The association of vitamin K status with lung function and disease in a general population.

Introduction: Matrix Gla protein (MGP) is an inhibitor of lung tissue calcification. The plasma level of dephosphorylated-uncarboxylated MGP (dp-ucMGP) is a biomarker of vitamin K status. The present study assessed whether lower vitamin K status (reflected by higher dp-ucMGP) was associated with lung function and lung disease/symptoms. Methods: A general population sample of 4092 individuals, aged 24 to 77 years, underwent a health examination including questionnaires, spirometry and measurements of plasma dp-ucMGP. Associations of dp-ucMGP with lung function and self-reported disease/symptoms were estimated using regression models adjusted for age, sex and height. Associations were expressed as ß-estimates or odds ratios (ORs) per doubling in dp-ucMGP. Results: Lower vitamin K status (higher dp-ucMGP) was associated with lower forced expiratory volume in 1 s (FEV1) (98 mL; 95% CI: 54-141 mL) and lower forced vital capacity (FVC) (136 mL; 95% CI: 85-187 mL). Dp-ucMGP was not associated with the FEV1/FVC ratio (0.0 percentage points higher than the expected value; 95% CI: -1.0-1.0). Furthermore, lower vitamin K status was associated with COPD (OR 2.24, 95% CI: 1.53-3.27), wheezing (OR 1.81, 95% CI: 1.44-2.28) and asthma (OR 1.44, 95% CI: 1.12-1.83). Conclusion: Lower vitamin K status was associated with lower ventilatory capacity (lower FEV1 and FVC), and with higher risk of self-reported asthma, COPD and wheezing. Vitamin K status was not associated with airflow obstruction (FEV1/FVC ratio).

Prevalence, predictors, and clinical relevance of α-gal sensitization in patients with chronic urticaria.

BACKGROUND: Little is known about α-gal (galactose-α-1,3-galactose) sensitization in patients with chronic urticaria (CU). The aim of this study was to examine the prevalence, predictors and clinical relevance of α-gal sensitization in patients with CU. METHODS: Two consecutive cohorts of newly referred patients with CU from a primary care allergology practice and a tertiary hospital dermatology department, plus a control group with allergic disease, but not CU, from the allergology practice, were interviewed and screened for α-gal sensitization (serum specific-IgE ≥0.35 KU/L). RESULTS: Of 733 patients included, 21 (5.6%) and 11 (3.9%) of CU patients from private practice and hospital, respectively, were α-gal sensitized. In total, 8 patients (38.1% of sensitized patients, and 2.1% of all CU patients) from private practice, and 2 patients (18.2% of sensitized patients, and 0.7% of all CU patients) from hospital, had clinically relevant α-gal allergy. In private practice, male sex (47.6 vs. 24.7%), p = 0.020, obesity (33.3 vs. 23.6%), p = 0.302, and frequency of angioedema (61.9 vs. 51.4%), p = 0.350; and in hospital, male sex (72.7 vs. 27.9%), p = 0.003, and high total immunoglobulin E (median 168 vs. 70.5 KU/L), p = 0.022 were associated with α-gal sensitization. CONCLUSION: α-gal sensitization is observed in a small fraction of CU patients with only few patients experiencing clinically relevant sensitization. Certain patients, particularly from primary care, may constitute a relevant population for aimed testing.

Can we identify allergic rhinitis from administrative data: A validation study.

BACKGROUND: Important insights on, for example, prevalence, disease progression, and treatment of allergic rhinitis can be obtained from large-scale database studies if researchers are able to identify allergic individuals. We aimed to assess the validity of 13 different algorithms based on Danish nationwide prescription and/or hospital data to identify adults with allergic rhinitis. METHODS: Our primary gold standard of allergic rhinitis was a positive serum specific IgE (≥0.35) and self-reported nasal symptoms retrieved from two general health examination studies conducted in Danish adults (18-69 years) during 2006 to 2008 (n = 3416) and 2012 to 2015 (n = 7237). The secondary gold standard of allergic rhinitis was self-reported physician diagnosis. We calculated sensitivity, specificity, positive predictive value (PPV), negative predictive value, and corresponding 95% confidence intervals (95% CI) for each register-based algorithm in the two time periods. RESULTS: Sensitivity (≤0.40) was low for all algorithms irrespective of definition of allergic rhinitis (gold standard) or time period. The highest PPVs were obtained for algorithms requiring both antihistamines and intranasal corticosteroids; yielding a PPV of 0.69 (0.62-0.75) and a corresponding sensitivity of 0.10 (0.09-0.12) for the primary gold standard of allergic rhinitis in 2012 to 2015. CONCLUSION: Algorithms based on both antihistamines and intranasal corticosteroids yielded the highest PPVs. However, the PPVs were still moderate and came at the expense of low sensitivity when applying the strict primary gold standard (sIgE and nasal symptom).

Reference equations for pulmonary diffusing capacity of carbon monoxide and nitric oxide in adult Caucasians.

The aim of this study was to determine reference equations for the combined measurement of diffusing capacity of the lung for carbon monoxide (CO) and nitric oxide (NO) (DLCONO). In addition, we wanted to appeal for consensus regarding methodology of the measurement including calculation of diffusing capacity of the alveolo-capillary membrane (Dm) and pulmonary capillary volume (Vc).DLCONO was measured in 282 healthy individuals aged 18-97 years using the single-breath technique and a breath-hold time of 5 s (true apnoea period). The following values were used: 1) specific conductance of nitric oxide (θNO)=4.5 mLNO·mLblood-1·min-1·mmHg-1; 2) ratio of diffusing capacity of the membrane for NO and CO (DmNO/DmCO)=1.97; and 3) 1/red cell CO conductance (1/θCO)=(1.30+0.0041·mean capillary oxygen pressure)·(14.6/Hb concentration in g·dL-1).Reference equations were established for the outcomes of DLCONO, including DLCO and DLNO and the calculated values Dm and Vc Independent variables were age, sex, height and age squared.By providing new reference equations and by appealing for consensus regarding the methodology, we hope to provide a basis for future studies and clinical use of this novel and interesting method.

Verbal learning and memory outcome in selective amygdalohippocampectomy versus temporal lobe resection in patients with hippocampal sclerosis.

PURPOSE: With the advent of new very selective techniques like thermal laser ablation to treat drug-resistant focal epilepsy, the controversy of resection size in relation to seizure outcome versus cognitive deficits has gained new relevance. The purpose of this study was to test the influence of the selective amygdalohippocampectomy (SAH) versus nonselective temporal lobe resection (TLR) on seizure outcome and cognition in patients with mesial temporal lobe epilepsy (MTLE) and histopathological verified hippocampal sclerosis (HS). METHODS: We identified 108 adults (>16years) with HS, operated between 1995 and 2009 in Denmark. Exclusion criteria are the following: Intelligence below normal range, right hemisphere dominance, other native languages than Danish, dual pathology, and missing follow-up data. Thus, 56 patients were analyzed. The patients were allocated to SAH (n=22) or TLR (n=34) based on intraoperative electrocorticography. Verbal learning and verbal memory were tested pre- and postsurgery. RESULTS: Seizure outcome did not differ between patients operated using the SAH versus the TLR at 1year (p=0.951) nor at 7years (p=0.177). Verbal learning was more affected in patients resected in the left hemisphere than in the right (p=0.002). In patients with left-sided TLR, a worsening in verbal memory performance was found (p=0.011). Altogether, 73% were seizure-free for 1year and 64% for 7years after surgery. CONCLUSION: In patients with drug-resistant focal MTLE, HS and no magnetic resonance imaging (MRI) signs of dual pathology, selective amygdalohippocampectomy results in sustained seizure freedom and better memory function compared with patients operated with nonselective temporal lobe resection.

[Idiopathic oedema].

Idiopathic oedema is a non-inflammatory interstitial oedema seen in fertile women. A hallmark is a daily increase in weight > 1.4 kg from morning until evening due to fluid retention, which shows as facial puffiness in the morning and more often abdominal increase and swollen lower extremities during the day. Patients may be disabled due to accompanying symptoms like headache, dizziness, fatigue, anxiety, and depression. The diagnosis is based on clinical features and exclusion of other causes of oedema. Non-pharmacological interventions and pharmacological therapies are reviewed.

Pharmacodynamics of remifentanil. Induced intracranial spike activity in mesial temporal lobe epilepsy.

Patients with medically refractory epilepsy may benefit from resective epilepsy surgery. However even the best centers experience surgical failures. It is therefore important to find techniques that may aid in neurosurgical planning of epileptic focus resection. Recordings of electrical brain activity with EEG during seizures reveal abnormal cortical hypersynchronization. Between seizures the EEG often shows interictal depolarizing phenomena such as spikes reflecting an irritable focus of the brain. In the present study we investigated the effect of intravenous remifentanil on the spike activity in the temporal neocortex and hippocampus. We examined 65 patients with mesial temporal lobe epilepsy during surgery, prior to resection. We used a 20-lead grid on the cortex and a 4-lead strip in the lateral ventricle on the hippocampus. At least two 3-min periods of ECoG were recorded - before and after remifentanil injection. In a number of patients we examined the effect of repeated injections in order to estimate the dose-response curve. We describe a significant effect of remifentanil on the average spike activity with an increment from 16 spikes per minute at baseline to 36 spikes per minute after remifentanil injection (p<0.0001). The increase in spike activity was typically seen after 40-50s. When mu-receptors were antagonized with a preceding injection of naloxone, spike activity increased 25% in response to remifentanil as opposed to 80% when remifentanil was preceded by placebo. In only seven out of 59 patients did the injection of remifentanil change the topographic location of the spike focus. Typically administration of remifentanil led to a focus of increased spike count. Activity in other areas was suppressed making the focus stand out from the background. Our observation that remifentanil potentiates spike activity is in agreement with previous findings from smaller studies. Furthermore, we were able to describe the pharmacodynamics of the remifentanil effect on spike activity. Peri-operative provocation with remifentanil may play a future role in guiding neurosurgical intervention during epilepsy resection surgery.

Danish experience with paediatric epilepsy surgery.

INTRODUCTION: Epilepsy surgery is increasingly used to treat children with medically intractable epilepsy. This study investigates the aetiology and seizure outcome in Danish children operated between 1996 and 2010. METHODS: Retrospectively collected data on structural magnetic resonance imaging (MRI) diagnoses, surgical procedures and seizure outcomes classified according to the Engel Classification were used. Changes over time grouped as 1996-2000, 2001-2005 and 2006-2010 were analysed. RESULTS: A total of 95 children underwent epilepsy surgery. Sixty-three operations were performed in Denmark and 50 abroad. In all, 14 children needed reoperation. The median follow-up period was four years. At the latest follow-up, Engel class I (indicating no disabling seizures) was found in 67% of the patients. Cortical dysplasia, mesial temporal sclerosis and tumour were the most common MRI findings. The percentage of tumours operated decreased over time, and frontal lobe resections increased. In the 2006-2010 period, resections with normal MRI were performed, resulting in a less favourable Engel outcome. Persistent, unexpected complications were seen in three of 113 operations. CONCLUSIONS: The majority of children who undergo epilepsy surgery have a good, worthwhile seizure outcome. The seizure outcome for Danish children corresponds to that of other epilepsy surgery centres. The clinical criteria for selection of patients changed over time. FUNDING: none. TRIAL REGISTRATION: The Danish Data Protection Agency approved the project with record number: 2013-41-2459.

The longitudinal relationship of changes of adiposity to changes in pulmonary function and risk of asthma in a general adult population.

BACKGROUND: Adiposity has been linked to both higher risk of asthma and reduced lung function. The effects of adiposity on asthma may depend on both atopic status and gender, while the relationship is less clear with respect to lung function. This study aimed to explore longitudinal weight changes to changes in forced expiratory volume in first second (FEV1) and forced vital capacity (FVC), as well as to incident cases of asthma and wheezing, according to atopy and gender. METHODS: A general population sample aged 19-72 years was examined with the same methodology five years apart. Longitudinal changes in weight, body mass index, waist circumference, and fat percentage (bio-impedance) were analyzed with respect to changes of FEV1 and FVC (spirometry), and incidence of asthma and wheezing (questionnaire). Gender, atopy (serum specific IgE-positivity to inhalant allergens) and adipose tissue mass prior to adiposity changes were examined as potential effect modifiers. RESULTS: A total of 2,308 persons participated in both baseline and five-year follow-up examinations. Over the entire span of adiposity changes, adiposity gain was associated with decreasing levels of lung function, whereas adiposity loss was associated with increasing levels of lung function. All associations were dependent on gender (p-interactions < 0.0001). For one standard deviation weight gain or weight loss, FEV1 changed with (+/-)72 ml (66-78 ml) and FVC with (+/-)103 ml (94-112 ml) in males. In females FEV1 changed with (+/-) 27 ml (22-32 ml) and FVC with (+/-) 36 ml (28-44 ml). There were no changes in the FEV1/FVC-ratio. The effect of adiposity changes increased with the level of adipose tissue mass at the start of the study (baseline), thus, indicating an aggregate effect of the total adipose tissue mass. Atopy did not modify these associations. There were no statistically significant associations between changes in adiposity measures and risk of incident asthma or wheeze. CONCLUSIONS: Over a five-year period, increasing adiposity was associated with decreasing lung function, whereas decreasing adiposity was associated with increasing lung function. This effect was significantly greater in males than in females and increased with pre-existing adiposity, but was independent of atopy.

Aberrant expression of miR-218 and miR-204 in human mesial temporal lobe epilepsy and hippocampal sclerosis-convergence on axonal guidance.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis (HS), which is characterized by pronounced loss of hippocampal pyramidal neurons. microRNAs (miRNAs) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that miRNAs could be involved in the pathogenesis of MTLE and HS. METHODS: miRNA expression was quantified in hippocampal specimens from human patients using miRNA microarray and quantitative real-time polymerase chain reaction RT-PCR, and by RNA-seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of miRNAs in the human hippocampus. The potential effect of miRNAs on targets genes was investigated using the dual luciferase reporter gene assay. RESULTS: miRNA expression profiling showed that 25 miRNAs were up-regulated and 5 were down-regulated in hippocampus biopsies of MTLE/HS patients compared to controls. We showed that miR-204 and miR-218 were significantly down-regulated in MTLE and HS, and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR-204 and miR-218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO1, GRM1, SLC1A2, and GNAI2, as bona fide targets of miR-218. GRM1 was also shown to be a direct target of miR-204. SIGNIFICANCE: miR-204 and miR-218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS.

[Angioedema].

Angioedema may be an overlooked common disease. Angioedema comprises the idiopathic, the allergic, pseudo allergic, the physical form as well as the hereditary form. Diagnosis is simple when symptoms are classical (lips, eyes and tongue) but might be missed if symptoms are nonspecific such as dizziness or dyspnoea. However, the most striking observation reviewing the literature is the absence of original research on angioedema considering the high prevalence of the disease. From a patient and physician perspective more information and research on angioedema is needed.

High levels of bed occupancy associated with increased inpatient and thirty-day hospital mortality in Denmark.

High bed occupancy rates have been considered a matter of reduced patient comfort and privacy and an indicator of high productivity for hospitals. Hospitals with bed occupancy rates of above 85 percent are generally considered to have bed shortages. Little attention has been paid to the impact of these shortages on patients' outcomes. We analyzed all 2.65 million admissions to Danish hospitals' departments of medicine in the period 1995-2012. We found that high bed occupancy rates were associated with a significant 9 percent increase in rates of in-hospital mortality and thirty-day mortality, compared to low bed occupancy rates. Being admitted to a hospital outside of normal working hours or on a weekend or holiday was also significantly associated with increased mortality. The health risks of bed shortages, including mortality, could be better documented as a priority health issue. Resources should be allocated to researching the causes and effects of bed shortages, with the aim of creating greater interest in exploring new methods to avoid or reduce bed shortages.

A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia.

OBJECT: The authors' aim was to compare the subthalamic nucleus (STN) with the globus pallidus internus (GPi) as a stimulation target for deep brain stimulation (DBS) for medically refractory dystonia. METHODS: In a prospective double-blind crossover study, electrodes were bilaterally implanted in the STN and GPi of 12 patients with focal, multifocal, or generalized dystonia. Each patient was randomly selected to undergo initial bilateral stimulation of either the STN or the GPi for 6 months, followed by bilateral stimulation of the other nucleus for another 6 months. Preoperative and postoperative ratings were assessed by using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and video recordings. Quality of life was evaluated by using questionnaires (36-item Short Form Health Survey). Supplemental Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were assessed for patients with focal dystonia (torticollis) by examining the video recordings. RESULTS: On average for all patients, DBS improved the BFMDRS movement scores (p < 0.05) and quality of life physical scores (p < 0.01). After stimulation of the STN, the mean 6-month improvement in BFMDRS movement score was 13.8 points; after stimulation of the GPi, this improvement was 9.1 points (p = 0.08). Quality of life did not differ significantly regardless of which nucleus was stimulated. All 12 patients accepted 6 months of stimulation of the STN, but only 7 accepted 6 months of stimulation of the GPi. Among those who rejected stimulation of the GPi, 3 accepted concomitant stimulation of both the STN and GPi for 6 months, resulting in improved quality of life physical and mental scores and BFMDRS movement scores. Among the 4 patients who were rated according to TWSTRS, after 6 months of stimulation of both the STN and GPi, TWSTRS scores improved by 4.7% after stimulation of the GPi and 50.8% after stimulation of the STN (p = 0.08). CONCLUSIONS: The STN seems to be a well-accepted, safe, and promising stimulation target in the treatment of dystonia, but further studies are necessary before the optimal target can be concluded. Simultaneous stimulation of the STN and GPi should be further investigated. Clinical trial registration no.: KF 01-110/01 (Committees on Biomedical Research Ethics of the Capital Region of Denmark).

Validation of spirometer calibration syringes.

The volume calibration syringe is probably the single most important instrument in pulmonary function laboratories, yet no validation results have been published. In this study a sample of volume calibration syringes was validated. We weighed a 1-L and two 3-L calibration syringes before and after emptying them of water and determined the corresponding volume of gas by using a modified rolling seal spirometer. In this way we established an unbroken calibration chain between a certified weight of water and the corresponding volume of gas. The volume of a spirometer calibration syringe could be verified with an accuracy of ± 15 ml. The modified rolling seal spirometer had an accuracy of ± 11 ml at a volume of 1 L and ± 13 ml at a volume of 3 L. A sample of spirometer calibration syringes was validated and all syringes except for two small 1-liter syringes all had volumes within the label claimed volume ± 0.5%. Spirometer calibration syringes have a stable stroke volume even after many years of use and storage but have to be calibrated yearly to comply with international standard.

Allergen-specific immunotherapy and risk of autoimmune disease.

PURPOSE OF REVIEW: After 100 years of experience with allergen-specific immunotherapy (SIT), an issue that is still unresolved is whether SIT can act as a trigger of, or as a risk factor for, autoimmune disease. We searched the literature for evidence on this topic. RECENT FINDINGS: Several case reports of autoimmune disease development with plausible relation to SIT have been published. Vasculitis reactions accounted for the majority of case reports retrieved in our literature search. Whether the number of reported cases is higher or lower than what would be expected by chance is not possible to determine from existing data. There are no published data on autoimmune disease development in patients participating in randomized trials of the effects of SIT. One nonrandomized pharmacoepidemiological study did not detect an increased risk of autoimmune disease development during SIT as compared with the risk during conventional allergy treatment. SUMMARY: In conclusion, development of autoimmune disease in allergic patients treated with SIT is rare. Nevertheless, as a principle of caution, it seems reasonable to carefully evaluate the indication for SIT, that is, risks versus benefits, in patients with established autoimmune disease or a strong family history of autoimmune disease.

Epidemiology of non-hereditary angioedema.

The prevalence of non-hereditary angioedema was investigated in a general population sample (n = 7,931) and in a sample of Danish patients (n = 7,433) tested for deficiency of functional complement C(1) esterase inhibitor protein (functional C(1) INH). The general population sample (44% response rate) reported a lifetime prevalence of 7.4% for angioedema. In both groups symptoms were most frequent in the lips, head, neck, eyes and tongue. In the C(1) INH test normal group angioedema was still active at the time of the study in 53% of the patients, and 36% reported symptoms in the throat, 23% in the abdominal area, 17% had diarrhoea, 11% had vomiting and 6% fainted during attacks. Non-hereditary angioedema has high lifetime prevalence and becomes chronic in approximately 50% of affected patients. Symptoms in the larynx and throat, as well as non-specific symptoms, such as dizziness and abdominal pain, were more frequent than previously reported.

Correct measurement of height is important when assessing lung function values.

INTRODUCTION: Measurement of stature is a prerequisite for determination of the normal lung function since reference equations are based on stature (standing height). We investigated the optimal method for measuring stature and for testing the current practice. MATERIAL AND METHODS: We measured the stature of 87 subjects using a digital-counter stadiometer and a wall-mounted bench rule. Stature was also estimated based on finger-reach measurement, and self-reported stature was recorded. Results were compared using Altman-Bland plots. An email survey asking about written instruction on the practice for measuring stature was performed. RESULTS: The Harpenden stadiometer delivered results reproducible within ± 0.29 cm and the bench rule compared with the Harpenden stadiometer yielded results within ± 0.59 cm. The Harpenden stadiometer was the faster of the two methods. With two exceptions, Danish lung function laboratories did not use a written instruction on measurement of stature in our sample. CONCLUSION: It is necessary to focus on correct measurement of stature. Measurement of stature can be performed accurately with stadiometers with either digital or analogue counters. The digital stadiometer was the faster of the two. FUNDING: Not relevant. TRIAL REGISTRATION: Not relevant.