Bitter taste receptors and α-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying

Ghrelin is a hunger hormone with gastroprokinetic properties but the factors controlling ghrelin secretion from the stomach are unknown. Bitter taste receptors (T2R) and the gustatory G proteins, α-gustducin (gust) and α-transducin, are expressed in the gut and are involved in the chemosensation of nutrients. This study aimed to investigate whether T2R-agonists affect (i) ghrelin release via α-gustducin and (ii) food intake and gastric emptying via the release of ghrelin. The mouse stomach contains two ghrelin cell populations: cells containing octanoyl and desoctanoyl ghrelin, which were colocalized with α-gustducin and α-transducin, and cells staining for desoctanoyl ghrelin. Gavage of T2R-agonists increased plasma octanoyl ghrelin levels in WT mice but the effect was partially blunted in gust(-/-) mice. Intragastric administration of T2R-agonists increased food intake during the first 30 min in WT but not in gust(-/-) and ghrelin receptor knockout mice. This increase was accompanied by an increase in the mRNA expression of agouti-related peptide in the hypothalamus of WT but not of gust(-/-) mice. The temporary increase in food intake was followed by a prolonged decrease (next 4 h), which correlated with an inhibition of gastric emptying. The delay in emptying, which was partially counteracted by ghrelin, was not mediated by cholecystokinin and GLP-1 but involved a direct inhibitory effect of T2R-agonists on gastric contractility. This study is unique in providing functional evidence that activation of bitter taste receptors stimulates ghrelin secretion. Modulation of endogenous ghrelin levels by tastants may provide novel therapeutic applications for the treatment of weight -and gastrointestinal motility disorders.     

Occupational allergic contact dermatitis and patch test results of leather workers at two Indonesian tanneries

Background. Tannery workers are at considerable risk of developing occupational contact dermatitis. Occupational skin diseases in tannery workers in newly industrialized countries have been reported, but neither the prevalence of occupational allergic contact dermatitis nor the skin‐sensitizing agents were specifically examined in those studies. Objectives. To assess the prevalence of occupational allergic contact dermatitis in Indonesian tanneries, identify the causative allergens, and propose a tannery work series of patch test allergens. Patients/methods A cross‐sectional study in all workers at two Indonesian tanneries was performed to assess the prevalence of occupational contact dermatitis via a questionnaire‐based interview and skin examination. Workers with occupational contact dermatitis were patch tested to identify the causative allergens. Results. Occupational contact dermatitis was suspected in 77 (16%) of the 472 workers. Thirteen (3%) of these 472 workers were confirmed to have occupational allergic contact dermatitis. Potassium dichromate (9.2%), N,N‐diphenylguanidine (5.3%), benzidine (3.9%) and sodium metabisulfite (2.6%) were found to be the occupationally relevant sensitizers. Conclusions. The sensitization pattern showed some differences from the data in studies reported from other newly industrial countries. We compiled a ‘tannery work series' of allergens for patch testing. A number of these allergens may also be considered for patch testing in patients with (leather) shoe dermatitis.     

Increase in vesicular hand eczema after house dust mite inhalation provocation: a double‐blind,placebo‐controlled,cross‐over study

Background. It is unclear whether the respiratory tract is involved in eliciting or aggravating eczematous lesions in patients with vesicular hand eczema. Objectives. To investigate the effect of inhalation of house dust mite (HDM) on vesicular hand eczema. Methods. Eighteen patients with vesicular hand eczema and HDM allergy received inhalation challenges with four concentrations of HDM in a randomized, double‐blind, placebo‐controlled, cross‐over study. Early asthmatic reactions and late asthmatic reactions were defined as a placebo‐corrected fall of 15% or more from baseline of forced expiratory volume in 1 second. Hand eczema was scored according to the Dyshidrotic Eczema Area and Severity Index (DASI) at baseline, and 1, 6, 24 and 48 hr. Results. The median DASI increased significantly as compared with baseline at 6 and 48 hr after HDM inhalation. This increase was significantly different between the provocations at 6 hr. The median vesicles score increased significantly from baseline at 24 and 48 hr. Patients with a placebo‐corrected increase in the number of vesicles at 24 hr and 48 hr had significantly more often late asthmatic reactions than those without an increase in the number of vesicles. Patients with a placebo‐corrected increase of the DASI score at 24 hours had as a group a higher mean total IgE level than those without an increase of the DASI score. Conclusion. Hand eczema increased significantly more after HDM provocation than after placebo provocation. An increase in the number of vesicles was preceded by late asthmatic reactions. The group patients with an increase of hand eczema tended to have a higher mean total IgE level.     

Inducible cardiac ischaemia is related to a decrease in the whole-blood Toll-like receptor 2 and 4 response

TLR (Toll-like receptor) activation-induced inflammatory responses are important in the progression of atherosclerosis. We previously showed that TLR-dependent leucocyte responsiveness is acutely attenuated following percutaneous coronary intervention or vascular surgery. Furthermore, cytokine release following whole-blood TLR-2 and TLR-4 stimulation is negatively correlated with fractional flow reserve, suggesting that chronic ischaemia can elicit an enhanced inflammatory response. In the present study, we assessed the association between leucocyte TLR-2 and TLR-4 responsiveness and pre-existent and inducible ischaemia in patients undergoing SPECT (single-photon emission computed tomography)-MPI (myocardial perfusion imaging). TLR-2, TLR-4 and CD11b expression on monocytes were measured in blood samples that were obtained from 100 patients with suspected coronary artery disease before and after myocardial stress testing for SPECT-MPI. IL-8 (interleukin-8) levels were determined after whole-blood stimulation with Pam3Cys (TLR-2) and LPS (lipopolysaccharide; TLR-4). On the basis of SPECT-MPI, patients were categorized into three groups: reversible defect, irreversible defect and no defect. Myocardial stress induced a reduction in TLR-4 expression (2.46±0.21 compared with 2.17±0.16 arbitrary units, P=0.001) and CD11b expression (83.2±1.73 compared with 76.0±1.89 arbitrary units, P<0.001). TLR-induced IL-8 production before myocardial stress induction was not associated with the results of SPECT-MPI. However, a significant decrease in IL-8 production following TLR stimulation was observed after stress, which was more pronounced in patients with a reversible defect. In conclusion, inducible ischaemia is associated with a decrease in whole-blood TLR-2 and TLR-4 response. These results point to a regulating role of TLRs in order to prevent excessive inflammatory events known to occur during acute ischaemia.     

Alitretinoin and acitretin in severe chronic hand eczema; results from a retrospective daily practice study

Acitretin has been used off‐label for years to treat chronic hand eczema, but acitretin is less often prescribed as alitretinoïne was approved. This study evaluates both retinoids in a daily practice cohort of patients with severe chronic hand eczema in terms of drug survival and reasons for discontinuation. Patients using alitretinoin or acitretin between 01‐01‐1994 and 01‐08‐2015 were included in this retrospective daily practice study and analyzed by Kaplan‐Meier drug survival curves. Potential determinants were analyzed by Cox regression analyses. Ninety‐five patients were treated with alitretinoin and 109 patients with acitretin. The main reasons for discontinuation were adverse events and cleared hand eczema, 29.5 and 27.4% in alitretinoin versus 43.1 and 23.9% in acitretin. Patients with hyperkeratotic hand eczema had most often a good effect of treatment: 68.3% in alitretinoin and 50.7% in acitretin treatment. The drug survival rates of alitretinoin and acitretin after 12, 24, 36, and 52 weeks were 69.3, 45.1, 19.6, 7.0% and 74.3, 45.5, 33.8, 23.2%, respectively. Alitretinoin and acitretin are effective treatment options for patients with hand eczema. However, both treatments were more effective in patients with hyperkeratotic hand eczema. Fewer patients discontinued alitretinoin compared with acitretin due to adverse events.     

Methyldibromoglutaronitrile is an important contact allergen in The Netherlands

From 15 May to 15 December 1994, 2943 patients sunspected of having contact dermatitis(1955 women, 988 men) were patch tested with methyldibromoglutarorutrile 0.3%, 0.1% and 0.05% pet. 119 patients (4.0%: women 4.1%, men 3.8%) proved to be allergic, 71% of the reactions were considered to be relevant. In 2/3 of the patients, causative products were cosmetics, in 1/3 moistened toilet tissues. Testing with methyldibromoghitaronitrile at lower concentrations (0.05% and 0.1%) commercial allergens (Euxyl® K 400 and methyldibromoglutaronitrile, both containing methyldibromoglutaronitrile 0.1%). resulted in a number of falsc-negative reactions. All preservatives in the European standard series had lower scores than the 4% positive reactions to methyldibromoglutaronitrile (formaldehyde 2.0% MCI/MI (Kathon® CG) 3.2% parabens 1.0% quaternium-15 1.3%). It is concluded that methyldibromoglutaronitrile (present in the commercial preservative Euxyl® K 400) is an important contact allergen in the Netherlands in cosmetics and moistened toilet tissues. It should be added to cosmetics series and to proctological series. The optimal test concentration is unknown, but may be 0.3% pet. The concentration of 0.1% methyldibromoglutaronitrile in the currenttly available commercial allergens appears to be too low. resulting in a number of false-negative reactions.