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1.  The influence of sulcus width on simulated electric fields induced by transcranial magnetic stimulation 
Physics in medicine and biology  2013;58(14):4881-4896.
Volume conduction models can help in acquiring knowledge about the distribution of the electric field induced by transcranial magnetic stimulation (TMS). One aspect of a detailed model is an accurate description of the cortical surface geometry. Since its estimation is difficult, it is important to know how accurate the geometry has to be represented. Previous studies only looked at the differences caused by neglecting the complete boundary between the CSF and GM (Thielscher et al. 2011; Bijsterbosch et al. 2012), or by resizing the whole brain (Wagner et al. 2008). However, due to the high conductive properties of the CSF, it can be expected that alterations in sulcus width can already have a significant effect on the distribution of the electric field. To answer this question, the sulcus width of a highly realistic head model, based on T1-, T2- and diffusion-weighted magnetic resonance images (MRI), was altered systematically. This study shows that alterations in the sulcus width do not cause large differences in the majority of the electric field values. However, considerable overestimation of sulcus width produces an overestimation of the calculated field strength, also at locations distant from the target location.
doi:10.1088/0031-9155/58/14/4881
PMCID: PMC3759999  PMID: 23787706
2.  The tWE lab Simplified IVF Procedure: First Births after freezing/thawing 
Background: Infertility care is one of the most neglected health care issues in developing countries (DC), affecting more than 50 million couples. The social stigma of childlessness still leads to isolation and abandonment. Bilateral tubal occlusion due to sexually transmitted diseases and pregnancy-related infections is the most common cause of infertility in DC. Consequently most cases of infertility are only treatable by using assisted reproductive technologies which are either unavailable or too costly. Lowering the laboratory costs associated with IVF is a crucial step to make IVF affordable for a larger part of the world population. We recently developed and described a new simplified method of IVF culturing, called the tWE lab method. Our initial results in fresh IVF cycles showed that IVF methodology can be significantly simplified and result in successful outcomes at levels that compare favourably to those obtained in high resource programs.
Case-reports: We report three pregnancies and four live births as a result of transferring five cryo/thawing embryos which were developed after using the simplified tWE lab system. The two singleton babies delivered vaginally, for the twin pregnancy a caesarean section was performed. All babies were healthy, the perinatal outcome was uneventful in all cases.
Conclusion: We provide proof-of-principle evidence that transferring cryopreserved/thawed embryos obtained with our tWE lab simplified culture system can lead to successful pregnancies and healthy live births.
PMCID: PMC4086002  PMID: 25009725
Accessible IVF; assisted reproduction; cryopreservation; developing countries; infertility care; low-cost IVF; simplified IVF; slow freezing; the walking egg project
3.  Inhibition of Bacterial Growth and Biofilm Production by Constituents from Hypericum spp 
Phytotherapy Research  2011;26(7):1012-1016.
Biofilm embedded bacterial pathogens such as Staphylococcus spp., Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii are difficult to eradicate and are major sources of bacterial infections. New drugs are needed to combat these pathogens. Hypericum is a plant genus that contains species known to have antimicrobial properties. However, the specific constituents responsible for the antimicrobial properties are not entirely known, nor have most compounds been tested as inhibitors of biofilm development. The investigation presented here tested seven secondary metabolites isolated from the species Hypericum densiflorum, Hypericumellipticum, Hypericum prolificum and Hypericum punctatum as inhibitors of bacterial growth and biofilm production. Assays were conducted against Staphylococcus epidermidis, Staphylococcusaureus, clinical methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii. Five of the seven compounds demonstrated growth inhibition against the Gram-positive bacteria with minimum inhibitory concentrations (MIC) ranging from 1.95 μg/mL to 7.81 μg/mL. Four of the secondary metabolites inhibited biofilm production by certain Gram-positive strains at sub-MIC concentrations.
doi:10.1002/ptr.3675
PMCID: PMC3339047  PMID: 22170780
antibacterial agents; Hypericum; acylphloroglucinol; Staphylococcus; biofilm
4.  Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study 
Quality of Life Research  2012;22(7):1717-1727.
Purpose
The aim of this study was to assess the measurement properties of the 5-level classification system of the EQ-5D (5L), in comparison with the 3-level EQ-5D (3L).
Methods
Participants (n = 3,919) from six countries, including eight patient groups with chronic conditions (cardiovascular disease, respiratory disease, depression, diabetes, liver disease, personality disorders, arthritis, and stroke) and a student cohort, completed the 3L and 5L and, for most participants, also dimension-specific rating scales. The 3L and 5L were compared in terms of feasibility (missing values), redistribution properties, ceiling, discriminatory power, convergent validity, and known-groups validity.
Results
Missing values were on average 0.8 % for 5L and 1.3 % for 3L. In total, 2.9 % of responses were inconsistent between 5L and 3L. Redistribution from 3L to 5L using EQ dimension-specific rating scales as reference was validated for all 35 3L–5L-level combinations. For 5L, 683 unique health states were observed versus 124 for 3L. The ceiling was reduced from 20.2 % (3L) to 16.0 % (5L). Absolute discriminatory power (Shannon index) improved considerably with 5L (mean 1.87 for 5L versus 1.24 for 3L), and relative discriminatory power (Shannon Evenness index) improved slightly (mean 0.81 for 5L versus 0.78 for 3L). Convergent validity with WHO-5 was demonstrated and improved slightly with 5L. Known-groups validity was confirmed for both 5L and 3L.
Conclusions
The EQ-5D-5L appears to be a valid extension of the 3-level system which improves upon the measurement properties, reducing the ceiling while improving discriminatory power and establishing convergent and known-groups validity.
doi:10.1007/s11136-012-0322-4
PMCID: PMC3764313  PMID: 23184421
EQ-5D; Health-related quality of life; Psychometrics; Patient-reported outcomes; Utility assessment
5.  Assessment of Helicobacter pylori eradication in patients on NSAID treatment 
BMC Gastroenterology  2012;12:133.
Background
In this post-hoc analysis of a randomized, double blind, placebo controlled trial, we measured the sensitivity and specificity of Helicobacter pylori IgG-antibody titer changes, hematoxylin and eosin (H&E) stains, immunohistochemical (IHC) stains and culture results in NSAID using patients, following H. pylori eradication therapy or placebo.
Methods
347 NSAID using patients who were H. pylori positive on serological testing for H. pylori IgG-antibodies were randomized for H. pylori eradication therapy or placebo. Three months after randomization, gastric mucosal biopsies were taken for H. pylori culture and histological examination. At 3 and 12 months, blood samples were taken for repeated serological testing. The gold standard for H. pylori infection was based on a positive culture or both a positive histological examination and a positive serological test. Sensitivity, specificity and receiver operating curves (ROC) were calculated.
Results
H. pylori eradication therapy was successful in 91% of patients. Culture provided an overall sensitivity of 82%, and 73% after eradication, with a specificity of 100%. Histological examination with either H&E or IHC stains provided sensitivities and specificities between 93% and 100%. Adding IHC to H&E stains did not improve these results. The ROC curve for percent change in H. pylori IgG-antibody titers had good diagnostic power in identifying H. pylori negative patients, with an area under the ROC curve of 0.70 (95 % CI 0.59 to 0.79, P = 0.085) at 3 months and 0.83 (95% CI 0.76 to 0.89, P < 0.0001) at 12 months. A cut-off point of at least 21% decrease in H. pylori IgG-antibody titers at 3 months and 58% at 12 months provided a sensitivity of 64% and 87% and a specificity of 81% and 74% respectively, for successful eradication of H. pylori.
Conclusions
In NSAID using patients, following H. pylori eradication therapy or placebo, histological examination of gastric mucosal tissue biopsies provided good sensitivity and specificity ratios for evaluating success of H. pylori eradication therapy. A percentual H. pylori IgG-antibody titer change has better sensitivity and specificity than an absolute titer change or a predefined H. pylori IgG-antibody titer cut-off point for evaluating success of H. pylori eradication therapy.
doi:10.1186/1471-230X-12-133
PMCID: PMC3515350  PMID: 23006807
6.  Risk factors for ischemic stroke and transient ischemic attack in patients under age 50 
To analyze risk factors for ischemic stroke and transient ischemic attack (TIA) in young adults under the age of 50. To make recommendations for additional research and practical consequences. From 97 patients with ischemic stroke or TIA under the age of 50, classical cardiovascular risk factors, coagulation disorders, history of migraine, use of oral contraceptives, cardiac abnormalities on ECG and echocardiography, and the results of duplex ultrasound were retrospectively analyzed. Literature was reviewed and compared to the results. 56.4% of the patients had hypertension, 12.1% increased total cholesterol, 20% hypertriglyceridemia, 31.5% an increased LDL-level, 32.6% a decreased HDL-level and 7.2% a disturbed glucose tolerance. Thrombophilia investigation was abnormal in 21 patients and auto-immune serology was abnormal in 15 patients. Ten of these patients were already known with a systemic disease associated with an increased risk for ischemic stroke (i.e. systemic lupus erythematosus). The ECG was abnormal in 16.7% of the cases, the echocardiography in 12.1% and duplex ultrasound of the carotid arteries was in 31.8% of the cases abnormal. Conventional cardiovascular risk factors are not only important in patients over the age of 50 with ischemic stroke or TIA, but also in this younger population under the age of 50. Thrombophilia investigation and/ or autoimmune serology should be restricted to patients without conventional cardiovascular risk factors and a history or other clinical symptoms associated with hypercoagulability and/ or autoimmune diseases.
doi:10.1007/s11239-010-0491-3
PMCID: PMC3017300  PMID: 20532956
Young stroke; Thrombophilia; Cardiovascular risk factors; Echocardiography; Duplex ultrasound
7.  Gout, not induced by diuretics? A case‐control study from primary care 
Annals of the Rheumatic Diseases  2005;65(8):1080-1083.
Background
It is taken for granted that diuretics may induce gout, but there is a general lack of evidence on this topic.
Objectives
To determine the incidence of gout in patients who use diuretics, taking into account concurrent hypertension and cardiovascular diseases.
Methods
A case‐control study was designed. From a primary care population all patients with a first gout registration (59 men, 11 women; mean (SD) age 55.1 (13.5)) were identified as cases. To relate the occurrence of gout to diuretic use a matched reference series of three controls for each case was compiled. Conditional logistic regression analyses were applied to estimate incidence rate ratios (IRRs) of gout, and 95% confidence intervals (CIs), in subjects with and without diuretic treatment, hypertension, and cardiovasculardiseases. Additional stratification analyses were made, particularly in the subjects not using diuretics.
Results
The IRRs of gout in subjects with v those without diuretic treatment, hypertension, heart failure, and myocardial infarction were 2.8 (95% CI 1.2 to 6.6), 2.6 (95% CI 1.2 to 5.6), 20.9 (95% CI 2.5 to 173.8), and 1.9 (95% CI 0.7 to 4.7), respectively. After adjustment, the IRR of gout for diuretic use dropped to 0.6 (95% CI 0.2 to 2.0), while the IRRs of gout for hypertension, heart failure, and myocardial infarction were still >1. This was also the case for subjects with hypertension or myocardial infarction, who had not used diuretics.
Conclusion
The results suggest that diuretics do not actually increase the risk of gout. Cardiovascular indications for treatment may have confounded previous inferences.
doi:10.1136/ard.2005.040360
PMCID: PMC1798248  PMID: 16291814
gout; diuretics; case‐control study; cardiovascular diseases; hypertension
8.  In search for the general population’s semen profile: the study of sperm parameters in partners of women with chronic anovulation 
Background: Human fertility is linked to sperm quality and therefore the establishment of reference values for normality is mandatory.
Aims: The first aim was to establish a reference profile of men in the general population by examining the semen of partners of women with chronic anovulation. The second aim was to determine the prevalence of sperm abnormalities in this patient group.
Methods: Sperm samples of 304 partners of patients with chronic anovulation were analysed prospectively. Semen samples were examined according to WHO guidelines, for sperm morphology Tygerberg strict criteria were used. We compared the results of this study with the cut-off values for normality we obtained in a previous study performed in our centre.
Results: The mean value was 3.1 ml for volume, 64.7 mill / ml for concentration, 51.9% for progressive motility (grade a + b motility) and 7.4% for sperm morphology. Single parameter and double parameter abnormalities were observed in 42.7% and 8.2% of cases respectively. A normal sperm sample for all three parameters was noted in 46% of cases. Oligo-Astheno-Teratozoospermia was present in 3.0% of cases while azoospermia was found in two patients (0.7%).
Conclusion: We believe that the study of sperm parameters in partners of patients with chronic anovulation can be used to study the prevalence of sperm abnormalities in the general population. Our data show that semen abnormalities are not uncommon in partners of women with chronic anovulation, highlighting the importance of a semen examination in every infertility work-up, even in case of obvious female pathology.
PMCID: PMC4251278  PMID: 25478067
Chronic anovulation; general population; human; semen analysis; sperm morphology
9.  POMT2 mutations cause α-dystroglycan hypoglycosylation and Walker-Warburg syndrome 
Journal of Medical Genetics  2005;42(12):907-912.
Background: Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of α-dystroglycan (α-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified.
Objective: To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity.
Methods: A candidate gene approach combined with homozygosity mapping.
Results: Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated α-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway.
Conclusions: A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of α-DG.
doi:10.1136/jmg.2005.031963
PMCID: PMC1735967  PMID: 15894594
10.  Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2004;64(4):569-574.
Background: Leflunomide is the prodrug of the disease modifying antirheumatic metabolite A77 1726. More than 50% of patients withdraw from leflunomide treatment within one year, mainly because of adverse drug reactions. Therapeutic drug monitoring of A77 1726 may be useful in predicting the efficacy of leflunomide treatment.
Objective: To study the relation between A77 1726 steady state serum concentrations and disease activity using the 28 joint (DAS28) response.
Methods: Outpatients with rheumatoid arthritis on a stable leflunomide dose for >4 months were included. DAS28 score and adverse drug reactions were recorded. Blood samples were taken for determination of A77 1726 concentrations. The primary end point was the relation of serum A77 1726 concentrations with DAS28 response category
Results: Serum A77 1726 concentrations were determined in 52 patients. A receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.73 (95% confidence interval, 0.54 to 0.93) (p<0.05). The sensitivity exceeded 99% at concentrations below 16 mg/l. DAS28 values at the point of sampling showed no relation with A77 1726 concentrations (AUC of the ROC curve = 0.50 (0.33 to 0.67) (NS)).
Conclusions: A77 1726 steady state serum concentrations show a relation with DAS28 response. Determination of serum A77 1726 concentrations in patients with insufficient response to treatment may help when decisions have to be made about continuation of treatment or dose adjustment.
doi:10.1136/ard.2004.025205
PMCID: PMC1755436  PMID: 15345501
11.  Quantification of the level descriptors for the standard EQ-5D three-level system and a five-level version according to two methods 
Quality of Life Research  2008;17(3):463-473.
Objectives
Our aim was to compare the quantitative position of the level descriptors of the standard EQ-5D three-level system (3L) and a newly developed, experimental five-level version (5L) using a direct and a vignette-based indirect method.
Methods
Eighty-two respondents took part in the study. The direct method represented a visual analog scale (VAS) rating of the nonextreme level descriptors for each dimension and each instrument separately. The indirect method required respondents to score 15 health scenarios with 3L, 5L and a VAS scale. Investigated were: (1) equidistance (Are 3L and 5L level descriptors distributed evenly over the VAS continuum?); (2) isoformity (Do the identical level descriptors on 3L and 5L yield similar results?); and (3) consistency between dimensions (Do the positions of similar level descriptors differ across dimensions within instruments?).
Results
Equidistance without transformation was rejected for all dimensions for both 3L and 5L but satisfied for 5L after transformation. Isoformity gave mixed results. Consistency between dimensions was satisfied for both instruments and both methods.
Discussion
The level descriptors have similar distributions across comparable dimensions within each system, but the pattern differs between 3L and 5L. This methodological study provides evidence of increased descriptive power and a broadened measurement continuum that encourages the further development of an official five-level EQ-5D.
doi:10.1007/s11136-008-9318-5
PMCID: PMC2275305  PMID: 18320352
EQ-5D; Methodology; Health-related quality of life; Psychometrics; Health status
12.  Individual and Combined Effects of pH and Lactic Acid Concentration on Listeria innocua Inactivation: Development of a Predictive Model and Assessment of Experimental Variability▿  
In food technology, organic acids (e.g., lactic acid, acetic acid, and citric acid) are popular preservatives. The purpose of this study was to separate the individual effects of the influencing factors pH and undissociated lactic acid on Listeria innocua inactivation. Therefore, the inactivation process was investigated under controlled, initial conditions of pH (pH0) and undissociated lactic acid ([LaH]0). The resulting inactivation curves consisted of a (sometimes negligible) shoulder period followed by a descent phase. In a few cases, a tailing phase was observed. Depending on the conditions, the descent phase contained one or two log-linear parts or had a convex or concave shape. In addition, the inactivation process was characterized by a certain variability, dependent on the severity of the conditions. Furthermore, in the neighborhood of the growth/no growth interface sometimes contradictory observations occurred. Overall, the individual effects of the influencing factors pH and undissociated lactic acid could clearly be distinguished and were also apparent based on fluorescence microscopy. Appropriate model types were developed and enabled prediction of which conditions of pH0 and [LaH]0 are necessary to obtain a predetermined inactivation (number of decimal reductions) within a predetermined time range.
doi:10.1128/AEM.02198-06
PMCID: PMC1828776  PMID: 17209071
13.  Heart rate variability and sympathovagal balance: pharmacological validation 
Netherlands Heart Journal  2003;11(6):250-259.
Rationale
We validated heart rate (HR) and six time and six frequency domain measures of heart rate variability (HRV) as estimators of autonomic outflow in 44 young healthy male subjects. Gold standards for autonomic outflow were the Rosenblueth-Simeone factors m (sympathetic tone) and n (vagal tone), and the sympathovagal balance m·n, determined by two-stage complete autonomic blockade.
Methods
Rank correlations were computed between HR and the HRV measures obtained before autonomic blockade, and m, n and m·n. Also, the maximal mean performances (averaged sensitivity and specificity) for HR and HRV as discriminators between low and high values of m, n or m·n were computed.
Results
The spectral HRV measures showed less good correlations and performances than the time domain HRV measures. Correlations with sympathetic tone were all below 0.31. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing was superior in estimating vagal tone and sympathovagal balance (correlations -0.71/-0.73; both performances 0.82), heart rate scored similarly for assessing the sympathovagal balance (correlation 0.71; performance 0.82).
Conclusions
It does not appear justified to evaluate HR or HRV in terms of sympathetic tone, vagal tone, or sympathovagal balance. HR and HRV are specifically weak in assessing sympathetic tone. Respiratory sinus arrhythmia during 15 cycles/min metronome breathing is superior in assessing vagal tone. Current HRV analysis techniques offer no advantages compared with HR in assessing the sympathovagal balance.
PMCID: PMC2499895
atropine; metoprolol; heart rate variability; Rosenblueth-Simeone model; sympathovagal balance
14.  Outcomes of allogenic cages in anterior and posterior lumbar interbody fusion 
European Spine Journal  2001;10(Suppl 2):S158-S168.
Abstract.
Interbody lumbar fusions provide a proven logical solution to diseases of the intervertebral discs by eliminating motion of the segment. Historically, there are many techniques to achieve spinal fusion in the lumbar spine. These include anterior, posterior, and foramenal approaches, often in combination with various internal fixation devices. The surgeon's choice of the approach and mechanical or biological implant is dependent on the patient's specific pathology and anatomy, in addition to the experience and training of the surgeon in similar conditions. In the past decade, new mechanical spine implants/spacers have been designed to provide restoration of disc height and improve stabilization of the spine. The ability to radiographically assess the "biology" of bone incorporation in these mechanical (metal) spacers has become a significant limitation.
The femoral ring allograft (FRA) and the posterior lumbar interbody fusion (PLIF) spacers have been developed as "biological cages" that permit restoration of the anterior column with machined allograft bone biological cages. Test results demonstrate that the FRA and PLIF spacers have a compressive strength of over 25,000 N. The pyramid-shaped teeth on the surfaces and the geometry of the implant increase the resistance to expulsion at clinically relevant loads (1053 and 1236 N). The technique of anterior column reconstruction with both the FRA and the PLIF biological cages have been previously reported.
Clinical outcomes and experience with the FRA spacer (137 patients) and the PLIF spacer (13 patients) were reported on and did not reveal any evidence of bone cage resorption or infectious inflammatory process. There was clinical migration with one PLIF spacer, which was later revised with an anterior approach and a FRA spacer. The radiographic outcomes demonstrated that 94% arthrodesis was achieved with the biological spacer and additional posterior instrumentation. The clinical success of every spine fusion procedure is dependent on many factors such as the extent of the instability, the pathology, type of graft used, the patient's pathology/anatomy and lifestyle.
doi:10.1007/s005860100292
PMCID: PMC3611548  PMID: 11716014
Biological cages Femoral ring allograft spacer Posterior lumbar interbody fusion spacer Interbody lumbar fusion Arthrodesis
15.  A clinical and serological comparison of group A versus non-group A streptococcal reactive arthritis and throat culture negative cases of post-streptococcal reactive arthritis 
Annals of the Rheumatic Diseases  1999;58(7):410-414.
OBJECTIVE—To identify clinical and serological differences of patients with reactive arthritis after infection with Lancefield group A β-haemolytic streptococci (GAS), compared with non-group A—that is, group C or G streptococci (NGAS:GCS/GGS), and a group of culture negative or unidentified streptococci (GUS).
METHODS—A prospective study of consecutive patients with reactive arthritis after serologically or culture confirmed infection with β-haemolytic streptococci, presenting to the outpatient department of rheumatology from January 1992 until January 1998. Alternative causes for reactive arthritis were excluded. Main outcome measures were clinical and serological characteristics including antistreptolysine-O (ASO) and antideoxyribonuclease-B (antiDNase-B) antibody titres.
RESULTS—41 patients (female/male ratio 22/19; mean (SD) age 38 (13) years) with reactive arthritis were included. Culture of throat swab was positive in 13 cases (32%): 6 (15%) GAS, 7 NGAS (17%), that is, 5 (12%) GCS, 2 (5%) GGS. In 28 cases throat culture remained negative resulting in a group of unidentified streptococci; antibiotic pre-treatment had been given by the general practitioner in 18 cases (64%). Arthritis was non-migratory, the number of arthritic joints in GAS and NGAS was similar, whereas in NGAS patients fewer joints were involved than in GUS: mean (SEM) 36 swollen joint index: 3.3 (1.0) in NGAS v 5.6 (1.0) in GUS (p<0.005); 28 swollen joint index: 2.9 (1.0) in NGAS v 4.3 (0.8) in GUS (p<0.05). Extra-articular manifestations—that is, erythema nodosum/ multiforme, AV conduction block or hepatitis—were observed after GAS or GUS infection, but not after NGAS infection. ASO and/or antiDNase-B rose significantly in all patients. The maximal titres for ASO and antiDNase-B in 41 PSRA patients were: mean (SEM) 1242 (232) U/l and 890 (100) U/l respectively; the maximal ASO titres were similar in the three groups: mean (SEM) 1125 (185) in GAS, 625 (160) in NGAS (GAS v NGAS: p=0.17), and 1430 (320) U/l in GUS (NGAS v GUS: p=0.10). AntiDNase-B titres were: mean (SEM) 1075 (180) in GAS, 375 (105) in NGAS (GAS v NGAS: p<0.01), and 995 (125) U/l in GUS (NGAS v GUS: p<0.005). ASO: antiDNase-B ratios were: mean (SEM) 0.89 (0.21) in GAS, 2.60 (0.76) in NGAS (GAS v NGAS: p<0.05), and 1.43 (0.28) in GUS (NGAS v GUS: p=0.12).
CONCLUSION—Post-streptococcal reactive arthritis occurs not infrequently. Differentiation of PSRA based on the causative streptococcal strain is frequently thwarted by negative throat cultures. Sometimes extra-articular manifestations are present that exclude NGAS as the causative organism. Serologically, lower antiDNase-B titres may be indicative for primary NGAS infection; the ASO/antiDNase-B ratio may be of additive value for differentiation in cases of a negative throat culture: the higher ASO/antiDNase-B ratios suggesting primary NGAS infection. In reactive arthritis, serological monitoring consisting of a simultaneous titration of antiDNase-B and ASO, seems to be of clinical importance to trace GAS induced cases, especially when throat cultures remain negative.


PMCID: PMC1752920  PMID: 10381484
16.  Biological cages 
European Spine Journal  2000;9(Suppl 1):S102-S109.
Restoring a stable anterior column is essential to achieve normal spinal biomechanics. A variety of mechanical spacers have been developed and advocated for both anterior and posterior approaches. The ability to radiographically assess the “biology” of bone incorporation in these mechanical (metal) spacers is an inherent limitation. The femoral ring allograft (FRA) and posterior lumbar interbody fusion (PLIF) spacers have been developed as biological cages that permit restoration of the anterior column with a machined allograft bone (biological cage). Test results demonstrate that the FRA and PLIF Spacers have a compressive strength over 25,000 N. The pyramid shaped teeth on the surfaces and the geometry of the implant increase the resistance to expulsion at clinically relevant loads (1053 and 1236 N). The technique of anterior column reconstruction with both the FRA and the PLIF biological cages are discussed. Clinical experience with the PLIF biological cage (10 patients) and the FRA biological cage (90 patients) has not revealed any graft migration, infection, or subsidence. Additional posterior instrumentation may increase the stability of the motion segment, but the degree of stability necessary to achieve a biological union remains unclear. The incorporation of these biological cages can be monitored by conventional radiographic techniques. The method of insertion preserves the vertebral end-plates and can be performed by a minimally invasive or standard open procedure.
doi:10.1007/PL00008315
PMCID: PMC3611444  PMID: 10766065
Key words Biological cages; FRA spacer; PLIF spacer; Interbody ¶lumbar fusion; Arthrodesis
17.  Superoxide dismutases in relation to the overall survival of colorectal cancer patients. 
British Journal of Cancer  1998;78(8):1051-1057.
Reactive oxygen metabolites are implicated in the initiation and promotion of cancer. In addition, oxidant scavengers, such as manganese--(Mn-SOD) and copper/zinc--superoxide dismutase (Cu/Zn-SOD), are thought to contribute to colorectal cancer treatment response. In the present study, the prognostic significance of the Mn- and Cu/Zn-SOD antigen content of normal mucosa and carcinomas of 163 patients with colorectal cancer was evaluated in comparison with major clinicopathological parameters, with respect to the 5-year overall survival. The Mn-SOD content of carcinomas was found to be significantly higher than that of normal mucosa, whereas there was no difference in the Cu/Zn-SOD content between the normal mucosa and carcinomas. No association was demonstrable between the Mn-SOD and Cu/Zn-SOD content of the tissues and the assessed clinicopathological parameters (gender, age, localization, differentiation grade, diameter and Dukes' stage), with the exception of the Cu/Zn-SOD and the differentiation grade of the carcinomas. Univariate analysis showed that a high Mn-SOD content of carcinomas was associated with a poor 5-year overall survival of the patients with colorectal cancer. Multivariate analysis including all clinicopathological parameters revealed that this Mn-SOD parameter was prognostically independent. The Mn- and Cu/Zn-SOD content of normal mucosa and the Cu/Zn-SOD content of carcinomas were not associated with the overall survival of the patients. In conclusion, this study demonstrates that for patients with colorectal cancer the Mn-SOD content of colorectal carcinomas has a significant prognostic value that is independent from major clinicopathological parameters, including Dukes' stage.
PMCID: PMC2063153  PMID: 9792149
18.  No effect of intramuscular gold therapy on serological parameters of Helicobacter pylori infection in patients with rheumatoid arthritis: a 12 month prospective study. 
Annals of the Rheumatic Diseases  1994;53(6):400-402.
OBJECTIVES--To assess prospectively the influence of intramuscular gold therapy on Helicobacter pylori serology in patients with rheumatoid arthritis (RA). METHODS--Fifty patients with RA were started on intramuscular gold or chloroquine, as the control group and were followed serologically for H pylori infection for 12 months. RESULTS--Twelve patients treated with gold and eight control patients treated with chloroquine, all with serological evidence for H pylori infection, showed no significant decline of IgA and IgG anti-H pylori antibody levels or serum pepsinogen A and C levels. Total serum IgA and IgG levels declined significantly during gold therapy, while they remained unchanged during chloroquine therapy. CONCLUSIONS--Intramuscular gold therapy in patients with RA does not influence the serological parameters of H pylori infection.
PMCID: PMC1005356  PMID: 8037498
19.  Decreased level of antibodies against Helicobacter pylori in patients with rheumatoid arthritis receiving intramuscular gold. 
Annals of the Rheumatic Diseases  1992;51(9):1036-1038.
BACKGROUND: Sodium aurothiomalate has been reported to have in vitro activity against Helicobacter pylori. Intramuscular gold, as given to patients with rheumatoid arthritis (RA), may therefore influence the colonisation of the gastric mucosa with H pylori. METHODS: Two groups were compared. One group of 42 patients was treated with intramuscular gold; the other group of 58 patients was treated with antimalarial drugs. Antibodies to H pylori (IgA and IgG) were assessed by an enzyme linked immunosorbent assay (ELISA) and total IgA and IgG were measured by nephelometry. RESULTS: IgA and IgG antibody titres against H pylori and total IgA and IgG levels were lower in the patients treated with gold than in the group treated with antimalarial drugs. The ratio of IgA antibodies to H pylori to total IgA antibodies and the ratio of IgG antibodies to H pylori to total IgG antibodies were lower in the group treated with gold. The percentage of seropositivity to H pylori was significantly lower in the group treated with gold than in the group treated with antimalarial drugs for the two IgA antibodies (35 and 55% respectively) and IgG antibodies to H pylori (40 and 65% respectively). CONCLUSIONS: Although this study cannot completely exclude the possibility that a suppressive effect of intramuscular gold on total immunoglobulin production plays a part in the decrease in the titres of IgA antibodies to H pylori and IgG antibodies to H pylori, the lower ratios of antibodies to H pylori to total immunoglobulin antibodies and the lower percentages of seropositivity to H pylori in the group treated with gold suggests that treatment with intramuscular gold decreases H pylori colonisation.
PMCID: PMC1004832  PMID: 1417132
20.  Intra-articular rheumatoid nodules and triggering of the knee joint. 
Annals of the Rheumatic Diseases  1992;51(4):533-535.
Rheumatoid nodules are a common extra-articular manifestation in rheumatoid arthritis. Intra-articular localisation of these nodules is rare and may produce clinical symptoms. Seven patients with walking problems due to an intra-articular rheumatoid nodule, which became entrapped on the ridge of the tibial plateau of the knee joint resulting in a phenomenon referred to as trigger knee, are described. After excision of the nodules all symptoms completely disappeared.
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PMCID: PMC1004708  PMID: 1586256
21.  New tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione derivatives are potent inhibitors of human immunodeficiency virus type 1 replication and are synergistic with 2',3'-dideoxynucleoside analogs. 
Antimicrobial Agents and Chemotherapy  1994;38(12):2863-2870.
Tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives were shown to specifically block human immunodeficiency virus type 1 (HIV-1) replication through a unique interaction with the HIV-1 reverse transcriptase (RT). Through further modification of the lead compounds and structure-activity relationship analysis several new TIBO derivatives that show high potency, selectivity, and specificity against HIV-1 have been obtained. A new TIBO derivative, R86183, inhibits the replication of HIV-1, but not HIV-2, in a variety of CD4+ T-cell lines and peripheral blood lymphocytes, at a concentration of 0.3 to 30 nM, which is at least 4 orders of magnitude lower than the 50% cytotoxic concentration. Whereas an HIV-1 strain containing the Leu-100-->Ile mutation in the RT gene is about 400-fold less susceptible, R86183 still inhibits the replication of an HIV-1 strain containing the Tyr-181-->Cys RT mutation by 50% at a concentration of 130 nM. R86183 inhibits the poly(C).oligo(dG)12-18-directed HIV-1 RT reaction by 50% at a concentration of 57 nM. The antiviral activity of 22 TIBO derivatives in cell culture correlated well with their activity against HIV-1 RT. No such correlation was found for their cytotoxicity. The combination of R86183 with either zidovudine or didanosine resulted in a synergistic inhibition of HIV-1 (strain IIIB) replication. Combination of R86183 with the protease inhibitor Ro31-8959 was found to be additive. Also described is a dilution protocol circumventing overestimation and underestimation of antiviral activity due to adherence to plastic surfaces.
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PMCID: PMC188298  PMID: 7535037
22.  Structural and functional aspects of the multiplicity of Neu differentiation factors. 
Molecular and Cellular Biology  1994;14(3):1909-1919.
We used molecular cloning and functional analyses to extend the family of Neu differentiation factors (NDFs) and to explore the biochemical activity of different NDF isoforms. Exhaustive cloning revealed the existence of six distinct fibroblastic pro-NDFs, whose basic transmembrane structure includes an immunoglobulin-like motif and an epidermal growth factor (EGF)-like domain. Structural variation is confined to three domains: the C-terminal portion of the EGF-like domain (isoforms alpha and beta), the adjacent juxtamembrane stretch (isoforms 1 to 4), and the variable-length cytoplasmic domain (isoforms a, b, and c). Only certain combinations of the variable domains exist, and they display partial tissue specificity in their expression: pro-NDF-alpha 2 is the predominant form in mesenchymal cells, whereas pro-NDF-beta 1 is the major neuronal isoform. Only the transmembrane isoforms were glycosylated and secreted as biologically active 44-kDa glycoproteins, implying that the transmembrane domain functions as an internal signal peptide. Extensive glycosylation precedes proteolytic cleavage of pro-NDF but has no effect on receptor binding. By contrast, the EGF-like domain fully retains receptor binding activity when expressed separately, but its beta-type C terminus displays higher affinity than alpha-type NDFs. Likewise, structural heterogeneity of the cytoplasmic tails may determine isoform-specific rate of pro-NDF processing. Taken together, these results suggest that different NDF isoforms are generated by alternative splicing and perform distinct tissue-specific functions.
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PMCID: PMC358549  PMID: 7509448
23.  Muscle cramps in the calf as presenting symptom of sarcoidosis. 
A patient is described, who presented with pain in the calf due to a palpable nodule as the presenting symptom of sarcoidosis. The patient was treated with rest and diclofenac, followed by intralesional injections with triamcinolone hexacetonide and became free from pain.
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PMCID: PMC1004325  PMID: 1994868
24.  Campylobacter species identification based on polymorphism of DNA encoding rRNA. 
Journal of Clinical Microbiology  1989;27(7):1514-1517.
Total DNA from five Campylobacter species was digested with a mixture of XhoI and BglII restriction endonucleases and analyzed by Southern hybridization by using a probe complementary to the DNA coding for the 16S rRNA. Each of the Campylobacter species, including C. jejuni, C. coli, C. laridis, C. fetus, and C. upsaliensis, displayed a characteristic pattern. Although some bands may be common to different species, the simplicity of the hybridization pattern enabled us to discriminate among the different species of Campylobacter.
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PMCID: PMC267606  PMID: 2570080

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