Cognitive and hedonic responses to meal ingestion correlate with changes in circulating metabolites.

BACKGROUND: We have previously shown that meal ingestion induces cognitive perception (sensations) with a hedonic dimension (well-being) that depends on the characteristics of the meal and the appropriateness of the digestive response. The aim of the present study is to identify metabolomic biomarkers of the cognitive response to meal ingestion. METHODS: In 18 healthy subjects, the response to a test meal (Edanec, 1 kcal/mL) ingested until maximum satiation (50 mL/min) was assessed. Perception measurements and blood samples were taken before, at the end of the meal, and 20 min after ingestion. The cognitive response and the hedonic dimension were measured on 10 cm scales. Metabolomic analysis was performed using nuclear magnetic resonance (NMR) spectroscopy and values of triglycerides, insulin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) were determined using conventional laboratory techniques. KEY RESULTS: Ingestion up to maximum satiation induced sensation of fullness and decreased digestive well-being. The total amount ingested by each subject correlated with the basal sensation of hunger, but not with other sensations or blood metabolite levels. Immediately after ingestion, satiation correlated with an increase in glucose (R = 0.49; p = 0.038) and valine levels (R = 0.48; p = 0.043). Twenty-minutes after finalizing ingestion, triglyceride levels had significantly increased which correlated with the recovery in well-being (R = 0.48; p = 0.046) and the decrease in desire to eat a food of choice (R = -0.56; p = 0.016). The increase in lipids inversely correlated with abdominal discomfort (R = -0.51; p = 0.032). CONCLUSIONS & INFERENCES: Cognitive and hedonic responses to meal ingestion correlate with changes in circulating metabolites, which may serve as objective biomarkers of perception.

Digestive, cognitive and hedonic responses to a meal.

BACKGROUND: Gut dysfunctions may be associated to digestive symptoms. We hypothesized that the gut can also originate pleasant sensations, and wished to demonstrate the hedonic component of the digestive response to a meal. METHODS: Healthy subjects (n = 42) were evaluated during basal fasting conditions and during experimentally induced fullness sensation (either by gastric distension or duodenal nutrient infusion). In each set of studies, a 240 mL test meal (12 kcal broth) and water, as inert control meal, were administered on separate days in a randomized, cross-over design. Gastric accommodation, the cognitive response and the hedonic dimension (both by 10 score scales) were measured 9 min before and 60 min after the meal. KEY RESULTS: In basal conditions, the test meal induced a significantly greater gastric relaxation than the control meal (166 ± 28 mL isotonic volume increase 67 ± 14 mL; p = 0.002). Both meals induced epigastric fullness (3.8 ± 0.7 score and 3.2 ± 0.8 score, respectively; p = 0.740), but contrary to the inert meal, with the active meal this conscious sensation had a pleasant dimension (digestive comfort increase by 1.3 ± 0.6 score with active meal vs -1.1 ± 0.6 decrease with inert meal; p = 0.015). Experimentally induced fullness was associated to a decrease in digestive well-being or abdominal discomfort, which improved only after the active meal but not the inert meal. CONCLUSIONS & INFERENCES: When appropriate conditions are met, the response to a meal includes a hedonic dimension involving pleasant sensation of digestive well-being.

POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands.

The EWSR1 gene is known to play a crucial role in the development of a number of different bone and soft tissue tumours, notably Ewing's sarcoma. POU5F1 is expressed during early development to maintain the totipotent status of embryonic stem and germ cells. In the present study, we report the fusion of EWSR1 and POU5F1 in two types of epithelial tumours: hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. This finding not only broadens considerably the spectrum of neoplasms associated with EWSR1 fusion genes but also strengthens the evidence for shared pathogenetic mechanisms in the development of adnexal and salivary gland tumours. Reminiscent of the previously reported fusion genes involving EWSR1, the identified transcript is predicted to encode a chimeric protein consisting of the EWSR1 amino-terminal domain and the POU5F1 carboxy-terminal domain. We assessed the transcriptional activation potential of the chimera compared to the wild-type proteins, as well as activation of transcription through the oct/sox composite element known to bind POU5F1. Among other POU5F1 target genes, this element is present in the promoter of NANOG and in the distal enhancer of POU5F1 itself. Our results show that although the chimera is capable of significant transcriptional activation, it may in fact convey a negative regulatory effect on target genes.

Bispectral fluorescence imaging of aggressive basal cell carcinoma combined with histopathological mapping: a preliminary study indicating a possible adjunct to Mohs micrographic surgery.

BACKGROUND: Fluorescence imaging is an attractive diagnostic technique for skin tumour demarcation with potential to move to clinical use. Bispectral fluorescence imaging combines skin autofluorescence with delta-aminolaevulinic acid-induced fluorescence. To evaluate the technique, fluorescence data must be compared with the histopathological extent of the tumour, which is the purpose of the current study. OBJECTIVES: To investigate the agreement between bispectral fluorescence images and the histopathological tumour boundary of ill-defined basal cell carcinomas (BCCs). After fluorescence imaging the tumours were removed using Mohs micrographic surgery (MMS) to obtain histopathological maps of the tumour boundaries. METHODS: Twelve patients with aggressive BCC of mean diameter 16 mm (range 5-32) in the face were included in the study. The patients were subjected to bispectral fluorescence imaging within the 2 months prior to MMS. The fluorescence images and histopathological maps were aligned using image warping. RESULTS: Five patients (42%) showed good agreement with the histopathological mapping and the remaining seven patients (58%) showed partial agreement. Bispectral investigation combining autofluorescence with protoporphyrin IX (PpIX) fluorescence generally yielded better agreement with the histopathological boundaries of the tumours compared with using only the PpIX fluorescence. CONCLUSIONS: In this preliminary study the fluorescence has been compared with the histopathological tumour boundaries. The result implies that the technique can be applied as a useful tool for indicating tumour boundary of aggressive BCCs. Further refinement is needed to be able to indicate the exact tumour border.

Role of gamma/delta T cell receptor-expressing lymphocytes in cutaneous infection caused by Staphylococcus aureus.

The high number of gamma/delta-expressing T cells found in the epithelial lining layer suggests that they form a first line of defence against invading pathogens. To evaluate the role of gamma/delta T cell-receptor (TCR)-expressing cells in cutaneous infection caused by Staphylococcus aureus, mice lacking gamma/delta-expressing T cells (TCRdelta-/-) were inoculated intradermally with S. aureus, and compared with S. aureus-infected congeneic TCRdelta+/- control mice. The number of bacteria recovered from the skin of TCRdelta-/- mice was significantly higher (P = 0.0071) at early time-points after inoculation compared to the number of bacteria isolated from infected TCRdelta+/- congeneic controls. Nevertheless, inflammatory responses measured as serum IL-6 levels, were significantly lower in TCRdelta-/- mice than in the control group. A possible explanation for this discrepancy was the observation of significantly decreased overall numbers of infiltrating cutaneous T lymphocytes, which are important producers of IL-6. These results support the notion that the gamma/delta-expressing T cells that reside at the epithelial lining layer of the skin is of importance for early containment of the bacteria, thereby limiting their replication and spread.

Role of neutrophil leukocytes in cutaneous infection caused by Staphylococcus aureus.

Despite the high prevalence of cutaneous infections, little is known about the role of host immune responsiveness during Staphylococcus aureus dermatitis. We have recently described a murine model of infectious dermatitis induced by superantigen-producing S. aureus. To assess the role of neutrophils in staphylococcal dermatitis, mice were given granulocyte-depleting monoclonal antibody prior to and on several occasions following intracutaneous inoculation with staphylococci. The granulocyte-depleted mice that had been intradermally inoculated with S. aureus developed crusted ulcerations which tended not to heal, whereas animals injected with control monoclonal antibody displayed only minor and transient skin lesions. The finding of severe ulcerations in neutropenic mice correlated with a significantly higher burden of bacteria in the blood and skin during the early phase of the infection. Importantly, while mice with an intact granulocyte population showed only limited skin infection, bacteremia occurred in the great majority of the neutrophil-depleted animals. As a consequence, the latter individuals exhibited significantly increased levels of the proinflammatory cytokine interleukin-6 and specific antibodies to staphylococcal cell wall components and toxic shock syndrome toxin-1 in the serum. Our data point to a crucial protective role of granulocytes in S. aureus dermatitis.

Mohs' micrographic surgery for basal cell carcinomas on the eyelids and medial canthal area. I. Characteristics of the tumours and details of the procedure.

PURPOSE: To analyse the characteristics of eyelid basal cell carcinomas excised using Mohs' micrographic technique. METHODS: Sixty-six eyelid basal cell carcinomas were excised using Mohs' micrographic technique. The tumours were classified into four subtypes; morpheiform, intermediate, nodular/micronodular and superficial. Data on previous treatment of the tumours were retrieved. RESULTS: Thirty-two tumours (48%) were primary, 8 tumours (12%) were incompletely excised using conventional excision surgery and 26 tumours (39%) were recurrent. Nineteen of the 26 (73%) recurrent tumours and 14 of the 32 (44%) primary tumours were nodular/micronodular. To achieve radical excision, superficial tumours needed an average of 2.0, nodular/micronodular 2.5, intermediate 2.0 and morpheiform tumours 2.9 excisions. CONCLUSIONS: Eyelid basal cell carcinomas with ill-defined borders or recurrent tumours are well suited for Mohs' micrographic surgery. The extensions of the tumours are difficult to determine even in some less aggressive subtypes such as superficial and nodular/micronodular basal cell carcinomas.

An experimental model of cutaneous infection induced by superantigen-producing Staphylococcus aureus.

Skin infections caused by Staphylococcus aureus, such as erysipelas, are commonly occurring, painful, and costly for society. Despite the high prevalence of this condition, little is known about the host immune responsiveness and bacterial virulence factors during S. aureus dermatitis. We present here a mouse model of infectious dermatitis in which S. aureus is inoculated by an intracutaneous injection to the shaved back of NMRI mice. Visible skin inflammation, characterized by redness and swelling, was noted 48 h after inoculation of staphylococci in mice that received 2 x 108 colony-forming units of S. aureus. Microscopic evaluation revealed a dermal and subcutaneous infiltrate rich in macrophages and neutrophilic granulocytes already within 6 h after inoculation. A sparse influx of T lymphocytes was noted somewhat later. Bacterial cultures from skin revealed high numbers of staphylococci early after inoculation, with a successive decline during 2 wk follow-up. Total white blood cell count as well as the number of polymorphonuclear leukocytes peaked 2 d after bacterial inoculation. Also, serum interleukin-6 levels peaked within 2 d, with a 10-fold increase compared to non-infected control mice, indicating a systemic reaction to skin infection. The role of toxic shock syndrome toxin 1 in the pathogenesis of the dermatitis was assessed using isogenic S. aureus strains. Even though the gross inflammatory skin reaction was similar for mice infected with either of the strains, it was apparent that bacteria secreting toxic shock syndrome toxin 1 preferentially triggered influx of T lymphocytes to the skin. In addition, mice inoculated with staphylococci producing toxic shock syndrome toxin 1 showed a weight decrease during the experiment whereas mice inoculated with the isogenic strain showed a weight increase. This model of staphylococcal dermatitis will enable future in-depth studies regarding the host-bacterium relationship.

In vivo detection of basal cell carcinoma using imaging spectroscopy.

Photodynamic therapy has become an interesting alternative to conventional therapy for basal cell carcinomas. Delta-aminolevulinic acid is a precursor in the biosynthesis of protoporphyrin IX that accumulates to a large extent in tumour tissue. We have compared in vivo protoporphyrin IX fluorescence with the extent of basal cell carcinomas on the face, trunk and thigh determined by histological mapping in 30 lesions in 22 patients. A new non-laser based set-up was used to record the fluorescence images. Delta-aminolevulinic acid was applied for 4 h inducing high concentrations of protoporphyrin IX. Routine vertical histological sections and Mohs micrographic surgery were used to map the extent of the tumours. In 50% of lesions we found a good correlation between the fluorescence imaging and histological mapping. In 23% the correlation was partial. In the other lesions we found no correlation at all. This method may be used to delineate basal cell carcinomas more accurately than current methods.