Validation of questionnaire-based response criteria of treatment efficacy in the fibromyalgia syndrome

Objective To compare the validity of self-reported questionnaires as response criteria of treatment efficacy in patients with fibromyalgia syndrome. Method At the beginning of the treatment period, 70 fibromyalgia patients, ranndomly allocated to electro-acupuncture or placebo, underwent a clinical evaluation by rheumatologists and answered 1) a generic quality of life questionnaire—the Psychological General Well-Being Index (PGWB), 2) a specific function and symptom questionnaire, and 3) a pain questionnaire—the Regional Pain Score (RPS). The same evaluation was repeated at the end of the treatment period. Severity of the condition was assessed by a composite outcome score, a combination of different clinical outcome measures forming a clinical severity index. The variations between these questionnaire scores before and after treatment and the variations between the clinical severity indices estimated by clinicians were used as measures of the treatment impact. The first rationale for the validation was a positive correlation between clinical and questionnaire score changes. Another rationale for validation of the new instruments was the ability to identify the different treatment interventions. Results The correlation between the clinical severity index and the RPS was good (r = 0.62). Moreover, the RPS demonstrated a good discriminant power in detecting patients with effective treatment: it showed a specificity of 74% and a sensitivity of 75%. The PGWB correlated less well with the clinical score and was less discriminant. The specific function and symptom questionnaire showed little additional validity. Conclusions. Outcomes of syndrome severity such as pain and subjective well-being, as measured by self reported questionnaires, can be valid instruments to evaluate treatment efficacy in short-term clinical trials. In the current study, the RPS proved to be particularly useful to assess the widespread tenderness of fibromyalgia and demonstmted high discriminative power.     

Histopathological changes in the oesophageal mucosa in Egyptian children with corrosive strictures: A single-centre vast experience

BACKGROUND The caustic ingestion continues to be a major problem worldwide especially in developing countries. The long-term complications include stricture and increased life time risk of oesophageal carcinoma. Patients suffered from corrosive induced oesophageal strictures have more than a 1000-fold risk of developing carcinoma of the oesophagus.AIM To determine the possibility of oesophageal mucosal dysplasia after prolonged dilatation in post corrosive stricture.METHODS This observational study was conducted at the Paediatric Endoscopy Unit in Cairo University Children's Hospital. It included children of both sexes older than 2 years of age who had an established diagnosis of post-corrosive oesophageal stricture and repeated endoscopic dilatation sessions for more than 6 mo. All patients were biopsied at the stricture site after 6 mo of endoscopic dilatation. A histopathological examination of an oesophageal mucosal biopsy was performed for the detection of chronic oesophagitis, inflammatory cellular infiltration and dysplasia.RESULTS The mean age of the enrolled children was 5.9 ± 2.6 years; 90% of the patients had ingested an alkaline corrosive substance(potash). The total number of endoscopic dilatation sessions were ranging from 16 to 100 with mean number of sessionswas 37.2 ± 14.9. Histopathological examination of the specimens showed that 85%of patients had evidence of chronic oesophagitis(group A) in the form of basal cell hyperplasia, hyperkeratosis and subepithelial fibrosis. Thirteen percent of the patients had evidence of reactive atypia(group B) in the form of severe neutrophilic intraepithelial inflammatory cellular infiltration, and 2 patients(2%)had mild squamous dysplasia(group C); we rebiopsied these two patients 6 mo after the initial pathological assessment, guided by chromoendoscopy by Lugol's iodine.CONCLUSION The histopathology of oesophageal mucosal biopsies in post-corrosive patients demonstrates evidence of chronic oesophagitis, intraepithelial inflammatory cellular infiltration and dysplasia. Dysplasia is one of the complications of postcorrosive oesophageal stricture.     

Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies

The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes.     

Crystal structure-based virtual screening for fragment-like ligands of the human histamine H(1) receptor

The recent crystal structure determinations of druggable class A G protein-coupled receptors (GPCRs) have opened up excellent opportunities in structure-based ligand discovery for this pharmaceutically important protein family. We have developed and validated a customized structure-based virtual fragment screening protocol against the recently determined human histamine H(1) receptor (H(1)R) crystal structure. The method combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. The optimized in silico screening approach was successfully applied to identify a chemically diverse set of novel fragment-like (≤22 heavy atoms) H(1)R ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 μM to 6 nM. The current study shows the potential of in silico screening against GPCR crystal structures to explore novel, fragment-like GPCR ligand space.     

FC04.6Characterisation of dendritic cell responses to ascaridol, an autoxidation product of tea tree oil

A large number of monoterpenes and their degradation products are likely skin sensitizing agents (Hausen et al., 1999). Terpenes are very common e.g., as constituents of cosmetics, food and other daily used products.
We investigated responses to the endoperoxide 1,4‐epidioxy‐2‐p‐menthen (ascaridol), an autoxidation product of tea tree oil, using monocyte derived dendritic cells (MDDC). Therefore, we isolated peripheral blood mononuclear cells (PBMC) from 9 healthy donors by the standard Ficoll‐Paque gradient centrifugation.
Monocytes were isolated by adherence and incubated in media (RPMI 1640) containing GM‐CSF (800 units/ml), IL‐4 (1000 units/ml) and 10% autologous serum. The immature MDDC (day 6) were characterized by flow cytometry (CD1a+, CD14−, CD40, CD45, CD80, CD83, CD86, HLA‐DR and CCR‐7) and incubated with various concentrations of ascaridol (1–70 μg/ml). After one hour incubation time LPS was added (1 μg/ml) for 23 h. Cell culture supernatants were collected after 24 h for cytokine analysis.
IL‐12p40, IL‐12p70 and prostaglandin E2 were measured by ELISA, TNF‐alpha and IL‐2 were measured by flow cytometry (FACS). Methods of the quantification of steady state mRNA levels were established for IL‐12 and CCR7 (real‐time RT‐PCR). Ascaridol enhanced significantly IL‐12p70 production (120% up to 396%) by MDDC as well as mRNA levels for IL‐12 and CCR7. Moreover, we detected a distinct increase of TNF‐alpha (110% up to 146%) secretion, IL‐2 (135%) and PGE2 (102% up to 155%).
Totally, these results suggest that ascaridol may be a potent modulator of maturation and antigen presenting function of dendritic cells, and we performing further experiments to verify this hypothesis.
This study was supported by the Deutsche Forschungsgemeinschaft.     

A new heparin fragment decreases liver ischemia-reperfusion injury

<正>To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca²⁺,showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1],     

Ethmoid sinus disease: CT evaluation in 400 cases. Part II. Postoperative findings

Clinical, pathologic, and computed tomographic (CT) findings were reviewed in 400 patients with ethmoid sinus disease, including 272 who had undergone surgery. The postoperative appearance of ethmoid sinuses on CT scans is a highly neglected subject in radiologic literature. The unique ethmoid anatomy permits a variety of surgical approaches, and radiologists must be familiar with the postoperative appearances if they are to recognize the effects of prior surgery and detect, when possible, the recurrence of disease. It is often difficult to evaluate the clinical significance of soft-tissue disease, despite good clinical correlation.