Contact allergy to methyldibromo glutaronitrile--data from a 'front line' network

The preservative methyldibromo glutaronitrile (MDBGN) has caused an epidemic of contact allergy in Europe. However, most data concerning contact allergy comes from hospital departments of dermatology. As a part of the primary health care sector, Danish dermatologists in private practice provide the front line of care for patients with skin diseases. Data from this source may therefore better reflect trends in the general population than material from hospital departments of dermatology. In this study, the frequency of MDBGN allergy and the characteristics of patients seen by dermatologists in private practice were studied. In 1 year, 2146 patients were patch tested by the participating dermatologists from 4 clinics in various parts of Denmark. 5% (110) had positive patch tests to MDBGN, with no difference between the sexes. After adjustment was made for other background variables, multivariate analysis using logistic regression showed a significant association between hand eczema and MDBGN allergy (OR 2.5, P < 0.001). In 53 cases (52.4%), the patch test reaction to MDBGN was judged to be of current relevance. Creams and lotions accounted for 31% of the identified causative products and liquid soaps for 23%. It is concluded that contact allergy to MDBGN is frequent among patients seen by dermatologists in private practice. This is consistent with results from hospital departments of dermatology in Europe and indicates a general trend and ongoing epidemic in the general population. The significant relationship between hand eczema and MDBGN allergy is of concern, and the finding that wash-off products, especially liquid soaps, play a significant role in MDBGN allergy calls for a revision of the safety assessment of MDBGN in wash-off products.     

Psychometric methods for diagnosing and monitoring minimal hepatic encephalopathy —current validation level and practical use

Metabolic Brain Disease - Hepatic encephalopathy (HE) is cerebral dysfunction caused by liver failure and inflicts 30-40% of patients with liver cirrhosis during their disease course. Clinically...     

The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects

CONTEXT: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein. OBJECTIVES: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study. DESIGN: The LIPC -250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360). RESULTS: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [95% confidence interval (CI) 0.039-0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10(-10)) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [0.038 mmol/liter per allele (95% CI 0.024-0.053); P = 2 x 10(-7)). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P(interaction) = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22-0.37) increase in HDL-c compared with homozygous G-allele carriers. CONCLUSIONS: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the -250 A allele. This interaction may have potential implications for public health and disease prevention.     

Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis.     

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.     

Inverse Association Between Birth Weight,Birth Length and Serum Total Cholesterol in Adulthood

Objectives - To investigate whether impaired fetal growth, measured by low birth weight and short birth length, is linked with raised levels of serum lipids and increased risk and mortality of coronary heart disease. Design - The association between birth length, birth weight, Ponderal Index and total serum cholesterol was examined in 545 Danish men and women aged 31 to 51 years who participated in the Ebeltoft Health Promotion Project in Denmark. Results - No associations were found in women. For men, a negative association was found between birth weight and serum total cholesterol, with a fall in mean serum total cholesterol from 6.03 mmol/l at birth weight below 3300 g to 5.64 mmol/l at birth weight above 4000. A similar association was found between birth length and serum cholesterol, with a mean value of 6.23 mmol/l at birth length below 51 cm and a mean value of 5.56 mmol/l at birth length above 54 cm. No associations were found for Ponderal Index. Between 3% and 8% of the variance in serum total cholesterol could be explained by the statistical models used in this study. Conclusion - Our findings support the hypothesis of a negative association between birth weight, birth length and elevated serum cholesterol in adult life, but only in men.     

SPRING-MEDIATED CRANIOPLASTY COMPARED WITH THE MODIFIED PI-PLASTY FOR SAGITTAL SYNOSTOSIS

The aim of this study was to compare the safety, morphological outcome, and degree of parental satisfaction of the new spring-mediated cranioplasty with those of the modified pi-plasty in the management of sagittal synostosis. Ten patients with non-syndromic sagittal synostosis treated with the spring-mediated cranioplasty were followed prospectively. A control group of 10 sex-matched patients operated on with the modified pi-plasty procedure was chosen. Cephalometric radiographs were obtained preoperatively and postoperatively at 1 year of age. Cephalic index, axial width ratio, length ratio, width ratio and height ratio were used as objective measures of outcome. Parents were sent a questionnaire to obtain a subjective aesthetic assessment of outcome. Significantly less blood replacement was required (p?=?0.003), and shorter duration of postoperative anaesthesia (p?=?0.030) and postoperative hospital stay (p?=?0.013) were found in the spring-mediated cranioplasty group. There were no complications or deaths in either group. Also significant was the inter-group difference in the postoperative change in the height ratio (p?=?0.030), the most change being seen in the spring group. The change in the subjective parental aesthetic evaluation of skull shape was significant in both groups. In conclusion, the spring-mediated procedure was morphologically more effective than the modified pi-plasty procedure in the management of sagittal synostosis with the additional benefits of less blood transfusion needed and shorter duration of hospital stay.