Effects of liraglutide on cardiovascular risk factors in patients with type 1 diabetes

We investigated the short‐term effect of adding liraglutide 1.8 mg once daily to insulin treatment on cardiovascular risk factors in patients with type 1 diabetes. In total, 100 overweight (BMI ≥25 kg/m²) adult patients (age ≥18 years) with type 1 diabetes and HbA1c ≥ 8% (64 mmol/mol) were randomized to liraglutide 1.8 mg or placebo added to insulin treatment in a 24‐week double‐blinded, placebo‐controlled trial. At baseline and after 24 weeks of treatment, 24‐hour blood pressure and heart rate, pulse pressure, pulse wave velocity and carotid intima‐media thickness were evaluated. Compared with placebo, liraglutide increased 24‐hour heart rate by 4.6 beats per minute (BPM); P = .0015, daytime heart rate by 3.7; P = .0240 and night‐time heart rate by 7.5 BPM; P < .001 after 24 weeks. Diastolic nocturnal blood pressure increased by 4 mm Hg; P = .0362 in the liraglutide group compared with placebo. In conclusion, in patients with long‐standing type 1 diabetes, liraglutide as add‐on to insulin increased heart rate and did not improve other cardiovascular risk factors after 24 weeks of treatment.     

Mechanisms of disease: mechanism-based classification of neuropathic pain-a critical analysis

Classification of neuropathic pain according to etiology or localization has clear limitations. The discovery of specific molecular and cellular events following experimental nerve injury has raised the possibility of classifying neuropathic pain on the basis of the underlying neurobiological mechanisms. Application of this approach in the clinic is problematic, however, owing to a lack of precise tools to assess symptoms and signs, and difficulties in correlating symptoms and signs with mechanisms. Development and validation of diagnostic methods to identify mechanisms, together with pharmacological agents that specifically target these mechanisms, seems to be the most logical and rational way of improving neuropathic pain treatment.     

Effects of CO<Subscript>2</Subscript>-enriched water on barrier recovery

The objective of the present study was to evaluate the impact of CO₂-enriched water on barrier recovery of detergent-damaged skin compared to tap water employing bioengineering methods and thin-layer chromatography (TLC) analysis of stratum corneum (SC) lipids. Irritation of the skin was elicited on the forearms of 20 volunteers using 1% sodium lauryl sulphate (SLS). The degree of skin irritation was followed over 10 days in terms of skin colour reflectance (L*a*b*), transepidermal water loss (TEWL), and skin capacitance expressed as median values. For TLC analysis, SC lipids were extracted prior to and during the observation period. Clinical examination showed the efficacy of CO₂-enriched water on barrier recovery. Compared to unenriched tap water, CO₂-enriched water produced a significant (P<0.01) increase in total SC lipids and in particular in the ceramide fraction. Furthermore, TEWL was significantly (P<0.01) lower in skin treated with CO₂-enriched water than in skin treated with unenriched water. These findings may indicate that rinsing with CO₂-enriched water enhances (1) clinical regeneration of detergent-damaged skin, (2) epidermal lipid synthesis, and (3) barrier repair after detergent-induced perturbation.     

Neuropathic pain: Peripheral and central mechanisms

Neuropathic pain refers to a specific pain syndrome characterized by pain and sensory abnormalities in body parts that have lost their normal peripheral innervation or sensory representation. They are to be distinguished from other types of pain because of differences in the underlying pathophysiology and treatment. Following a peripheral nerve injury, a cascade of events occurs in primary afferents causing peripheral sensitization. Central sensitization, which is increased responsiveness in central neurons, is usually the result of an increased barrage from the periphery, but may also occur independent of such peripheral input. Again, a series of molecular changes contribute to this central sensitization. These peripheral and central sensitization phenomena in neuropathic pain represent the pathophysiological reason for the beneficial effect of antihyperalgesic treatment in this type of pain. In future, such treatment is likely to be replaced by agents that in a more specific ways attack the pain-generating mechanisms.     

Serine protease signaling of epidermal permeability barrier homeostasis

Evidence is growing that protease-activated receptor-2 (PAR-2) plays a key role in epithelial inflammation. We hypothesized here that PAR-2 plays a central role in epidermal permeability barrier homeostasis by mediating signaling from serine proteases (SP) in the stratum corneum (SC). Since the SC contains tryptic- and chymotryptic-like activity, we assessed the influence of SP activation/inhibition on barrier function. Acute barrier disruption increases SP activity and blockade by topical SP inhibitors (SPI) accelerates barrier recovery after acute abrogation. This improvement in barrier function is due to accelerated lamellar body (LB) secretion. Since tryptic SP signal certain downstream responses through PAR-2, we assessed its potential role in mediating the negative effects of SP on permeability barrier. Firstly, PAR-2 is expressed in the outer nucleated layers of the epidermis and most specifically under basal condition to the lipid raft (LR) domains. Secondly, tape stripping-induced barrier abrogation provokes PAR-2 activation, as shown by receptor internalization (i.e. receptor movement from LR to cytolpasmic domains). Thirdly, topical applications of PAR-2 agonist peptide, SLIGRL, delay permeability barrier recovery and inhibit LB secretion, while, conversely, PAR-2 knockout mice display accelerated barrier recovery kinetics and enhanced LB secretion, paralleled by increased LR formation and caveolin-1 expression. These results demonstrate first, the importance of SP/SPI balance for normal permeability barrier homeostasis, and second, they identify PAR-2 as a novel signaling mechanism of permeability barrier, that is, of response linked to LB secretion.