Objectives. The aim of the study was to investigate whether the use of the antifolate antibiotic trimethoprim during the 12 weeks before conception was associated with congenital malformations. Methods. We conducted a nationwide register-based cohort study including all Danish women giving birth from 1997 to 2004. All women with at least one prescription of trimethoprim dispensed during the 12 weeks before conception were identified. Results. There was a doubling of congenital malformations in offspring to women exposed to trimethoprim in the 12 weeks before conception. The adjusted odds ratio (OR) of major congenital malformation was 1.87, 95% confidence interval (CI) 1.25–2.81. There was a significant increase in major malformations of the heart (OR = 2.49; 1.18–5.26) and limbs (OR = 2.18; 1.13–4.23). Conclusions. In this study, we found an association between exposure to trimethoprim during the 12 weeks before conception and an increased risk of heart and limb defects.

Background

Emergency abdominal surgery carries a 15% to 20% short-term mortality rate. Postoperative medical complications are strongly associated with increased mortality. Recent research suggests that timely recognition and effective management of complications may reduce mortality. The aim of the present trial is to evaluate the effect of postoperative intermediate care following emergency major abdominal surgery in high-risk patients.

Methods and design

The InCare trial is a randomised, parallel-group, non-blinded clinical trial with 1:1 allocation. Patients undergoing emergency laparotomy or laparoscopic surgery with a perioperative Acute Physiology and Chronic Health Evaluation II score of 10 or above, who are ready to be transferred to the surgical ward within 24 h of surgery are allocated to either intermediate care for 48 h, or surgical ward care. The primary outcome measure is all-cause 30-day mortality. We aim to enrol 400 patients in seven Danish hospitals. The sample size allows us to detect or refute a 34% relative risk reduction of mortality with 80% power.

Discussion

This trial evaluates the benefits and possible harm of intermediate care. The results may potentially influence the survival of many high-risk surgical patients. As a pioneer trial in the area, it will provide important data on the feasibility of future large-scale randomised clinical trials evaluating different levels of postoperative care.

Trial registration

Clinicaltrials.gov identifier: NCT01209663

Molecular genotyping of Mycobacterium tuberculosis has proved to be a powerful tool in tuberculosis surveillance, epidemiology, and control. Based on results obtained through 15 years of nationwide IS6110 restriction fragment length polymorphism (RFLP) genotyping of M. tuberculosis cases in Denmark, a country on the way toward tuberculosis elimination, we discuss M. tuberculosis transmission dynamics and point to areas for control interventions. Cases with 100% identical genotypes (RFLP patterns) were defined as clustered, and a cluster was defined as cases with an identical genotype. Of 4,601 included cases, corresponding to 76% of reported and 97% of culture-verified tuberculosis cases in the country, 56% were clustered, of which 69% were Danes. Generally, Danes were more often in large clusters (≥50 persons), older (mean age, 45 years), and male (male/female ratio, 2.5). Also, Danes had a higher cluster frequency within a 2-year observation window (60.8%), and higher clustering rate of new patterns over time, compared to immigrants. A dominant genotype, cluster 2, constituted 44% of all clustered and 35% of all genotyped cases. This cluster was primarily found among Danish males, 30 to 59 years of age, often socially marginalized, and with records of alcohol abuse. In Danes, cluster 2 alone was responsible for the high cluster frequency level. Immigrants had a higher incidence of clustered tuberculosis at a younger age (0 to 39 years). To achieve tuberculosis elimination in Denmark, high-risk transmission environments, like the cluster 2 enviornment in Danes, and specific transmission chains in immigrants in the capital area, e.g., homeless/socially marginalized Somalis/Greenlanders, often with alcohol abuse, must be targeted, including groups with a high risk of reactivation.

Background

The antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major malformations.

Methods

We conducted a nationwide cohort study including all women in Denmark with a known conception between 1997 and 2007. The Fertility Database was used to identify all women giving birth and the National Hospital Register was used to identify all women with a record of miscarriage or induced abortion. Prescription data was obtained from the National Prescription Register. The primary outcome was the number of miscarriages and offspring with major congenital malformations among users of clarithromycin compared to non-users.

Results

We identified 931 504 pregnancies (705 837 live births, 77 553 miscarriages, and 148 114 induced abortions). 401 women redeemed a prescription of clarithromycin in the first trimester of which 40 (10.0%) experienced a miscarriage and among the live born nine (3.6%) had offspring with malformations. The hazard ratio (HR) of having a miscarriage after exposure to clarithromycin was 1.56 (CI95% 1.14–2.13). There was no increased hazard of having a miscarriage when being exposed to penicillin or erythromycin. There was no increased prevalence (OR = 1.03 (CI95% 0.52–2.00)) of having offspring with malformations after exposure to clarithromycin.

Conclusions

We found an increased hazard of miscarriage but no increased prevalance of having offspring with malformations among women redeeming a prescription of clarithromycin in early pregnancy. This is supported by previous studies in animals and humans. However, further research is required to explore the possible effect of treatment indication on the associations found.

In spite of the fact that they occur at high rates, the clinical responses of BRAFV600 mutant metastatic melanoma to BRAF inhibitors are usually short-lasting, with most cases progressing within less than 8 mo. Immunomodulatory strategies initiated after progression have recently been reported to be poorly efficient. By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system, we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer, which represents one of the most promising approaches currently in clinical development for the treatment of metastatic melanoma. Here we show that blocking the BRAF-MAPK pathway in BRAF signaling-addicted melanoma cells significantly increases the ability of T cells contained in clinical grade tumor-infiltrating lymphocytes to recognize autologous BRAFV600 mutant melanoma cell lines in vitro. Antitumor reactivity was improved regardless of the class of antigen recognized by tumor-specific CD8+ T cells. Microarray data suggests that improved tumor recognition is associated with modified expression of MHC Class I-associated proteins as well as of heat-shock proteins. In conclusion, our preclinical data suggest that an appropriately timed sequential treatment of BRAFV600 mutant melanoma with vemurafenib and adoptive T-cell transfer might result in synergistic antineoplastic effects owing to an increased immunogenicity of cancer cells.

Background/Purpose:

While elastic resistance training, targeting the upper body is effective for strength training, the effect of elastic resistance training on lower body muscle activity remains questionable. The purpose of this study was to evaluate the EMG‐angle relationship of the quadriceps muscle during 10‐RM knee‐extensions performed with elastic tubing and an isotonic strength training machine.

Methods:

7 women and 9 men aged 28‐67 years (mean age 44 and 41 years, respectively) participated. Electromyographic (EMG) activity was recorded in 10 muscles during the concentric and eccentric contraction phase of a knee extension exercise performed with elastic tubing and in training machine and normalized to maximal voluntary isometric contraction (MVC) EMG (nEMG). Knee joint angle was measured during the exercises using electronic inclinometers (range of motion 0‐90°).

Results:

When comparing the machine and elastic resistance exercises there were no significant differences in peak EMG of the rectus femoris (RF), vastus lateralis (VL), vastus medialis (VM) during the concentric contraction phase. However, during the eccentric phase, peak EMG was significantly higher (p<0.01) in RF and VM when performing knee extensions using the training machine. In VL and VM the EMG‐angle pattern was different between the two training modalities (significant angle by exercise interaction). When using elastic resistance, the EMG‐angle pattern peaked towards full knee extension (0°), whereas angle at peak EMG occurred closer to knee flexion position (90°) during the machine exercise. Perceived loading (Borg CR10) was similar during knee extensions performed with elastic tubing (5.7±0.6) compared with knee extensions performed in training machine (5.9±0.5).

Conclusion:

Knee extensions performed with elastic tubing induces similar high (>70% nEMG) quadriceps muscle activity during the concentric contraction phase, but slightly lower during the eccentric contraction phase, as knee extensions performed using an isotonic training machine. During the concentric contraction phase the two different conditions displayed reciprocal EMG‐angle patterns during the range of motion.

Level of Evidence:

5

Background

Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.

Methods

This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day.

Results

Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission.

Conclusion

Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

Background:

Swiss ball training is recommended as a low intensity modality to improve joint position, posture, balance, and neural feedback. However, proper training intensity is difficult to obtain during Swiss ball exercises whereas strengthening exercises on machines usually are performed to induce high level of muscle activation.

Purpose:

To compare muscle activation as measured by electromyography (EMG) of global core and thigh muscles during abdominal crunches performed on Swiss ball with elastic resistance or on an isotonic training machine when normalized for training intensity.

Methods:

42 untrained individuals (18 men and 24 women) aged 28–67 years participated in the study. EMG activity was measured in 13 muscles during 3 repetitions with a 10 RM load during both abdominal crunches on training ball with elastic resistance and in the same movement utilizing a training machine (seated crunch, Technogym, Cesena, Italy). The order of performance of the exercises was randomized, and EMG amplitude was normalized to maximum voluntary isometric contraction (MVIC) EMG.

Results:

When comparing between muscles, normalized EMG was highest in the rectus abdominis (P<0.01) and the external obliques (P<0.01). However, crunches on Swiss ball with elastic resistance showed higher activity of the rectus abdominis than crunches performed on the machine (104±3.8 vs 84±3.8% nEMG respectively, P<0.0001). By contrast, crunches performed on Swiss ball induced lower activity of the rectus femoris than crunches in training machine (27±3.7 vs 65±3.8% nEMG respectively, P<0.0001) Further, gender, age and musculoskeletal pain did not significantly influence the findings.

Conclusion:

Crunches on a Swiss ball with added elastic resistance induces high rectus abdominis activity accompanied by low hip flexor activity which could be beneficial for individuals with low back pain. In opposition, the lower rectus abdominis activity and higher rectus femoris activity observed in machine warrant caution for individuals with lumbar pain. Importantly, both men and women, younger and elderly, and individuals with and without pain benefitted equally from the exercises.

Objectives

To investigate the relationship between different indicators of socioeconomic position and the risk of spontaneous abortion.

Design

Cohort study.

Setting

1996–2002, Denmark.

Participants

All first time participants, a total of 89 829 pregnant women, enrolled in the Danish National Birth Cohort were included in the present study. Overall, 4062 pregnancies ended in spontaneous abortion. Information on education, income and labour market attachment in the year before pregnancy was drawn from national registers.

Main outcome measure

Spontaneous abortion, that is, fetal death within the first 22 weeks of pregnancy, was the outcome of interest. The authors estimated HRs of spontaneous abortion using Cox regression analysis with gestational age as the underlying time scale.

Results

Women with <10 years of education had an elevated risk of spontaneous abortion when compared with women with >12 years of education (HR 1.19 (95% CI 1.05 to 1.34)). The HR estimates for the four lowest income quintiles were all increased (HRs between 1.09 and 1.15) as compared with the upper quintile but did not differ considerably from each other. In general, no statistically significant association was found between labour market attachment and the risk of spontaneous abortion; however, the group of women on disability pension had an increased HR of spontaneous abortion when compared with women who were employed (HR 1.32 (95% CI 0.82 to 2.13)).

Conclusions

Educational level and income were inversely associated with the risk of spontaneous abortion. As these factors most likely are non-causally related to spontaneous abortion, the findings indicate that factors related to social position, probably of the environmental and behavioural type, may affect spontaneous abortion risk. The study highlights the need for studies addressing such exposures in order to prevent spontaneous abortions.

Article summary

Article focus

The focus of the study was to investigate the relationship between different indicators of socioeconomic position and the risk of spontaneous abortion, with the prospect of examining whether a proportion of spontaneous abortions are preventable.

Key messages

Women of lower educational status have an elevated risk of spontaneous abortion, and women in the highest income quintile have lower risk of spontaneous abortion than those in the lower quintiles.

The socially patterned risk indicates that a proportion of spontaneous abortions may be preventable and that factors related to social position, probably of the environmental and behavioural type, may affect spontaneous abortion risk.

Strengths and limitations of this study

The present study is based upon a large population and a considerable number of spontaneous abortions, which offers a good foundation to examine the association between different indicators of socioeconomic position and spontaneous abortion.

The study design is prospective and therefore the decision whether to participate or not does not depend upon the outcome of the pregnancy.

To study spontaneous abortion is difficult since a great part of spontaneous abortions happen very early in the pregnancy period—many even before the women themselves know that they are pregnant—which is why we are restricted from being able to conclude anything about the association between socioeconomic position and the very early spontaneous abortions.

Background

Human migration caused by political unrest, wars and poverty is a major topic in international health. Infectious diseases like tuberculosis follow their host, with potential impact on both the migrants and the population in the recipient countries. In this study, we evaluate Mycobacterium tuberculosis transmission between the national population and migrants in Denmark.

Methods

Register study based on IS6110-RFLP results from nationwide genotyping of tuberculosis cases during 1992 through 2004. Cases with 100% identical genotypes were defined as clustered and part of a transmission chain. Origin of clusters involving both Danes and migrants was defined as Danish/migrant/uncertain. Subsequently, the proportion of cases likely infected by the "opposite" ethnic group was estimated.

Results

4,631 cases were included, representing 99% of culture confirmed cases during 1992 through 2004. Migrants contributed 61.6% of cases. Up to 7.9% (95% CI 7.0-8.9) of migrants were infected by Danes. The corresponding figure was 5.8% (95% CI 4.8-7.0) for Danes. Thus, transmission from Danes to migrants occurred up to 2.5 (95% CI 1.8-3.5) times more frequent than vice versa (OR = 1). A dominant strain, Cluster-2, was almost exclusively found in Danes, particular younger-middle-aged males.

Conclusions

Transmission between Danes and migrants is limited, and risk of being infected by the "opposite" ethnic group is highest for migrants. TB-control efforts should focus on continues micro-epidemics, e.g. with Cluster-2 in Danes, prevention of reactivation TB in high-risk migrants, and outbreaks in socially marginalized migrants, such as Somalis and Greenlanders. Fears that TB in migrants poses a threat for resident Danes seem exaggerated and unjustified. We believe this to be true for other low incidence countries as well.

Background:

A positive association between socio-economic position and breast cancer has been widely observed, but not hitherto within twin pairs, where shared familial factors were adjusted for.

Methods:

We used data on education and other factors from the Danish Twin Registry, The Danish Cancer Registry, and official registers on a total of 16 310 twins. Unpaired and intrapair Cox regression analyses were compared.

Results:

In the unpaired analysis, an educational gradient in breast cancer risk was found. Similar results were seen in the intrapair analyses of all twins, although no longer statistically significant. When intrapair analyses were stratified on zygosity, the effect of education was attenuated in the monozygotic twins.

Conclusion:

The main findings support an effect of education beyond shared familial factors.

Introduction

Telomere shortening is associated with a number of common age-related diseases. A role of telomere shortening in osteoarthritis (OA) has been suggested, mainly based on the assessment of mean telomere length in ex vivo expanded chondrocytes. We addressed this role directly in vivo by using a newly developed assay, which measures specifically the load of ultra-short single telomeres (below 1,500 base pairs), that is, the telomere subpopulation believed to promote cellular senescence.

Methods

Samples were obtained from human OA knees at two distances from the central lesion site. Each sample was split into three: one was used for quantification of ultra-short single telomeres through the Universal single telomere length assay (STELA), one for histological Mankin grading of OA, and one for mean telomere length measurement through quantitative fluorescence in situ hybridization (Q-FISH) as well as for assessment of senescence through quantification of senescence-associated heterochromatin foci (SAHF).

Results

The load of ultra-short telomeres as well as mean telomere length was significantly associated with proximity to lesions, OA severity, and senescence level. The degree of significance was higher when assessed through load of ultra-short telomeres per cell compared with mean telomere length.

Conclusions

These in vivo data, especially the quantification of ultra-short telomeres, stress a role of telomere shortening in human OA.

Objectives

Greenland reports the highest rates of chlamydial infection and gonorrhea in the Arctic. Our objective was to determine the presence, and describe the basic epidemiology, of Mycoplasma genitalium for Greenland.

Study design

Cross-sectional study.

Methods

314 residents from Nuuk and Sisimiut, between the ages of 15 and 65 years, participated in “Inuulluataarneq” (the Greenland Sexual Health Project) between July 2008 and November 2009. Participants provided self-collected samples for sexually transmitted infection (STI) testing and completed a sexual health survey. Descriptive statistics and logistic regression were used to summarize the basic characteristics of STI cases overall and M. genitalium and Chlamydia trachomatis specifically. Clinically relevant characteristics in each full model were gender (male or female), age (in years), age at sexual debut (in years), number of sexual partners in the past 3 months (continuous) and history of forced sex and community.

Results

The overall prevalence of STIs was 19.0%, specifically: 9.8% for M. genitalium and 9.4% for C. trachomatis; 100% of M. genitalium-positive cases carried macrolide resistance determinants. Being female [OR =3.2; 95% confidence interval (CI): 1.1–9.8] and younger age (OR=0.9; 95% CI: 0.9–1.0) were associated with M. genitalium positivity. Age was also associated with C. trachomatis (OR=0.9; 95% CI: 0.8–0.9) and STI positivity overall (OR=0.9; 95% CI: 0.9–0.9).

Conclusions

We observed a high prevalence of M. genitalium and macrolide resistance in this study. A better understanding of M. genitalium sequelae is needed to inform policy around testing, treatment, control and antibiotic use.

Older people are at increased risk of non-union after spinal fusion, but little is known about the factors determining the quality of the fusion mass in this patient group. The aim of this study was to investigate fusion mass bone quality after uninstrumented spinal fusion and to evaluate if it could be improved by additional direct current (DC) electrical stimulation. A multicenter RCT compared 40 and 100 μA DC stimulation with a control group of uninstrumented posterolateral fusion in patients older than 60 years. This report comprised 80 patients who underwent DEXA scanning at the 1 year follow-up. The study population consisted of 29 men with a mean age of 72 years (range 62–85) and 51 women with a mean age of 72 years (range 61–84). All patients underwent DEXA scanning of their fusion mass. Fusion rate was assessed at the 2 year follow-up using thin slice CT scanning. DC electrical stimulation did not improve fusion mass bone quality. Smokers had lower fusion mass BMD (0.447 g/cm2) compared to non-smokers (0.517 g/cm2) (P = 0.086). Women had lower fusion mass BMD (0.460 g/cm2) compared to men (0.552 g/cm2) (P = 0.057). Using linear regression, fusion mass bone quality, measured as BMD, was significantly influenced by gender, age of the patient, bone density of the remaining part of the lumbar spine, amount of bone graft applied and smoking. Fusion rates in this cohort was 34% in the control group and 33 and 43% in the 40 and 100 μA groups, respectively (not significant). Patients classified as fused after 2 years had significant higher fusion mass BMD at 1 year (0.592 vs. 0.466 g/cm2, P = 0.0001). Fusion mass bone quality in older patients depends on several factors. Special attention should be given to women with manifest or borderline osteoporosis. Furthermore, bone graft materials with inductive potential might be considered for this patient population.

Background

With high short-term mortality and substantial excess morbidity among survivors, tuberculous meningitis (TBM) is the most severe manifestation of extra-pulmonary tuberculosis (TB). The objective of this study was to assess the long-term mortality and causes of death in a TBM patient population compared to the background population.

Methods

A nationwide cohort study was conducted enrolling patients notified with TBM in Denmark from 1972–2008 and alive one year after TBM diagnosis. Data was extracted from national registries. From the background population we identified a control cohort of individuals matched on gender and date of birth. Kaplan-Meier survival curves and Cox regression analysis were used to estimate mortality rate ratios (MRR) and analyse causes of death.

Findings

A total of 55 TBM patients and 550 individuals from the background population were included in the study. Eighteen patients (32.7%) and 107 population controls (19.5%) died during the observation period. The overall MRR was 1.79 (95%CI: 1.09–2.95) for TBM patients compared to the population control cohort. TBM patients in the age group 31–60 years at time of diagnosis had the highest relative risk of death (MRR 2.68; 95%CI 1.34–5.34). The TBM patients had a higher risk of death due to infectious disease, but not from other causes of death.

Conclusion

Adult TBM patients have an almost two-fold increased long-term mortality and the excess mortality stems from infectious disease related causes of death.

Background

Although leisure-time physical activity is important for health, adherence to regular exercise is challenging for many adults. The workplace may provide an optimal setting to reach a large proportion of the adult population needing regular physical exercise. This study evaluates the effect of implementing strength training at the workplace on non-specific neck and shoulder pain among industrial workers.

Methods

Cluster-randomized controlled trial involving 537 adults from occupations with high prevalence of neck and shoulder pain (industrial production units). Participants were randomized to 20 weeks of high-intensity strength training for the neck and shoulders three times a week (n = 282) or a control group receiving advice to stay physically active (n = 255). The strength training program followed principles of progressive overload and periodization. The primary outcome was changes in self-reported neck and shoulder pain intensity (scale 0-9).

Results

85% of the participants followed the strength training program on a weekly basis. In the training group compared with the control group, neck pain intensity decreased significantly (-0.6, 95% CI -1.0 to -0.1) and shoulder pain intensity tended to decrease (-0.2, 95% CI -0.5 to 0.1, P = 0.07). For pain-cases at baseline (pain intensity > = 3) the odds ratio - in the training group compared with the control group - for being a non-case at follow-up (pain intensity < 3) was 2.0 (95% CI 1.0 to 4.2) for the neck and 3.9 (95% CI 1.7 to 9.4) for the shoulders.

Conclusion

High-intensity strength training relying on principles of progressive overload can be successfully implemented at industrial workplaces, and results in significant reductions of neck and shoulder pain.

Trial registration

NCT01071980.

Background

In Plasmodium falciparum malaria endemic areas placental malaria (PM) is an important complication of malaria. The recurrence of malaria in primigravidae women irrespective of acquired protection during childhood is caused by the interaction between the parasite-expressed VAR2CSA antigen and chondroitin sulfate A (CSA) in the placental intervillous space and lack of protective antibodies. PM impairs fetal development mainly by excessive inflammation processes. After infections during pregnancy women acquire immunity to PM conferred by antibodies against VAR2CSA. Ideally, a vaccine against PM will induce antibody-mediated immune responses that block the adhesion of infected erythrocytes (IE) in the placenta.

Principal Findings

We have previously shown that antibodies raised in rat against individual domains of VAR2CSA can block IE binding to CSA. In this study we have immunized mice, rats and rabbits with each individual domain and the full-length protein corresponding to the FCR3 VAR2CSA variant. We found there is an inherently higher immunogenicity of C-terminal domains compared to N-terminally located domains. This was irrespective of whether antibodies were induced against single domains or the full-length protein. Species-specific antibody responses were also found, these were mainly directed against single domains and not the full-length VAR2CSA protein.

Conclusions/Significance

Binding inhibitory antibodies appeared to be against conformational B-cell epitopes. Non-binding inhibitory antibodies reacted highly against the C-terminal end of the VAR2CSA molecule especially the highly polymorphic DBL6ε domain. Differential species-specific induction of antibody responses may allow for more direct analysis of functional versus non-functional B-cell epitopes.

Background

Tuberculous meningitis is the most severe manifestation of extrapulmonary tuberculosis with a high mortality rate and a high rate of sequelae among survivors. The aim of this study is to assess the current epidemiology, clinical features, diagnostic procedures, treatment and outcome in patients with tuberculous meningitis in Denmark, a country with a low tuberculosis incidence.

Methods

A nationwide retrospective study was conducted, comprising all patients notified with tuberculous meningitis (TBM) in Denmark from 2000-2008. Medical records were reviewed using a standardised protocol.

Results

Fifty patients, including 12 paediatric patients, were identified. 78% of the patients were immigrants from countries of high tuberculosis endemicity. 64% of all patients had a pre-existing immunosuppressive condition; 10% were HIV positive, 48% were HIV seronegative and 42% had an unknown HIV status. Median symptom duration before admission was 14 days in the Danish patient population and 20 days in the immigrant group. Biochemical analysis of cerebrospinal fluid (CSF) samples revealed pleocytosis in 90% with lymphocyte predominance in 66%. Protein levels were elevated in 86%. The most common findings on neuro-radiological imaging were basal meningeal enhancement, tuberculomas and hydrocephalus. Lumbar puncture was performed on 42 patients; 31 of these specimens (74%) had a positive CSF culture for mycobacteria and 9.5% were smear positive for acid-fast bacilli. The overall mortality rate was 19% and 48% of the remaining patients had neurological sequelae of varying degree.

Conclusion

TBM is a rare but severe manifestation of extrapulmonary TB in Denmark. The clinician must be prepared to treat empirically if the suspicion of TBM has arisen to improve treatment outcome.

Background

Neck and shoulder complaints are common among employees in sedentary occupations characterized by intensive computer use. Such musculoskeletal pain - which is often associated with restricted range of motion and loss of muscle strength - is one of the most common conditions treated by physical therapists. The exact mechanism of neck pain is rarely revealed by clinical examination and the treatment has varied from passive rest to active treatments. Active treatments have often been divided into either training of the painful area or the surrounding musculature avoiding direct training of the painful area. Our study investigates the effect of the latter approach.

Methods/Design

A randomized controlled trial of 10 weeks duration is currently being conducted. Employed office workers with severe neck-shoulder pain are randomized to 3 × 20 min shoulder function training with training supervision or to a reference group receiving advice to stay physically active. Shoulder function training primarily focuses on the serratus anterior and lower trapezius muscle with only minimal activation the upper trapezius.

An announcement was sent to the administrative section of the university including jobs characterized by intensive computer work. The first 100 positive replies entered the study. Among these inclusion criteria were pain intensity in the neck/shoulder of at least 3 on a 0-9 scale. Exclusion criteria were cardiovascular disease, trauma, hypertension, or serious chronic disease. Before and after the intervention period the participants replied to a questionnaire about musculoskeletal disorders and work disability, and underwent a standardized clinical examination of the neck and shoulder girdle. Further, on a weekly basis the participants log pain intensity of the neck and shoulder during the previous week.

The primary outcome measure is pain in the neck and shoulders at week 10 based on the weekly pain registration and results from the clinical examination. Secondary outcomes are strength and work disability.

Trial Registration

ClinicalTrials (NCT): NCT01205542

With the aim to identify cyclin B1-derived peptides with high affinity for HLA-A2, we used three in silico prediction algorithms to screen the protein sequence for possible HLA-A2 binders. One peptide scored highest in all three algorithms, and the high HLA-A2-binding affinity of this peptide was verified in an HLA stabilization assay. By stimulation with peptide-loaded dendritic cells a CTL clone was established, which was able to kill two breast cancer cell lines in an HLA-A2-dependent and peptide-specific manner, demonstrating presentation of the peptide on the surface of cancer cells. Furthermore, blood from cancer patients and healthy donors was screened for spontaneous T-cell reactivity against the peptide in IFN-γ ELISPOT assays. Patients with breast cancer, malignant melanoma, or renal cell carcinoma hosted powerful and high-frequency T-cell responses against the peptide. In addition, when blood from healthy donors was tested, similar responses were observed. Ultimately, serum from cancer patients and healthy donors was analyzed for anti-cyclin B1 antibodies. Humoral responses against cyclin B1 were frequently detected in both cancer patients and healthy donors. In conclusion, a high-affinity cyclin B1-derived HLA-A2-restricted CTL epitope was identified, which was presented on the cell surface of cancer cells, and elicited spontaneous T-cell responses in cancer patients and healthy donors.

Background

Neck and shoulder complaints are common among employees in sedentary occupations characterized by intensive computer use. Specific strength training is a promising type of physical exercise for relieving neck and shoulder pain in office workers. However, the optimal combination of frequency and exercise duration, as well as the importance of exercise supervision, is unknown. The VIMS study investigates in a cluster randomized controlled design the effectiveness of different time wise combinations of specific strength training with identical accumulated volume, and the relevance of training supervision for safe and effective training.

Methods/design

A cluster randomized controlled trial of 20 weeks duration where employed office workers are randomized to 1 × 60 min, 3 × 20 min, 9 × 7 min per week of specific strength training with training supervision, to 3 × 20 min per week of specific strength training with a minimal amount of training supervision, or to a reference group without training. A questionnaire will be sent to 2000 employees in jobs characterized by intensive computer work. Employees with cardiovascular disease, trauma, hypertension, or serious chronic disease will be excluded. The main outcome measure is pain in the neck and shoulders at week 20.

Trial Registration

The trial is registered at ClinicalTrials.gov, number NCT01027390.

Background

Tuberculin is still the only available skin test reagent for the diagnosis of mycobacterial infection. The product has a remarkable sensitivity, but poor specificity. Previous studies, including two human phase I clinical trials, have indicated that rdESAT-6 has a potential as an improved skin test reagent. Animal studies have shown that the sensitivity may be increased by inclusion of the genetically related CFP-10 antigen in the preparation without loosing specificity.

Methodology

In this study a Lactococcus fermented, recombinant skin test reagent consisting of a 1∶1 wt/wt of rdESAT-6 and CFP-10 was manufactured according to GMP standards and tested for the first time in 42 healthy adult volunteers. The two doses of 0.01 µg or 0.1 µg were injected intradermally by the Mantoux technique with 6 or 12 weeks interval. No serious adverse events and only mild adverse reactions were reported. The reagent elicited a positive skin test reaction after the first injection in one participant, who most likely was latently infected with M. tuberculosis as indicated by an appreciable IFN γ response just below the Quantiferon® cut-off level at the screening visit. None of the remaining participants in the four groups had any skin test reactions and sensitisation by the reagent could therefore be excluded.

Conclusion

The investigational skin test reagent rdESAT-6 and CFP-10 appeared safe and non-sensitising in this first-in-man clinical trial in human volunteers and can now be tested in larger clinical trials involving individuals with latent M. tuberculosis infection or active TB disease.

Trial Registration

ClinicalTrials.gov NCT00793702

To disentangle an independent effect of educational status on mortality risk from direct and indirect selection mechanisms, the authors used a discordant twin pair design, which allowed them to isolate the effect of education by means of adjustment for genetic and environmental confounding per design. The study is based on data from the Danish Twin Registry and Statistics Denmark. Using Cox regression, they estimated hazard ratios for mortality according to the highest attained education among 5,260 monozygotic and 11,088 dizygotic same-sex twin pairs born during 1921–1950 and followed during 1980–2008. Both standard cohort and intrapair analyses were conducted separately for zygosity, gender, and birth cohort. Educational differences in mortality were demonstrated in the standard cohort analyses but attenuated in the intrapair analyses in all subgroups but men born during 1921–1935, and no effect modification by zygosity was observed. Hence, the results are most compatible with an effect of early family environment in explaining the educational inequality in mortality. However, large educational differences were still reflected in mortality risk differences within twin pairs, thus supporting some degree of independent effect of education. In addition, the effect of education may be more pronounced in older cohorts of Danish men.

Hydroxyurea (HU) is a well tolerated ribonucleotide reductase inhibitor effective in HIV, sickle cell disease, and blood cancer therapy. Despite a positive initial response, however, most treated cancers eventually progress due to development of HU resistance. Although RNR properties influence HU resistance in cell lines, the mechanisms underlying cancer HU resistance in vivo remain unclear. To address this issue, we screened for HU resistance in the plant Arabidopsis thaliana and identified seventeen unique catalase mutants, thereby establishing that HU toxicity depends on catalase in vivo. We further demonstrated that catalase is a direct HU target by showing that HU acts as a competitive inhibitor of catalase-mediated hydrogen peroxide decomposition. Considering also that catalase can accelerate HU decomposition in vitro and that co-treatment with another catalase inhibitor alleviates HU effects in vivo, our findings suggests that HU could act as a catalase-activated pro-drug. Clinically, we found high catalase activity in circulating cells from untreated chronic myeloid leukemia, offering a possible explanation for the efficacy of HU against this malignancy.