Genetic and environmental influences on plasma homocysteine: results from a Danish twin study

BACKGROUND: Increased plasma homocysteine has been linked to many clinical conditions including atherosclerosis and ischemic stroke. We assessed the genetic and environmental influences on homocysteine in adult twins and tested the influence of 3 candidate polymorphisms. METHODS: Homocysteine was analyzed in 1206 healthy twins, who were genotyped for 3 polymorphisms: MTHFR 677C>T, MTR 2756A>G, and NNMT (dbSNP: rs694539). To perform quantitative trait linkage analysis of the MTHFR locus, the genotyping was supplemented with 2 genetic markers localized on each site of the MTHFR locus. The twin data were analyzed using biometric structural equation models as well as a combined association and linkage analysis in 2 age cohorts. RESULTS: Age, sex, and MTHFR genotype have a significant impact on homocysteine concentrations, whereas the other genotypes were not associated with homocysteine concentrations. The variance in homocysteine could be solely ascribed to additive genetic and nonshared environmental factors, with an estimated additive genetic proportion of total variation at age 18-39 years of 0.63 (95% CI, 0.53-0.71) and at age 40-65 years of 0.27 (95% CI, 0.10-0.41). The impact of the MTHFR locus is estimated to explain 53% (95% CI, 0.07-0.67) of the total phenotypic variation in persons 18-39 years old and 24% (95% CI, 0.00-0.39) in persons 40-65 years old, i.e., almost all additive genetic variance. CONCLUSIONS: Homocysteine concentrations have a high heritability that decreases with age. The MTHFR gene locus is responsible for almost all the variation attributable to genetic factors, leaving very little influence of other genetic variations.     

Relationship between Optimum Mini‐doses of Glucagon and Insulin Levels when Treating Mild Hypoglycaemia in Patients with Type 1 Diabetes – A Simulation Study

Hypoglycaemia remains the main limiting factor in type 1 diabetes management. We developed an insulin‐dependent glucagon dosing regimen for treatment of mild hypoglycaemia based on simulations. A validated glucose–insulin–glucagon model was used to describe seven virtual patients with insulin pump‐treated type 1 diabetes. In each simulation, one of ten different and individualized subcutaneous insulin boluses was administered to decrease plasma glucose (PG) from 7.0 to ≤3.9 mmol/l. Insulin levels were estimated as ratio of actual to baseline serum insulin concentration (se/ba‐insulin), insulin on board (IOB) or percentage of IOB to total daily insulin dose (IOB/TDD). Insulin bolus sizes were chosen to provide pre‐defined insulin levels when PG reached 3.9 mmol/l, where one of 17 subcutaneous glucagon boluses was administered. Optimum glucagon bolus to treat mild hypoglycaemia at varying insulin levels was the lowest dose that in most patients caused PG peak between 5.0 and 10.0 mmol/l and sustained PG ≥ 3.9 mmol/l for 2 hr after the bolus. PG response to glucagon declined with increasing insulin levels. The glucagon dose to optimally treat mild hypoglycaemia depended exponentially on insulin levels, regardless of how insulin was estimated. A 125‐μg glucagon dose was needed to optimally treat mild hypoglycaemia when insulin levels were equal to baseline levels. In contrast, glucagon doses >500 μg were needed when se/ba‐insulin >2.5, IOB >2.0 U or IOB/TDD >6%. Although the proposed model‐based glucagon regimen needs confirmation in clinical trials, this is the first attempt to develop an insulin‐dependent glucagon dosing regimen for treatment of insulin‐induced mild hypoglycaemia in patients with type 1 diabetes.     

Fatal Adverse Event with Dabigatran in Elderly Patient with Reduced Kidney Function

An elderly man with decreased kidney function was admitted to hospital with gastrointestinal bleeding. After remaining stable for 2 days in hospital, he became haemodynamically unstable and an adverse effect of dabigatran was suspected, but efforts to treat the patient failed and the following morning he passed away. In conjunction with the autopsy, blood samples from his hospital stay were analysed for dabigatran, revealing the highest concentration (6400 ng/mL) apparently reported to date. Supra‐therapeutic dosing was, however, never suspected. Dabigatran is largely excreted through the kidneys. A possible cause of the high dabigatran concentrations could be a rapid decrease in kidney function that seemingly occurred over a period of 2 months, sometime between his initiation of treatment (eGFR 51–55 mL/min/1.73 m²) and subsequent hospital admission (eGFR 31 mL/min/1.73 m²). The increasing dabigatran concentrations in the patient was, however, not apparent to the prescribing doctor, as therapeutic drug monitoring of dabigatran is not recommended in current guidelines and no such analyses were performed. There may be a need to evaluate blood concentrations of dabigatran, in the light of the reported differences in interindividual concentrations, along with the increased risks of thromboembolic events with lower concentrations and major bleeding events with higher concentrations. Functional assays to assess concentrations of dabigatran in blood have been developed and are available in some hospitals to be used in suspected overdoses or before emergency surgeries. Methods to determine concentrations of dabigatran specifically have also been developed and can additionally be used for therapeutic drug monitoring in an outpatient setting, especially in high‐risk individuals.     

The Effect of a Combination of Diclofenac and Methadone Applied as Gel in a Human Experimental Pain Model – A Randomized,Placebo‐controlled Trial

Pain involves responses in which both peripheral and central mechanisms contribute to the generation of pain. Pre‐clinical laboratory data have supported that a topical formulation of combined diclofenac and methadone (Diclometh) may alleviate local pain, and potentially, the side effect profile should be low. We hypothesized that antiallodynic and antihyperalgesic effects of Diclometh could be demonstrated in a human experimental pain model and that Diclometh would be safe to administer. Thus, the aims were as follows: (i) to compare two doses of Diclometh versus placebo; and (ii) to assess the safety profile of Diclometh. The study was a crossover, randomized, double‐blind, placebo‐controlled comparison of two doses of Diclometh gel (0.1% and 0.2%) administered topically in healthy participants. Nerve growth factor (NGF) and capsaicin intradermal injections were used as human pain models. Pressure stimulation, contact heat stimulation, hyperalgesia (pinprick stimulation) and allodynia (brush stimulation) to mechanical stimulation were performed in the area where capsaicin and NGF were injected. Side effects were recorded on a four‐point Likert scale. Twenty‐one men completed the study (mean age 26.14 ± 5.3). Diclometh 0.2% reduced the capsaicin‐induced dynamic mechanical allodynia compared to placebo (primary end‐point, p = 0.03). No other primary or secondary end‐points were found significantly different (all p > 0.05). All side effects were reported as mild with no differences between treatments (p = 0.15). Indication of antiallodynic effect of Diclometh 0.2% was found. Additionally, it was demonstrated that Diclometh was safe to use.     

Perceptions of patients' smiles: a comparison of patients' and dentists' opinions

BACKGROUND: Little information has been published regarding the difference between how patients perceive their own smiles and how dentists view them. METHODOLOGY: The authors interviewed 78 consecutively seen patients in a general dental practice in Norway about esthetic features of their faces. The patients were not actively seeking esthetic treatment. Patients rated themselves using a 100-point visual analog scale (VAS), and then two dentists (the patients' regular dentist and an independent periodontist), working with photographs of the patients, used the same VAS in rating the patients' smiles. RESULTS: The average age of the patients was 51.2 years (range, 22-84 years). There were 50 women (average age, 51.5 years; range, 22-84 years) and 28 men (average age, 52 years; range, 30-78 years). Patients' satisfaction with their own smiles reached an average of 59.1 (standard deviation [SD], 21.1; range, 5-100) on the VAS. The dentists' scores (38.6 and 40.7) were significantly lower than the patients' scores. The authors observed poor correlation between the periodontist's scores of dentogingival features and the patients' scores. Patients were most satisfied with the gingiva when smiling and least satisfied with tooth shade. Patients younger than 50 years were most satisfied with their smiles. Patients rated teeth and eyes as the most important features in an attractive face. Women gave teeth and hair significantly higher scores and head shape lower scores than did men. CONCLUSION: Patients' opinions of their own smiles were significantly higher than the two clinicians' assessments of their smiles. Dentists should be aware that patients who seek esthetic services may have different perceptions of their smiles than may patients who do not express such desires.     

Slowly resorbable biosynthetic mesh: 2-year results in VHWG grade 3 hernia repair

Introduction

Information on the long-term performance of biosynthetic meshes is scarce. This study analyses the performance of biosynthetic mesh (Phasix?) over 24 months.

Methods

A prospective, international European multi-center trial is described. Adult patients with a Ventral Hernia Working Group (VHWG) grade 3 incisional hernia larger than 10 cm², scheduled for elective repair, were included. Biosynthetic mesh was placed in sublay position. Short-term outcomes included 3-month surgical site occurrences (SSO), and long-term outcomes comprised hernia recurrence, reoperation, and quality of life assessments until 24 months.

Results

Eighty-four patients were treated with biosynthetic mesh. Twenty-two patients (26.2%) developed 34 SSOs, of which 32 occurred within 3 months (primary endpoint). Eight patients (11.0%) developed a hernia recurrence. In 13 patients (15.5%), 14 reoperations took place, of which 6 were performed for hernia recurrence (42.9%), 3 for mesh infection (21.4%), and in 7 of which the mesh was explanted (50%). Compared to baseline, quality of life outcomes showed no significant difference after 24 months. Despite theoretical resorption, 10.7% of patients reported presence of mesh sensation in daily life 24 months after surgery.

Conclusion

After 2 years of follow-up, hernia repair with biosynthetic mesh shows manageable SSO rates and favorable recurrence rates in VHWG grade 3 patients. No statistically significant improvement in quality of life or reduction of pain was observed. Few patients report lasting presence of mesh sensation. Results of biosynthetic mesh after longer periods of follow-up on recurrences and remodeling will provide further valuable information to make clear recommendations.

Trial registration

Registered on clinicaltrials.gov (NCT02720042), March 25, 2016.

     

On the learning of addictive behavior: Sensation-seeking propensity predicts dopamine turnover in dorsal striatum

Brain Imaging and Behavior - We asked if sensation-seeking is linked to premorbid personality characteristics in patients with addictive disorders, or the characteristics follow the...     

Experimental infusion thrombophlebitis

On the basis of clinical experience it has been claimed that glucose results in a higher incidence of infusion thrombophlebitis than fructose, and that glucose solutions in concentrations higher than 5% are extremely irritant to the venous endothelium. The validity of these two assertions has been investigated by an experimental method based on a quantitative histological study of rabbit-ear veins into which infusions were given under standardized conditions. In two series of experiments, it was shown (1) that fructose solutions caused significantly more inflammatory changes in the veins than did glucose solutions, and (2) that glucose in 10% solutions caused significantly more injury to the veins than 5% solutions, although the difference in the average inflammatory changes was only slight.