administered the first day (1.5 mg/kg) with methylprednisolone (2 mg/kg), and on the second day (1.5 mg/kg) without glucocorticoid to avoid potential toxicity to the anticipated islet transplant.
At the end of the rATG infusion on the second day she developed hives over her face, chest, and back and tender erythema at her intravenous site (Arthus reaction). Islet transplantation was not performed. She reported exposure to a pet rabbit for 2 years in childhood. Overnight, fever developed and the rash evolved into an erythematous morbilliform eruption affecting the torso. Serum high-sensitivity C-reactive protein (hsCRP) and the erythrocyte sedimentation rate (ESR) were elevated; serum complements C3 and C4 were normal. She received prednisone (50 mg) with subsequent resolution of the rash. Nine days after her initial reaction, she developed a recurrence of the rash and fever with arthralgias; levels of C3 and C4 had fallen. Methylprednisolone (125 mg, twice) was required for symptom improvement, and was gradually tapered as prednisone over the next 4 weeks with resolution of the complement, ESR, and hsCRP abnormalities. Five months after the initial attempt at islet transplantation, she returned to receive 7,879 IE/kg via portal vein infusion under basiliximab, etanercept, tacrolimus, and sirolimus immunosuppression and has required no to low-dose (0.1 U/kg/d) insulin to maintain near-normal glycemic control for > 12 months after transplantation.
Our patient’s initial hypersensitivity reaction to rATG was followed by immune-complex type 3 hypersensitivity (serum sickness) requiring high-dose glucocorticoids. Canceling the initial islet infusion proved to be wise, and the patient subsequently did well with islet transplantation under an alternative induction agent.
PMCID: PMC3234161  PMID: 22099783
19.  Lumbar Disc Degenerative Disease: Disc Degeneration Symptoms and Magnetic Resonance Image Findings 
Asian Spine Journal  2013;7(4):322-334.
Study Design
Cross sectional and observational.
To evaluate the different aspects of lumbar disc degenerative disc disease and relate them with magnetic resonance image (MRI) findings and symptoms.
Overview of Literature
Lumbar disc degenerative disease has now been proven as the most common cause of low back pain throughout the world. It may present as disc herniation, lumbar spinal stenosis, facet joint arthropathy or any combination. Presenting symptoms of lumbar disc degeneration are lower back pain and sciatica which may be aggravated by standing, walking, bending, straining and coughing.
This study was conducted from January 2012 to June 2012. Study was conducted on the diagnosed patients of lumbar disc degeneration. Diagnostic criteria were based upon abnormal findings in MRI. Patients with prior back surgery, spine fractures, sacroiliac arthritis, metabolic bone disease, spinal infection, rheumatoid arthritis, active malignancy, and pregnancy were excluded.
During the targeted months, 163 patients of lumbar disc degeneration with mean age of 43.92±11.76 years, came into Neurosurgery department. Disc degeneration was most commonly present at the level of L4/L5 105 (64.4%).Commonest types of disc degeneration were disc herniation 109 (66.9%) and lumbar spinal stenosis 37 (22.7%). Spondylolisthesis was commonly present at L5/S1 10 (6.1%) and associated mostly with lumbar spinal stenosis 7 (18.9%).
Results reported the frequent occurrence of lumbar disc degenerative disease in advance age. Research efforts should endeavor to reduce risk factors and improve the quality of life.
PMCID: PMC3863659  PMID: 24353850
Claudication; Low back pain; Spondylolisthesis
20.  Low back pain (chronic) 
Clinical Evidence  2010;2010:1116.
Over 70% of people in developed countries develop low back pain (LBP) at some time. But recovery is not always favourable: 82% of non recent-onset patients still experience pain 1 year later. Many patients with chronic LBP who were initially told that their natural history was good spend months or years seeking relief.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatments? What are the effects of injection therapy? What are the effects of non-drug treatments? What are the effects of non-surgical and surgical treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 64 systematic reviews or RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acupuncture, analgesics, antidepressants, back schools, behavioural therapy, electromyographic biofeedback, exercise, injections (epidural corticosteroid injections, facet joint injections, local injections), intensive multidisciplinary treatment programmes, lumbar supports, massage, muscle relaxants, non-steroidal anti-inflammatory drugs (NSAIDs), non-surgical interventional therapies (intradiscal electrothermal therapy, radiofrequency denervation), spinal manipulative therapy, surgery, traction, and transcutaneous electrical nerve stimulation (TENS).
Key Points
Over 70% of people in developed countries develop low back pain at some time, which usually improves within 2 weeks, however about 10% remained off work and about 20% had persistent symptoms at 1 year.
Non-steroidal anti-inflammatory drugs (NSAIDs) may be more effective than placebo at improving pain intensity in people with chronic low back pain.
Opioid analgesics (with or without paracetamol) may improve pain and function compared with placebo. However, long-term use of NSAIDs or opioids may be associated with well-recognised adverse effects. We don't know whether antidepressants decrease chronic low back pain or improve function compared with placebo in people with or without depression. Benzodiazepines may improve pain, but studies of non-benzodiazepine muscle relaxants have given conflicting results.
CAUTION: Since the last update of this review, a drug safety alert has been issued on increased suicidal behaviour with antidepressants (
We don't know whether epidural corticosteroid injections or local injections with corticosteroids and local anaesthetic improve chronic low back pain in people without sciatica. Facet-joint corticosteroid injections may be no more effective than placebo at reducing pain.
Fusion surgery is more effective than standard rehabilitation for improving pain in people with chronic non-radicular low back pain, but it is no better than intensive rehabilitation with a cognitive behavioural component.
Exercise improves pain and function compared with other conservative treatments.
Intensive multidisciplinary treatment programmes improve pain and function compared with usual care, but less-intensive programmes do not seem beneficial.
Acupuncture, back schools, behavioural therapy, and spinal manipulation may reduce pain in the short term, but effects on function are unclear.
Massage may improve pain and function compared with sham or other active treatment.
We don't know whether electromyographic biofeedback, lumbar supports, traction, or TENS improve pain relief.
We also don't know whether intradiscal electrothermal therapy, radiofrequency denervation, or disc replacement improve pain relief or function.
PMCID: PMC3217809  PMID: 21418678
21.  Vertebral Bone Mineral Measures and Psychological Wellbeing Among Individuals with Modic Changes 
This case-control pilot study examined whether vertebral bone mineral measures were associated with the presence of chronic low back pain (CLBP) and Modic changes (MCs), and to compare psychological wellbeing and inflammation among individuals with CLBP and MCs, compared to individuals with no history of low back pain and without MCs.
Eleven individuals with MRI-defined MCs in the lumbar spine and CLBP (cases) and 10 individuals with no history of CLBP or MCs (controls) responded to standard questionnaires regarding pain characteristics and psychological health. Bone mineral density (BMD) was measured with postero-anterior and lateral-projection dual energy X-ray absorptiometry (DXA) to estimate areal BMD (aBMD) and apparent volumetric BMD (ap.vBMD). High sensitivity serum C-reactive protein (hsCRP) was measured as an index of inflammation.
While there was no difference between the groups in measures of depression, anxiety and stress, cases reported significantly greater pain catastrophizing attitudes (P < 0.01). hsCRP concentrations did not differ between groups (P = 0.54). Among the 7 cases where MCs were identified between L3–4, significantly higher mean aBMD was observed at the affected vertebral level, compared to the adjacent, unaffected, cephalad level (P = 0.01–0.04), but not when ap.vBMD was calculated (P = 0.36).
Vertebral BMD is not reduced among individuals with CLBP and MCs compared to a control group, although pain catastrophizing attitudes are increased among individuals with CLBP and MCs.
PMCID: PMC3320114  PMID: 22493564
Modic change; bone mineral density; hsCRP; psychological health
22.  Disc degeneration of cervical spine on MRI in patients with lumbar disc herniation: comparison study with asymptomatic volunteers 
European Spine Journal  2010;20(4):585-591.
An association between progression of cervical disc degeneration and that of lumbar disc degeneration has been considered to exist. To date, however, this association has not yet been adequately studied. Age-related changes in the cervical intervertebral discs were evaluated by magnetic resonance imaging (MRI) in patients with lumbar disc herniation, and compared with the MRI findings of healthy volunteers without lower back pain. The purpose of this study was to clarify whether the prevalence of asymptomatic cervical disc degeneration is higher in patients with lumbar disc herniation than in healthy volunteers. The study was conducted on 51 patients who were diagnosed as having lumbar disc herniation and underwent cervical spine MRI. The patients consisted of 34 males and 17 females ranging in age from 21–83 years (mean 46.9 ± 14.5 years) at the time of the study. The control group was composed of 113 healthy volunteers (70 males and 43 females) aged 24–77 years (mean 48.9 ± 14.7 years), without neck pain or low back pain. The percentage of subjects with degenerative changes in the cervical discs was 98.0% in the lumbar disc herniation group and 88.5% in the control group (p = 0.034). The presence of lumbar disc herniation was associated significantly with decrease in signal intensity of intervertebral disc and posterior disc protrusion in the cervical spine. None of the MRI findings was significantly associated with the gender, smoking, sports activities, or BMI. As compared to healthy volunteers, patients with lumbar disc herniation showed a higher prevalence of decrease in signal intensity of intervertebral disc and posterior disc protrusion on MRI of the cervical spine. The result of this study suggests that disc degeneration appears to be a systemic phenomenon.
PMCID: PMC3065617  PMID: 21127918
Lumbar disc herniation; Asymptomatic volunteers; MRI; Cervical spine; Disc degeneration
23.  Elevated Homocysteine and C-reactive Protein Levels Independently Predict Worsening Prognosis after Stroke in Chinese Patients* 
Increased plasma total homocysteine (tHcy) and high sensitivity C-reactive protein (hsCRP) levels are independent risk factors for cardiovascular disease. However, the predictive value of tHcy in combination with hsCRP in patients with stroke is not known. To determine the relationship between tHcy and hsCRP, we enrolled 291 patients with first-onset stroke (196 ischemic and 95 hemorrhagic). Plasma tHcy and hsCRP levels were measured and subsequent vascular events and deaths were determined over a 5-year period. Using the arbitrary cutoff for tHcy (<18 μmol/L and ≥18 μmol/L) and hsCRP (<1 mg/L, 1–3 mg/L and >3 mg/L), the patients were divided into 6 groups. Survival analysis showed that the probability of death or new vascular events during a 5-year follow-up increased according to tHcy and hsCRP levels (P<0.01). The relative risk (RR) of death or new vascular events was 4.67 (95% CI, 1.96 to 11.14, P=0.001) in patients with high tHcy (≥18 μmol/L) and hsCRP (>3 mg/L) compared with those with low tHcy (<18 μmol/L) and hsCRP (<1 mg/L). The increased tHcy level (≥18 μmol/L) combined with increased hsCRP level (>3 mg/L) was still significantly associated with the risk of death or new vascular events (RR, 4.10, 95% CI, 1.61 to 10.45, P=0.003) even when adjusted for other risk factors at inclusion. The combination of increased tHcy and hsCRP levels had a stronger predictive value than increased hsCRP alone or increased tHcy level alone. Further studies are required to evaluate the potential decrease in risks associated with lowering both Hcy and hsCRP levels in patients that present with both increased tHcy and hsCRP.
PMCID: PMC3807101  PMID: 21063849
homocysteine; C-reactive protein; inflammation; stroke
24.  Mechanical supplementation by non-rigid fixation in degenerative intervertebral lumbar segments: the Wallis system 
European Spine Journal  2002;11(Suppl 2):S164-S169.
A first-generation implant for non-rigid stabilization of lumbar segments was developed in 1986. It included a titanium interspinous blocker and an artificial ligament made of dacron. Following an initial observational study in 1988 and a prospective controlled study from 1988 to 1993, more than 300 patients have been treated for degenerative lesions with this type of implant with clinical and mechanical follow-up. After careful analysis of the points that could be improved, a second-generation implant called the "Wallis" implant, was developed. This interspinous blocker, which was made of metal in the preliminary version, is made of PEEK (polyetheretherketone) in the new model. The overall implant constitutes a "floating" system, with no permanent fixation in the vertebral bone, to avoid the risk of loosening. It achieves an increase in the rigidity of destabilized segments beyond normal values. The clinical trials of the first-generation implant provided evidence that the interspinous system of non-rigid stabilization is efficacious against low-back pain due to degenerative instability and free of serious complications. The first-generation devices achieved marked, significant resolution of residual low-back pain. These results warrant confirmation. A randomized clinical trial and an observational study of the new implant are currently underway. Non-rigid fixation clearly appears to be a useful technique in the management of initial forms of degenerative intervertebral lumbar disc disease. This method should rapidly assume a specific role along with total disc prostheses in the new step-wise surgical strategy to obviate definitive fusion of degenerative intervertebral segments. At present, the Wallis system is recommended for lumbar disc disease in the following indications: (i) discectomy for massive herniated disc leading to substantial loss of disc material, (ii) a second discectomy for recurrence of herniated disc, (iii) discectomy for herniation of a transitional disc with sacralization of L5, (iv) degenerative disc disease at a level adjacent to a previous fusion, and (v) isolated Modic I lesion leading to chronic low-back pain.
PMCID: PMC3611564  PMID: 12384740
Non-rigid fixation Degenerative lumbar disc Low-back pain
25.  Akt/PKB isoforms expression in the human lumbar herniated disc: correlation with clinical and MRI findings 
European Spine Journal  2011;20(10):1676-1683.
Intervertebral disc (IVD) degeneration suggests a complex process influenced by genetics, lifestyle and biomechanics, which accounts for the development of low back pain (LBP) and lumbar radiculopathy, a major cause of musculoskeletal disability in humans. The family of Akt/PKB kinases is a principal mediator in the signal transduction pathways, which contribute to transcriptional regulation, cell growth, proliferation, apoptosis, and survival ability. The purpose of this study was to evaluate the transcriptional profile of the AKT family genes in human herniated discs and the involvement of the PI3K-Akt signaling pathway in human IVD degeneration. Real-time PCR analysis was used to assess the mRNA expression pattern of the three Akt/PKB isoforms in 63 herniated and 10 control disc specimens. Our results showed a significant positive correlation between AKT1 and AKT3 mRNA in herniated discs suggesting a synergistic action between these isoforms in disc herniation. Interestingly, AKT2 mRNA was up-regulated in patients with acute pain during the first 12 months, indicating that AKT2 transcriptional activation may be associated with acute rather than chronic inflammation and phagocytosis. Finally, Akt1/PKB transcription presented a stepwise activation as disc herniation deteriorated. Our findings provide evidence on the transcriptional activation of the Akt/PKB pathway indicating that it is involved in lumbar disc degeneration. There is need for further studies to elucidate the exact role and down-stream signaling action of Akt/PKB isoforms in the pathogenesis of lumbar disc herniation.
PMCID: PMC3175883  PMID: 21590431
Akt/PKB; mRNA expression; RT-PCR; Lumbar disc herniation

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