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1.  Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer. 
British Journal of Cancer  1998;77(6):932-940.
The uPA-mediated pathway of plasminogen activation is central to cancer metastasis. Whether uPA and PAI-1 are related to local recurrence, metastatic spread or both is not clear. We present a retrospective study of 429 primary breast cancer patients with a median follow-up of 5.1 years, in which the levels of uPA and PAI-1 in tumour extracts were analysed by means of an enzyme-linked immunosorbent assay. The median values of uPA and PAI-1, which were used as cut-off points, were 4.5 and 11.1 ng mg(-1) protein respectively. The levels of uPA and PAI-1 were correlated with tumour size, degree of anaplasia, steroid receptor status and number of positive nodes. Patients with high content of either uPA or PAI-1 had increased risk of relapse and death. We demonstrated an independent ability of PAI-1 to predict distant metastasis (relative risk 1.7, confidence limits 1.22 and 2.46) and that neither uPA nor PAI-1 provided any information regarding local recurrence.
PMCID: PMC2150087  PMID: 9528837
2.  Safety and efficacy of resistance training in germ cell cancer patients undergoing chemotherapy: a randomized controlled trial 
British Journal of Cancer  2014;111(1):8-16.
Bleomycin–etoposid–cisplatin (BEP) chemotherapy is curative in most patients with disseminated germ cell cancer (GCC) but also associated with toxic actions and dysfunction in non-targeted tissues. We investigated changes in muscle function during BEP and the safety and efficacy of resistance training to modulate these changes.
Thirty GCC patients were randomly assigned to resistance training (resistance training group (INT), n=15) or usual care (CON, n=15) during 9 weeks of BEP therapy. Resistance training consisted of thrice weekly sessions of four exercises, 3–4 sets/exercise of 10–15 repetitions at 12–15 repetition maximum load. The primary endpoint was muscle fibre size, assessed in muscle biopsies from musculus vastus lateralis. Secondary endpoints were fibre phenotype composition, body composition, strength, blood biochemistry and patient-reported endpoints. Healthy age-matched subjects (REF, n=19) performed the same RT-programme for comparison purposes.
Muscle fibre size decreased by −322 μm2 (95% confidence interval (CI): −899 to 255; P=0.473) in the CON-group and increased by +206 μm2 (95% CI: −384 to 796; P=0.257) in the INT-group (adjusted mean difference (AMD), +625 μm2, 95% CI: −253 to 1503, P=0.149). Mean differences in type II fibre size (AMD, +823 μm2, P=0.09) and lean mass (AMD, +1.49 kg, P=0.07) in favour of the INT-group approached significance. The REF-group improved all muscular endpoints and had significantly superior changes compared with the INT-group (P<0.05).
BEP was associated with significant reduction in lean mass and strength and trends toward unfavourable changes in muscle fibre size and phenotype composition. Resistance training was safe and attenuated dysfunction in selected endpoints, but BEP blunted several positive adaptations observed in healthy controls. Thus, our study does not support the general application of resistance training in this setting but larger-scaled trials are required to confirm this finding.
PMCID: PMC4090736  PMID: 24867693
germ cell cancer; chemotherapy; resistance training; skeletal muscle
3.  Intracellular patterns of sialophorin expression define a new molecular classification of breast cancer and represent new targets for therapy 
British Journal of Cancer  2013;110(1):146-155.
Sialophorin is a transmembrane sialoglycoprotein. Normally, the molecule is only produced by white blood cells where it regulates functions such as intercellular adhesion, intracellular signalling, apoptosis, migration and proliferation.
Normal breast tissue and primary breast tumours were analysed by immunohistochemistry for sialophorin expression. The sialophorin-positive breast cancer cell line MCF7 was engineered to stably express either non-targeted or sialophorin-targeted small interfering RNA (siRNA). Assays were then performed in vitro to assess apoptosis, intracellular adhesion, transendothelial migration and cytotoxicity. An orthotopic mouse model assayed ability to produce tumours in vivo.
Normal breast epithelial cells exhibit expression of the N-terminal domain of sialophorin in the cytoplasm but not the nucleus. The majority of these normal cells are also negative for expression of the C-terminal domain. In contrast, malignant breast epithelial cells exhibit N-terminal expression both in the cytoplasm and nucleus and the majority express the C-terminus in the nucleus. Using differential patterns of intracellular expression of the N and C termini of sialophorin, we define six subtypes of breast cancer that are independent of histological and receptor status classification. Targeting sialophorin with siRNA resulted in the MCF7 breast cancer cell line exhibiting increased homotypic adhesion, decreased transendothelial migration, increased susceptibility to apoptosis, increased vulnerability to lysis by natural killer cells and decreased ability to produce tumours in mice.
Our results indicate that intracellular patterns of sialophorin expression define a new molecular classification of breast cancer and that sialophorin represents a novel therapeutic target.
PMCID: PMC3887278  PMID: 24281005
breast cancer; molecular subcategories; sialophorin; CD43; adhesion; migration; apoptosis and cytotoxicity; orthotopic mouse model
4.  Total drug treatment and comorbidity in myasthenia gravis: a population-based cohort study 
European Journal of Neurology  2014;21(7):948-955.
Background and purpose
Comorbidity in myasthenia gravis (MG) is important for diagnosis, treatment and prognosis. Disease complexity was assessed by examining total drug treatment, immune therapy and comorbidity in a complete national MG cohort.
All recipients of the MG-specific drug pyridostigmine 2004–2010 registered in the compulsory Norwegian Prescription Database who met the inclusion criteria were included. The pyridostigmine group was compared with the general Norwegian population.
Myasthenia gravis patients received co-medication more often than the controls for nearly all groups of medication, including insulins (95% confidence interval 2.0–3.7), thyroid therapy (1.7–2.5), antidepressants (1.3–1.7), anti-infectives (1.2–1.4), lipid-modifying agents (1.1–1.4) and immunomodulating agents (6.8–8.8).
Myasthenia gravis patients are more often treated with non-MG prescription drugs than controls, reflecting frequent co-medication and comorbidity.
PMCID: PMC4238850  PMID: 24712740
comorbidity; drug therapy; myasthenia gravis
5.  The effects of 12 weeks of beta-hydroxy-beta-methylbutyrate free acid supplementation on muscle mass, strength, and power in resistance-trained individuals: a randomized, double-blind, placebo-controlled study 
European Journal of Applied Physiology  2014;114(6):1217-1227.
Studies utilizing beta-hydroxy-beta-methylbutyrate (HMB) supplementation in trained populations are limited. No long-term studies utilizing HMB free acid (HMB-FA) have been conducted. Therefore, we investigated the effects of 12 weeks of HMB-FA supplementation on skeletal muscle hypertrophy, body composition, strength, and power in trained individuals. We also determined the effects of HMB-FA on muscle damage and performance during an overreaching cycle.
A three-phase double-blind, placebo- and diet-controlled randomized intervention study was conducted. Phase 1 was an 8-week-periodized resistance-training program; Phase 2 was a 2-week overreaching cycle; and Phase 3 was a 2-week taper. Muscle mass, strength, and power were examined at weeks 0, 4, 8, and 12 to assess the chronic effects of HMB-FA; and assessment of these, as well as cortisol, testosterone, and creatine kinase (CK) was performed at weeks 9 and 10 of the overreaching cycle.
HMB-FA resulted in increased total strength (bench press, squat, and deadlift combined) over the 12-week training (77.1 ± 18.4 vs. 25.3 ± 22.0 kg, p < 0.001); a greater increase in vertical jump power (991 ± 168 vs. 630 ± 167 W, p < 0.001); and increased lean body mass gain (7.4 ± 4.2 vs. 2.1 ± 6.1 kg, p < 0.001) in HMB-FA- and placebo-supplemented groups, respectively. During the overreaching cycle, HMB-FA attenuated increases in CK (−6 ± 91 vs. 277 ± 229 IU/l, p < 0.001) and cortisol (−0.2 ± 2.9 vs. 4.5 ± 1.7 μg/dl, p < 0.003) in the HMB-FA- and placebo-supplemented groups, respectively.
These results suggest that HMB-FA enhances hypertrophy, strength, and power following chronic resistance training, and prevents decrements in performance following the overreaching.
Electronic supplementary material
The online version of this article (doi:10.1007/s00421-014-2854-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4019830  PMID: 24599749
Leucine metabolite; Resistance training; Overreaching; Recovery; Sports supplements
6.  Screening for pulmonary tuberculosis in HIV-infected individuals: AIDS Clinical Trials Group Protocol A5253 
Improved tuberculosis (TB) screening is urgently needed for human immunodeficiency virus (HIV) infected patients.
An observational, multicountry, cross-sectional study of HIV-infected patients to compare a standardized diagnostic evaluation (SDE) for TB with standard of care (SOC). SOC evaluations included TB symptom review (current cough, fever, night sweats and/or weight loss), sputum Ziehl-Neelsen staining and chest radiography. SDE screening added extended clinical signs and symptoms and fluorescent microscopy (FM). All participants underwent all evaluations. Mycobacterium tuberculosis on sputum culture was the primary outcome.
A total of 801 participants enrolled from Botswana, Malawi, South Africa, Zimbabwe, India, Peru and Brazil. The median age was 33 years; 37% were male, and median CD4 count was 275 cells/mm3. Thirty-one participants (4%) had a positive culture on Löwenstein-Jensen media and 54 (8%) on MGIT. All but one positive culture came from sub-Saharan Africa, where the prevalence of TB was 54/445 (12%). SOC screening had 54% sensitivity (95%CI 40–67) and 76% specificity (95%CI 72–80). Positive and negative predictive values were 24% and 92%. No elements of the SDE improved the predictive values of SOC.
Symptom-based screening with smear microscopy was insufficiently sensitive. More sensitive diagnostic testing is required for HIV-infected patients.
PMCID: PMC3923622  PMID: 23485388
tuberculosis; diagnostics; HIV infection; sensitivity; specificity
8.  Exposure to Mebendazole and Pyrvinium during Pregnancy: A Danish Nationwide Cohort Study 
Purpose. Families with children are frequently exposed to pinworm infection and treatment involves the whole family. Information on consequences of exposure during, pregnancy is limited. The aim of this study was to investigate the exposure to pyrvinium and mebendazole before, during, and after pregnancy in a Danish nationwide cohort. Methods. From nationwide administrative registers, we identified 718, 900 births in Denmark between January 1997 and December 2007 as well as maternal prescription data of anthelmintics and maternal characteristics. Redemption of a prescription for pyrvinium or mebendazole was used to identify exposure. Results. 4715 women redeemed a prescription for pyrvinium or mebendazole during pregnancy; 1606 for pyrvinium, 2575 for mebendazole, and 534 for both drugs. Having >2 children compared to having no previous children was associated with exposure to pyrvinium (OR: 7.1, 95% CI: 5.8–8.7) and mebendazole (OR: 20.8, 95% CI: 17.3–24.9). Conclusion. 4715 pregnant women redeemed a prescription for either mebendazole or pyrvinium. We believe the exposure to be even higher since pyrvinium is also sold over-the-counter. Limited information on birth outcomes is available at present time, and considering the number of exposed pregnancies, we recommend that studies are to be undertaken to assess the safety of pyrvinium and mebendazole during pregnancy.
PMCID: PMC3458300  PMID: 23028209
9.  Development of a Biocrystallisation Assay for Examining Effects of Homeopathic Preparations Using Cress Seedlings 
A major challenge in basic research into homeopathic potentisation is to develop bioassays that yield consistent results. We evaluated the potential of a seedling-biocrystallisation method. Cress seeds (Lepidium sativum L.) germinated and grew for 4 days in vitro in Stannum metallicum 30x or water 30x in blinded and randomized assignment. 15 experiments were performed at two laboratories. CuCl2-biocrystallisation of seedlings extracted in the homeopathic preparations was performed on circular glass plates. Resulting biocrystallograms were analysed by computerized textural image analysis. All texture analysis variables analysed yielded significant results for the homeopathic treatment; thus the texture of the biocrystallograms of homeopathically treated cress exhibited specific characteristics. Two texture analysis variables yielded differences between the internal replicates, most probably due to a processing order effect. There were only minor differences between the results of the two laboratories. The biocrystallisation method seems to be a promising complementary outcome measure for plant bioassays investigating effects of homeopathic preparations.
PMCID: PMC3434472  PMID: 22969820
11.  The incidence, predictors and management of anaemia and its association with virological response in HCV/HIV coinfected persons treated with long-term pegylated interferon alfa 2a and ribavirin 
Alimentary pharmacology & therapeutics  2011;33(11):1234-1244.
The association of anaemia with outcomes in the HCV/HIV coinfected persons undergoing HCV treatment remains unclear.
To study the incidence, predictors and management of anaemia, and its association with outcomes among persons treated with pegylated interferon and weight-based ribavirin.
Retrospective analysis of a prospective controlled treatment trial of HCV/HIV coinfection.
Among 329 subjects enrolled, 40% developed anaemia during the first 12–18 weeks of treatment (median haemoglobin decrease at week 4: 2.2 g/dL). Among 169 subjects who achieved early virological response and received therapy for 72 weeks, 55% eventually developed anaemia. However, median haemoglobin levels stayed stable after 12–18 weeks of initial therapy. Among these 169 subjects, 45% were prescribed an erythropoiesis stimulating agent (ESA), with 17% receiving it prior to a drop in haemoglobin meeting protocol definition of anaemia. Only 27% completed the study without any ribavirin dose modification. Age >40 years, lower BMI, zidovudine use and lower entry haemoglobin were significant predictors of anaemia in the multi-covariate model. Among all 329, sustained virological response (SVR) rate was similar in those with or without anaemia (23% vs. 30%; P = 0.17) with no evidence of association between anaemia or ESA use and treatment response.
Anaemia is common in HCV/HIV coinfected persons undergoing HCV treatment, and only a minority of them are able to maintain ribavirin dose. Persons with age >40 years, lower baseline haemoglobin and lower baseline BMI should be monitored carefully. Prescription of erythropoiesis stimulating agent is common, but anaemia or erythropoiesis stimulating agent use is not associated with SVR.
PMCID: PMC3184244  PMID: 21535051
12.  Timing of Antiretroviral Therapy for HIV-1 Infection and Tuberculosis 
The New England Journal of Medicine  2011;365(16):1482-1491.
Antiretroviral therapy (ART) is indicated during tuberculosis (TB) treatment of patients infected with HIV-1, but the urgency to start ART at TB diagnosis for patients of varying levels of immune compromise is not known.
We conducted an open label, randomized study comparing immediate (within 2 weeks of TB treatment initiation) to early (8–12 weeks) ART among HIV-1 infected patients with CD4+ lymphocytes < 250/mm3 and suspected TB. The primary study endpoint was proportion of patients who survived without an AIDS-defining illness at 48 weeks.
809 patients with median baseline CD4+ lymphocytes of 77 cells/mm3 and HIV-1 RNA of 5.43 log10 copies/mL were enrolled. In the immediate arm, 12.9% of patients experienced an AIDS-defining illness or death by 48 weeks compared to 16.1% in the early arm (p=0.45; 95% confidence interval (CI) for difference: −1.8%, 8.1%). In patients with screening CD4+ lymphocytes <50 cells/mm3, 15.5% of patients on the immediate arm vs. 26.6% on early ART experienced an AIDS defining illness or death (p=0.02; difference CI: 1.5%, 20.5%). TB immune reconstitution inflammatory syndrome (IRIS) was more common with immediate ART (11% vs. 5%: p=0.002). Viral suppression at 48 weeks was 74% and did not differ between arms (p=0.38).
Overall, immediate ART did not reduce AIDS-defining illnesses and death compared to early ART. For persons with CD4+ lymphocytes < 50 cells/mm3, immediate ART had 42% less AIDS defining illnesses and death compared to early ART. ( number NCT00108862.)
PMCID: PMC3327101  PMID: 22010914
13.  Is Immediate Imaging Important in Managing Low Back Pain? 
Journal of Athletic Training  2011;46(1):99-102.
Chou R, Fu R, Carrino JA, Deyo RA. Imaging strategies for low-back pain: systematic review and meta-analysis. Lancet. 2009;373(9662):463–472.
Clinical Questions:
In patients with low back pain (LBP) who do not have indications of a serious underlying condition, does routine, immediate lumbar imaging result in improved patient outcomes when compared with clinical care without immediate imaging?
Data Sources:
Studies were identified by searching MEDLINE (1966 through first week of August 2008) and the Cochrane Central Register of Controlled Trials (third quarter of 2008). The reference lists of identified studies were manually reviewed for additional citations. The search terms spine, low-back pain, diagnostic imaging, and randomized controlled trials were used in both databases. The complete search strategy was made available as an online supplement.
Study Selection:
The search criteria were applied to the articles obtained from the electronic searches and the subsequent manual searches with no language restrictions. This systematic review and meta-analysis included randomized, controlled trials that compared immediate, routine lumbar imaging (or routine provision of imaging findings) with usual clinical care without immediate lumbar imaging (or not routinely providing results of imaging) for LBP without indications of serious underlying conditions.
Data Extraction:
Data extraction and assessment of study quality were well described. The trials assessed one or more of the following outcomes: pain, function, mental health, quality of life, patient satisfaction, and overall patient-reported improvement. Two reviewers independently appraised citations considered potentially relevant, with disagreements between reviewers resolved by consensus. Two independent reviewers abstracted data from the trials and assessed quality with modified Cochrane Back Review Group criteria. The criterion for blinding of patients and providers was excluded because of lack of applicability to imaging studies. In addition, the criterion of co-intervention similarity was excluded because a potential effect of different imaging strategies is to alter subsequent treatment decisions. As a result of excluding these criteria, quality ratings were based on the remaining 8 criteria. The authors resolved disagreements about quality ratings through discussion and consensus. Trials that met 4 or more of the 8 criteria were classified as higher quality, whereas those that met 3 or fewer of the 8 criteria were classified as lower quality. In addition, the authors categorized duration of symptoms as acute (<4 weeks), subacute (4–12 weeks), or chronic (>12 weeks). The investigators also contacted the study authors for additional data if included outcomes were not published or if median (rather than mean) outcomes were reported. Statistical analysis was conducted on the primary outcomes of improvement in pain or function. Secondary outcomes of improvement in mental health, quality of life, patient satisfaction, and overall improvement were also analyzed. Outcomes were categorized as short term (≤3 months), long term (>6 months to ≤1 year), or extended (>1 year). For continuous outcomes, standardized mean differences (SMDs) of interventions for change between baseline and follow-up measurements were calculated. In studies reporting the same pain (visual analog scale [VAS] or Short Form-36 bodily pain score) or function (Roland-Morris Disability Questionnaire [RDQ]) outcomes, weighted mean differences (WMDs) were calculated. In all analyses, lower pain and function scores indicated better outcomes. For quality-of-life and mental health outcomes, higher scores indicated improved outcomes. All statistical analyses were performed with Stata 10.0. For outcomes in which SMDs were calculated, values of 0.2 to 0.5 were considered small, 0.5 to 0.8 were considered moderate, and values greater than 0.8 were considered large. For WMDs, mean improvements of 5 to 10 points on a 100-point scale (or equivalent) were considered small, 10-point to 20-point changes were considered moderate, and changes greater than 20 points were considered large. For the RDQ, mean improvements of 1 to 2 points were termed small, and improvements of 2 to 5 points were termed moderate.
Main Results:
The total number of citations identified using the search criteria was 479 articles and abstracts. Of these, 466 were excluded because either they were not randomized trials or they did not use imaging strategies for LBP. At this step, 13 articles were retrieved for further analysis. This analysis resulted in 3 additional articles being excluded (1 was not a randomized trial and the other 2 compared 2 imaging techniques rather than immediate imaging versus no imaging). The final step resulted in the inclusion of 6 trials reported in 10 publications for the meta-analysis. In the studies meeting the inclusion criteria, 4 assessed lumbar radiography and 2 assessed magnetic resonance imaging (MRI) or computed tomography (CT) scans. In these 6 trials, 1804 patients were randomly assigned to the intervention group. The duration of patient follow-up ranged from 3 weeks to 2 years. In addition, 1 trial excluded patients with sciatica or other radiculopathy symptoms, whereas another did not report the proportion of patients with these symptoms. In the other 4 studies, the proportion of patients with sciatica or radiculopathy ranged from 24% to 44%. Of the included trials, 3 compared immediate lumbar radiography with usual clinical care without immediate radiography, and a fourth study compared immediate lumbar radiography and a brief educational intervention with lumbar radiography if no improvement was seen by 3 weeks. The final 2 studies assessed advanced imaging modalities. Specifically, one group compared immediate MRI or CT with usual clinical care without advanced imaging in patients with primarily chronic LBP (82% with LBP for >3 months) who were referred to a surgeon. In the other advanced imaging study, all patients with LBP for <3 weeks underwent MRI and were then randomized to routine notification of results or to notification of results only if clinically indicated. With respect to study quality, 5 trials met at least 4 of the 8 predetermined quality criteria, leading to a classification of higher quality. In addition, 5 trials were included in the primary meta-analysis on pain or function improvement at 1 or more follow-up periods. With regard to short-term and long-term improvements in pain, no differences were noted between routine, immediate lumbar imaging and usual clinical care without immediate imaging (Table 1). In studies using the VAS pain score, the WMD (0.62, 95% confidence interval [CI]  =  0.03, 1.21) at short-term follow-up slightly favored no immediate imaging. No differences in outcome were seen in studies using the Short Form-36 bodily pain score. No improvements in function at short-term or long-term follow-up were noted between imaging strategies. Specifically, short-term function measured with the RDQ in 3 studies showed a WMD of 0.48 points (95% CI  =  −1.39, 2.35) between imaging strategies, whereas long-term function in 3 studies, also measured with the RDQ, showed a WMD of 0.33 points (95% CI  =  −0.65, 1.32). One included trial reported pain outcomes at extended (2-year) follow-up and found no differences between imaging strategies for pain (Short Form-36 bodily pain or Aberdeen pain score), with SMDs of −2.7 (95% CI  =  −6.17, 0.79) and −1.6 (−4.04, 0.84), respectively. The outcomes between immediate imaging and usual clinical care without immediate imaging did not differ for short-term follow-up in those studies reporting quality of life (SMD  =  −0.10, 95% CI  =  −0.53, 0.34), mental health (SMD  =  0.12, 95% CI  =  −0.37, 0.62), or overall improvement (mean risk ratio  =  0.83, 95% CI  =  0.65, 1.06). In those studies reporting long-term follow-up periods, similar results can be seen for quality of life (SMD  =  −0.15, 95% CI  =  −0.33, 0.04) and mental health (SMD  =  0.01, 95% CI  =  −0.32, 0.34). In the study reporting extended follow-up, immediate imaging was not better in terms of improving quality of life (SMD  =  0.02, 95% CI  =  −0.02, 0.07) or mental health (SMD  =  −1.50, 95% CI  =  −4.09, 1.09) when compared with usual clinical care without immediate imaging. In the included studies, no cases of cancer, infection, cauda equina syndrome, or other serious diagnoses were reported in patients randomly assigned to either imaging strategy.
Available evidence indicates that immediate, routine lumbar spine imaging in patients with LBP and without features indicating a serious underlying condition did not improve outcomes compared with usual clinical care without immediate imaging. Clinical care without immediate imaging seems to result in no increased odds of failure in identifying serious underlying conditions in patients without risk factors for these conditions. In addition to lacking clinical benefit, routine lumbar imaging is associated with radiation exposure (radiography and CT) and increased direct expenses for patients and may lead to unnecessary procedures. This evidence confirms that clinicians should refrain from routine, immediate lumbar imaging in primary care patients with nonspecific, acute or subacute LBP and no indications of underlying serious conditions. Specific consideration of patient expectations about the value of imaging was not addressed here; however, this aspect must be considered to avoid unnecessary imaging while also meeting patient expectations and increasing patient satisfaction.
PMCID: PMC3017496  PMID: 21214357
spine; assessment; outcomes
14.  Strategies for Incorporating Novel Post-Translational Modification Enrichment Methods in a Quantitative Proteomics Environment 
Low-stoichiometry post-translational modifications (PTMs) such as phosphorylation, acetylation, s-nitrosylation (SNO), and s-acylation are integral to intracellular signaling and are thought to capture the most immediate response of a cell upon external stimulus. These modifications, among others, have been the subject of intense focus in the mass spectrometry world because of the ability of the mass spectrometer to identify the peptide and many times the site of modification with a much higher degree of specificity than antibody-based approaches. However, PTMs present a distinct analytical challenge because they exist at low levels in biological samples and therefore must be enriched in order to be measured with the mass spectrometer in a high-throughput manner from a complex system. Three categorical methods exist to enrich PTMs, including chemical enrichment, antibody enrichment, and PTM-switch methods.
In a biomedical research environment, one of the most challenging aspects to implementing any enrichment strategy is to properly qualify a technique so that it can be performed with high specificity and reproducibility. Each of the three categories of enrichments has unique analytical concerns and challenges. Recently, our laboratory has sought to extend the study of PTMs from primarily a qualitative environment to a quantitative one, in order to study selected PTMs in systems where isotopic labeling is not possible, such as animal models or clinical studies.[1-4] This presentation will focus on the key steps in the development and deployment of label-free quantitation using three of our recently-published PTM-switch enrichment approaches, S-nitrosothiol resin-assisted capture (SNO-RAC), S-acylation resin-assisted capture (Acyl-RAC), and the acetyl biotin-switch technique (Acetyl-BST).
PMCID: PMC3630577
15.  Women Experience Higher Rates of Adverse Events During HCV Therapy in HIV Infection: A Meta-Analysis 
In HIV/HCV coinfection, adverse events (AE) during HCV therapy account for 12-39% of treatment discontinuations. It is unknown whether sex influences complications.
Meta-analysis to study the effect of sex and other predictors of AEs in 3 randomized trials, ACTG 5071, APRICOT, and ANRSHCO2-RIBAVIC of Interferon (IFN) and Pegylated IFN (PEG), both with and without Ribavirin, in HIV/HCV coinfection. Primary endpoints were AEs requiring treatment discontinuation (AETD) or first dose modification (AEDM). Multi-covariate stratified logistic regression was used to study predictors and assess interactions with sex.
21% of 1376 subjects were women; 61% had undetectable HIV RNA; 14% were antiretroviral therapy (ARV) naïve at entry; median CD4 was 485 cells/mm3. 17% had an AETD and 50% AEDM; women had more AETD than men, (24% vs. 16% p=0.003) and AEDM (61% vs. 48% p<0.0001). AETD and AEDM occurred earlier in women; but the types of AETD and AEDM were similar between sexes. 74% of AETDs and 49% of AEDMs involved constitutional AEs; 18% of AETDs depression; and 26% of AEDM neutropenia. We identified interactions with sex and BMI (p=0.04, continuous) and NNRTI (p=0.03); more AETDs were seen in men with lower BMI (p=0.01) and in women on NNRTIs (p=0.009). More AEDMs were seen with PEG (OR=2.07); older age (OR=1.48 per 10yrs); decreasing BMI (OR=1.04 per kg/m2); HCV genotype 1,4 (OR=1.31); Ishak 5,6 (OR=1.42); decreasing Hgb (OR=1.23 per g/dL); and decreasing ANC (1.04 per 500 cells/mm3). Interactions between sex and ARV-naïve status (p=0.001) and AZT (p=0.001) were identified: there were more AEDMs in ARV naïve women (p=0.06) and ARV experienced men (p=0.001); and higher AEDMs in women with AZT (p=0.0002).
Although there was no difference in type of AE, AETD and AEDM were more frequent and occurred earlier in women. In women, ARV regimen may be an important predictor of AETDs during HCV therapy and should be explored as a predictor of AEs in HIV/HCV coinfection trials.
PMCID: PMC2943974  PMID: 20622678
HIV; hepatitis C virus; sex differences; toxicity; drug therapy
16.  Risk factors for hand‐wrist disorders in repetitive work 
To identify the risk of hand‐wrist disorders related to repetitive movements, use of hand force and wrist position in repetitive monotonous work.
Using questionnaires and physical examinations, the prevalence and incidence of hand‐wrist pain and possible extensor tendonitis (wrist pain and palpation tenderness) were determined in 3123 employees in 19 industrial settings. With the use of questionnaires and video recordings of homogenous work tasks number of wrist movements, hand force requirements and wrist position were analysed as risk factors for hand‐wrist disorders, controlling for potential personal and psychosocial confounders. All participants were re‐examined three times during a follow‐up period of three years.
Force but not repetition and position was related to hand‐wrist pain and possible tendonitis in the baseline analyses showing an exposure‐response pattern. Odds ratios for the risk of hand pain was 1.7 (95% CI 1.3 to 2.2) and for possible tendonitis 1.9 (95% CI 1.1 to 3.3). There was no significant interaction between the ergonomic factors. In the follow‐up analyses force remained a risk factor for hand pain (OR 1.4, 95% CI 1.1 to 1.8) and for possible tendonitis (OR 2.9, 95% CI 1.3 to 6.8). Repetition was also a risk factor for the onset of hand‐wrist pain (OR 1.6, 95% CI 1.2 to 2.3).
Increasing levels of force were associated with prevalent and incident hand‐wrist pain and possible extensor tendonitis. The results for repetition were less consistent. Working with the hand in a non‐neutral position could not be identified as a risk factor.
PMCID: PMC2078496  PMID: 17387137
Neuroscience  2008;153(3):664-670.
In response to injury, endogenous precursors in the adult brain can proliferate and generate new neurons, which may have the capacity to replace dysfunctional or dead cells. Although injury-induced neurogenesis has been demonstrated in animal models of stroke, Alzheimer’s disease (AD) and Huntington’s disease (HD), studies of Parkinson’s disease (PD) have produced conflicting results. In this study, we investigated the ability of adult mice to generate new neurons in response to the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes selective degeneration of nigrostriatal dopamine neurons. MPTP lesions increased the incorporation of 5-bromo-2′-deoxyuridine-5′-monophosphate (BrdU), as well as the number of cells that co-expressed BrdU and the immature neuronal marker doublecortin (DCX), in two neuroproliferative regions—the subgranular zone of the dentate gyrus (DG) and the rostral subventricular zone (SVZ). BrdU-labeled, DCX-expressing cells were not found in the substantia nigra (SN) of MPTP-treated mice, where neuronal cell bodies are destroyed, but were present in increased numbers in the striatum, where SN neurons lost in PD normally project. Fibroblast growth factor-2 (FGF-2), which enhances neurogenesis in a mouse model of HD, also increased the number of BrdU/DCX-immunopositive cells in the SN of MPTP-treated mice. Thus, MPTP-induced brain injury increases striatal neurogenesis and, in combination with FGF-2 treatment, also stimulates neurogenesis in SN.
PMCID: PMC2864598  PMID: 18407421
fibroblast growth factor; Parkinson’s disease; proliferation; progenitor; striatum; substantia nigra
19.  Low Rate of CMV End-Organ Disease in HIV-Infected Patients Despite Low CD4+ Cell Counts and CMV Viremia: Results of ACTG Protocol A5030 
HIV clinical trials  2009;10(3):143-152.
To describe cytomegalovirus (CMV) end-organ disease (EOD) rate in AIDS patients with low CD4+ cell count despite HAART who were enrolled in a randomized, placebo-controlled trial of preemptive valganciclovir (VGCV) to prevent CMV EOD in those with CMV viremia.
Subjects (N = 338) were HIV-infected with CD4+ count <100 cells/mm3, plasma HIV RNA >400 copies/mL, and on stable or no HAART. All underwent plasma CMV DNA PCR testing every 8 weeks (Step 1); those with detectable CMV DNA were randomized to VGCV or placebo (Step 2).
Plasma CMV DNA was detected in 68 (20%), of whom 4 developed CMV EOD. During Step 1, 53 died. Of the 47 who entered Step 2 (24 VGCV, 23 placebo), CMV EOD was diagnosed in 10 (4 VGCV, 6 placebo) and 15 died (7 VGCV, 8 placebo). Of those randomized to placebo, 14% were diagnosed with CMV EOD at 12 months.
We observed a lower CMV EOD rate among subjects receiving HAART than predicted based on published literature. However, mortality was high in this study. Our findings suggest that preemptive anti-CMV therapy in patients with persistently low CD4+ cell counts in the current treatment era may not be warranted given the low incidence of CMV EOD and high all-cause mortality observed in this study population.
PMCID: PMC2754189  PMID: 19632953
AIDS; CMV; opportunistic disease prevention; valganciclovir
20.  Intervention trials on upper body pain among computer operators 
Commentary on the paper by Rempel et al (see page 300)
PMCID: PMC2092495  PMID: 16621847
computer operators; upper body pain
21.  Incidence of shoulder and neck pain in a working population: effect modification between mechanical and psychosocial exposures at work? Results from a one year follow up of the Malmö shoulder and neck study cohort 
Study objective: To assess the impact of mechanical exposure and work related psychosocial factors on shoulder and neck pain.
Design: A prospective cohort study.
Participants: 4919 randomly chosen, vocationally active men and women ages 45–65 residing in a Swedish city. Neck and shoulder pain were determined by the standardised Nordic questionnaire. Mechanical exposure was assessed by an index based on 11 items designed and evaluated for shoulder and neck disorders. Work related psychosocial factors were measured by the Karasek and Theorell demand-control instrument.
Main results: High mechanical exposure was associated with heightened risk for shoulder and neck pain among men and women during follow up. Age adjusted odds ratios (OR) were 2.17 (95% confidence intervals (CI): 1.65, 2.85) and 1.59 (95% CI: 1.22, 2.06), respectively. In women, job strain (high psychological job demands and low job decision latitude) correlated with heightened risk (OR = 1.73, 95% CI: 1.29, 2.31). These risk estimates remained statistically significant when controlled for high mechanical exposure regarding job strain (and vice versa), and for sociodemographic factors. Testing for effect modification between high mechanical exposure and job strain showed them acting synergistically only in women.
Conclusion: Job related mechanical exposure in both sexes, and psychosocial factors in women, seem independently of each other to play a part for development of shoulder and neck pain in vocationally active people. The effect of psychosocial factors was more prominent in women, which could be the result of biological factors as well as gender issues. These results suggest that interventions aiming at reducing the occurrence of shoulder and neck pain should include both mechanical and psychosocial factors.
PMCID: PMC1733134  PMID: 16100307
22.  Exercises versus arthroscopic decompression in patients with subacromial impingement: a randomised, controlled study in 90 cases with a one year follow up 
Annals of the Rheumatic Diseases  2005;64(5):760-764.
Objectives: To compare the effect of graded physiotherapeutic training of the rotator cuff versus arthroscopic subacromial decompression in patients with subacromial impingement.
Methods: Randomised controlled trial with 12 months' follow up in a hospital setting. Ninety consecutive patients aged 18 to 55 years were enrolled. Symptom duration was between six months and three years. All fulfilled a set of diagnostic criteria for rotator cuff disease, including a positive impingement sign. Patients were randomised either to arthroscopic subacromial decompression, or to physiotherapy with exercises aiming at strengthening the stabilisers and decompressors of the shoulder. Outcome was shoulder function as measured by the Constant score and a pain and dysfunction score. "Intention to treat" analysis was used, with comparison of means and control of confounding variables by general equation estimation analysis.
Results: Of 90 patients enrolled, 84 completed follow up (41 in the surgery group, 43 in the training group). The mean Constant score at baseline was 34.8 in the training group and 33.7 in the surgery group. After 12 months the mean scores improved to 57.0 and 52.7, respectively, the difference being non-significant. No group differences in mean pain and dysfunction score improvement were found.
Conclusions: Surgical treatment of rotator cuff syndrome with subacromial impingement was not superior to physiotherapy with training. Further studies are needed to qualify treatment choice decisions, and it is recommended that samples are stratified according to disability level.
PMCID: PMC1755495  PMID: 15834056
23.  Cigarette smoking accelerates progression of alcoholic chronic pancreatitis 
Gut  2005;54(4):510-514.
Background: Smoking is a recognised risk factor for pancreatic cancer and has been associated with chronic pancreatitis and also with type II diabetes.
Aims: The aim of this study was to investigate the effect of tobacco on the age of diagnosis of pancreatitis and progression of disease, as measured by the appearance of calcification and diabetes.
Patients: We used data from a retrospective cohort of 934 patients with chronic alcoholic pancreatitis where information on smoking was available, who were diagnosed and followed in clinical centres in five countries.
Methods: We compared age at diagnosis of pancreatitis in smokers versus non-smokers, and used the Cox proportional hazards model to evaluate the effects of tobacco on the development of calcification and diabetes, after adjustment for age, sex, centre, and alcohol consumption.
Results: The diagnosis of pancreatitis was made, on average, 4.7 years earlier in smokers than in non-smokers (p = 0.001). Tobacco smoking increased significantly the risk of pancreatic calcifications (hazard ratio (HR) 4.9 (95% confidence interval (CI) 2.3–10.5) for smokers v non-smokers) and to a lesser extent the risk of diabetes (HR 2.3 (95% CI 1.2–4.2)) during the course of pancreatitis.
Conclusions: In this study, tobacco smoking was associated with earlier diagnosis of chronic alcoholic pancreatitis and with the appearance of calcifications and diabetes, independent of alcohol consumption.
PMCID: PMC1774435  PMID: 15753536
chronic alcoholic pancreatitis; diabetes; calcification; tobacco smoking
24.  Understanding work related musculoskeletal pain: does repetitive work cause stress symptoms? 
Background: Pain in the neck and upper extremity is reported with high frequency in repetitive work. Mechanical overload of soft tissues seems a plausible mechanism, but psychological factors have received considerable attention during the past decade. If psychological factors are important for development of regional pain in repetitive work, stress symptoms would likely be on the causal path.
Aims: To examine whether objective measures of repetitive monotonous work are related to occurrence and development of stress symptoms.
Methods: In 1994–95, 2033 unskilled workers with continuous repetitive work and 813 workers with varied work were enrolled. Measures of repetitiveness and force requirements were quantified using video observations to obtain individual exposure estimates. Stress symptoms were recorded at baseline and after approximately one, two, and three years by the Setterlind Stress Profile Inventory.
Results: Repetitive work, task cycle time, and quantified measures of repetitive upper extremity movements including force requirements were not related to occurrence of stress symptoms at baseline or development of stress symptoms during three years of follow up.
Conclusions: The findings do not indicate that repetitive work is associated with stress symptoms, but small effects cannot be ruled out. Thus the results question the importance of mental stress mechanisms in the causation of regional pain related to repetitive work. However, the findings should be interpreted with caution because the stress inventory has not been validated against a gold standard.
PMCID: PMC1740840  PMID: 15613607
25.  Stage-associated overexpression of the ubiquitin-like protein, ISG15, in bladder cancer 
British Journal of Cancer  2006;94(10):1465-1471.
Bladder cancer is among the most prevalent malignancies, and is characterised by frequent tumour recurrences and localised inflammation, which may promote tissue invasion and metastasis. Microarray analysis was used to compare gene expression in normal bladder urothelium with that in tumours at different stages of progression. The innate immune response gene, interferon-stimulated gene 15 kDa (ISG15, GIP2), was highly expressed at all stages of bladder cancer as compared to normal urothelium. Western blotting revealed a tumour-associated expression of ISG15 protein. ISG15 exhibited a stage-associated expression, with significantly (P<0.05) higher levels of ISG15 protein in muscle-invasive T2–T4 tumours, compared with normal urothelium. Although ISG15 is involved in the primary immune response, ISG15 expression did not correlate with bladder inflammation. However, immunohistochemical staining revealed expression of ISG15 protein in both cancer cells and stromal immune cells. Interestingly, a significant fraction of ISG15 protein was localised to the nuclei of tumour cells, whereas no nuclear ISG15 staining was observed in ISG15-positive stromal cells. Taken together, our findings identify ISG15 as a novel component of bladder cancer-associated gene expression.
PMCID: PMC2361278  PMID: 16641915
bladder cancer; interferon; ISG15; ubiquitin-like protein; inflammation

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